HK1227325B - Composition comprising calcium phosphate and sulfate powders and tri - calcium phosphate particles used in the treatment of degenerative bone conditions - Google Patents

Description

Composition comprising calcium phosphate and calcium sulfate powders and tricalcium phosphate granules for treating degenerative bone conditions

The present application is a divisional application of a Chinese patent application filed on June 30, 2011, with application number 201180038621.3 and invention name “Composition comprising calcium phosphate and calcium sulfate powder and tricalcium phosphate particles for treating degenerative bone diseases”.

Technical Field

The present invention relates to methods of treating patients suffering from bone degeneration, such as osteopenia and osteoporosis. More specifically, the present invention provides methods of treating patients suffering from bone degeneration by replacing at least a portion of the degenerated bone material.

Background Art

Bone mineral density (BMD) is generally recognized as a term referring to the amount of calcified material present per cubic centimeter of bone. It should be understood that this term does not refer to the actual density (mass of material per unit volume), but is used to convey information about bone strength and the susceptibility of bone to fracture. Typically, BMD is assessed using methods such as Dual Energy X-Ray Absorptiometry (or DEXA scanning), ultrasound, and quantitative computed tomography (QCT). Of the aforementioned methods, DEXA scanning is generally considered to be the most reliable assessment of BMD. For example, ultrasound is generally limited to evaluating the calcaneus and cannot be used to directly measure common sites of osteoporotic fractures, such as the hip and spine. QCT is commonly used for the spine and must be performed according to strict laboratory procedures to provide acceptable reproducibility. Other tests used to evaluate BMD include single photon absorptiometry (SPA), dual photon absorptiometry (DPA), digital X-ray radiogammetry (DXR), and single energy X-ray absorptiometry (SEXA).

BMD is a very important physical characteristic because it can be a direct indicator of fracture susceptibility. In most adult populations, BMD peaks around the age of 30 to 35 and tends to decline slowly thereafter. The decrease in BMD is due to a decrease in the production of new bone cells, which causes the body to absorb existing bone cells faster than the rate at which new bone cells are produced. Figure 1 (which can be obtained online at http://courses.washington.edu/bonephys/opbmd.html) shows the typical BMD decline in adults (shown in mg/ ^cm2 ) and illustrates how the decline may differ based on race and gender. Menopause in women is a highly important event related to BMD because the decrease in BMD accelerates dramatically in the period after menopause. Therefore, postmenopausal women are generally encouraged to have BMD tests regularly to assess whether treatment is needed and what treatment should be performed. The National Osteoporosis Foundation recommends BMD testing for the following individuals: all women 65 years and older, regardless of risk factors; younger postmenopausal women with one or more risk factors; postmenopausal women who experience a fracture (to confirm the diagnosis and determine the severity of the disease); estrogen-deficient women who are at clinical risk for osteoporosis; individuals with vertebral abnormalities; individuals who are receiving or plan to receive long-term glucocorticoid (steroid) therapy; individuals with primary hyperparathyroidism; individuals who are being monitored to evaluate the response or efficacy of approved osteoporosis drug treatments; and individuals with a history of eating disorders.

It is generally believed that BMD reduction is associated with osteopenia and osteoporosis, and the presence of these conditions is defined by the patient's BMD test score (particularly the T score of a DEXA scan). The T score of a DEXA scan is a normalized value, which indicates the degree of the patient's BMD value compared to the mean value of a young adult at peak BMD. The normalized value is expressed as the standard deviation of the mean value. Therefore, a T score of 0 indicates no difference in BMD compared to the mean value of a young adult, a negative T score indicates that BMD is below the mean value, and a positive T score indicates that BMD is above the mean value. The T score is a normalized value, because the mean value depends on race and gender. The T scores of different bones in the same individual may also be different. It is generally believed that bones with a T score greater than -1 are within the normal range (although a negative score still indicates that BMD is below the normalized mean value). It is generally believed that there are bones with a T score of -1 to -2.5 in the conditions of osteopenia. It is generally believed that there are bones with a T score lower than -2.5 in the conditions of osteoporosis.

BMD can be associated with bone strength and therefore can be used as a fracture risk predictor. Generally speaking, for each standard deviation below normal, the expected fracture risk increases. In the elderly, fractures (particularly hip or vertebral fractures) can be associated with increased mortality. Therefore, because BMD can be associated with increased fracture risk, improving BMD can be the target of medical intervention osteopenia and/or osteoporosis patients. Although several interventions have been attempted, there is still a need in this area for the treatment that can effectively improve BMD.

Treatment and prevention of bone deterioration (i.e., decreased BMD) can present many aspects. Prevention generally begins with exercise and proper nutrition (including adequate calcium and vitamin D) during childhood, as both exercise and nutrition have been shown to be necessary for the development of the highest possible BMD. This is important because it has been shown that when actual BMD at peak age is greater, BMD declines more slowly with age.

When osteopenia and osteoporosis occur, a lot of different treatments can be utilized. The estrogen therapy of postmenopausal women can slow down the generation and/or progress of bone degeneration. Similarly, selective estrogen receptor modulators (SERM) (for example, raloxifene (raloxefine)) can be used for slowing down bone loss by simulating the rising of estrogen in the body. Calcitonin prescription can be prescribed, and the calcitonin is the material that thyroid cells naturally produce. Calcitonin acts directly on osteoclasts (through the calcitonin receptors on the cell surface) to regulate osteoclasts to stop bone resorption. Bisphosphonates (bisphosphonate) (for example, etidronate (etidronate) pamidronate (pamidronate) alendronate (alendronate) risedronate (risedronate) zoledronate (zoledronate) (or) and ibandronate (ibandronate)) can improve bone strength by improving mineral density and reducing bone resorption. Bisphosphonates are all related to pyrophosphate, a byproduct of cellular metabolism and a natural circulating inhibitor of mineralization in the blood and urine. Although pyrophosphate cannot enter bone (i.e., because alkaline phosphatase in the cell lining breaks it down), bisphosphonates can enter bone (and adhere very strongly) due to chemical substitutions in the compound. Although this class of drugs can provide a certain level of effectiveness, recent studies have shown that long-term use of bisphosphonates can increase the risk of spontaneous subtrochanteric fractures and femoral shaft fractures (i.e., atypical fractures). Denosumab is another drug recently approved by the Food and Drug Administration for twice-yearly injections in osteoporosis patients at high risk of fracture or those who cannot tolerate other treatments. Denosumab is a fully human monoclonal antibody that binds to the RANK ligand and alters the body's natural bone remodeling process. Although the long-term effects of this antibody are not yet clear, doctors have been warned to monitor patients for adverse reactions such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. In addition, because antibodies alter the body's immune system, there is evidence that their use can increase the risk of serious infections in patients. Another treatment (teriparatide) is recombinant parathyroid hormone (rPTH), which has the paradoxical effect of increasing bone mass by altering the pattern of exposure to the body's natural parathyroid hormone (PTH) and thereby altering the skeletal effects of chronically elevated PTH, which can lead to increased bone destruction, calcium loss, and osteoporosis. While activating multiple bone metabolic pathways, rPTH increases the number of active osteoblasts, reduces osteoblast apoptosis, and recruits bone-lining cells to become osteoblasts. The drug appears to act primarily on bone-building osteoblasts and stimulates them to overactivity. Safety studies in rats suggest that the risk of osteosarcoma may be increased with the use of rPTH. Therefore, there remains a need in the art for treatments that do not require long-term medication, which may still have harmful (although undesirable) effects.

Non-pharmacological treatments are typically used only after a fracture has occurred. For example, fractures (particularly vertebral) can be treated by immediate fixation, where poly(methyl methacrylate) cement (commonly referred to as "bone cement") or a similar non-absorbable material is inserted into the crack to permanently harden and "fix" the bone in place. Although such treatments can address existing fractures, it is believed that the non-natural physical properties of the bone (i.e., hardness, modulus, etc.) after treatment increase the likelihood of adjacent bone fractures, particularly when the adjacent bone is in an advanced state of osteoporosis. Furthermore, such treatments do not result in the formation of natural bone in the fracture, but rather serve as a non-absorbable bone substitute.

Despite the emergence of medical and surgical treatments for bone degeneration and fractures, there remains a need in the art for additional treatments that can increase BMD in key areas to reduce fracture risk and the attendant health risks (including mortality). In particular, it would be useful to have treatments that target specific areas of the skeleton at high risk of fracture by actually forming new healthy (i.e., normal) bone material. Such treatments would not be limited by current limitations in the art.

Summary of the Invention

The present invention provides the improvement of the bone structure of the patient suffering from degenerative bone disease (such as osteopenia or osteoporosis). Specifically, the present invention allows to selectively replace the degenerative bone material of bone local area with the bone regeneration material that is absorbed by the body and replaced by the newly generated bone material over time. Advantageously, the newly formed bone material is a natural bone material for the patient because it is not a bone graft (such as, the bone of a corpse) or a non-absorbable bone substitute (such as, bone cement). In addition, the newly formed bone material is not degenerate but healthy bone material in nature, because the characteristics (such as BMD and compressive strength) shown by the bone material (which may include the surrounding part of the next-to-bone) make the newly formed bone material in specific embodiments substantially similar to the average value of healthy 30 years old (that is, BMD is usually in the age of its peak value) individual. In other embodiments, the characteristics of the newly formed bone can be characterized as the improvement relative to the bone of osteopenia or the bone of osteoporosis. The improvement can also be characterized relative to a specific scale (such as relative to the T score from DEXA scanning).

In certain embodiments, the present invention may therefore relate to a method for treating a patient suffering from a degenerative bone condition. Specifically, the method may include forming a void in a localized area of the bone, for example, by mechanically debridement of the degenerate bone material or otherwise separating the degenerate bone material to form the void. Optionally, a portion of the degenerate bone material may be removed from the formed void. In some embodiments, the degenerate bone material may remain in the void, but due to the degraded state of the bone material, the material does not occupy a significant volume of the formed void. The method may also include at least partially filling the formed void with a bone regeneration material.

In certain embodiments, the degenerative bone disorder may be selected from osteopenia and osteoporosis. While the patient to be treated may be suffering from any disorder caused by bone degeneration, the terms osteopenia and osteoporosis can be considered to generally include any disorder caused by a decrease in BMD to the extent that the T-score calculated by DEXA scanning is below a certain threshold. For example, because osteopenia is technically defined as having a T-score of less than -1.0 for the scanned bone area, and because osteoporosis is technically defined as having a T-score of less than -2.5 for the scanned bone area, these clinical terms (and their current treatment methods) can be considered applicable to treating bone degeneration regardless of the underlying disorder causing the bone loss (whether natural bone loss with age or a side effect of a specific underlying disease or medical treatment (e.g., steroid treatment)).

In some specific embodiments, the bone regeneration material used according to the present invention may include osteoinductive material, osteoconductive material, osteogenic material, osteopromotive material or osteophilic material. Preferably, the bone regeneration material comprises calcium sulfate. In other embodiments, the bone regeneration material may comprise calcium phosphate. In other embodiments, the bone regeneration material may comprise tricalcium phosphate particles. In some specific embodiments, the bone regeneration material may comprise a combination of all three materials. In some embodiments, the bone regeneration material may comprise a material that exhibits a three-phase absorption spectrum in vivo.

The bone regeneration material can be characterized as a material that causes the formation of new, non-degenerate bone material in the formed cavity. In particular, the non-degenerate bone material can have a density that is substantially consistent with normal bone (i.e., bone from a typical healthy 30-year-old individual), particularly bone from the same general area. In particular, this can be characterized relative to a T score measured by dual-energy X-ray absorptiometry (DEXA). Preferably, the bone portion comprising the newly formed bone material has a T score greater than -1.0, greater than -0.5, or at least 0.

In certain embodiments, the bone regeneration material can be characterized as promoting the local area of bone to be remodeled to be substantially consistent with normal bone over time. In particular, remodeling can be manifested as starting with a T score greater than 2.0 in the local area of bone (after implanting the bone regeneration material into the cavity), and the T score gradually decreases over time to a T score of about 0 to about 2. Preferably, the remodeled local area of bone maintains a T score greater than about 0 for at least one year, which is measured from the time when the new bone material is formed.

In other embodiments, the bone regeneration material can be characterized as promoting the formation of new bone material having substantially normal BMD in the bone region adjacent to the formed cavity. This can be described as a gradient effect, which is discussed further herein.

The bone for cavitation can be any bone in the desired area that is degenerative in nature and can be treated according to the present invention (e.g., to prevent future fractures). In some embodiments, the bone can be selected from the group consisting of hip, femur, vertebra, radius, ulna, humerus, tibia, and fibula.

In other embodiments, the present invention can be specifically characterized as providing a method for increasing the BMD of a localized area of bone. The method can include forming a cavity in the localized area of bone and optionally removing a portion of the cleared bone material. The method can also include at least partially filling the formed cavity with a bone regeneration material, thereby generating new bone material in the cavity, the density of the generated bone material being greater than the density of the bone material originally present in the cavity space. Preferably, the increase in BMD is manifested as a T score of the generated bone material being at least 0.5 units greater than the T score of the natural bone material before being removed to form the cavity. As further described herein, even greater increases in T scores can be seen. In some specific embodiments, the T score of the natural bone material before being removed to form the cavity can be less than about -1.0, and the generated bone material can have a T score greater than -1.0 or at least about -0.5. A further advantage of the present invention is that the increase in BMD can be maintained for at least about 1 year, measured from the time the new bone material is generated.

In other embodiments, the present invention can be characterized as providing a method for producing a defined BMD profile in a localized bone region. As further described herein, the methods of the present invention unexpectedly not only improve the bone quality of the treated localized bone region, but also provide a specific BMD profile, wherein the BMD of the localized region increases sharply and then gradually returns to a substantially normal density. The methods of the present invention can include forming a cavity in the localized bone region and at least partially filling the formed cavity with a bone regeneration material, thereby generating new bone material in the cavity over time and absorbing at least a portion of the bone regeneration material. Preferably, a majority of the bone regeneration material is absorbed. The BMD profile of the localized bone region can be: from the time the cavity is filled with the bone regeneration material, the T score increases from an initial score below -1 measured before the cavity is formed to a maximum score of at least about 5 within a defined time. Thereafter, the T score of the localized bone region can decrease over time to a score of about -0.5 to about -2.0 (i.e., a substantially normal range).

In other embodiments, the present invention can be characterized as providing a method for remodeling the local area of degenerate bone into a method substantially consistent with normal bone. Similar to the above, the inventive method can unexpectedly be used to substantially reset the bone quality of the treated bone local area. In other words, the bone in a degenerate state is replaced with bone regeneration material, and new natural bone material is grown inwardly, which is not a degenerate bone material but a normal bone material. Therefore, the bone in the local area can be characterized as being remodeled into a normal bone material by the degenerate bone material. As described more completely below, remodeling does not refer to a spontaneous natural process in the body, but refers to restoring bone quality by implementing the inventive method operation. Specifically, the method can include forming a cavity in the bone local area and at least partially filling the formed cavity with bone regeneration material, thereby producing new bone material in the formed cavity. Preferably, the bone material in the local area has a T score of less than -1 before the cavity is formed, indicating bone degradation, and the new bone material after remodeling has a T score greater than -1.0 (more preferably greater than about 0), indicating that the bone in the local area has been remodeled to be substantially consistent with normal bone.

In other embodiments, the present invention can be characterized as providing a method for restoring the height of the vertebral body or correcting angular deformities in a fractured vertebra (particularly a vertebra with osteopenia or osteoporosis) by causing the ingrowth of new bone material that is substantially consistent with normal bone. The method can include forming a cavity in the fracture area, which can include mechanically enlarging the space of the crack and optionally removing a portion of the bone material in the fracture area. The method can also include at least partially filling the formed cavity with a bone regeneration material so that new bone material is produced in the cavity over time. Preferably, the new bone material has a T score indicating that the new bone material is substantially consistent with normal bone (e.g., a T score of at least -0.5 or at least 0).

In other embodiments, the present invention can be characterized as providing a method for improving the bone quality of a bone local area. As described herein, bone quality can be described relative to measurable characteristics (e.g., BMD, compressive strength, and fracture resistance). Therefore, the method for improving bone quality can be demonstrated by the improvement of one or two of these characteristics (and other measurable characteristics that can be used to define bone quality). In some embodiments, the method can include replacing the degenerate bone material in a bone local area with a T score lower than -1.0 in a certain volume with a newly formed natural bone material so that the same bone local area has a T score greater than -1.0 (preferably at least -0.5 or at least 0). In other preferred embodiments, the T score of the bone local area after the operation of the present invention can exceed at least 1.0 units compared to the T score of the degenerated bone. In some specific embodiments, the replacement of the degenerated bone material can include forming a cavity in the bone local area and filling the formed cavity at least partially with a bone regeneration material, thereby generating new natural bone material in the formed cavity.

In other aspects, the present invention can be provided for the multiple materials used in the method for treating degenerative bone material.Such material can specifically be provided to help easily implement multiple methods of the present invention with combination (such as tool kit (kit)).Therefore, the present invention can be characterized as providing for replacing the tool kit of the degenerative bone material of bone local area with the bone regeneration material that promotes to produce the new bone material that is basically consistent with normal bone.

