KR20050084094A - Formulation for a cement preparation as bone substitute - Google Patents

Abstract

A bone cement comprises a powdery component including calcium phosphate and an aqueous liquid component. A radiopaque material is added to at least one of the powder and liquid components, and the components may be combined into a pasty substance for application to bone.

Description

Formulation For a Cement Preparation As Bone Substitute

The present invention relates to a composition for cement preparations as bone substitutes comprising calcium phosphate as a main component and mixed with water or an aqueous liquid to produce a paste or paste like mass. The invention also relates to a process for producing phosphate cements, in particular apatite and struvite cement, from the composition.

Calcium phosphate ceramics have been commercially available as synthetic bone grafts since the 1970s. However, such ceramics have fixed dimensions and are difficult to apply to bone defects, which usually have irregular shapes. A further disadvantage is that calcium phosphate ceramics are insufficiently absorbed into the tissue. This poor absorption is due to the sintering manufacturing method which produces a very dense structure.

The introduction of calcium phosphate cements in the 1980s was a significant advance in conventional bone ceramics because it allowed full filling of bone defects with irregular shapes and improved load transfer between bone and implants. The calcium phosphate cement is a powder that mixes with the liquid to form a paste material that can be easily introduced into bone defects.

Calcium phosphate precipitates during solidification of the calcium phosphate cement because it is thermodynamically stable. The calcium phosphate thus precipitated is much better degraded by cells in the body than the sintered material since the solidified cement has a less dense structure than the sintered material. Such cements are described in US Pat. No. 4,612,053, US Pat. No. 5,149,368, US Pat. No. 4,518,430, WO 96/14265, EP 1 296 909 A1 and EP 0 835 668 A1, which are incorporated herein by reference. . The cement is commercially available under trade names such as BonSource, Norian SRS, Biobon, Calcibon and Cementek.

It is an object of the present invention to provide curable and absorbable bone or other cement formulations which have improved stability and require less time for implantation, thus increasing the freedom of choice of the surgeon when implanting or applying cement formulations. will be. A further object is to provide cement formulations with improved processing properties and to provide increased strength of the hardened cement. A further object is that the cement preparations have improved X-ray contrast.

Description of Background Art

U.S. Patent 4,612,053, U.S. Patent 5,149,368, U.S. Patent 4,518,430, PCT Publication WO 96/14265, EP Publication EP 1 296 909 A1 and EP 0 835 668 A1 are described above. Various calcium phosphates and other bone cements and fillers including radiopaque materials are disclosed in US Pat. No. 6,641,587, US Pat. No. 6,599,520, US Pat. No. 6,075,067, US Pat. No. 6,375,659, WO 02/32474 (US Pat. No. 6,599,520). Counterpart) and WO 02/17801 (corresponding to US Pat. No. 6,641,587). The entire description of each of these patents and published applications is incorporated herein by reference.

Brief summary of the invention

In a first aspect, the present invention provides cement formulations useful as bone substitutes or fillers comprising calcium phosphate as a main component. The calcium phosphate component will generally be a powder and will include other substances. The powder will mix with water or an aqueous liquid to form a paste (viscous) material for introduction into bone defects or other bone target sites. Before combining the components, an additive that enhances X-ray contrast (radiation impermeability) is mixed with the cement preparation, preferably the dry powder calcium phosphate component, but in some cases the aqueous component.

In a further aspect, the present invention provides a process for preparing cement, comprising mixing calcium phosphate powder, preferably apatite material with additives to enhance X-ray contrast and water or aqueous components, and curing the mixture do. The hardening results in the formation of cement, preferably apatite cement, as a reaction product.

In a particularly preferred embodiment, the cement preparations of the present invention comprise a mixture of calcium salts, magnesium salts and / or orthophosphates to be mixed with water and / or aqueous liquids, wherein the additive which enhances X-ray contrast is barium salt; Metals, and inorganic and organometallic compounds, preferably metal oxides, wherein the metal is iron, titanium, tantalum, gold, silver, rare earth elements, yttrium, ytterbium, zirconium, niobium, molybdenum, ruthenium, rhodium, palladium and tungsten Selected from the group consisting of; Rare earth elements, preferably compounds of gadolinium or cerium; Inorganic or organic iodine compounds; And at least one material selected from the group consisting of sintered hydroxyapatite and sintered tricalcium phosphate.