In some embodiments, tool kit according to the present invention may include one or more of the following: tubular drill bit (cannulated drill bit), guide wire (guide wire), working cannula, debridement probe (debridement probe), a certain amount of bone regeneration material suitable for filling the cavity of bone local area and the injection device for delivering bone regeneration material. In other embodiments, tool kit according to the present invention may include a tool bender (instrument bender) suitable for adjusting the geometry of probe (that is, can be used for making bone material break away from or otherwise debride or for material tamping (tamp) or filling (pack) into any device in the cavity), to adapt to the anatomical part of bone local area cavity. In particular, probe device may include the head shaped to adapt to the anatomical part of bone local area cavity. In other words, probe can be bent into the angle (or the multiple angles formed by multiple bending) of limitation in advance. In other embodiments, a kit according to the present invention may include one or more of the following: a tissue protector, a cannulated obdurator, a guidewire, a drill, a flexible working cannula, a working cannula obdurator, a debridement probe, and a suction/irrigation device. The kit may also include any form of instruction set suitable for teaching, illustrating, describing, or otherwise showing how to use the various components of the kit to treat a patient with a degenerative bone disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

Having thus generally described the invention, reference is now made to the several drawings attached hereto, in which:

FIG1 is a graph showing the typical decline in total hip BMD (mg/cm ² ) relative to age, sex, and race;

Figure 2a is a scanning electron micrograph of normal bone;

Figure 2b is a scanning electron micrograph of osteoporotic bone;

3a-3i are radiographic images showing the injection of bone regeneration material into a cavity created in the proximal femur of a patient in a medial-to-lateral manner according to one embodiment of the present invention;

FIG4 is a contrast-enhanced radiographic image of the proximal femur showing some embodiments of the present invention, wherein filled cavities of various shapes and sizes for filling with bone regeneration material may be produced;

5a-5c are diagrams illustrating steps in setting up a surgical technique for replacing degenerated bone material at the distal end of a patient's radius according to one embodiment of the present invention;

6a-6c are diagrams illustrating steps in a surgical technique for replacing degenerated bone material of a patient's vertebrae according to one embodiment of the present invention;

7a to 7e are scanning electron microscope images showing changes over time in a bone regeneration material used as a graft according to one embodiment of the present invention, such changes contributing to controlled ingrowth of new bone material;

8 is a gross specimen showing the proximal end of a canine humerus 13 weeks after insertion of a graft formed of a bone regeneration material according to the present invention, and showing the formation of dense cancellous bone even beyond the boundaries of the initial defect;

FIG9 is a graphical representation of an exemplary BMD profile that may be obtained for a localized region of bone according to one embodiment of the present invention;

FIG10 is a graph illustrating bone remodeling in a localized region of bone, showing that BMD changes from an osteoporotic model to a model substantially consistent with normal bone;

FIG11 is an illustration of a tissue protector tool that may be used to implement a method according to one embodiment of the present invention;

FIG12 is a diagram of a cannula occluder that can be used to implement a method according to one embodiment of the present invention;

FIG13 is a diagram of a guidewire that may be used to implement a method according to one embodiment of the present invention;

FIG14 is an enlarged view of a drill tip that may be used to practice a method according to one embodiment of the present invention;

FIG15 is an illustration of a flexible working cannula that may be used to practice a method according to one embodiment of the present invention;

FIG16 is a diagram of a working cannula occluder that can be used to implement a method according to one embodiment of the present invention;

FIG17 is a diagram of a debridement probe that may be used to practice a method according to one embodiment of the present invention;

FIG18 is a diagram of an aspiration/infusion tool that may be used to implement a method according to one embodiment of the present invention;

FIG19 is an illustration of a 180° working cannula that may be used to practice a method according to one embodiment of the present invention;

20 is a radiographic image showing a debridement probe inserted for creating a cavity in the proximal femur according to one embodiment of the present invention;

FIG21 is a radiographic image showing in situ filling of the formed cavity with a graft material according to one embodiment of the present invention;

22 is a graph showing the average peak load observed in testing paired cadaver femora for fracture resistance after cavity formation and filling with bone regeneration material according to one embodiment of the present invention;

FIG23 provides a radiographic image of the proximal femur prior to injection of bone regeneration material according to a method according to one embodiment of the present invention;

FIG. 24 provides a CT image of the same region of the proximal femur shown in FIG. 23 prior to injection of bone regeneration material.

25 provides an intraoperative radiographic image of the proximal femur of FIG. 23 during injection of a bone regeneration material in accordance with the present invention.

FIGURE 26 provides a radiographic image of the left femur of FIGURE 23 six weeks after treatment according to a method according to one embodiment of the present invention;

FIG27 provides a CT image of the left femur of FIG23 12 weeks after treatment according to a method according to one embodiment of the present invention;

FIG28 provides a CT image of the treated left femur of FIG23 at 24 weeks after treatment;

FIG29 is a graph providing data over a two-year period of mean T-scores at the femoral neck in treated hips of patients treated according to certain embodiments of the present invention;

FIG30 is a graph providing data over a two-year period of mean total hip T-scores in treated hips of patients treated according to certain embodiments of the present invention;

FIG31 is a graph providing data over a two-year period showing mean T-scores in the Ward's riangle area of treated hips of patients treated according to certain embodiments of the present invention;

FIG32 is a graph providing data over a two-year period showing the mean percent increase in bone mineral density (BMD) of the femoral neck in treated hips of patients treated according to certain embodiments of the present invention relative to the BMD of the femoral neck in the untreated contralateral hips of the same patients;

FIG33 is a graph providing data over the course of two years showing the mean percent increase in total hip bone mineral density (BMD) in treated hips of patients treated according to certain embodiments of the present invention relative to the total hip BMD in the untreated contralateral hips of the same patients; and

Figure 34 is a graph of data providing the average percent increase in bone mineral density (BMD) in the Ward's triangle in the treated hips of patients treated according to certain embodiments of the present invention relative to the BMD in the Ward's triangle in the untreated contralateral hips of the same patients over the course of up to two years.

DETAILED DESCRIPTION

The present invention will be described more fully below with reference to a plurality of embodiments. These embodiments are provided to make this disclosure thorough and complete, and will fully convey the scope of the invention to those skilled in the art. In fact, the present invention can take many different forms and should not be interpreted as being limited to the embodiments given herein. On the contrary, these embodiments are provided to ensure that this disclosure meets applicable legal requirements. Unless otherwise clearly indicated in the context, nouns that are not limited by quantifiers in this specification and the appended claims include one/kind or more/kind of indicators.

The present invention is derived from the recognition that a variety of bone regeneration materials can be used in the replacement therapy of degenerative bone materials. In particular, it has been found that when the degenerative bone material in the local area of bone is replaced with a specific bone regeneration material, new bone material is produced in the local area of bone as the bone regeneration material is absorbed by the body. Unexpectedly, it is found that even when the existing bone is in a late stage of degradation (e.g., osteoporosis), the body still maintains the ability to form a new healthy bone material that is substantially consistent with normal bone.

As used herein, the terms "normal bone" or "normal bone material" refer to bone or bone material that exhibits the characteristics of healthy bone in a person (preferably of the same sex and ethnicity as the treated patient) at an age when BMD is essentially at its peak (i.e., approximately 30 to 35 years of age). In other words, according to one embodiment, when treating elderly Caucasian women with osteoporosis according to the present invention, new bone is found to grow that is not osteoporotic but essentially consistent with the bone of an average Caucasian woman aged 30 to 35 years (i.e., in terms of BMD and/or compressive strength). This effect is, of course, seen in both sexes and across all ethnic groups. Thus, the present invention is capable of locally altering bone mass. More specifically, the present invention is capable of increasing bone mass in a localized area from a degraded state to a less degraded state, preferably from a degraded state to a substantially normal state. In other words, bone mass in a localized area can be increased so that the bone material has a density that is essentially consistent with the BMD of a person of the same ethnicity and sex at the average age of peak BMD (i.e., approximately 30 to 35 years of age). Such localized areas may include newly formed bone and surrounding portions of bone that have not been replaced according to the present invention.

As described above, there are a variety of methods in the art for evaluating BMD, and any suitable method that can quantify BMD in a meaningful way to distinguish between normal and degenerative states can be used in the present invention. For ease of understanding, the effectiveness of the present method is described throughout this disclosure relative to the T score evaluated by dual energy X-ray absorptiometry (DEXA) scanning. This is a recognized method for evaluating BMD. In addition, because common conditions of bone degeneration can actually be defined by the patient's T score, the DEXA scan results provide a meaningful way to quantify the results of the present invention relative to the improvement of BMD. DEXA scanners typically report BMD in g/ ^cm2 . However, due to differences between machine manufacturers, reporting BMD in g/ ^cm2 is not standardized. To aid in standardization, the T score can be converted to BMD in g/ ^cm2 according to the following formula:

T score = (BMD-reference BMD)/SD

Wherein both the reference BMD and the standard deviation (SD) are referenced to the mean value of patients aged 30 to 35 years old at which BMD is expected to be at its peak, and both BMD and SD are provided in mg/ ^cm2 . The resulting T-score provides a consistent and reproducible assessment of BMD, which can be used to provide evidence of changes in BMD. In the United States, T-scores are typically calculated with reference to the same race and gender. According to the World Health Organization (WHO) standards, T-scores are evaluated based on reference values for Caucasian females. For ease of reference, the T-scores discussed herein are obtained from DEXA scans using a Hologic Delphi ^™ Bone Densitometer (available from Hologic, Inc., Danbury, CT). Another way to characterize scan data is the Z-score, which is the number of standard deviations from the mean value for people of the same age, gender, and race as the patient being tested. However, the present invention also encompasses other methods for assessing improvements in bone quality (e.g., BMD, compressive strength, or fracture resistance), such as those that can be achieved using one or more alternative testing methods (e.g., ultrasound, QCT, SPA, DPA, DXR, or SEXA).

In some embodiments, the benefits of the present invention can be characterized based on a relative increase in BMD following use of one or more of the methods of the present invention. "Relative increase" refers to an improvement in a bone quality factor (e.g., BMD, compressive strength, or fracture resistance) relative to the condition of a localized region of bone prior to initiation of treatment according to the present invention. This approach to characterizing the present invention can be independent of implementing criteria intended to define normal bone status for young, healthy adults. For example, relative improvement can specifically consider the improvement in bone quality and the impact on quality of life for an individual patient. For example, increasing the T-score by perhaps 1.5 units in a patient with extremely low proximal femoral BMD (e.g., a T-score of -3) can significantly improve quality of life. A final T-score of -1.5 may still indicate an osteoporotic state, but a relative increase in bone quality in the proximal femoral region can be sufficiently significant to indicate effective treatment, regardless of whether the defined normal BMD is achieved. However, in some embodiments, effective treatment can be specifically correlated with the ability of the treated localized region of bone to achieve normal BMD.

In some embodiments, the methods of the present invention can be described relative to an increase in BMD, as demonstrated by an increase in the T score (specific bone material replaced versus new bone material generated, or overall localized bone area), which can be reproduced by a person skilled in the art using the methods described herein. Thus, the benefits of the present invention can be described relative to an increase in the T score, which can be associated with a reduced degenerative state (i.e., a relative increase in BMD) or with a change in BMD such that the bone is classified as normal (i.e., non-degenerate) or better. In some embodiments, the T score can be increased by at least 0.25 units, at least 0.5 units, at least 0.75 units, at least 1.0 units, at least 1.25 units, at least 1.5 units, at least 1.75 units, at least 2.0 units, at least 2.25 units, at least 2.5 units, at least 2.75 units, or at least 3.0 units. In other embodiments, BMD can be increased so that the T score is at least the minimum level. For example, BMD can be increased so that the T score is at least -1, at least -0.75, at least -0.5, at least -0.25, at least 0, at least 0.25, at least 0.5, at least 0.75, at least 1.0, at least 1.25, at least 1.5, at least 1.75, at least 2.0, at least 2.5, at least 3.0, at least 4.0, or at least 5.0. In other embodiments, the T score can be defined as greater than -1, which can indicate that BMD falls within an acceptable normal range. In other embodiments, the T score can be about -1.0 to about 2.0, about -1.0 to about 1.0, about -1.0 to about 0.5, about -1.0 to about 0, about -0.5 to about 2.0, about -0.5 to about 1.5, about -0.5 to about 1.0, about -0.5 to about 0.5, about 0 to about 2.0, about 0 to about 1.5, or about 0 to about 1.0. Furthermore, degenerated bone material according to the present invention can be described as bone having a T score below -1.0, below about -1.5, below -2.0, below -2.5, or below -3.0. The significance of the above values will become more apparent from the further description of the invention provided below.

The invention described herein can be found to be applicable to any bone in a patient's body where it is desired to increase BMD. In some specific embodiments, it is contemplated that replacement methods will be used only in localized areas of bone. In other words, rather than replacing or regenerating the entire length of a bone, only discontinuous or localized segments or regions of a particular bone will be replaced. The method is preferably used in localized areas of bone because it utilizes the body's natural ability to absorb the bone regeneration material used and replace it with newly generated bone material. In some specific embodiments, it has been found that such bone regeneration can be achieved by bone material that grows inward from the surrounding bone material. For the sake of clarity, it should be understood that in certain embodiments, the terms "bone" and "bone material" can have independent meanings. Specifically, "bone" can refer to a general, overall anatomical structure (e.g., a femur or vertebra), while "bone material" can refer to multiple bone cells and calcified extracellular matrix present (or generated) in or near discontinuous, localized areas of a larger bone structure. Therefore, when bone material is removed, the overall bone remains. In addition, when a cavity is formed in a bone, new bone material can be generated therein.

In some embodiments, the methods of the present invention can be implemented specifically in bones that are particularly likely to suffer fractures in patients suffering from bone degenerative disorders. Such bone degenerative disorders can refer to any condition characterized by loss of BMD. In some specific embodiments, bone degenerative disorders can refer to osteopenia or osteoporosis. Because these conditions can be defined relative to T scores within a defined range, these terms can be used herein to refer to bone degeneration, generally without regard to whether the degeneration is due to insufficient production of new bone cells to counteract resorption by natural bone cells, or whether the degeneration is due to an independent condition that causes bone degeneration as a symptom or side effect.

In some specific embodiments, the method of the present invention can be carried out in the bone associated with the hip joint. This can especially include the bone structure that is generally considered to be the hip bone, innominate bone or coxal bone (that is, ischium, ilium and pubis) and the proximal portion of the femur and the subtrochanteric portion of the femur (although the present invention generally includes femur). Parts of the femur of particular interest according to the present invention are the head, neck, greater trochanter and lesser trochanter and the region identified as "Ward area" (or "Ward's triangle"). These regions of bone are especially prone to fractures or atypical fractures associated with falls in the elderly.

Other bones that can be treated according to the present invention include the vertebrae and other major bones associated with the legs and arms, such as the radius, ulna, humerus, tibia, and fibula. In addition to the bones in the hip area, of particular interest are the vertebrae, the distal radius, and specific bone segments that can be subject to atypical fractures.

The present invention uses specific bone regeneration materials. This term can include a variety of materials that can be used for regenerating bone or bone material, in particular, materials that can also be filled into a cavity and promote the ingrowth of new bone material into the filled cavity. Therefore, in some embodiments, the bone regeneration material can be characterized as a bone filling material. Preferably, the bone regeneration material comprises a considerable proportion of materials that can be absorbed by the mammalian body. For example, the bone regeneration material can comprise at least 40%, by weight at least 50%, by weight at least 60%, by weight at least 70%, by weight at least 80% or by weight at least 90% of the materials that can be absorbed by the mammalian body. In addition, preferably, the absorption rate is substantially similar to the rate of ingrowth of new bone material. In some embodiments, the bone regeneration material can include a portion of a material that is easily absorbed but also compatible with the formation of new bone material (for example, it can be absorbed into the bone structure (including newly generated bone material)).

In certain embodiments, the bone regeneration material can be a material that is considered to be an osteoconductive material or an osteoinductive material." Osteoconduction" refers to a material that causes undifferentiated perivascular mesenchymal cells to divide into mitoses and then to form osteoprogenitors (osteoprogenitors) (i.e., cells that can form new bone or bone material). "Osteoinduction" refers to a material that promotes vascular invasion and new bone or bone material formation in a limited passive trellis structure. Known various compounds, minerals, proteins, etc. show osteoconduction, osteoinduction, osteogenesis, bone promotion, or bone affinity activity. Therefore, such a material can be used according to the present invention.

Specifically, the following are non-limiting examples of materials that can be used in view of their osteoconductive or osteoinductive capabilities according to the present invention: demineralized bone matrix (DBM), bone morphogenetic protein (BMP), transforming growth factor (TGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), peptides, anorganic bone mineral (ABM), vascular permeability factor (VPF), cell adhesion molecules (CAM), calcium aluminate, hydroxyapatite, coralline hydroxyapatite, alumina, zirconium oxide, aluminum silicate, calcium phosphate, tricalcium phosphate, brushite (dicalcium phosphate dihydrate), tetracalcium phosphate, octacalcium phosphate, calcium sulfate, polypropylene fumarate, pyrolytic carbon, Carbon), bioactive glass, porous titanium, porous nickel-titanium alloy, porous tantalum, sintered cobalt-chromium beads, ceramics, collagen, autologous bone, allogeneic bone, xenogeneic bone, coralline, their derivatives or combinations, or other biologically produced composite materials containing calcium or hydroxyapatite structural elements. These can be used as bone regeneration materials or as additives to specific bone regeneration material compositions.

In some specific embodiments, the bone regeneration material used in the present invention can be a material especially comprising calcium sulfate, and can include desired other ingredients. Calcium sulfate can specifically be hemihydrate α-calcium sulfate, hemihydrate β-calcium sulfate, dihydrate calcium sulfate or its mixture. In some embodiments, particularly when calcium sulfate is combined with other materials, the calcium sulfate composition can be provided as an aqueous solution or slurry, which can include water and one or more additives optionally selected from inorganic salts and surfactants, such as sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium acetate and sodium acetate. Calcium sulfate can also include other ingredients, including any bone guidance and bone induction materials described herein and accelerators, plasticizers or bioactivators that can be used to accelerate the reaction of hemihydrate calcium sulfate to dihydrate calcium sulfate.

In some embodiments, the bone regeneration material may specifically include calcium phosphate. In particular, the material may include calcium sulfate and calcium phosphate. Calcium phosphate can be the form of a bioceramic material having a specific geometric structure or shape (e.g., pellets, particles, wedges, blocks, or sheets of varying sizes). Non-limiting examples of calcium phosphate that can be used according to the present invention include hydroxyapatite, tricalcium phosphate (e.g., α-tricalcium phosphate, β-tricalcium phosphate), tetracalcium phosphate, anhydrous dicalcium phosphate, monocalcium phosphate monohydrate, dicalcium phosphate dihydrate, heptacalcium phosphate, octacalcium phosphate, calcium pyrophosphate, oxyapatite, calcium metaphosphate, carbonate apatite, dahlite, and combinations or mixtures thereof. In some specific embodiments, calcium phosphate is α-tricalcium phosphate, β-tricalcium phosphate, or a mixture thereof. In some embodiments, calcium phosphate can exist in two or more forms that can result in the formation of brushite, such as tricalcium phosphate and calcium phosphate monohydrate.

In certain preferred embodiments, the bone regeneration material used in the present invention can include calcium sulfate, calcium phosphate and particulate material (such as tricalcium phosphate particles) or further granulated osteoconduction or osteoinductive material (such as demineralized bone matrix (DBM)). The specific example of the material that can be used in accordance with the present invention has trade names PRO- and (Wright Medical Technology, Inc., Arlington, Term.) commercially available materials. Although such material is particularly useful for the implementation of the present invention, other materials that can be used for bone applications also can be used in certain embodiments of the present invention. Although not wishing to be bound by theory, it is believed that the material showing bone regeneration properties (particularly the material showing a heterogeneous spectrum) can provide more favorable results in different embodiments, as described in addition herein. Examples of additional materials that may be used in certain embodiments of the present invention include those designated as RCS, CEM-500R, α-TCP, γ-β-Chondromimetic, Bone Void Filler, BVF, Fast Set Putty, Fast Set Putty, DBMPutty, 100, OPTIUM DBM Putty, DBM, Demineralized Bone Matrix, Bone Graft, OP-TRINITY ^™ Matrix, and TRINITYREVOLUTION ^™ . Various embodiments of bone regeneration materials that can be used in accordance with the present invention are those described in U.S. Patent No. 6,652,887, U.S. Patent No. 7,211,266, U.S. Patent No. 7,250,550, U.S. Patent No. 7,371,408, U.S. Patent No. 7,371,409, U.S. Patent No. 7,371,410, U.S. Patent No. 7,507,257, U.S. Patent No. 7,658,768, and U.S. Patent Application Publication No. 2007/0059281, the disclosures of which are incorporated herein by reference in their entirety.

In some embodiments, the bone regeneration material can be in the form of a granular composition that is hardened or constructed by mixing with an aqueous solution. Such a composition can include one or more forms of calcium sulfate and one or more forms of calcium phosphate. Preferably, the composition can include at least one form of calcium sulfate and at least two forms of calcium phosphate. Specifically, the composition can include calcium sulfate hemihydrate (hereinafter referred to as "CSH") powder and a calcium phosphate mixture for forming brushite comprising monocalcium phosphate monohydrate (hereinafter referred to as "MCPM") powder and beta-tricalcium phosphate (hereinafter referred to as "β-TCP") powder.

Such a particle composition can be used to form a bone regeneration material comprising calcium phosphate dihydrate (which is the reaction product of CSH and water) (hereinafter referred to as "CSD"). The CSD component can impart good mechanical strength to the bone regeneration material, stimulate bone growth, and provide a relatively fast in vivo absorption rate, thereby quickly generating a porous structure in the bone regeneration material after implantation. Therefore, the CSD component can be rapidly replaced by bone tissue that grows inward into the implantation site.

The two calcium phosphate components react to form brushite upon mixing with an aqueous solution. The presence of brushite in the bone regeneration material can slow the resorption rate of the bone regeneration material compared to a composition containing only CSD. Thus, the use of such a biphasic bone regeneration material can provide a dual resorption rate defined by the CSD component and the brushite component.

In addition to the slower absorption rate, the use of such granular compositions as bone regeneration materials in the present invention can provide high mechanical strength, good handling characteristics and reasonable construction time. In addition, when used according to the present invention, such bone regeneration materials are particularly useful for producing high-quality bone.

In some embodiments, the CSH powder may have a bimodal particle distribution, i.e., a particle distribution characterized by two peaks in a plot of particle size versus volume percentage of particles of each size, although other particle distributions are contemplated herein. For example, a bimodal particle distribution of a CSH powder may be characterized by having a mode of about 30 to about 60 volume percent of particles ranging from about 1.0 to about 3.0 microns and a mode of about 40 to about 70 volume percent of particles ranging from about 20 to about 30 microns, based on the total volume of the CSH powder. In another embodiment, the bimodal particle distribution includes a mode of about 40 to about 60 volume percent of particles ranging from about 1.0 to about 2.0 microns and a mode of about 40 to about 60 volume percent of particles ranging from about 20 to about 25 microns. The median particle size of the CSH powder is preferably about 5 to about 20 microns, more preferably about 8 to about 15 microns, and most preferably about 10 to about 15 microns.

The granular composition useful as a bone regeneration material according to the present invention preferably contains at least 50 weight percent of CSH powder, based on the total weight of the granular composition. In other embodiments, the bone regeneration material useful according to the present invention may contain CSH powder in an amount of at least 60 weight percent, at least 65 weight percent, at least 70 weight percent, at least 75 weight percent, at least 80 weight percent, at least 85 weight percent, or at least 90 weight percent. In other embodiments, the CSH powder may be present in an amount of 50 weight percent to about 99 weight percent, about 60 weight percent to about 98 weight percent, about 65 weight percent to about 95 weight percent, about 70 weight percent to about 95 weight percent, or about 70 weight percent to about 90 weight percent.

CSH is preferably hemihydrated α-calcium sulfate, which exhibits higher mechanical strength than the β form after being constructed to form CSD. The presence of CSD in the bone regeneration material used in the present invention can help to quickly produce bone material. CSH powder can be prepared by the method disclosed in U.S. Patent No. 2,616,789, which is incorporated herein by reference in its entirety. CSH powder may contain other components, such as an accelerator that can accelerate the conversion of CSH to the dihydrate form, thereby causing a faster construction of the bone regeneration material thus made. Example accelerators include calcium sulfate dihydrate crystals (obtained from U.S. Gypsum), in particular CSD coated with sucrose (obtained from VWR Scientific Products). The method of stabilizing dihydrate crystals by coating sucrose is described in U.S. Patent No. 3,573,947, which is incorporated herein by reference in its entirety. Other non-limiting examples of accelerators that can be used include sulfates and sulfides of alkali metals (e.g., potassium sulfate, sodium sulfate and calcium sulfide - including hydrates thereof). The accelerator can be present in an amount of up to 1.0 weight percent based on the total weight of the granular composition. In some embodiments, the granule composition comprises from about 0.001 to about 0.5 weight percent accelerator, more typically from about 0.01 to about 0.3 weight percent.Mixtures of two or more accelerators can be used.

The calcium phosphate portion of the granular composition that can be used in the bone regeneration material according to the present invention can include MCPM powder (Ca(H ₂ PO ₄ ) ₂ H ₂ O) and β-TCP powder (Ca ₃ (PO ₄ ) ₂ ). As is understood in the art, the main reaction product of MCPM, β-TCP, and water is brushite, also known as dicalcium phosphate dihydrate (CaHPO ₄ .2H ₂ O) (DCPD). The powder that forms brushite can also participate in other reactions that can lead to the formation of certain calcium phosphates that are more thermally stable than DCPD (e.g., hydroxyapatite, octacalcium phosphate, etc.). A certain amount of β-TCP powder can also remain unreacted. The β-TCP powder can have a median particle size of less than about 20 microns. The β-TCP powder typically has a median particle size of about 10 microns to about 20 microns. The β-TCP powder portion of the granular composition can have a bimodal particle distribution characterized by about 30 to about 70 volume percent of particles having a mode of about 2.0 to about 6.0 microns and about 30 to about 70 volume percent of particles having a mode of about 40 to about 70 microns, based on the total volume of the β-tricalcium phosphate powder. In another embodiment, the β-TCP powder can have a bimodal particle distribution characterized by about 50 to about 65 volume percent of particles having a mode of about 4.0 to about 5.5 microns and about 35 to about 50 volume percent of particles having a mode of about 60 to about 70 microns, based on the total volume of the β-tricalcium phosphate powder.

References to MCPM are intended to include monocalcium phosphate (MCP), which is a simple anhydrous form of MCPM that releases the same amount of calcium and phosphate ions in solution. However, if MCP is used instead of MCPM, the amount of water used to form the bone regeneration material may need to be increased to compensate for the loss of water molecules from MCP (if it is desired to produce exactly the same dissolved product as that formed when MCPM is used).

Compared to calcium phosphate, the presence of the brushite component can slow the absorption of the bone regeneration material in the body. In turn, the slower absorption rate can allow the bone regeneration material to provide structural support for a longer period of time.

The bone regeneration material described above is particularly useful according to the present invention because, after administration into the body, it can become a highly porous calcium phosphate matrix due to the relatively rapid absorption rate of the calcium sulfate component of the mixture. During the natural healing process, the remaining porous calcium phosphate matrix provides an excellent scaffold for bone ingrowth.

The amounts of MCPM powder and β-TCP powder present in the granular composition can vary and depend primarily on the desired amount of brushite in the bone graft replacement cement. The brushite-forming calcium sulfate composition (i.e., the combined amount of MCPM and β-TCP powders) can be present in a concentration of about 3 to about 30 weight percent based on the total weight of the granular composition. In other embodiments, the brushite-forming calcium phosphate composition can be present in a concentration of about 5 to about 25 weight percent, about 10 to about 20 weight percent, about 12 to about 18 weight percent, or about 15 weight percent. The relative amounts of MCPM and β-TCP can be selected based on their equimolar stoichiometry in the brushite-forming reaction. In one embodiment, MCPM powder can be present in a concentration of about 3 to about 7 weight percent, and β-TCP can be present in an amount of about 3.72 to about 8.67 weight percent, based on the total weight of the granular composition.

The granular composition can also comprise the granules, granules or powder components described elsewhere herein. In some specific embodiments, the composition can comprise a plurality of β-TCP granules having a median particle size greater than the median particle size of β-TCP. The median particle size of the β-TCP granules is generally about 75 to about 1,000 microns, about 100 to about 400 microns or about 180 to about 240 microns. The granules are used to further reduce the absorption rate of the bone graft substitute cement and contribute to the formation of the scaffold. The presence concentration of the β-TCP granules can be a maximum of 20 weight percents based on the granular composition weight. In other embodiments, the presence concentration of the β-TCP granules can be a maximum of 15 weight percents or a maximum of 12 weight percents based on the total composition weight. The granules are particularly useful for providing a third phase (such as herein described about the more complete description of the third phase material) that shows that the remaining materials used in the bone regeneration material absorb more slowly (for example, compared with above-mentioned calcium sulfate phase and brushite phase).

The water component that can be mixed with the granular composition to form the bone regeneration material that can be used according to the present invention so that the composition provides desired consistency and hardening or building time. Generally, the mass ratio (L/P) of liquid to powder is provided to be at least 0.2, at least 0.21 or at least 0.23 required amount. The scope of preferred L/P ratio is from about 0.2 to about 0.3 or from about 0.2 to about 0.25. The example of suitable aqueous composition includes water (such as sterile water) and its solution. Optionally, the bone regeneration material according to the present invention can include one or more additives selected from the following: sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium acetate and sodium acetate. In a preferred embodiment, the water mixed solution used is saline solution or phosphate buffered saline solution. Exemplary aqueous solution is 0.9% saline solution etc. available from Baxter International (Deerfield, I11). The aqueous solution may contain one or more organic or inorganic carboxylic acid-containing compounds (hereinafter referred to as carboxylic acids or carboxylic acid compounds), which may or may not contain hydroxyl groups on the α carbon, and is optionally titrated to a neutral pH with a suitable base (e.g., neutralized to a pH of about 6.5 to about 7.5 using an alkali metal base such as sodium hydroxide or potassium hydroxide), which can change the demand for water, fluidity, and/or viscosity of the bone regeneration material after mixing. Exemplary carboxylic acids include glycolic acid and lactic acid. Preferably, the carboxylic acid has a single carboxylic acid group, a total of 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, including carbonyl carbon) and 0 to 5 (e.g., 0, 1, 2, 3, 4, 5) hydroxyl groups attached to the carbon chain. In one embodiment, the mixed solution is a 0.6 M glycolic acid solution neutralized to 7.0 pH with NaOH. The carboxylic acid compounds mentioned herein include free acid and salt forms. Carboxylic acid can be neutralized to a pH of about 6.5 to about 7.5 with, for example, an alkali metal base in a solution, and then separated in a crystalline powder form by evaporating a solvent (such as water). Crystalline powder is usually separated in the form of a salt, such as an alkali metal salt form (such as, a salt of lithium, sodium or potassium). Exemplary dry crystalline powders of salt form carboxylic acids include sodium glycolate, potassium glycolate, sodium acetate and potassium lactate. Powdered carboxylates can be added to any other powdered ingredients, which together form the particle portion of bone regeneration material, such as CSH components or any calcium phosphate component. However, in certain embodiments, powdered carboxylic acid is stored in a separate container so that it can be reconstructed with an aqueous solution, and then the solution is mixed with the remaining particle components of the composition.

The bone regeneration material that can be used according to the present invention may contain one or more additives, which can be selected from any of the individual materials described herein. The additives can be in powder, liquid or solid form and can be mixed with or encapsulated by the bone regeneration material. Exemplary additives suitable for use in the present invention include accelerators (e.g., sucrose-coated calcium sulfate dihydrate particles), cancellous bone chips, salts (e.g., chloride, potassium chloride, sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium acetate, and sodium acetate), plasticizers that can alter the consistency and setting time of the composition (e.g., glycerol and other polyols, vinyl alcohol, stearic acid, hyaluronic acid, cellulose derivatives and mixtures thereof, including alkylcelluloses such as methylhydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate butyrate, and mixtures or salts thereof), and any "bioactive agent" (i.e., any agent, drug, compound, combination of substances, or mixture thereof that provides some pharmacological effect that can be demonstrated in vivo or in vitro), particularly any agent recognized as an anti-osteopenic or anti-osteoporotic agent. Specific pharmacological agents may include medicines for the treatment of osteoporosis, such as bisphosphonates, RANKI inhibitors, proton pump inhibitors, hormone therapy agents and SERMs, teriparatide and rPTH. Other examples of bioactive agents include but are not limited to peptides, proteins, enzymes, small molecule drugs, dyes, lipids, nucleosides, oligonucleotides, polynucleotides, nucleic acids, cells, viruses, liposomes, microparticles and micelles. It is included in the medicaments that produce local or systemic effects in patients. The example of bioactive agent also includes antibiotics, chemotherapeutic agents, pesticides (for example, antifungal agents and antiparasitic agents), antivirals, anti-inflammatory agents and analgesics. The antibiotics of example include ciprofloxacin, tetracycline, oxytetracycline, chlortetracycline, cephalosporins, aminoglycosides (for example, tobramycin, kanamycin, neomycin, erythromycin (erithromycin), vancomycin, gentamicin and streptomycin), bacitracin, rifampicin, N-dimethyl rifampicin, chloramphenicol and derivatives thereof. Exemplary chemotherapeutic agents include cisplatin, 5-fluorouracil (5-FU), Taxol and/or Taxotere, ifosfamide, methotrexate, and doxorubicin hydrochloride. Exemplary analgesics include lidocaine hydrochloride, bupivacaine, and nonsteroidal anti-inflammatory drugs such as ketorolac tromethamine. Exemplary antiviral agents include ganciclovir, zidovudine, amantadine, vidarabine, ribavirin, trifluridine, acyclovir, dideoxyuridine, antibodies to viral components or gene products, cytokines, and interleukins. An exemplary antiparasitic agent is pentamidine. Exemplary anti-inflammatory agents include α-1-trypsin and α-1-antichymotrypsin. Useful antifungal agents include diflucan, ketaconizole, nystatin, griseofulvin, mycostatin, miconazole, and derivatives thereof (as described in U.S. Pat. No. 3,717,655, the entire teaching of which is incorporated herein by reference); bisdiguanides, such as chlorhexidine; and more particularly quaternary ammonium compounds, such as domiphene bromide, domiphene chloride, domiphene fluoride, benzalkonium chloride, cetyl pyridinium chloride, dequalinium chloride, the cis isomer of 1-(3-chloroallyl)-3,5,7-triaza-1-azaadamantane chloride (available from Dow Chemical Company under the trade name Dowicil 200) and its analogs (as described in U.S. Pat. No. 3,228,828, the entire teaching of which is incorporated herein by reference), cetyltrimethylammonium bromide and benzethonium chloride and methylbenzethonium chloride, such as described in U.S. Pat. Nos. 2,170,111, 2,115,250, and 2,229,024, the entire teaching of which is incorporated herein by reference; carbanilides and salicylanilides, such as 3,4,4′-trichlorocarbanilide and 3,4,5-tribromosalicylanilide; hydroxydiphenyls, such as dichlorophen, tetrachlorophen, hexachlorophene, and 2,4,4′-trichloro-2′-hydroxydiphenyl ether; and organometallic and halogen preservatives, such as sinc pyrithione, silver sulfadiazine, and pyrithione. sulfadiazone), silver uracil, iodine, and iodine carriers derived from nonionic surfactants (e.g., as described in U.S. Pat. Nos. 2,710,277 and 2,977,315, the entire teachings of which are incorporated herein by reference), and iodine carriers derived from polyvinylpyrrolidone (e.g., as described in U.S. Pat. Nos. 2,706,701, 2,826,532, and 2,900,305, the entire teachings of which are incorporated herein by reference). Useful growth factors include any cellular product that regulates the growth or differentiation of other cells, particularly connective tissue progenitor cells. Growth factors that can be used in accordance with the present invention include, but are not limited to, fibroblast growth factors (e.g., FGF-1, FGF-2, FGF-4); platelet-derived growth factor (PDGF), including PDGF-AB, PDGF-BB, and PDGF-AA; bone morphogenic proteins (BMPs), such as any of BMP-1 to BMP-18; osteogenic proteins (e.g., OP-1, OP-2, or OP-3); transforming growth factor-α, transforming growth factor-β (e.g., β1, β2, β3); LIM mineralization protein (LMP); osteoid-inducing factor (OIF); angiogenin; endothelin; growth differentiation factor (GDF); ADMP-1; endothelin; hepatocyte growth factor and keratinocyte growth factor; osteogenin (bone morphogenetic protein-3); heparin-binding growth factor (HBGF); [0013] The bioactive agent may also be an antibody. Suitable antibodies include, for example, STRO-1, SH-2, SH-3, SH-4, SB-10, SB-20, and antibodies against alkaline phosphatase. These antibodies are described in Haynesworth et al., Bone (1992), 13:69-80; Bruder, S. et al., Trans Ortho Res Soc (1996), 21:574; Haynesworth, S.E. et al., Bone (1992), 13:69-80; Stewart, K. et al., J Bone Miner Res (1996), 11 (Suppl.): S142; Flemming J E et al., in "Embryonic Human Skin. Developmental Dynamics," 212:119-132, (1998); and Bruder S P et al., Bone (1997), 21 (3):225-235, the entire teachings of which are incorporated herein by reference. Other examples of bioactive agents include bone marrow aspirates, platelet concentrates, blood, allograft bone, cancellous bone chips, mineral (e.g., calcium phosphate or calcium carbonate) chips of synthetic or natural origin, mesenchymal stem cells, and chunks, shards, and/or pellets of calcium sulfate. Additives (especially pharmacological additives, more especially anti-osteoporosis additives) can be present in solid form, which is mixed in the bone regeneration material or placed in the bone cavity and encapsulated with the bone regeneration material. The pharmacological therapeutic agent can be eluted, dissolved, decomposed, or evaporated from the bone regeneration material.

The bone regeneration material that can be used in the method for the present invention can be formed by a variety of methods depending on the exact properties of the composition. In some embodiments, the bone regeneration material can be a granular form that can be loaded into the formed bone cavity. In other embodiments, the bone regeneration material can be an injectable, flowable form, which can be prepared by utilizing manual or mechanical mixing techniques and devices known in the art such as the above-mentioned granular composition mixed with the aqueous solution described herein. Specifically, components can be mixed at atmospheric pressure or below atmospheric pressure (for example, under vacuum) and at a temperature that does not cause the aqueous component of the mixture to freeze or significantly evaporate. After mixing, uniform composition generally has an injectable paste consistency, although the viscosity and fluidity of the mixture can depend on the additives therein and different. The bone regeneration material can be transferred to a delivery device (for example, a syringe) and injected into the cavity produced. In some embodiments, the material can be injected by a needle of, for example, 11 to 16, up to 10 cm.