The cement formulations defined above are particularly useful as bone substitutes. The term "bone substitute" includes bone substitutes, bone grafts, bone fillers, bone cements, bone adhesives, and the like. Such bone substitutes are useful for the treatment of bone defects and fractures, and disease states of the bone system such as osteoporosis or cancer.

The compositions and methods of the present invention solve the problem of conventional calcium phosphate containing cements that do not provide satisfactory X-ray contrast due to the similar chemical structure of natural bone and the applied calcium phosphate containing cements. In the present invention, additives having the property of enhancing or enhancing X-ray contrast (radiation impermeability), compared to compositions without this additive, often significantly improve the ability to visualize the treated locations of bone that cannot be directly observed. And allow the surgeon to assess the progress and / or outcome of the treatment on the X-ray image. The availability of images with higher X-ray contrast improves the safety of the treatment. In addition, the cured cement of the present invention has good absorption properties.

Due to the additives selected to improve X-ray contrast, optionally supplemented with auxiliary additives, the calcium phosphate powder in combination with the aqueous liquid component according to the present invention has a paste like roughness with good flowability properties. It provides a substance having. In addition, the material forms hardened cement with minimal or little loss of product strength. The calcium phosphate composition of the present invention is preferably free of plastic materials such as poly (methyl methacrylate) (PMMA), so that calcium phosphate cement is not cured through a polymerization chain reaction, so that various X-ray contrast enhancing additives can be used in a wide range of concentrations. Can be used as Many X-ray additives will interfere with the polymerization reaction in the PMMA cement, especially at high concentrations, and will reduce the strength of the cured PMMA cement. In addition, the radiopaque bone-enhanced bone cement formulations of the present invention that are cured at the target site often have improved absorption properties. Therefore, the composition of the present invention can be optimized according to the intended use. Depending on the type of X-ray contrast enhancer chosen, the composition is a very stable composition so that radiopacity can be observed for a long time. Alternatively, radiopacity may be reduced after surgery to reduce the likelihood of body irritation due to the additive. Overall, the present invention provides a good combination of processability, cure properties and enhanced visualization of surgery.

Detailed description of the invention

Cement formulations of the present invention are primarily calcium phosphate, preferably at least about 50% by weight, to be mixed with an aqueous liquid component comprising water or a normal aqueous solution for the hardening and formation of cement reaction products generally used as bone substitutes. More preferably at least about 65 wt%, most preferably at least about 75 wt% calcium phosphate. The base powder component preferably further comprises ortho phosphate or magnesium and optionally other salts of other metals in addition to calcium phosphate. Particular preference is given to α and / or β-type calcium triphosphate (TCP). The liquid component may correspond to water and optionally further components, preferably salts, more preferably salts having a buffering effect, in particular sodium, potassium and / or ammonium salts of carbonic acid in primary and / or secondary basic form or carbonic acid. It contains a salt. The pH of the liquid component is suitably adjusted, for example, in the range of about 5 to about 12, preferably about 7 to about 12.

In order to provide cement formulations with enhanced radiation impermeability, improved flow properties and improved mechanical properties (particularly improved strength upon curing), the cement formulations are preferably calcium (Ca), magnesium (Mg) and Powder component comprising ortho phosphate (P); Additives that enhance X-ray contrast, which are also referred to herein as radiopaque enhancers or radiopaque materials, which will be described in more detail below, are preferably combined with the powder component, and the curing properties and / or mechanical properties It is advantageous in that it is not inherently worsened. In addition, cured cements exhibit particularly good absorption properties. In a more preferred embodiment, the basic cement preparation is prepared by adding ammonium salts, in particular ammonium phosphate salts, such as (NH ₄ ) ₂ HPO ₄ and / or (NH ₄ ) H ₂ PO _4, to the powder component or preferably to the aqueous liquid component. It includes more. The molar ratios of Ca, Mg and P are preferably in the range of 1.00 <Ca / P <1.50 and 0 <Mg / P <0.50. Particularly preferred compositions for cement formulations are the magnesium ammonium phosphate cement formulations disclosed in EP-A-1 296 909.