In certain embodiments, the properties of the bone regeneration material can be characterized relative to the injection force range of the injectable material. In multiple embodiments, the material can have an injection force of up to 1,200N, up to 1,000N, up to 800N, up to 600N, up to 500N, or up to 400N. In other embodiments, the injection force range can be from about 1N to about 1,200N, from about 2N to about 1,000N, from about 3N to about 800N, from about 4N to about 700N, from about 5N to about 660N, from about 10N to about 660N, or from about 10N to about 330N.

In some specific embodiments, the bone regeneration material that can be used according to the present invention can be the material that solidifies generally in about 3 to about 25 minutes (more preferably from about 10 to about 20 minutes) (determined by following Vicat needle drop test (Vicat needle drop test)).The bone regeneration material preferably reaches the hardness suitable with bone or exceeds bone in about 30 to about 60 minutes.The solidification of material can occur in multiple environments (comprising air, water, body and under the in vitro condition of any number).

The sclerotic bone regeneration material that can be used according to the present invention preferably shows the complex solubility and certain mechanical strength characteristics with self formation porous scaffold, especially the characteristic characterized by radial tensile strength (diametral tensilestrength) and compressive strength (compressivestrength).For example, after material is prepared into the state for delivery, the material solidifies under ambient air after 1 hour with the radial tensile strength of at least 4MPa, more preferably the radial tensile strength of at least 5MPa, most preferably the radial tensile strength of at least 6MPa.In addition, after the material for delivery is prepared, the material solidifies under ambient air after 24 hours with the radial tensile strength of at least 8MPa, more preferably solidifies after 24 hours with the radial tensile strength of at least 9MPa, most preferably at least 10MPa.

The bone regeneration materials that can be used in the present invention also exhibit a high level of compressive strength, for example, after the material is prepared for delivery, the material has a compressive strength of at least 15 MPa, more preferably at least 40 MPa, after curing for 1 hour under ambient air. In addition, some preferred embodiments of the bone regeneration materials can exhibit a compressive strength of at least 50 MPa, more preferably at least 80 MPa, after curing for 24 hours under ambient air, after the material is prepared for delivery.

In certain embodiments, the intensity of the bone regeneration material of sclerosis can be improved by adding multiple materials. Although the present invention includes any material for improving one or both of tensile strength and compressive strength as known in the art, it can be especially useful to include one or more fiber materials. Therefore, the present invention especially includes the fiber composite material (fiber composite) of bone regeneration material.

The fiber composite material that can be used in the present invention can especially include biodegradable polymer fibers.Such fiber can not only provide the strength characteristics of improvement for bone regeneration material, and can provide the sustained delivery of one or more disclosed bioactivators (for example, growth factors, antibiotics etc.), because activating agent can be mixed with polymer before fiber formation and described activating agent will slowly release in vivo along with the biodegradation of fiber.In other embodiments, non-biodegradable fibers can also be used, but any non-biodegradable fibers are preferably inert. The limiting examples of the material that has been shown to be used as fiber for improving the intensity of bone regeneration material include poly (L-lactic acid) (PLLA), polyethylene terephthalate (PET) (for example, suture), polyethylene, polyester (for example, ), poliglecaprone (poliglecaprone) (for example, ), polyglycolic acid and polypropylene.Certainly, those skilled in the art will be able to utilize the benefit identification of present disclosure to even more can provide or otherwise improve the material of the intensity of bone regeneration material used according to the present invention in fiber form.

The fibers used to enhance the strength of the bone regeneration material can have a variety of sizes. Preferably, the fibers used in various embodiments can have an average diameter of about 1 μm to about 100 μm, about 2 μm to about 75 μm, about 3 μm to about 50 μm, about 4 μm to about 40 μm, or about 5 μm to about 25 μm. Such fibers also preferably have an average length of about 100 μm to about 1,000 μm, about 150 μm to about 900 μm, about 200 μm to about 800 μm, or about 250 μm to about 750 μm.

The fibers used to increase the strength of the bone regeneration material may also have varying concentrations. Specifically, the fibers may comprise from about 0.1% to about 10%, from about 0.25% to about 9%, from about 0.5% to about 8%, from about 0.75% to about 7%, from about 1% to about 6%, or from about 1.5% to about 5% bone regeneration material by weight.

Preferably, the fibers are added in a concentration such that the strength of the bone regeneration material is significantly increased compared to a material without any fiber additive. Specifically, the fibers can be added in an amount that increases the tensile strength of the bone regeneration material by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%. Similarly, the addition of the fiber component can increase the compressive strength by at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%.

In some embodiments, the addition of a fiber component can increase the viscosity of the bone regeneration material, which can reduce the material's injectability. To overcome this increased viscosity, a syringe with a tapered nozzle can be used to inject the material. This nozzle configuration can reduce the force required to inject a thicker paste through the needle.

During preparation, fibers can be added to a dry mixture of materials used in the bone regeneration material. The combined materials can be moistened to form a paste. Additional processing steps may also be included to improve the mixing of fibers into the bone regeneration material and reduce the presence of fused fiber groups. For example, the cut fibers can be ultrasonically stirred for a limited time (e.g., 30 to 60 minutes), and such stirring can be performed while the fibers are in a liquid medium (e.g., isopropyl alcohol) in which the fiber polymer is insoluble. The ultrasonicated fibers can then be added to the dry ingredients for the bone regeneration material and mixed (e.g., by stirring). The combination is then filtered and dried under vacuum. The combined materials are then moistened to form a paste material for use.

The method of the present invention generally includes that the degenerate bone material (optionally in the zone with limited shape) of limited volume is replaced with bone regeneration material, and described bone regeneration material can cause to produce the new bone material higher than the degenerate bone material density (or other bone measurements as described herein) replaced.Term " degenerate bone material " or " degenerate bone material " can refer to the bone material that clinical classification is osteopenia or osteoporosis.More particularly, this term can refer to T score lower than-1, lower than-1.5, lower than-2, lower than-2.5 or lower than-3 bone.Such degenerated bone regeneration material is usually present in the bone that is generally also classified as osteopenia or osteoporosis.

Method of the present invention can be generally described as the method for improving the bone quality of bone specific area. Specifically, bone quality can directly correspond to BMD, but can also refer to the general strength (including compressive strength) of bone in or around the bone local area and the ability of bone to resist fracture. The ability part that improves bone quality comes from known bone quality that can effectively reconstruct bone local area into healthier normal bone or the bone quality of similar patient under the condition that BMD is recognized as being in its peak value. Unexpectedly, it is found that the degenerated bone material of bone local area (for example, deriving from the patient suffering from osteoporosis) can be replaced with the bone regeneration material that causes to produce new bone material in local area. What is particularly unexpected is that the newly produced bone material does not have the quality of osteoporosis. This is unexpected, because when the patient is expected to suffer from systemic osteoporosis, any new bone material formed in this patient's body will have the quality of reduction (that is, will be osteoporotic and show low density). But the present invention shows that after implanting bone regeneration material in osteopenia or osteoporotic bone, material will be absorbed at a predictable rate and is not negatively affected by systemic disease. The dense new bone material that bone local area produces subsequently improves bone quality and the BMD measured by the T score of DEXA.Particularly, T score shows that the newly produced bone material is basically similar to normal bone, because it has the density (for example, the T score of about-1 to about 1 scope) of expected visible level at least in the patient being in peak BMD and is not in osteopenia or osteoporosis state.In other embodiments, the newly produced bone material can show the compressive strength that is basically similar to (or exceeds) the compressive strength of normal bone.Such feature can be relevant to the newly formed bone material, particularly relevant to general bone local area (that is, the bone material existing in the newly formed bone material and the surrounding area next to each other).

In certain embodiments, the method of the present invention may include an active step of forming a cavity in the patient's bone. Specifically, the method may include forming a cavity in the local area of the bone. Any method that can be used to form this cavity can be used according to the present invention. In some embodiments, the method may include chemical dissolution or otherwise remove the bone material in the bone confined area to form a cavity. In other embodiments, liquid lavage can be used to produce a cavity in the bone, such as the method described in U.S. Patent Publication No. 2008/0300603, which is incorporated herein by reference. In other embodiments, sonic degradation can be used to clean the bone material in the local area. In other embodiments, a cavity can be produced by using an expandable or expandable device (such as a balloon or an expandable reamer in situ). Expandable mesh can also be used. In some specific embodiments, the method may include any mechanical means for producing a cavity in the local area of the bone.

In some embodiments, the method may include drilling or otherwise forming a channel into a local area of bone (e.g., by piercing with a tubular or solid needle, probe, etc.). In some embodiments, the channel formed in this manner may provide a cavity that is desired for a specific treatment method. In other preferred embodiments, drilling or forming a channel may be characterized as a method for forming a channel to the inside of a local area of bone to be treated, so that a cavity larger than the channel can be formed. Utilizing the channel to the bone area to be treated, any method that can be used to produce a cavity can be used to form a cavity of a predetermined shape and size, including any of the methods described above. Depending on the degenerative state of the bone (i.e., the progression of osteopenia or osteoporosis), the formation of the cavity may include removing at least a portion of the degenerated bone material.

Fig. 2a and Fig. 2b respectively show scanning electron microscope photographs of normal bone and osteoporotic bone. As seen therein, normal bone shows the pattern of strong interconnected plates (plates) of bone material. In osteoporosis, a lot of this material is lost, and the remaining bone has a weaker rod-like structure, and some rods are completely disconnected. This disconnected bone can be measured as bone mass, but does not contribute to bone strength. In some embodiments, the cavity can be formed simply by breaking up the degenerated bone material, for example, by scraping, drilling or using a specialized material for reamed (ream out) bone to form a cavity. Such cleaning can be described in addition as destroying, crushing, crushing, pulverizing, reamed, expanding or otherwise disassembling or pushing out or removing the bone material in the region for forming the cavity. In some embodiments, this can be referred to as debridement, insufflation or zigzag (snaking) of localized bone. Preferably, the debridement area meets the predetermined shape and size of the desired cavity.

Because of the loss of BMD, the degenerate bone material that is broken up to form a cavity can simply remain as residual material in the formed cavity. In other embodiments, it is desirable to remove some or all of the degenerate bone material that is cleaned up to form a cavity. Therefore, the cavity formation according to the present invention can be characterized as breaking up the degenerate bone material in the local area and removing at least a portion of the material, or the cavity formation can be simply characterized as a breaking up step. In some embodiments, the effective step of forming a cavity in the bone can refer to cleaning up damaged and/or degenerated bone material from the local area of the bone. Therefore, cleaning can include completely or partially destroying the degenerate bone material and/or removing all and or part of the degenerate bone material from the cavity. In some specific embodiments, the present invention can be characterized as removing damaged and/or degenerated bone material from the local area of the bone to form a cavity of a predetermined shape and size. In other embodiments, the method can be characterized as forming a disorganized cavity of a determined volume.

Described method can also comprise with for example bone regeneration material described herein at least partially filling the formed cavity.The usage amount of bone regeneration material can depend on the volume of the cavity formed in the aforementioned steps.In multiple embodiments, the volume range of the bone regeneration material used can be about 1cm ³ to about 200cm ³ , about 2cm ³ to about 150cm ³ , about 2cm ³ to about 100cm ³ , about 2cm ³ to about 75cm ³ , about 5cm ³ to about 50cm ³ , about 10cm ³ to about 40cm ³ or about 15cm ³ to about 35cm ^3.As mentioned above, the aforementioned volume can therefore represent the actual volume of the cavity formed in the bone.In some specific embodiments, volume can be specifically relevant to the bone being treated and the region.For example, for distal radius, volume can be about 1cm ³ to about 10cm ³ , about 1cm ³ to about 8cm ³ or about 1cm ³ to about 5cm ³ . For the vertebral body, the volume can be about 1 cm ³ to about 30 cm ³ , about 2 cm ³ to about 25 cm ³ , or about 2 cm ³ to about 20 cm ³ . For the proximal femur, the volume can be about 5 cm ³ to about 100 cm ³ , about 5 cm ³ to about 80 cm ³ , or about 10 cm ³ to about 50 cm ³ . For the proximal humerus, the volume can be about 5 cm ³ to about 200 cm ³ , about 5 cm ³ to about 150 cm ³ , about 5 cm ³ to about 100 cm ³ , or about 10 cm ³ to about 80 cm ³ .

The shape of the cavity formed in the bone can vary depending on the bone being treated. In some embodiments, the shape of the cavity formed can generally correspond to the shape of an area in the proximal femur known as the Ward's area. In some embodiments, the shape of the cavity can generally conform to the shape of a localized area of the bone being treated. For example, for treatment of the distal end of the deflection, the cavity can generally conform to the shape of the distal 1-5 cm of the bone. In some specific embodiments, the shape of the cavity formed is not critical to the success of the method; however, the present invention is intended to encompass the formation of a cavity that can be a definite shape and size desired in the specific bone being treated.

In certain embodiments, particularly when treating patients in a particularly advanced stage of bone degeneration, not creating a cavity before injecting the bone regeneration material can achieve at least some degree of treatment. As discussed above, the effect of bone loss associated with osteoporosis is to reduce the density of the bone material or to form larger, more significant spaces in the bone. In advanced osteoporosis, the cavitation of the bone allows the bone regeneration material to be injected directly into the localized area of the bone that exhibits this increased porosity. In some specific embodiments, the force of injecting the bone regeneration material itself can artificially expand the space within the bone, thereby effectively forming an immediately filled cavity. In other embodiments, the injected bone regeneration material can simply infiltrate the degenerate bone with increased porosity, thereby substantially filling the pore volume of the treated localized area of the bone. Therefore, in certain embodiments, the present invention includes simultaneously creating and filling cavities in the localized area of the bone. Although such embodiments may occur, it is expected that the most effective result is achieved by at least forming a channel into the degenerate bone area to be filled with the bone regeneration material. More preferably, the cavity is formed as described above.

Any method that can be used for inserting bone regeneration material into the formed cavity can be used.For example, when bone regeneration material is in a flowable form, the material can be injected into the formed cavity by, for example, using a syringe. Therefore, in some specific embodiments, bone regeneration material can be introduced into the cavity under a substantially flowable state and then hardened in vivo. In other embodiments, bone regeneration material can be made to substantially harden in vitro and then the hardened material is filled into the cavity. In addition, bone regeneration material can present other physical states, such as the consistency of putty. In some embodiments, bone regeneration material can be a particle form of different sizes that can be filled into the cavity. In addition, in addition to being able to fill the cavity with bone regeneration material, one or more additional materials can also be filled, which can contribute to filling the cavity and can provide one or more other beneficial functions, such as providing temporary or permanent support for a local area. In some specific embodiments, an elution matrix, such as the expansion sponge (peptide soaked expanding sponge) soaked with BMP or peptide can be inserted into the cavity before inserting the bone regeneration material.

In some embodiments, bone regeneration material can be inserted into the cavity produced together with extra reinforcing agent (for example, coated with reinforcing agent or comprising screw or other cylinder or hollow material of reinforcing agent in hollow).But, beneficially, method of the present invention allows filling formed cavity without the need for any extra reinforcing agent (no matter reinforcing agent is absorbable or non-absorbable).In some specific embodiments, bone regeneration material used in the present invention can be such material, and its hardening provides enough intensity so that the fracture resistance of treated bone region is at least equal to the fracture resistance of bone before treatment for the bone local area treated immediately.Such advantage is described more specifically in the embodiments hereinafter.Equally as described herein, the substantial raising of the bone strength established by the ingrowth of the new bone material identical with natural healthy bone substantially eliminates the demand for reinforcing agent further.Relatively early (for example, less than 1 week to the time of about 16 weeks) see this raising of bone quality.

In some embodiments, the present invention may provide methods for treating a patient suffering from a degenerative bone disorder. In particular, the patient may suffer from and/or be diagnosed with an osteopenic disorder or an osteoporotic disorder. Alternatively, the patient may suffer from any other disorder that has a degenerative effect on bone, particularly loss of BMD and/or bone strength.

The present invention is particularly useful for cleaning the cavity formation of degenerate bone material, thereby can provide bone regeneration material therein.Preferably, bone regeneration material promotes the formation of new non-degenerate bone material in the cavity.Advantageously, the newly formed bone material is natural to the patient.Preferably, the newly formed bone material has a density substantially equal to or greater than that of natural bone.In other words, the density of the newly formed bone material is substantially equal to the bone density of people (preferably of the same race and sex) aged 30 to 35 years old.In some specific embodiments, this may refer to the newly formed bone material having a T score greater than -1 when measured with DEXA, preferably at least -0.5 or at least 0. In other embodiments, the T score of the newly formed bone can be about -1.0 to about 2.0, about -1.0 to about 1.0, about -1.0 to about 0.5, about -1.0 to about 0, about -0.5 to about 2.0, about -0.5 to about 1.5, about -0.5 to about 1.0, about -0.5 to about 0.5, about 0 to about 2.0, about 0 to about 1.5, or about 0 to about 1.0. In another embodiment, the BMD of the newly formed bone material is sufficient to exceed the BMD before treatment (indicated by an increase in the T score) so that the patient is considered to have a significantly increased relative BMD. The newly formed bone may also have a compressive strength that is substantially equal to or greater than that of normal bone.

Method of the present invention is particularly beneficial, is that can effectively be remodeled into and be equal to (that is, show normal BMD and/or normal compressive strength and/or normal fracture resistance) substantially with normal bone in the bone local area in time.In addition, in some embodiments, the effect of the bone regeneration material for producing new natural bone growth can actually extend to outside the scope of formed cavity.Particularly, according to the present invention, find that the gradual effect of density improvement can be provided in the new natural bone material in the cavity initially formed, but can also produce new bone material in the bone region near the cavity formed.This is especially beneficial, is also to strengthen the bone near the bone region of the cavity formed, thereby reduce the incidence rate near fracture.

As noted before, the method of the present invention can be used for the skeleton in multiple mammalian bodies.In particularly useful embodiments, the method of the present invention can be used for the bone in patient's coxal region.For example, the following is an illustrative method for treating the patient with degenerative bone disease by replacing the bone material of patient's femoral local region (particularly proximal femur).Surgical technique uses the lateral cutting mode of core decompression (core decompression) or hip screw similar to standard.A difference of technology is to produce the geometry of defect or cavity to accept graft (that is, bone regeneration material), which subsequently regenerates dense new natural bone to improve the bone quality of bone local region, strengthens femoral neck and Ward's triangle, and reduces the risk of incomplete fracture.The following operation (geometry is different) can be used in other regions of metaphyseal bone (for example, vertebral body, distal radius, proximal humerus and tibia).

In order to carry out this technology, the patient can be placed on a radiolucent table in a supine position. During the operation, radiation support can be provided by a C-arm device, and an X-ray technician provides X-ray navigation. As mentioned above, the side cutting method of the proximal end of the radius can be used. In other embodiments, the larger trochanter method can also be used. A small incision can be made on the slightly distal side of the larger trochanter, and a guide wire can be introduced into the proximal femur under the front-back (AP) view and side view of a fluoroscopic guide (fluoroscopic guidance). A tubular 5.3mm drill can be introduced above the guide wire to a height of the femoral head, and a channel can be formed to form a cavity as high as (or alternately through) the side. This channel can be referred to as a core. In some alternative embodiments, any device for crushing weak osteoporotic bone material can be used, for example, using a countersink or cortical punch and a blunt sealer to create space. The drill and guide wire can be removed, and a working cannula can be introduced into the core to form a defect or cavity produced through surgery. A debridement probe can be used to create space in the local area of the femur for implanting bone regeneration material. In particular, the probe can have a head with a precise angle to adapt to the intraosseous anatomical structure of the femoral neck and Ward's triangle. This geometry is produced to allow the neck and Ward's triangle to be completely filled, which provides the maximum possibility for achieving regeneration and higher final bone strength. Preferably, the defect (or cavity) produced by the operation is washed and aspirated before continuing. If necessary, the bone regeneration material is prepared and injected into the defect produced by the operation through a long cannula. The injection through the cannula eliminates the potential for self-ventilation along the medullary canal downward. After the bone regeneration material is injected, the incision is closed in a standard manner. Beneficially, the process can be completed within the patient's minimum downtime and preferably does not require overnight hospitalization (for example, only a total of about 6 to 8 hours is required in a clinic, hospital or other medical facility). Figures 3a to 3i provide radiographic images of the bone regeneration material PRO- (obtained from Wright Medical, Arlington, TN) injected into the cavity produced at the patient's proximal femur just before the injection of the bone regeneration material. As shown in the images, bone regeneration material is injected into the cavity through a long cannula that is initially inserted as high as the femoral head (FIG. 3a), manipulated to completely fill the cavity (FIG. 3b-3h) and the cannula is removed once backfilling is complete (FIG. 3i).

The various variations of the above-mentioned operation can be implemented within the scope of the present invention. For example, Fig. 4 provides the enhanced radiographic image of the proximal femur of the target filling area, and any part of the filling area can be filled (initially to regional debridement or not). The figure also shows the approximate area and size of the initial passage that can be formed by the side cut mode. Specifically, Fig. 4 shows the passage extending laterally to the femoral head by the proximal femur, and provides a hatching line (hatching) to illustrate that it is an example area in the proximal femur, and any part thereof can be used as a candidate for cleaning bone material and filling bone regeneration material. As other non-limiting examples, one or more " struts (strut) " can be formed in the proximal femur as branches of the initial passage, and then fill bone regeneration material. In addition, one or more struts can have one or more parts, and the part significantly expands to improve the amount of the bone regeneration material that can be placed in the limited area of bone. In addition, the larger area of the general proximal femur can be cleaned and filled. In addition, similar embodiments in the present disclosure can be considered.

Another surgical technique that can be used according to the present invention is described below for a critical atypical femoral fracture (impending atypical femoral fracture). Although such fractures most commonly occur near the femoral shaft one-third, they can occur at any position along the femoral shaft from the distal end of the lesser trochanter to the proximal end of the femoral metaphysis distal condyle expansion. The fracture is atypical, that is, it usually occurs as a result of no trauma or minimal trauma (equivalent to falling from a standing height or lower). The fracture can be complete (extending completely through the entire femoral shaft, usually forming a medial protrusion) or incomplete (showing as a transverse radiolucent line of the lateral cortex).

Specifically described below is the technology for introducing bone regeneration material into the femoral body of the patient (for example, the patient of osteopenia or osteoporosis) suffering from critical atypical fracture by producing a cavity in the complete femoral body before atypical femoral fracture occurs. Initial step (guide pin arrangement) is included in forming a skin incision (for example, 1 cm) near the top of the greater trochanter. The serrated tissue protector sleeve with intubation stabilizer (cannulated centering guide) and guide pin (guide pin) is inserted into the cortex of the greater trochanter. The guide pin is forward through the cortex of the greater trochanter and continues to the region of critical fracture in the femoral shaft. The depth and position of the guide pin can be confirmed by the fluoroscopic view of two planes.

Next, a defect is created and prepared for injection of bone regeneration material. Specifically, the cannula stabilizer is removed while the jagged tissue protector is held in place and a 5.3mm tubular drill is inserted and passed forward through the trochanter. The drill is then removed, the guide pin is left in place, and a flexible reamer is introduced. The reamer is advanced over the guide wire and through the trochanter, and the guide pin is then removed. The reamer is then advanced to the area near the fracture and removed. A working cannula with a trocar is inserted through the jagged tissue protector and placed inside the cortex (i.e., providing a "comfortable" fit). The jagged tissue protector is subsequently removed and the trocar is inserted. An injection cannula can be inserted through the working cannula and advanced to the femoral fracture area, and cannula aspiration can be used to remove any particles produced in the femur. The bone regeneration material is then injected, preferably while being monitored (e.g., by fluoroscopy). For optimal filling results, the injection operation time is typically about 2 to 4 minutes. The injection cannula and working cannula are then removed. The soft tissue can then be perfused, and the skin is then closed using an appropriate method (e.g., suturing).

Another description of the surgical technique that can be used according to the present invention is described below for the distal radius. The following specifically describes a technique for introducing bone regeneration material into the distal radius of a patient with osteopenia or osteoporosis by creating a cavity in the intact distal radius before any fragility fracture. To perform this technique, the patient places their arm with their palm facing up on a radiolucent table. During the operation, radiation support can be provided by a C-arm device and X-ray navigation can be provided by an X-ray technician. To form an injection portal, a 1 cm incision is made centered on the radial styloid process, and the subcutaneous tissue between the first and second dorsi extensor compartments is bluntly dissected to the periosteum. Under fluoroscopic guidance, a k-wire is inserted into the radial styloid process 3 to 4 mm proximal to the scaphoid junction and centered (facing away from the palm). A tubular drill is used to drill into the metaphysis of the distal radius. A debridement probe can be used to create space in a local area of the distal radius for implanting bone regeneration material. Specifically, the probe can have a head with a precise angle to adapt to the intraosseous anatomical structure of the distal radius. Preferably, the defect produced by the operation is washed and aspirated before continuing. If necessary, bone regeneration material is prepared and injected into the defect produced by the operation through a cannula. After the bone regeneration material is injected, the incision is closed in a standard manner. This surgical technique is not expected to require the patient to be hospitalized, which allows the bone degeneration to be beneficially treated within the patient's shortest downtime. Figures 5a to 5c provide illustrations of the specific steps of the above-mentioned surgical technique. Figure 5a shows the formation of a channel leading to the distal end of the radial metaphysis. Figure 5b shows a cavity mechanically formed in the distal end of the radius. Figure 5c shows a local area of the radius after the cavity is filled with bone regeneration material.

Another description of surgical techniques that may be used in accordance with the present invention is described below for the vertebrae. The following techniques utilize an inflatable tamp (or balloon), such as those available from Kyphon, Inc. (now a subsidiary of Medtronic, Inc.). Thus, as further described herein, some methods according to the present invention may be an improvement over kyphoplasty techniques. In other embodiments, however, the techniques for replacing degenerated bone in the vertebrae may be substantially similar in nature to the techniques described above for the proximal femur and distal radius. An essential difference over known techniques for treating vertebral fractures is that the methods of the present invention can be performed on the vertebrae before they suffer an osteoporotic compression fracture (or any other type of fracture).

In an exemplary surgical technique for replacing degenerative bone in the vertebrae, the patient can be placed on a radiolucent table in a prone position. During the operation, radiation support can be provided by a C-arm device and X-ray navigation is provided by an X-ray technician. After the vertebrae to be treated and their corresponding pedicles are confined in the radiation tubes projected front and back, a small skin incision (about 1 cm) can be made in the back or waist area, into which a bone biopsy needle of size 11/13 is introduced through the pedicle rear portion (front, middle and tail tilt). In this exemplary method, the method is bilateral. Once the accurate position of the needle has been determined, a Kirshner wire is introduced. The drill bit is advanced from the anterior cortical edge into the wall a few millimeters to form an intraspinal bone channel for the balloon to pass continuously.

Continuously, under the guidance of lateral fluoroscopic examination, the probe is carefully advanced and placed at the front two-thirds of the vertebra. Its length range includes 15 to 20 mm, and the maximum volume is 4 and 6 mL respectively. Once the accurate position of the balloon in the two hemivertebral bodies is determined with the help of the radiopaque markers located at the end (proximal or distal end), the balloon is inflated with a liquid containing 60% contrast medium, achieving the lifting of the upper vertebral end plate and creating a cavity therein by compression of the surrounding cancellous bone. When the space is in contact with the cortical body surface, or after reaching the maximum pressure (220 PSI) or maximum expansion of the balloon, the expansion stops. The cavity produced by the operation can then be washed and aspirated.

If necessary, bone regeneration material can be prepared. The bone regeneration material is then loaded into a dedicated cannula and advanced through the working cannula until it corresponds to the front third of the cavity. Immediately thereafter, under continuous fluoroscopic guidance, the bone regeneration material is pushed in with a piston stylet using gentle pressure. The filling volume is typically 1 to 2 mL larger than that achieved using a balloon, which allows the bone regeneration material to distribute itself effectively. To complete the procedure, all cannulas are removed, the skin incisions are sutured, and the patient may be instructed to remain in bed for several hours. The procedure typically lasts approximately 35 to 45 minutes for each treated vertebra. Routine radiographic examinations may be performed after the procedure to evaluate the results obtained. Figures 6a to 6c illustrate the specific steps of an exemplary procedure for replacing bone regeneration material in a vertebra. Figure 6a shows the insertion of a balloon into the treated vertebra from both sides. Figure 6b shows the balloon being inflated to mechanically create a cavity in the vertebra. Figure 6c shows the balloon being removed and the cavity formed in the vertebra being backfilled with the bone regeneration material.

While the methods of the present invention may be characterized in terms of treating patients with degenerative bone disorders, such as osteopenia or osteoporosis, the invention may also be characterized in terms of its ability to specifically alter a localized region of bone, for example, by increasing BMD, increasing bone mass, increasing bone strength, increasing natural bone structure, etc. The invention may also be characterized in terms of its ability to remodel a localized region of bone, including providing a localized region of bone with greatly increased density that gradually decreases to normal BMD.

In certain embodiments, the present invention can be characterized as providing a method for the bone quality of multiple improving bone local areas. Bone quality can be characterized specifically with respect to BMD, and described BMD can be evaluated with respect to the T score of DEXA scanning. Bone quality can also more generally relate to the overall structure of the bone material for bone scaffold. In addition, bone quality can specifically relate to bone strength, i.e. compressive strength.

The specific mechanical strength of bone (whether involving natural bone material or bone material regenerated in surgically created defects (including those in patients with osteopenia or osteoporosis)) is not currently directly measured in living subjects because such testing typically requires the removal of large bone segments. Therefore, direct measurements of bone mechanical strength can only be measured through postmortem clinical retrieval studies. However, studies have shown that a substantial increase in strength can be expected as BMD increases, as discussed herein. Further increases in bone properties (e.g., bone mass, trabecular thickness, trabecular number, trabecular separation, measurements of interconnectivity, and cortical wall thickness) can also be expected. Evidence supporting this increase in mechanical strength is provided in the accompanying examples involving canine studies, where compressive strength and the amount of calcified bone were directly measured on graft samples of regenerated bone 13 and 26 weeks after the cavity creation and filling process according to the present invention. As measured by quantitative histology, after 13 weeks, the bone segments containing the regenerated bone material showed a substantial increase in calcified bone of 172% compared to normal bone in the same anatomical region. The compressive strength of the bone with the regenerated bone material increased by over 283% compared to that of native bone. By 26 weeks post-surgery, the newly regenerated bone material had undergone remodeling, leading to a gradual restoration of normal bone structure and properties. Histological analysis showed a 24% increase in calcified bone (again, compared to native bone), corresponding to a compressive strength 59% higher than normal controls. Also noteworthy was the increase in radiographic density observed, which correlated with the quantitative results from histology.

The clinical evidence that BMD improves in human subjects is provided in the accompanying examples, and it is believed that the inference that the improvement of BMD can be appropriately related to the improvement of bone mechanical strength, particularly compressive strength is supported. In brief, 12 human patients were studied, and according to the definition of the World Health Organization (WHO), they were all considered to suffer from osteoporosis. For the purpose of comparison, the contralateral hip of each patient treated at one hip according to the present invention remained untreated. Before treatment (baseline) and at predetermined time intervals (comprising 6, 12 and 24 weeks), the BMD of both hips was measured by DEXA. Compared with baseline, the average femoral neck BMD of each interval improved by 120%, 96% and 74% respectively. Compared with baseline, the average Ward's area BMD of each interval improved by 350%, 286% and 189% respectively. Further, two patients were evaluated at the study endpoint of 24 months. These two patients showed that the average BMD at the endpoint improved by 35% (femoral neck area) and 133% (Ward's area). As observed in the canine study, percentage values of this level indicate that the graft material was resorbed and replaced by new bone material. In the untreated side, there was no appreciable change in BMD measurements from baseline.

To date, there are no known studies demonstrating that increases in BMD and strength in human osteoporotic bone can be accurately correlated with these values measured in healthy canine subjects. However, the large increases in both properties in the canine studies, combined with the increases in BMD measured in the clinical trials, strongly suggest that bone strength is correspondingly increased in human osteoporotic bone treated according to the methods described herein.

Bone quality can also be related to the ability of bone to resist fracture. Thus, some embodiments of the present invention that can be characterized as being related to an increase in bone quality can specifically include improving bone structure in such a way that the risk of fracture in the treated bone area is lower than the risk of fracture before treatment (e.g., when the patient has osteopenia or osteoporosis).

Low BMD is the strongest risk factor for fragility fractures. In addition, the degradation of cancellous bone structure is a contributing factor to bone fragility. Therefore, although osteoporosis is traditionally defined as a disease characterized by reduced bone strength, it should also be defined as a disease of low bone density and deterioration of bone quality. Although the measurement of BMD is a powerful clinical tool and "gold standard" for determining bone quality, bone quality is also primarily defined by bone turnover and microarchitecture. When these aspects of bone deteriorate (e.g., trabecular thinning and loss of connectivity), bone fragility and fracture risk increase accordingly.

However, a variety of non-invasive methods are used to measure microstructure, including but not limited to high-resolution peripheral quantitative computed tomography (pQCT), micro computed tomography (uCT), and functional magnetic resonance imaging (fMRI). Images obtained using these methods can be used to differentiate between cortical and cancellous bone and visualize details of trabecular microstructure that were previously only measurable by invasive biopsies. Bone stiffness can be assessed using microstructural finite element analysis (FEA) computer simulations of CT scans (and possibly MRI). Each of these methods can be used to assess the structure of bone. These structural measurements include bone volume, trabecular thickness, trabecular number, trabecular separation, interconnectivity, and cortical wall thickness.

As technology improves, the measurement results of computer software have improved a lot. pQCT and FEA can be combined to predict the fracture starting point and fracture probability under a specific load. This analysis is also known as biomechanical computation tomography (biomechanical computation tomography, BCT). In combination with conventional studies such as comprehensive healthy animal studies, osteoporosis animal studies or corpse biomechanical studies, BCT can be used to predict the fracture probability (including the risk of fracture during the fall) of the patient and provide information to assess the improvement of the bone quality of the surviving patient, without the need for invasive biopsy. Because of its quantitative assessment, along with focusing on the patient's bone quality spectrum, BCT can limit the inclusion/exclusion criteria of any study. In addition, the duration of any study can be potentially reduced because only the specific subgroup of the patient "at risk" who is "estimated to be at risk" needs to be "at risk". In addition, BCT can reduce the need for limited endpoints (such as actual hip fractures, which are highly correlated with mortality) to determine the benefit of the treatment provided.

Therefore, in certain embodiments, the evidence of bone quality improvement according to the present invention can be obtained by using BCT analysis to the implanted bone matrix as described above and in combination with other recognized scientific bone quality assessments. The combined results can be used to analyze the changes in bone density and bone quality over time, thereby proving that the overall fracture risk is low after treatment according to the present invention compared to the condition of the natural bone before treatment (that is, when the bone is in an osteopenia or osteoporosis state). Therefore, these methods can be used to quantify the fracture risk before and after treatment according to the present invention, and based on quantitative data, the present invention reduces fracture susceptibility or improves the ability to resist fracture. For example, the T score of BMD analysis can be used to measure fracture probability, so a score of about 0 represents a fracture probability similar to the average probability of a 30-year-old healthy adult (or even including gender, race and/or nationality data, if there is evidence that these factors need to be considered). Negative scores can represent fracture probability greater than the average value of healthy adults, and as the value becomes more negative, the possibility increases (for example, a score of -2 represents a greater fracture probability than a score of -1). Positive scores can represent fracture probability lower than the average value of healthy adults, and as the positive value becomes larger, the fracture probability decreases (for example, a score of 2 represents a lower fracture probability than a score of 1).

In some embodiments, a method for improving bone quality in a localized area of bone may include replacing a volume of degenerated bone having a T score less than -1.0 with newly formed natural bone material having a T score greater than -1.0. Preferably, the bone having the newly formed natural bone material has a T score of at least -0.5, at least 0, at least 0.5, or at least 1.0. In certain implementations, the T score of the treated bone may exceed the T score of the degenerated bone by at least 0.5 units, at least 1.0 units, at least 1.5 units, at least 2.0 units, at least 2.5 units, or at least 3.0 units. In some embodiments where the T score of the treated bone exceeds the T score of the degenerated bone by at least a specific amount, the T score need not be greater than a defined minimum value as long as the increase in BMD demonstrated by the increase in T score indicates a sufficiently significant improvement in bone quality for the patient to be treated (e.g., converting the localized area of bone from a severe osteoporotic condition to a mild osteoporotic condition or from an osteoporotic condition to an osteopenic condition).

In the method for improving bone quality, the replacing step may include forming a cavity in the area by cleaning the degenerated bone material in the local area and optionally removing a portion of the degenerated bone material. The method may also include at least partially filling the formed cavity with a bone regeneration material, thereby forming an ingrowth of new natural bone material within the formed cavity.

In some embodiments, the ability of replacing degraded bone material with the bone material of quality improvement can be particularly from the beneficial quality of the bone regeneration material for filling the cavity formed in bone.Preferably, bone regeneration material is the material that can provide the speed that produces new bone material regeneration with body remarkably consistent with the speed described herein and is reliably and consistently absorbed by body.For example, can be particularly usefully utilized the material that provides multiphase absorption spectrum in vivo as described herein, it can optimize the ingrowth of new bone.Such material can be biphasic (that is, including at least two different materials that absorb at different rates in vivo), three-phase (that is, including at least three different materials that absorb at different rates in vivo), or can include even more number of different materials that absorb at different rates in vivo.