For the enhancement of X-ray imaging (radiation impermeability), in principle all elements with an atomic number of> 20 in the periodic table of the elements, and therefore higher than calcium, can be used. Depending on the element or elemental compound used, the cement formulation is sufficiently enhanced radiopacity by selecting the appropriate type of radiopaque element or compound, and by using the appropriate amount, concentration and / or density of radiopaque additives. Should be considered.

Additives that enhance X-ray contrast (radiation impermeability) may be mixed with the powder component or the liquid component or both of the cement formulation. The cured reaction product obtained from the composition of the present invention may advantageously comprise a crystalline compound, in particular a monocrystalline phosphate compound, apatite structure, hydroxyapatite structure, struvite cement or tribarium phosphate.

The amount of radiopaque enhancer additive is from about 0.5% to about 25% by weight, preferably from about 3% to about 20%, depending on the type of the additive and the radiopaque enhancement effect on the cured calcium-containing phosphate cement. %, More preferably about 5% by weight to about 15% by weight, most preferably about 10% by weight or more. The upper limit may be appropriately selected depending on the kind of radiopaque enhancement additive and the intended use, and may be, for example, about 50% by weight, more preferably 25% by weight. When applying the cement formulation to the desired target site, in view of the useful combination of significantly enhanced radiopaque enhancement while preserving or even improving the dispersion properties of the cement formulation during surgery, the abovementioned preferred amount of radiopaque enhancement additive The lower limit and the upper limit are particularly selected. The weight percentages are relative to the weight of the powder component. The aqueous liquid component is mixed with the powder component in an amount ranging from about 0.1 to about 1.5 ml per mg of powder, preferably from about 0.2 to about 0.65 ml per mg of powder.

In a preferred embodiment of the invention, additives are used simultaneously which maintain and preferably improve the dispersibility of the cement formulations which are mixed to form the paste mass. Examples of such additives are strontium salts used alone or in combination and especially compounds selected from the group consisting of barium salts such as strontium carbonate, strontium phosphate and barium sulfate. Since the mixing of the compound significantly improves the dispersibility of the cement formulation to be mixed with the liquid component, the mixing of the compound further improves the processability, in particular the injectability, of the calcium phosphate-containing cement formulation. In addition, the pressure required to inject the cement formulation is thus substantially reduced. The reduced infusion pressure is not only more comfortable and convenient for the surgeon, but also minimizes the so-called "filter pressing" effect. This effect is understood to mean compressing and removing the liquid from the cement mixture made of the paste (cement paste) when pressure is applied. This effect is not very desirable as it leads to unsatisfactory solidification of the initial paste cement mixture through liquid loss. In a particularly improved embodiment, strontium salts, such as strontium carbonate or strontium phosphate, are not used or used alone, or in whole or in part replaced by barium salts such as barium sulfate, the cured phosphoric acid from which the barium salt is obtained. This is because it has a beneficial effect on the strength of the calcium-containing cement.

By mixing the barium salt according to the invention, better bonding is achieved while ensuring adequate curing properties. In addition, when combined additionally with calcium phosphate, preferably magnesium phosphate in cement formulations, the barium salt significantly enhances the mechanical properties, in particular the strength of the hardened cement. Thus, by adding barium salts, in particular barium sulfate, tribarium phosphate, barium iodide, barium zirconate and barium manganese barium wolframate, considerably improved radiopacity, improved processability and in particular flow properties, suitable Combination of curing and mechanical properties is achieved.