In some specific embodiments, the bone regeneration material may include calcium sulfate as a first phase component that is rapidly absorbed (usually by simple dissolution), a second phase component of brushite (CaPO ₄ ) that undergoes osteoclast absorption (also simple dissolution), and a third phase of tricalcium phosphate that undergoes primary osteoclast absorption. Any material exhibiting this three-phase absorption spectrum can be used according to the present invention. Figures 7a to 7e show changes over time in a bone regeneration material having such a structure that can be beneficial for controlling the ingrowth of new bone regeneration material. The figures show the dissolution of the implant in an accelerated in vitro model, which is approximately 6 times greater than the absorption mass seen in canines. A more detailed discussion of the bone regeneration material absorption spectrum of Figures 7a to 7e is provided in the Examples below.

Although all phases in a multiphasic material may begin to resorb to some extent shortly after implant placement, a multiphasic resorbable material can be described as one in which a first phase is dominated by the resorption of a first material (e.g., a calcium sulfate material) until most of the first phase disappears, a second phase is dominated by a second material (e.g., brushite), and any additional phases can be described as remaining graft material (e.g., particulate TCP) resorbed over time. The specific time for complete resorption of each phase may depend on the specific material used and the size of the defect.

Angiogenesis is a key early event in the first phase of absorption because as the calcium sulfate material is absorbed, the porous second phase is exposed and facilitates vascular invasion. The porous second phase can also bind to free proteins such as VEGF and BMP-2 at the implant/defect interface. The absorption of the second phase can then release bound proteins, which can recruit cells to the graft surface. Growth factors in the interfacial region can stimulate the proliferation and differentiation of mesenchymal stem cells. Afterwards, differentiated osteoblasts are localized in the osteoid, which is then mineralized into newly formed bone. The principles of Wolff's Law can then drive the remodeling of the newly formed bone material. This is further beneficial to the patient in that strengthening areas prone to weakened fractures (e.g., the hip bone) can encourage the patient to build confidence leading to more exercise and training, which in turn can have a positive effect on total bone mass and overall health.

In other embodiments, the invention provides a method for improving the BMD of a bone local area. Said method may include, for example, cleaning the natural degenerated bone material of the local area according to a suitable method (such as method described herein) and forming a cavity in the bone local area. Optionally, the natural bone material after cleaning can be removed from the formed cavity. The formed cavity is then at least partially filled with bone regeneration material described herein. The bone regeneration material filling cavity can cause new bone material to be produced in the cavity, and the density of the newly produced bone material is greater than the density of the degenerated natural bone material that is cleaned to form a cavity in the bone.

The raising of BMD can be shown by comparing the BMD scanning of the bone material of the local area before removing the degenerated natural bone material with the BMD scanning of the bone material of the local area after producing new bone material in the formed cavity. For example, when using DEXA scanning, preferably, the density of the bone material produced in the cavity has a T score greater than the T score of the natural bone material that is cleaned up to form degenerated before the cavity. In other embodiments, the T score can improve at least 0.75 unit, at least 1.0 unit, at least 1.25 units, at least 1.5 units, at least 1.75 units, at least 2.0 units, at least 2.25 units, at least 2.5 units, at least 2.75 units or at least 3.0 units. In other embodiments, the T score of the natural bone that degenerated before the cavity is formed in the bone local area can specifically be the scope of showing the presence of osteopenia or osteoporosis, and BMD can fully improve so that the bone local area will no longer be characterized as osteopenia or osteoporosis. For example, before forming the cavity, the BMD of the bone local area can be lower than -1.0, lower than -1.5, lower than -2.0, lower than -2.5, lower than -3.0, lower than -3.5 or lower than -4.0. In these embodiments, BMD can be improved so that the T score is at least at the lowest level. For example, BMD can be improved so that the T score is greater than -1.0 or is at least -0.75, at least -0.5, at least -0.25, at least 0, at least 0.25, at least 0.5, at least 0.75 or at least 1.0. In other embodiments, the BMD of the bone local area can be improved so that the T score of the bone local area can be the scope indicating that BMD falls within an acceptable normal range. For example, the T score can be greater than -1 to about 2.0, about -0.5 to about 2.0, about 0 to about 2.0, about -1.0 to about 1.0, about -0.5 to about 1.0, about -0.5 to about 0.5 or about 0 to about 1.0. In some embodiments, the T score of the native bone material before being cleaned to form the cavity may be less than -1.0, while the bone material produced in the formed cavity may have a T score of at least -0.5 or at least 0. This can indicate that the local area of bone would be considered at least osteopenic before treatment, and that after the new bone material is produced in the cavity, the local area of bone would be considered to have a BMD that is substantially consistent with the normal BMD of a person of the same sex and race at the age of peak BMD. As previously described, an increase in BMD may simply be sufficient to demonstrate a relative increase in BMD in the local area.

In addition to its ability to form new, natural bone of normal density, the present invention advantageously allows for sustained increases in BMD over time. As described above, according to the present invention, it was unexpectedly discovered that newly formed bone material in osteoporotic patients is not of osteoporotic quality, but rather is essentially of the quality expected in individuals of the same gender and ethnicity at their peak BMD age. Therefore, it has been discovered that the methods of the present invention can be used to substantially reset the bone mass of the treated local region to its peak state (or to a normal state). Furthermore, this reset of the bone local region appears to be unaffected by the patient's overall osteoporotic state. In other words, the increase in BMD is not a temporary phenomenon in which the newly formed bone material rapidly degenerates into an osteoporotic state commensurate with the patient's overall state. Instead, the newly formed bone material appears to exhibit all the characteristics of a reset state of newly formed bone material along the natural decline in BMD, such as that shown in FIG1 . For example, as shown in FIG1 , a 70-year-old Caucasian woman experiencing a typical decline in BMD may have a local hip bone BMD of approximately 775 mg/cm2. After treatment according to the present invention, the hip local region can be reset to normal BMD, e.g., approximately 950 mg/ ^cm2 (or the typical BMD of a 30-year-old). After another 10 years (a typical decline in BMD), the same patient would be expected to have an average BMD of approximately 700 mg/ ^cm2 (i.e., a typical decline in BMD between 70 and 80 years of age). However, bone material in the localized region of the hip treated in accordance with the present invention would be expected to be approximately 930 mg/ ^cm2 (i.e., a typical decline in BMD between 30 and 40 years of age). Of course, it should be understood that the foregoing is merely an exemplary characterization based on average values, and actual values are expected to vary between patients. Thus, it is clear that the present method is not a temporary solution, but rather can provide a long-term increase in BMD, because the bone material produced using the present method is effectively reset to a peak state and then continues through the typical natural decline in density that accompanies age (i.e., rather than declining at an accelerated rate to "catch up" with the patient's systemic osteoporotic state).

According to this feature of the present invention, some embodiments may include maintaining a BMD improvement for a limited time. For example, the improvement of the bone local area BMD can be maintained for at least 6 months, at least 1 year, at least 18 months, at least 2 years, at least 3 years, at least 4 years, at least 5 years or even longer. The measurement of time can be calculated by the time when new bone material is produced in the formed cavity. Preferably, the BMD improved includes maintaining a T score of greater than -1.0, greater than -0.5, greater than 0 or greater than 0.5. In other embodiments, the BMD improved includes maintaining a T score of greater than -1.0 to 1.0, -0.5 to 1.0 or -0.5 to about 0.5. Similarly, the improvement can be characterized by the percentage ratio improved compared with untreated bone. Thus, the treated bone can exhibit an increase in BMD over any of the time periods described above, for example, the increase in BMD can be at least 10% higher, at least 15% higher, at least 20% higher, at least 25% higher, at least 30% higher, at least 35% higher, at least 40% higher, at least 45% higher, at least 50% higher, at least 60% higher, at least 70% higher, at least 80% higher, or at least 90% higher than a reference untreated bone in the same subject.

A further benefit of the method for increasing BMD is that the increase in BMD in a localized area of bone can extend beyond the boundaries of the cavity created in the bone. As shown in Figures 2a and 2b, bone material is porous and is essentially a series of interpenetrating networks of scaffold material formed by osteocytes. In healthy bone, this network is formed by a dense and strong scaffold material. In osteoporotic bone, this network degenerates, the scaffold becomes thinner, fragile, and even broken, and the porosity of the bone increases. Although not wishing to be bound by theory, it is believed that due to this property of osteoporotic bone, filling the cavity formed in the bone according to the present invention can result in filling the bone adjacent to the formed cavity with bone regeneration material. Therefore, although new normal bone material is formed within the formed cavity as the bone regeneration material is absorbed by the body, because the bone regeneration material extends beyond the boundaries of the filled cavity, such new normal bone material is also generated in the bone area adjacent to the formed cavity. In addition, this formation of new healthy bone material outside the formed cavity can be due to increased bioactivity, such as the inclusion of growth factors and cytokines at the interface, which promote bioactivity outside the cavity edge. In some embodiments, this can even result in a gradient effect of bone material density in the local area of the bone treated according to the present invention, where the density of the bone material is lowest outside the cavity and away from any area accessible to the bone regeneration material, and gradually increases toward the area of the formed cavity. Thus, a gradient effect can be induced according to the following example of osteoporotic bone: the bone material directly in the area of the formed cavity can have a normal or greater density (e.g., a T score of about 0 to 1); the bone material in the area immediately adjacent to the formed cavity can also have a substantially normal density, although lower than the inner area of the formed cavity (e.g., a T score of about -0.5 to 0.5); the bone material slightly further away from the formed cavity can also have an increased bone density, although lower than the bone material immediately adjacent to the formed cavity (e.g., a T score of about -2 to -1); the bone material further away from the formed cavity can maintain its original osteoporotic density (e.g., a T score of less than -2.5). Of course, the above is only an example of a gradient effect. The actual T score and degree of effect associated with the effective distance from the formed cavity may vary depending on the actual density of the bone during the operation, the type of bone regeneration material used, and the force used to place the bone regeneration material in the formed cavity and thus extend beyond its boundaries. Further illustrated in FIG8 , which shows a gross specimen of the proximal humerus in a dog 13 weeks after insertion of a graft formed of bone regeneration material according to the present invention. The figure shows the formation of dense cancellous bone at the transplant site and the extension of new bone material even beyond the initial defect indicated by the dotted line.

In other embodiments, the methods of the present invention can be characterized relative to a specific BMD profile derived within a localized region of bone. As mentioned above, the methods of the present invention have been found to not only reset newly formed bone material to normal density, but also to cause the density of the localized region of bone to increase dramatically before reaching a substantially normal density. This can be characterized as remodeling the localized region of bone according to a specific density profile.

In some embodiments, a method for generating a defined BMD spectrum in a localized bone region may include forming a cavity in the localized bone region by clearing degraded bone material in the region, and optionally removing a portion of the cleared degraded bone material. Although bone material need not be removed from the cavity during and after cavity formation, in some embodiments it may be desirable to partially or completely remove the degraded bone material from the cavity so that a maximum amount of bone regeneration material can be placed in the cavity. Therefore, after the cavity is formed, the method may further include at least partially filling the formed cavity with bone regeneration material so that new bone material is generated in the cavity over time.

As new bone material is produced in the cavity, some or all of the bone regeneration material can be absorbed by the body. Specifically, new bone can continue to grow inward, particularly from the outside to the inside relative to the formed cavity at a rate substantially similar to the rate at which the body absorbs the bone regeneration material.

Most importantly, the newly generated bone material in the formed cavity can be accurately characterized as natural bone material (relative to the patient) because the formed bone material comes from the influx of bone cells from the treated patient rather than allogeneic or xenogeneic bone. Therefore, the bone regeneration material has no or little chance of eliciting an immune response that can limit the effectiveness of bone replacement therapy.

For a defined BMD spectrum, continuously evaluating BMD over time (e.g., continuous DEXA scans) can provide a time-lapse profile of the BMD of a local region of bone derived from implanted bone regeneration material. The BMD spectrum provided according to the present invention is particularly surprising because the use of bone regeneration material in a surgically created cavity causes changes in the local region of bone, resulting in an initial peak of BMD significantly denser than normal bone, which is then remodeled over time as new bone material grows inward, such that the density of the local region of bone treated according to the present invention approaches a substantially normal value. FIG. 9 illustrates a natural BMD spectrum achieved according to certain embodiments of the present invention, wherein BMD recorded as a T score from a DEXA scan is plotted as a function of time, where time 0 is the time when the cavity is formed and the bone regeneration material is implanted. FIG. 9 illustrates a spectrum where the local BMD of a bone to be treated according to the present invention results in the bone being considered osteopenic or osteoporotic (i.e., a T score below -1 or below -2.5). The dotted line before time 0 indicates that the actual BMD characterized by the T score can be any value below the defined threshold (e.g., below -1, below about -2.5, etc.). After replacing the degenerative bone (0 moment) of local area with bone regeneration material, the BMD of local area is sharply increased to arrive maximum density.As described in the representative figure of Figure 9, in the time of about 1 week to about 13 weeks, the maximum density corresponding to T score greater than about 5 is obtained.The solid line in Fig. 9 represents this sharp improvement of BMD, and the dotted line representation of T score more than 5 obtains the maximum T score, can be some value exceeding 5 and can typically occur in some time within the scope covered by dotted line.In some specific embodiments, the maximum T score obtained according to the BMD spectrum defined is at least 2.0, at least 3.0, at least 4.0, at least 5.0, at least 6.0, at least 7.0, at least 8.0, at least 9.0 or at least 10.0. The time to maximum density (i.e., maximum T score) achieved after implantation can be about 1 week to about 6 weeks, about 1 week to about 10 weeks, about 1 week to about 13 weeks, about 1 week to about 18 weeks, about 2 weeks to about 10 weeks, about 2 weeks to about 13 weeks, about 2 weeks to about 18 weeks, about 3 weeks to about 10 weeks, about 3 weeks to about 13 weeks, about 3 weeks to about 18 weeks, about 4 weeks to about 10 weeks, about 4 weeks to about 13 weeks, about 4 weeks to about 18 weeks, about 6 weeks to about 10 weeks, about 6 weeks to about 13 weeks, or about 6 weeks to about 18 weeks. After reaching maximum density, the density of the local area of bone begins to decline for up to about 6 months, up to about 9 months, up to about 12 months, up to about 18 months, up to about 24 months, about 6 weeks to about 24 months, about 13 weeks to about 18 months, or about 18 weeks to about 12 months. Thereafter, the BMD of the localized region of bone stabilizes within a substantially normal range of about -1.0 to about 2.0, about -1.0 to about 1.0, about -1.0 to about 0.5, about -1.0 to about 0, about -0.5 to about 2.0, about -0.5 to about 1.5, about -0.5 to about 1.0, about -0.5 to about 0.5, about 0 to about 2.0, about 0 to about 1.5, or about 0 to about 1.0. Given the above values, a graph similar to that shown in FIG9 can be prepared to provide representative BMD profiles encompassed by the present invention, the only differences being the maximum BMD achieved and/or the time to achieve maximum BMD, and/or the time after achieving maximum BMD until BMD decreases to a substantially normal range. Actual embodiments of BMD profiles obtained in test subjects are described in the Examples presented below.

In other embodiments, BMD can be substantially maintained as defined for an extended period of time. In other words, the BMD corresponding to a T-score of about -1.0 to about 2.0, about -1.0 to about 1.0, about -1.0 to about 0.5, about -1.0 to about 0, about -0.5 to about 2.0, about -0.5 to about 1.5, about -0.5 to about 1.0, about -0.5 to about 0.5, about 0 to about 2.0, about 0 to about 1.5, or about 0 to about 1.0 can be maintained for an additional year or longer (i.e., the BMD profile of the localized region of bone can be such that the BMD reported using the T-score within the indicated range can be established and maintained for at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, or even longer).

In other methods, the present invention can be characterized relative to the aforementioned effects of remodeling a localized area of degenerative bone to substantially resemble normal bone. In certain embodiments, the present invention may specifically relate to a method for remodeling a localized area of degenerative bone comprising the steps of: forming a cavity within the localized area of bone by clearing the area of degenerative bone material and optionally removing a portion of the degenerate bone material; and at least partially filling the formed cavity with a bone regeneration material, thereby generating ingrowth of new bone material within the formed cavity. Specifically, remodeling of the localized area of bone can be demonstrated by the ability to induce growth of new natural bone material in a previously osteopenic or osteoporotic area of bone (i.e., bone that is considered degenerate or diseased and/or has low quality, strength, and/or density).

In certain embodiments, the bone material of the local area treated according to the present invention (i.e., before the formation of the cavity) has a T score of less than -1.0, indicating that the bone degeneration exceeds the level generally considered normal; and the new bone material that appears after remodeling has a T score greater than -0.1, indicating that the bone in the local area has been remodeled to be substantially consistent with normal bone. In these embodiments, the bone can be considered to have been remodeled in the local area because the bone area has been effectively changed to no longer be considered degenerate bone, osteopenic bone, or osteoporotic bone, etc., but is considered to be bone of normal density (i.e., normal bone) that is significantly similar to that of a person of the same sex and race at peak BMD. In other words, the bone is remodeled from low-density natural bone to normal-density natural bone.

This was not an effect that could be expected before the present invention. Osteoporosis (i.e., a significant loss of BMD) is generally seen as a systemic condition. Although the actual T-score may be different on one side of the body from the other side in the same patient, generally when osteoporosis occurs, the condition persists throughout the body (e.g., a T-score of -2.8 in the distal radius versus a T-score of -3 in the hip bone). As described above, according to the present invention, it has been found that although osteoporosis develops systemically, the body's bone mass can be locally reset. In other words, a local area of bone can be remodeled from an osteoporotic state to a normal state. This is surprising because osteoporosis is believed to be caused by a decrease in the body's ability to form new bone cells, resulting in the resorption rate of bone cells exceeding the formation rate of new cells. It can be assumed that the newly formed bone growing into the damaged area may simply be an extension of the surrounding bone, i.e., low-quality bone will cause low-quality bone. The present invention shows that the opposite is true. By systematically removing a limited volume of bone material from a localized area of bone and replacing said material with the bone regeneration material described herein, the entire process mobilizes the regenerative process, wherein the influx of new bone cells results in the formation of new natural bone material that is not just a simple extension of the degenerated bone material in the surrounding area, but rather is bone material that is essentially consistent with normal bone of normal density.

This remodeling is illustrated in Figure 10, has wherein assessed the decline of BMD in the Caucasian women's bone local area.As seen here, the BMD of local area begins to decline by the normal range of about 30 years old, and the rate of decline improves near the menopause, then tends to be stable (not significantly declining).The point representative of 70 years old in the figure is carried out according to the time of operation of the present invention.The BMD of local area sharply improves and is reset to normal range (that is, with 30 years old roughly the same density).From this time, the new bone material of local area continues to decline with the natural BMD associated with age.Therefore, the bone local area has been effectively remodeled to normal state by osteoporosis state.

The exact values shown in Figure 10 are representative only, as actual T-scores may vary between patients. However, the overall remodeling results are expected to be consistent across patients. In other words, although the exact BMD values may be slightly higher or lower than those shown, remodeling will be consistent with: bone will exhibit a decrease in density to the point where osteopenia or osteoporosis is reached; after implantation of the bone regeneration material according to the present invention, BMD will rapidly increase to above the approximately normal range; BMD will decrease to the approximately normal range; and BMD will decrease at the rate typically exhibited by healthy, normal bone material. Most importantly, when the normal rate of decline is re-established after implantation, the BMD point typically exhibited by a healthy individual at their peak BMD age begins to decline. Therefore, while BMD does continue to decline, its basis has shifted to a normal density range rather than an osteopenia or osteoporosis density range. This is particularly important when performing the present invention on women who have entered menopause, as the rapid BMD decline associated with menopause will not be able to affect the newly formed, growing, compact bone. Depending on the age of the female patient at the time of treatment and the lifespan of the individual, the remodeling of the bone properties of the local region can effectively change the structure of the local region so that the local region will not re-reach an osteopenic or osteoporotic state during the patient's life after treatment. This ability to remodel osteopenic and osteoporotic bone material into a structure that is substantially similar to normal bone material is further described in the examples provided below.

Except causing the remodeling of the degenerate bone region limited by formed cavity, the present invention can also cause the remodeling of the degenerate bone material near formed cavity substantially.As above description about Fig. 8, in formed cavity, providing bone regeneration material can cause gradient effect, wherein not only is to produce new bone material in the cavity having filled bone regeneration material, and new bone material also can form new bone material in the bone region of the cavity of contiguous formed filling.Similarly, the present invention can provide the degenerate bone material of bone local area to be remodeled to the following degree: can form the bone material that T scores are within the description range in the bone region contiguous to formed cavity.Therefore, not being cleaned up and/or removing to form the degenerate bone material of cavity in bone local area also can be remodeled to normal substantially.Particularly, the newly formed bone material will have gradient structurally, thereby the T scoring of bone material will raise from cavity periphery area to cavity interior region.

As also discussed above, the localized region of degenerative bone that has been remodeled to be substantially consistent with normal bone preferably maintains the characteristics of the remodeled state over an extended period of time. For example, the remodeled localized region of bone may remain substantially consistent with normal bone for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or even longer.

The present invention can be applied relative to existing surgical procedures (such as kyphoplasty or vertebroplasty). Different from existing operations, the method used according to the present invention can be implemented in patients who do not currently suffer from vertebral fractures or other fragile vertebrae. On the contrary, this method can be characterized as a preventive implementation (that is, preventing the fracture of degenerative bone in the future). Specifically, in terms of vertebrae, this surgical method can be implemented on unfractured osteoporotic vertebrae, but the surgical method used can be similar to the surgical method used in conventional kyphoplasty. In these embodiments, the method of the present invention can be as described elsewhere herein and is carried out on one or more vertebrae of the patient.

In other embodiments, the present invention can be practiced on vertebrae that have already been fractured. Rather than performing conventional kyphoplasty, which typically involves filling the fracture area with an adhesive material such as poly(methyl methacrylate) (PMMA), the present invention can provide for enlarging or increasing the fracture to form a cavity in the vertebra and filling the cavity with a bone regeneration material, as needed. In some specific embodiments, the vertebrae treated according to the present invention are osteopenic or osteoporotic.

Therefore, in certain embodiments, the present invention can be described as providing a method for restoring vertebral body height or correcting angular deformity in a fractured vertebra (particularly a fractured osteopenia or osteoporotic vertebra) by causing the ingrowth of new bone material that is substantially consistent with normal bone. Specifically, the method can include forming a cavity in the fracture region by mechanically cleaning the damaged or degenerated bone material in or around the fracture and optionally removing a portion of the cleaned bone material. The method can also include at least partially filling the formed cavity with bone regeneration material so that new bone material is produced in the cavity over time. Preferably, the formed new bone material has a T score indicating that the new bone material is substantially consistent with normal bone. In some specific embodiments, the T score of the new bone material can be greater than -1, at least -0.5, at least 0, at least 0.5 or at least 1.0 (or other values within the normal range described herein). In addition, an advantage of the present invention is that the new bone material can remain substantially consistent with normal bone over a period of at least about 1 year (or longer, as disclosed elsewhere herein). This time can be measured from the time when the cavity is formed and the new bone material is produced in the bone region filled with the bone regeneration material.

Although believe that the present invention provides more significant advantages than other known methods and materials for the treatment of osteoporosis and/or osteopenia, the use of the present invention may not exclude other treatments. Specifically, the method of the present invention can be used together with art-recognized useful drug interventions for the treatment of osteoporosis and/or osteopenia with the bone material of the patient's own and substantially normal new growth on bone quality. For example, according to the present invention, the treatment of the patient can be carried out while the patient is undergoing drug therapy, and the drug therapy includes hormone therapy (for example, estrogen, SERM, calcitonin and recombinant such as rPTH), bisphosphonates and antibodies (for example Denosumab). Such drug therapy can be carried out before, simultaneously or afterwards according to the treatment of the present invention. Especially, such treatment can be stopped to implement the inventive method by the specific length time period. With the same, such treatment can be started after implementing the inventive method specific time.

In another aspect, the present invention also provides materials useful in the methods for replacing degenerative bone described herein. In particular, a variety of materials can be prepackaged into a kit format. Thus, the methods of the present invention, or specific steps thereof, can be performed using a kit comprising a variety of components. Exemplary materials that may be provided in a kit according to the present invention are provided below.

The kit of tools of the present invention can preferably include a drilling tool, which can include a drill and/or a drill head, such as a tubular drill bit. For example, a 5.3mm OD tubular drill can be included. The kit of tools can also include one or more of the following: a guide wire, a syringe, a device for delivering bone regeneration material in a cavity such as a large injection needle, a working cannula, a suction device, a suction device, a tamping device, a curette (curette), a reaming device, and a device for bending an instrument (such as a needle or a tamping rod) to a defined angle. In some embodiments, the kit of tools can include a tamping device (such as a debridement probe) with a defined geometry including one or more heads. In other embodiments, the kit of tools can include a reaming device such as X-REAM ^™ Percutaneous Expandable Reamer (available from Wright Medical Technology, Inc., Arlington, Tenn.) or similar instruments of suitable size used according to the inventive method. For example, any in situ expansion device suitable for removing bone or producing a defect through surgery can be used. In some embodiments, a kit can include an amount of bone regeneration material suitable for filling a void in a localized area of bone.

The tool kit of the present invention can include any material that can be used for removing bone. For example, in addition to curettes, files, trephine, etc., expansion devices can be used to create space (expanded by balloons, beaded bags, mesh bags, flexible wires, flexible and/or perforated tubes, expanding whisks, rotating wires, expansion blades, non-expanded flexible blades or other similar devices). All of the aforementioned tools can be manually driven or mechanically operated. They can be constrained (for example, preformed blades that pierce an opening in a tube) or unconstrained (for example, deformed blades that pass through an opening in a tube).

Figures 11 to 19 illustrate specific examples of tools that can be used to implement embodiments of the present invention and, therefore, can be included in a tool kit according to the present invention. Figure 11 shows a tissue protector, the function of which is to provide a safe passage for other tools (e.g., drilling tools) to enter the body from outside the body by protecting surrounding tissue from damage. Tissue protector 110 comprises a handle 111 and an elongated body 112 having an open passage 113 therein. Figure 12 shows a cannula sealer, which can be used to centrally place a guidewire (and which can pass through the interior of the tissue protector). Sealer 120 comprises an expanded head 121, an elongated body 122, and an open passage 123 therein. Figure 13 shows a guidewire cutting head portion, which facilitates cutting into bone and maintaining placement within the body. Guidewire 130 comprises a body 131 (partially shown) and a cutting head 132, which is sufficient to cut into bone without forming a solid drill path. Figure 14 shows a drill, which is used to create a channel or tunnel of a defined size (e.g., 5.3 mm in diameter) in bone. Drill 140 comprises a body 141 and a cutting head 142. FIG15 shows a flexible working cannula. The function of the working cannula is to provide other working tools (e.g., debridement tools and injection needles) with a safe passage into the interior of the bone while protecting the surrounding tissue. The cannula 150 shown comprises a head 151 (shaped to be attached to other devices), a body 152, a cutting head 153, and an open channel 154 therein. FIG16 shows another obturator that can be used with the cannula, the obturator 160 comprising an expanded head 161 and a long body 16, and may comprise a central channel (not shown). FIG17 shows a debridement probe that is inserted into the bone to clean degraded bone material and form a cavity in the bone. The probe 170 comprises a handle 171, a long body 172, a head 173 (which may be of a specific size or shape to remove bone material), and a curved portion 174. The presence of the curved portion can be particularly advantageous in placing the head 173 to form a cavity with a desired shape and volume. The curved portion 174 can define an angle of about 5° to about 90°, about 10° to about 75°, about 10° to about 60°, about 15° to about 50°, or about 15° to about 45° relative to the body 172. FIG18 shows an aspiration/irrigation device 180 comprising an elongated body 181 having an open passage 182 therethrough. The device also comprises a base 183 that accommodates an irrigation assembly (such as a syringe body 184 as shown) and an aspiration assembly (such as a port 185 as shown) that can be connected to a vacuum source (not shown). The device also comprises a control valve 186 that controls the application of aspiration and/or irrigation through the passage 182. FIG19 shows another working cannula (slot working cannula 190) comprising a body 191 having a passage 192 therethrough.

Instrument set according to the present invention can comprise one or more or shown in any combination instrument, or can be used for carrying out other instruments of the method according to the present invention.In certain embodiments, instrument set can comprise all instruments and the bone regeneration material required for carrying out bone supplement operation.This can comprise providing skin incision, producing bone cavity, debridement, mixing bone regeneration material and delivering the required instrument of bone regeneration material.Bone supplement instrument set according to the present invention can especially comprise the multiple combination of following assembly: scalpel, tissue protector, cannula sealer, guide wire, drill, working cannula, debridement probe, suction/irrigation device, bone regeneration material (comprising for forming in being implanted in the formed cavity (preferably by injection) front flowable material solid and liquid component), syringe and delivery pin (or can be used for bone regeneration material being delivered into other instruments in the cavity produced).

In some embodiments, tool kit can only comprise minimum assembly required for carrying out the present invention.For example, tool kit can minimally comprise debridement probe (for example, probe with specific bending geometry such as angle within the scope described herein) and/or be used to form a drill and/or bone regeneration material for the access passage of a specific size.In other embodiments, cannula sealer can also be comprised.And in other embodiments, working cannula can be comprised.And in other embodiments, suction/irrigation device can be comprised.And in other embodiments, tissue protector can be provided.And in other embodiments, guide wire can also be comprised.And in other embodiments, mixing device can be comprised.In another embodiment, syringe and delivery needle can be comprised.As can be proved to be useful to present disclosure by those skilled in the art, tool kit according to the present invention can comprise even more tools.

In addition to any of the above-mentioned components, the kit according to the present invention may include instructions for using the kit components to treat patients with degenerative bone conditions. For example, the instructions may provide instructions for the following: using a scalpel to prepare an entrance on the bone to be treated, using a tissue protector in the incision to protect surrounding tissue, using a guide wire or guide pin to form an initial access channel into the bone, using a debridement tool to clean the degraded bone material, using a suction tool to remove the cleaned degraded bone material, mixing the bone regeneration material (if necessary), using a syringe to inject the bone regeneration material into the formed cavity, using an irrigation device to clean the tissue area, and using a sealing tool to seal the tissue channel incision. Similar instructions for use for any combination of the tools included in a specific kit may be included. In addition, the instructions for use may be in any suitable form (e.g., written (e.g., manual, brochure, one or more written materials (written sheets), etc.) or digital media (e.g., CD, DVD, flash drive (flash drive), memory card, etc.).

Example

The present invention will be more fully described by the following examples, which are given to illustrate the invention and provide a complete disclosure, but should not be construed as limiting the invention.

Example 1 Absorption characteristics of three-phase bone regeneration material

An accelerated model illustrating the absorption characteristics of a three-phase bone regeneration material was conducted using precast and weighed 4.8 mm x 3.2 mm pellets of a bone regeneration material commercially available under the name PRO-. The test was designed to describe changes in the bone regeneration material over time to facilitate controlled ingrowth of new bone material. The accelerated in vivo model showed approximately six times faster absorption than that seen in the canine model in vivo, and the in vitro model showed even faster absorption rates relative to the human model.

To begin the evaluation, the pellets were immersed in distilled water. For each day of testing, the pellets were removed from the water, dried, and weighed to determine the remaining weight percentage. After the measurement, the pellets were placed in a fresh aliquot of distilled water. For microscopic analysis, the pellets were embedded, cross-sectioned, and analyzed using a scanning electron microscope (SEM) at 35× magnification.

Fig. 7 a shows the initial state of bone regeneration material. Fig. 7 b shows the pellet after 4 days in vitro (expectedly corresponding to the state of about 24 days in vivo). Calcium sulfate begins to dissolve from the pellet surface, exposing the outer layer of fine brushite crystals and larger TCP particles (bright white in the SEM image). Brushite forms a diffusion barrier, which slows down the rate of CaSO ₄ dissolving. The process of dissolving for 8 days (about 48 days in vivo) in visible external body in Fig. 7 c, observes that the brushite crystals (initially exposed ones) outside the pellet become denser, indicating that brushite has also dissolved. Fig. 7 d shows the pellet for 12 days in vitro (about 72 days in vivo), and it can be seen that the relatively dense brushite region surrounding the intact part of the pellet continues to move inwards as dissolving. Finally, most of CaSO ₄ and brushite dissolve after, along with TCP particles form evenly distributed scaffolds, the dissolving of all calcium sulfates is visible in Fig. 7 e. It is likely that some brushites remain attached to TCP and act as particles are kept together.

Example 2 Comparative fracture resistance of osteoporotic bone before and after cavity formation and filling with bone regeneration material

To evaluate the effect of the procedure according to the present invention on fracture susceptibility, a cadaveric study was conducted using 10 paired proximal femurs of either osteopenia or osteoporosis. Initial DEXA scans were performed at the femoral neck and Ward's area, and all tested bones had a T score of less than or equal to -2.0, indicating that the bone material was in an osteopenic or osteoporotic condition at the time of the test. Paired femurs were the right and left femurs of the same cadaver. In each test, a defect was created in one femur and filled with graft material. The radiographs in Figures 20 and 21 show, respectively, the space (dark area) where a debridement probe was inserted to create a cavity in the proximal femur and the graft material that filled the resulting cavity. The contralateral femur was left intact as a control. After allowing time for the graft material to settle, each proximal femur in the paired group was placed under 20 mm/second compression until a fracture occurred.

The test result shows that there is no significant difference between the proximal femur treated according to the present invention and the control (complete) femur under peak load. The average peak load of all 10 pairs of paired cadaver femurs of test is shown in the figure provided in Figure 22. As seen therein, all proximal femur fractures under the peak load of about 8,000N. Therefore, this test shows that the proximal femur that forms a cavity therein and is filled with bone regeneration material according to the operation of the present invention does not have the clinical risk relevant to strength decline. Particularly, immediately after implementing the operation, even when there is no external supporting material such as nail, insert etc., there is no raising of the fracture risk associated with the inventive method.

Example 3 In vivo canine study using bone regeneration materials in a large, precisely sized longitudinal proximal humerus model

A study was conducted to evaluate the in vivo performance of bone regeneration materials in a precisely sized canine longitudinal proximal humeral defect model at weeks 13 and 26. The biological response, i.e., new bone formation, implant degradation, and biocompatibility, was qualitatively evaluated by radiographs and histological sections.

In this study, 16 skeletally mature canine subjects received bilateral longitudinal cylindrical defects (13 mm OD x 50 mm) in the proximal humerus. All subjects received calcium sulfate bone graft substitute pellets (Wright Medical Technology, Inc., Arlington Term.) in one or both defects. The contralateral defect was injected with either a flowable PRO-graft bolus or preformed pellets of PRO-substance, both of which are commercially available. Half of each experimental group was evaluated after 13 weeks and the other half after 26 weeks. In order to generate comparative data on normal bone at the same site, an additional 10 humeri from 5 unoperated dogs were obtained. All samples were tested for compressive strength and tissue morphology.

A limited cranial approach to the greater tuberosity of the left and right humerus was performed in each subject with incision and retrieval of the brachialis muscle. Defects of the above-mentioned sizes were created at each experimental site using a drill and reamer. The created defects were then backfilled with one of the test materials, alternating between left and right materials to randomize the defect site and the material used. A pellet was tightly packed into each defect using forceps. Injectable boluses were prepared by combining the liquid and powder components in a vacuum bone cement mixing device (Summit Medical; Gloucestershire, UK). After mixing for 30 seconds under a 20-23" Hg vacuum, the material was transferred to a 20 ^cm3 syringe and the bolus was delivered into the defect using a backfill technique through an 11-gauge, 6 ^cm3 , grafting jamshidi-type needle. The wound was then closed.

Biomechanical testing was performed using mechanical test samples obtained from the subject's test site to determine the ultimate compressive strength and modulus of newly formed bone. The test was performed on an Instron Model 8874 hydraulically driven mechanical testing system (system, load cell, and software: Instron Corp., Canton, MA) equipped with 1 kN Dynacell Dynamic Load Cell and Bluehill Materials Testing Software. A small pressure compressor (Wyoming Test Fixtures, Inc., Laramie, Wyoming, serial number WTF-SP-9) ASTM D695 conformant was modified to remove the spherical cap and process the loading rod into a drive that screwed into the test frame. Tests were also conducted to evaluate the amount of new bone material formed in each test sample. Before the test was about to proceed, the length of the sample and the sample diameter (+/- 0.01 mm) of each sample at half its length were determined.

The samples were subjected to unrestrained uniaxial compression testing at a rate of 0.5 mm/min until a significant sample fracture was observed, a significant drop in the load curve was observed, or a sample strain of 30% was reached. The ultimate compressive strength and modulus of the samples were calculated from the stress-strain curves obtained using the software. Nine mechanical samples from five additional dogs were cored and tested in the same manner as "normal bones" for comparison.

Bluehill Materials Testing Software was used to generate a pressure-to-strain plot of the pressure corresponding to the pressure of each sample, and the ultimate compressive strength was determined by the pressure at which the slope of the pressure-strain plot was 0. The ultimate compressive strength (MPa) and elastic modulus E (MPa) of the sample are shown in Table 1 below. The average values obtained by using the sample of the used material and in each test (I and II) in two independent tests are included. The value of normal bone is included as a comparison. Table 2 similarly shows the area fractions of new bone and residual material at 13 weeks and 26 weeks. These average values are determined by standard point counting techniques.