Particularly suitable additives which can be used according to the invention for enhancing radiopacity are iron, titanium, tantalum, gold, silver, rare earth elements, yttrium, ytterbium, molybdenum, zirconium, niobium, ruthenium, rhodium, palladium and tungsten. Metals, inorganic metal compounds such as metal oxides, metal nitrides, metal carbides, metal silicides, metal halides, metal phosphates, metal gluconates, metal citrates, metal fumarates and metal sulfates, and Material selected from the group of metal-organic compounds. Preferred metallic elements are iron and rare earth elements (lanthanides), cerium and especially gadolinium being the preferred rare earth elements. Iron compounds, especially iron compounds with organic acids such as iron phosphate, iron oxides, iron hydroxides or iron citrate, are particularly effective in stably incorporated into cured cement products and do not deteriorate the mechanical properties of the cured products. Tungsten salicylate and water-soluble lanthanum or rare earth compounds, for example, lanthanum acetate, lanthanum nitrate, lanthanum sulfate, lanthanum ammonium nitrate, cerium citrate, cerium nitrate, cerium chloride, cerium ammonium sulfate and in particular, Also preferred are gadolinium compounds (eg, gadolinium fluoride, gadolinium chloride, gadolinium chelate (eg, gadolinium diethylenetriamino pentaacetate), gadoteridol (available from Bristol-Myers Squibb)) that have been found to be advantageous.

Suitable metals and inorganic metal compounds such as oxides, nitrides, carbides, silicides and halides may preferably be added in particulate form. The average particle size (d ₅₀ ) of the particulate metal or inorganic metal compound in terms of processability and in particular flow characteristics is suitably in the range of about 0.1 nm to about 10 μm. The lower limit of the average particle size d ₅₀ is preferably about 5 nm, and the upper limit of the average particle size d ₅₀ is preferably about 1 μm, more preferably about 500 nm, and more preferably about 100 nm. to be. The particulate material is preferably added to the powder component of the cement composition.

Bromine compounds and especially iodine compounds, preferably organic bromine and / or iodo compounds are also suitable. As a particularly preferred example, water-soluble compounds of the ionic or nonionic type, such as ditricoate, deoxythalamate, iomidolol, iohexol and ioxaglate and the like, are used according to the invention. Suitable examples of such iodine compounds can be found in chapter 35.2.2 of the "Rote Liste" (Red List), ECV-Editio Cantor Verlag, Aulendorf (2003).

In addition, sintered materials, preferably highly sintered materials, can be used as the radiation control additive (s). As preferred additives of this kind, sintered hydroxyapatite and sintered tricalcium phosphate are preferred. As described above with regard to metals and inorganic metal compounds, the sintered material is suitably in particulate form and may preferably be added to the powder component of the cement composition.

The additive (s) for enhancing the radiopacity mentioned above may be added to the powder component or liquid component of the cement preparation. The dry or particulate material is preferably added to the cement powder component and the water soluble component is suitably added to the liquid component of the cement formulation. Mixtures of the above additives may also be used.

In addition, depending on the purpose and the intended use, additives for enhancing radiopacity, for example iron compounds such as oxides, sulfates or phosphates or compounds of other radiopaque enhancement metal elements are stable to the reaction product of cement preparations. Can be incorporated. Alternatively, to improve biocompatibility and minimize tissue irritation at the target site, additives for enhancing radiopacity may be loosely incorporated but removed or leaked from the cured cement product after being applied to the desired target site. For example, water soluble additives may be selected to enhance radiopacity, such as water soluble iodine compounds.

The composition for the cement preparation according to the invention may contain other suitable additives. For example, the cement preparations of the present invention are particularly suitable as carrier materials for biological and / or pharmaceutical actives. To this end, the cement preparations of the present invention may contain pharmaceutical and / or biologically active substances, such as antibiotics, cytostatic agents, analgesics, fungicides, preservatives, growth factors, growth factors, proteins in powder and / or liquid components. Or peptides, biopolymers, or the like, or combinations of the aforementioned active substances. Particularly preferred active agents are selected from the group consisting of gentamicin, thromamycin, clindamycin, vancomycin, β-TGF or analogs thereof, bone morphogenic protein (BMP) series compounds, or combinations thereof.

Further additives include substances in the form of granular particles which are added to the powder component of the cement formulation of the present invention, wherein the substance of the granular particles has the property of being water soluble in the liquid component of the cement formulation. Examples of such additives include salts, carbohydrates or sugars, and polymers that can be hydrolyzed. The granular particles present in the powder component in suitable granule sizes, such as 10 to 300 μm, create a porous system that increases the surface area of the reaction product and promotes absorption performance during the mixing and curing process.

The main use of the calcium phosphate containing cement preparations according to the invention is in the strengthening (filling) of bone defects. In this regard, in the case of compression fractures of spondyplasty or osteoporotic vertebral bodies, metaphysical coarse fractures and filling of the vertebral bodies for stabilization are particularly important.

Insufficient visualization controls present a particularly high risk in the case of vertebral body filling with calcium phosphate containing cement. When introducing or applying the cement paste, the material may leach out of the vertebral body and enter the spinal cord passage, for example, resulting in compression of the spinal cord. As paralysis may occur, the result will be extreme to the patient.

To avoid this, surgery in the vertebral body region is performed under image transfer control (X-ray control). Due to the essentially equivalent X-ray density of cortical bone and calcium phosphate containing cements, imaging is very unsatisfactory when conventional cement mixtures are used. Interference by other bone structures is also often present. This is especially true in the front / rear beam paths.

The composition of the present invention with enhanced X-ray contrast results in a significant improvement when implanting the calcium phosphate containing cement according to the present invention, especially for surgery in the vertebral body region. The surgery can be performed much faster, and the surgical risk of the patient is significantly reduced. In addition, excellent properties are possible in terms of processability and product strength. However, the advantages mentioned here apply equally to surgery or treatment at other locations in the bone or skeleton.

In addition, the calcium phosphate-containing cement formulations of the present invention can be used to fill cavities or voids produced by kyphoplasty. Posterior capsuloplasty is a transdermal technique that involves the use of an inflatable structure, such as a balloon catheter, to correct the posterior spinal deformity associated with vertebral compression fractures. Methods and apparatuses suitable for such treatment are disclosed in U.S. Patents 4,969,888, 5,108,404, 5,827,289, 5,972,015, 6,048,346, 6,066,154, 6,235,043, which are incorporated herein by reference. 6,241,734, 6,248,110, 6,280,456, 6,423,083, 6,440,138, 6,468,279, 6,575,919, 6,607,544, 6,613,054, 6,623,505 6,641,587 and 6,645,213. The optimal use of the calcium phosphate containing cement preparations is in posterior vertebral grafting in which pores or cavities of known size are created in bone, with the corresponding amounts of calcium phosphate containing cement preparations introduced into the pores.

Example 1

A cement powder composition was provided having the following components, thoroughly mixed with a 3.5 M (NH ₄ ) ₂ HPO ₄ aqueous solution (liquid component) to a paste mass, and then cured:

65 g TCP (tricalcium phosphate)

12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄

3 g SrCO ₃

2 g BaSO ₄

The resulting cured calcium phosphate cement was evaluated for its radiopacity visualized on the X-ray film. A recognizable X-ray contrast was obtained.

Example 2

Example 1 was repeated except that the amount of BaSO ₄ was increased to 8 g as follows:

65 g TCP

12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄

3 g SrCO ₃

8 g BaSO ₄

Due to the higher amount of BaSO ₄ , radiopacity was increased. The hardened cement was incubated at 37 ° C. in an aqueous 0.9 wt% NaCl solution for 2 hours and then the strength was measured. A strength of 24.11 MPa was obtained.