As can be seen from the above data, the flowable PRO-material demonstrated an effect on bone formation and mineralization that exceeded that of normal bone at 13 weeks (5.29 MPa vs. 1.38 MPa). This phenomenon decreased by the 26-week time point, at which time the average values of compressive strength and elastic modulus more closely matched those of normal bone. This phenomenon of remodeling back to normal bone density is consistent with the bone density values in Table 2, where the bone area fraction of the flowable PRO-material tested at 13 weeks was significantly higher than that of normal bone density, but the value for the flowable PRO-material was closer to normal bone density at 26 weeks. These findings are consistent with the high levels of radiodensity seen in the 13-week radiographs of samples treated with the flowable PRO-material. Samples treated with the granulated PRO-material did not demonstrate the same degree of bone formation as seen in defects treated with the flowable material. However, it is important to note that at both the 13-week and 26-week time points, the granulated material still resulted in bone formation with properties that were substantially similar to or even higher than those seen in the normal bone samples.

The mean values of mechanical properties of defects treated with PRO-particles were lower than those of normal bone. However, this difference was determined to be not statistically significant. It should also be noted that relatively large standard deviations (as provided above) are very common when utilizing this type of mechanical testing.

Example 4 Production of New Densified Material in the Created Cavity Filled with Bone Regeneration Material

To evaluate the formation of new bone growth in osteoporosis patients, the left femur of an 80-year-old woman was treated according to the present invention. Specifically, a cavity was formed in the proximal femur and filled with PRO-graft material. Figure 23 provides a radiographic image of the proximal femur before injection of the graft, and Figure 24 provides a CT image of the same area of the proximal femur before injection. Figure 25 provides a radiographic image of the proximal femur during surgery showing the graft material in the proper position of the proximal femur.

The table below provides the T-score and Z-score values for the left femur before the procedure. The table also provides the same values for the right femur (untreated) for comparison.

After surgery, patients were evaluated at various time intervals to determine changes in density in localized bone regions after treatment according to the present invention and over time in controls. Table 4 below shows the test values at one week after treatment. As can be seen, the treated femurs showed a dramatic increase in density, while the control femurs showed osteoporotic values similar to pre-treatment values.

Figure 26 provides a radiographic image of the treated left femur at 6 weeks of treatment. As can be seen, the graft begins to be absorbed by the body as the bone remodels in the local area. Table 5 provides the values of the DEXA scan at 6 weeks after treatment.

Figure 27 provides a CT image of the treated left femur at 12 weeks post-treatment. The presence of the graft material (bright mass) is evident and demonstrates further absorption. Table 6 provides the DEXA scan values at 12 weeks post-treatment, and Table 7 provides the DEXA scan values at 18 weeks post-treatment.

Figure 28 provides CT images of the treated left femur after 24 weeks of treatment. As the graft material is continuously absorbed and replaced by dense bone material, the presence of the graft material (bright mass) is significantly reduced. Table 8 provides DEXA scan values after 24 weeks of treatment, and Table 9 provides DEXA scan values after 12 months of treatment.

Example 5: Increase in BMP in a Local Area of Osteoporotic Bone After Cavity Formation and Filling with Bone Regeneration Material

The test was carried out on 12 human patients, all of whom were considered to have osteoporosis according to the definition of the World Health Organization (WHO). In each patient, one femur was treated according to the invention, while the contralateral side remained untreated for control purposes.

First, to obtain a baseline, BMD of both hips was measured by DEXA. Subsequently, a cavity was created in the proximal femur at the test site of a single hip in each patient by removing a portion of osteoporotic bone. The cavity was then filled with PRO-graft material in a manner similar to that described in Example 4. Patients performed their normal daily activities while follow-up scans were performed at weeks 1, 6, 12, 18, 24, 52, 78, and 104. Note that all 12 patients were evaluated up to 24 weeks, 8 patients were tested up to 52 weeks, 3 patients were tested up to 78 weeks, and 2 patients were tested for all 104 weeks.

At each follow-up examination (as well as at baseline), the DEXA scan T-scores for each patient's femoral neck and total hip were recorded. As can be seen with reference to FIG29 , at baseline, the T-scores for the femoral neck of all patients were below -2; however, at the 1-week mark, each patient showed a significant improvement in T-score (ranging from approximately 1 to almost 6). After the initial rapid improvement, each patient's T-score gradually returned to the normal range for healthy bone (using the average value of a 30-year-old as a reference). In as little as 12 weeks, very few patients' T-scores dropped to near 0 or slightly below 0. Even for patients tested for 104 weeks, the T-scores continued to approach normal values (although below 0). As shown in FIG30 , a similar trend was observed in the T-scores of the total hip. Although the rapid improvement in T-scores was not as high as that for the femoral neck, the initial improvement was roughly proportional (i.e., each patient showed an improvement of 3 points or more 1 week after the procedure). Once again, the T-scores in the total hip decreased as the testing period progressed, but the final scores obtained in each patient showed a remodeling of the baseline scores to a significantly improved state. Even greater improvements were seen in the Ward's zone of the treated hip. As seen in Figure 31, within one week, the T scores of most patients increased to a range of 5 to as much as 17. Once again, this area of the hip of the treated patients was remodeled to bone of normal quality (i.e., T scores were greater than 0 in these patients) through the practice of the present invention.

FIG32 further illustrates the significant improvement in bone mass at the treated area following the replacement procedure according to the present invention, which shows the average increase in femoral neck BMD across the entire patient population at various time intervals. In addition to the T-score, which illustrates the absolute change in bone mass from osteoporotic bone to normal bone, a comparison of the average changes shown in FIG32 demonstrates that the procedure according to the present invention reshapes the underlying bone structure of the treated area by removing bone with low BMD and promoting the growth of new bone with significantly increased BMD. As shown in FIG32 , within one week of the procedure according to the present invention, BMD increased by approximately 150% relative to the control (the average BMD of the contralateral, untreated hip in each patient). Thereafter, for up to approximately 24 weeks, the relative increase in femoral neck BMD indicates a relatively rapid remodeling toward normal bone BMD (BMD was 120% greater than controls at 6 weeks, 96% greater at 12 weeks, and 74% greater at 24 weeks). From this point on, BMD slowly declines in a more normal manner. At the two-year evaluation, the two patients who remained in the study still showed a mean femoral neck BMD that was 35% higher than controls.

Similar results are seen in Figure 33, which shows the average increase in BMD across the entire patient population at multiple time intervals. As seen therein, within one week of performing the present invention, BMD increased by approximately 68% relative to the control (the average BMD of the contralateral untreated hip in each patient). Afterwards, for approximately 24 weeks, the relative increase in BMD of the entire hip indicated a relatively rapid remodeling toward normal bone BMD (at 6 weeks, BMD was 54% greater than the control, at 12 weeks, BMD was 45% greater than the control, and at 24 weeks, BMD was 36% greater than the control). From this point on, BMD slowly declined in a more normal manner. In the two-year evaluation, the two patients retained in the study still showed an average BMD of 18% higher than the control for the entire hip. Because this increase in BMD runs through the entire test period, it is expected that the treated bone region will show increased compressive strength (as demonstrated in the above-mentioned canine study), and because BMD increases and compressive strength increases, there will be increased fracture resistance. There were no appreciable changes in BMD measurements from baseline on the untreated side (although Figure 33 demonstrates a progressive decrease in BMD of the entire total hip on the untreated side from 20 weeks onward).

Once again, as shown in FIG34 , even greater improvements in BMD were seen in the Ward's area. Within one week of treatment according to the present invention, mean BMD increased by 400%. This was seen to decrease over time—with a 355% increase in BMD at 6 weeks, a 295% increase at 12 weeks, and a 220% increase at 24 weeks. From 52 weeks to 104 weeks after treatment, BMD in the Ward's area treated hips was approximately 140% to about 200% higher than in the control hips.

Many modifications and other embodiments of the present invention will be apparent to those skilled in the art having the benefit of the teachings presented in the foregoing description and accompanying drawings. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

The following content corresponds to the original claims in the parent application and is incorporated herein as part of the specification:

1. A method of treating a patient suffering from a degenerative bone disorder, comprising:

forming a cavity in a localized area of bone by cleaning degenerate bone material and optionally removing a portion of the degenerate bone material; and

The formed cavity is at least partially filled with a bone regeneration material that facilitates the formation of new, non-degenerated bone material in the cavity.

2. The method of claim 1, wherein the degenerative bone disorder is selected from osteopenia and osteoporosis.

3. The method according to item 1, wherein the bone regeneration material comprises an osteoinductive material, an osteoconductive material, an osteogenic material, an osteopromoting material, an anti-osteoporosis material or an osteophilic material.

4. The method according to claim 1, wherein the bone regeneration material comprises calcium sulfate.

5. The method according to item 4, wherein the bone regeneration material further comprises calcium phosphate.

6. The method according to item 5, wherein the bone regeneration material further comprises tricalcium phosphate particles.

7. The method according to item 1, wherein the bone regeneration material comprises a material that exhibits a multiphase absorption spectrum in vivo.

8. The method according to item 1, wherein the bone regeneration material comprises a material that exhibits a biphasic absorption spectrum in vivo.

9. The method according to item 1, wherein the bone regeneration material comprises a material that exhibits a three-phase absorption spectrum in vivo.

10. The method according to item 1, wherein the bone for cavity formation is selected from the group consisting of: hip, femur, vertebra, radius, ulna, humerus, tibia and fibula.

11. The method according to claim 1, wherein the bone regeneration material hardens in vivo.

12. The method according to item 1, wherein the bone regeneration material is flowable when it is filled into the formed cavity.

13. The method of claim 1, wherein the newly formed non-degenerated bone material has a bone mineral density (BMD) substantially consistent with that of normal bone.

14. The method of claim 13, wherein the new bone material has a T score as measured by dual-energy X-ray absorptiometry (DEXA) greater than -1.0.

15. The method of claim 13, wherein the new bone material has a T score greater than -0.5 as measured by dual-energy X-ray absorptiometry (DEXA).

16. The method according to claim 1, wherein the bone regeneration material helps to form new bone material with substantially normal BMD in the bone area adjacent to the formed cavity.

17. The method of claim 1 , wherein the BMD of the localized region of bone is increased such that the T score of the newly formed non-degenerated bone material measured by dual-energy X-ray absorptiometry (DEXA) is greater than the T score of the native bone material before being cleared.

18. The method of claim 17, wherein the natural bone material prior to mechanical cleaning has a T score of less than -1.0, and the newly formed non-degenerated bone material has a T score greater than -1.0.

19. The method of claim 17, wherein the T score of the newly formed non-degenerated bone material is at least 0.5 units greater than the T score of the native bone material before being cleared.

20. The method of claim 17, wherein the natural bone material prior to mechanical cleaning has a T score of less than -1.0, and the newly formed non-degenerated bone material has a T score of at least -0.5.

21. The method of claim 17, wherein the natural bone material prior to mechanical cleaning has a T score of less than -1.0, and the newly formed non-degenerated bone material has a T score of at least 0.

22. The method of claim 17, wherein the increase in BMD in the local area of bone is maintained for a period of at least 1 year, the period being measured from the time of formation of new bone material.

23. The method according to item 1, wherein after at least partially filling the formed cavity with the bone regeneration material, new bone material is formed in the cavity over time and at least a portion of the bone regeneration material is absorbed.

24. A method according to claim 23, wherein a BMD spectrum is generated in the local area of the bone so that the T score measured by dual-energy X-ray absorptiometry (DEXA) increases from an initial score of less than -1.0 measured before the cavity is formed to a maximum score of at least 5.0 within about 1 week to about 18 weeks from the time the cavity is filled with the bone regeneration material, and decreases over time to a score that is substantially equivalent to the score of normal bone.

25. The method of claim 24, wherein the T score decreases over time to a score of about -0.5 to about 2.0.

26. The method of claim 25, wherein the T score decreases to a score of about -0.5 to about 2.0 within a period of about 6 weeks to about 12 months after reaching the maximum T score.

27. The method of claim 24, wherein the BMD profile of the localized region of bone is such that the T score remains in a range substantially equivalent to normal bone for at least 1 year after reaching the normal range.

28. A method according to claim 1, wherein the local area of the degenerated bone is remodeled to be substantially consistent with normal bone, that is, the bone material in the local area before the formation of the cavity has a T score measured by dual-energy X-ray absorptiometry (DEXA) of less than -1.0 indicating bone degeneration, and the new bone material appearing after remodeling has a T score greater than -1.0 indicating that the bone in the local area has been remodeled to be substantially consistent with normal bone.

29. The method of claim 28, wherein the new bone material that appears after remodeling has a T score of at least -0.5.

30. The method of claim 28, wherein the new bone material that appears after remodeling has a T score of at least 0.

31. The method of claim 28, wherein the new bone material that appears after remodeling has a T score of about -0.5 to about 2.

32. The method of claim 1 , wherein the method restores vertebral body height or corrects angular deformity in a fractured vertebra with osteopenia or osteoporosis by causing ingrowth of new bone material having a T score as measured by dual-energy X-ray absorptiometry (DEXA) indicating that the new bone material is substantially consistent with normal bone.

33. A method according to claim 32, wherein the T score of the new bone material is at least -0.5.

34. A method according to claim 1, wherein the steps of the method are implemented using tools in a kit, the kit comprising a drill arranged to form a channel of a defined diameter through a portion of bone, a debridement probe and a certain amount of the bone regeneration material suitable for filling the cavity in the local area of the bone.

35. The method of clause 34, wherein the steps of the method are performed according to instructions contained in the kit, the instructions indicating how to use the components of the kit to treat a patient suffering from the degenerative bone disorder.

36. A method of improving bone mass in a localized area of bone, the method comprising replacing a portion of degenerated bone having a T score of less than -1.0 with newly formed natural bone material having a T score of greater than -1.0, the T score being measured using dual-energy x-ray absorptiometry (DEXA).

37. The method of claim 36, wherein the T-score of the newly formed natural bone material exceeds the T-score of the degenerated bone by at least 1 unit.

38. A method according to claim 36, wherein the newly formed natural bone material has a T score of at least -0.5.

39. The method of claim 36, wherein the newly formed natural bone material has a T score of at least 0.

40. The method of clause 36, wherein the replacing step comprises:

forming a cavity in the localized area by cleaning degenerated bone material in the localized area and optionally removing an amount of the cleaned bone material; and

The formed cavity is at least partially filled with a bone regeneration material to produce ingrowth of new natural bone material in the formed cavity.

41. The method of item 40, wherein the degenerative bone disorder is selected from osteopenia and osteoporosis.

42. The method according to item 40, wherein the bone regeneration material comprises an osteoinductive material, an osteoconductive material, an osteogenic material, an osteopromoting material, an anti-osteoporosis material or an osteophilic material.

43. A method according to claim 40, wherein the bone regeneration material comprises calcium sulfate.

44. The method of claim 43, wherein the bone regeneration material further comprises calcium phosphate.

45. The method of claim 44, wherein the bone regeneration material further comprises tricalcium phosphate particles.

46. A method according to claim 40, wherein the bone regeneration material comprises a material that exhibits a multiphase absorption spectrum in vivo.

47. A method according to claim 40, wherein the bone regeneration material comprises a material that exhibits a biphasic absorption spectrum in vivo.

48. A method according to claim 40, wherein the bone regeneration material comprises a material that exhibits a three-phase absorption spectrum in vivo.

49. The method of claim 40, wherein the bone for cavity formation is selected from the group consisting of: hip, femur, vertebra, radius, ulna, humerus, tibia, and fibula.

50. The method of claim 40, wherein the bone regeneration material hardens in vivo.

51. The method according to item 40, wherein the bone regeneration material is flowable when it is filled into the formed cavity.

52. A kit for replacing degraded bone material in a localized area of bone with a bone regeneration material that facilitates the formation of new bone material that is substantially consistent with normal bone, the kit comprising:

a drill arranged to form a passage having a defined diameter through a portion of the bone;

Debridement probe; and

A quantity of bone regeneration material adapted to fill the void in the localized region of the bone.

53. The kit according to item 52, further comprising one or more of the following:

Intubation sealer;

Guidewire;

Working cannula; and

An injection device for delivering the bone regeneration material.

54. The tool kit according to item 52, further comprising a tool bender adapted to adjust the geometry of the probe device to the anatomy of the cavity in the local area of the bone.

55. The kit of clause 52, wherein the debridement probe has a curved tip defining a geometric shape.

56. The kit of claim 55, wherein the debridement probe tip is bent at an angle of 5° to about 90° relative to the elongated body of the probe.

57. The kit of claim 52, further comprising a reamer device.

58. The kit of claim 52, further comprising one or more of a suction device, an aspiration device, and a bone scraping device.

59. The kit of claim 52, further comprising instructions for using the kit components to treat a patient suffering from a degenerative bone disorder.

Claims (7)

1. Use of bone regeneration materials in the preparation of a medicament for treating patients with degenerative bone conditions, said degenerative bone conditions being osteopenia or osteoporosis, said treatment comprising: A cavity is formed in a localized area of bone in a patient diagnosed with degenerative bone disease, the localized area being intact bone prior to the formation step; and The cavity formed is at least partially filled with bone regeneration material, which helps to form new non-degenerative bone material in the cavity that has been at least partially filled with bone regeneration material. The bone regeneration material is formed from a particulate composition comprising the following: i) Hemihydrated calcium sulfate powder with a total weight concentration of 50% to 90% based on the particulate composition; ii) A combination of two calcium phosphate powders that can react in the presence of an aqueous solution to form permeapatite. 2. The use according to claim 1, wherein the particulate composition further comprises β-tricalcium phosphate particles. 3. The use according to claim 2, wherein the β-tricalcium phosphate particles are present in the particulate composition at a concentration of 8 to 12% by weight, based on the total weight of the particulate composition. 4. The use according to claim 3, wherein the concentration of the hemihydrated calcium sulfate powder is 70% to 90% by weight based on the total weight of the particulate composition. 5. The use according to claim 4, wherein the combination of the two calcium phosphate powders is present at a concentration of 10 to 20% by weight, based on the total weight of the particulate composition. 6. The use according to claim 5, wherein the hemihydrated calcium sulfate is hemihydrated α-calcium sulfate. 7. The use according to claim 1, wherein the drug is used to reduce the incidence of vertebral compression fractures in patients with osteopenia or osteoporosis, the treatment comprising: A cavity is formed in a localized area of a vertebra in a patient diagnosed with osteopenia or osteoporosis, the vertebra being located between a first adjacent intact vertebra on one side of the vertebra and a second adjacent intact vertebra on the other side of the vertebra, and the localized area was intact bone prior to the formation step; and The cavity is at least partially filled with bone regeneration material that helps to form new non-degenerative bone material in the cavity, which has been at least partially filled with bone regeneration material, wherein the bone regeneration material is flowable when it is filled into the cavity.