Example 3

Example 1 was repeated except that the radiopaque enhancer was replaced with the ionic organic iodine compound Ioxaglic (available from Guerbet GmbH, Schulzbach-Tauners, Germany):

65 g TCP

12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄

3 g SrCO ₃

2 g gyozaglick

Example 4

Example 3 was repeated except that the radiopaque enhancer ioxaglyc was replaced with a nonionic organic iodine compound, Iobitridol (available from Guerbet GmbH, Schulzbach-Tauners, Germany). Was:

65 g TCP

12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄

3 g SrCO ₃

2 g iovitridol

Results: Radiopacity similar to Example 3 was obtained. In comparison, iovitridol provides a cement composition with improved processability, since this compound is mixed with other components in a beneficial and more homogeneous manner. X-ray contrast was improved compared to the addition of BaSO ₄ according to the same amount of Example 2.

Example 5

Example 4 was repeated except that the amount of iobitridol was increased to 8 g as follows:

65 g TCP

12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄

3 g SrCO ₃

8 g Iovitridol

Results: X-ray contrast was significantly higher than the addition of 8 g BaSO ₄ (darker developed X-ray imaging levels). The cured cement was incubated at 37 ° C. in an aqueous 0.9 wt.% NaCl solution for 2 hours and then the strength was measured to obtain a strength of 17.5 MPa.

Examples 6 and 7

Examples 3 and 4 were repeated except that the amount of iosaaglic or iovitridol was 6 g as follows:

65 g TCP 65 g TCP

12 g Mg ₃ (PO ₄ ) ₂ 12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄ 4 g MgHPO ₄

3 g SrCO ₃ 3 g SrCO ₃

6 g Io Saglic 6 g Iovitridol

Results: The wettability of the powder component of the cement composition to the mixed liquid component (3.5 M (NH ₄ ) ₂ HPO ₄ solution) was better when adding iovitridol than when adding iozaglyc.

Example 8

Example 1 was repeated except that BaSO ₄ was replaced with another radiopaque enhancer, ammonium ser (IV) sulphate-dihydrate, as follows:

65 g TCP

12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄

3 g SrCO ₃

5 g ammonium ser (IV) sulphate-dihydrate

Results: The contrast corresponded to the addition of 9 g BaSO ₄ .

Example 9

Further experiments were performed by adding various amounts of BaSO ₄ or SrCO ₃ to the cement powder. By adding about 10 to about 15% by weight of BaSO ₄ , best results were obtained in terms of homogeneous and more efficient mixing performance and strength of the cured product.

The results of cement compositions comprising BaSO ₄ are advantageously reproducible in terms of strength properties, since this material has a lower tendency to solidify during the grinding process.

Example 10

All the examples described above were performed using the following cement powder formulations with the liquid component, wherein the composition did not contain SrCO ₃ , and the radiopaque enhancer according to Examples 1-9 was added:

65 g TCP, 12 g Mg ₃ (PO ₄ ) ₂ , 4 g MgHPO ₄ .

 There was no discernible effect on radiopacity.

Example 11

Example 1 was repeated except that the radiopaque enhancer was replaced with placer added in the form of fine metal particles:

65 g TCP

12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄

3 g SrCO ₃

2 g placer

Results: Excellent and homogeneous mixing performance was possible. X-ray imaging was equivalent to adding 15 g BaSO ₄ to the same cement formulation instead of 2 g placer.

Examples 12 and 13

Example 1 was repeated except that the radiopaque enhancer was replaced with iron (II) or iron (III) oxide added as a metal oxide as follows:

65 g TCP 65 g TCP

12 g Mg ₃ (PO ₄ ) ₂ 12 g Mg ₃ (PO ₄ ) ₂

4 g MgHPO ₄ 4 g MgHPO ₄

3 g SrCO ₃ 3 g SrCO ₃

5 g FeO 5 g Fe ₂ O ₃

Results: The addition of 5 g Fe ₂ O ₃ resulted in particularly high X-ray contrast. The final strength of the hardened cement did not deteriorate.

While the above preferred embodiments and embodiments have been described to illustrate the invention, it should be noted that the features, examples, and embodiments of the invention include, but are not limited to, equivalents, modifications, and combinations thereof. In particular, the invention should not be construed more narrowly than is indicated by the spirit and scope of the appended claims.

Claims (29)

A cement preparation useful as a bone substitute, comprising calcium phosphate powder, which can be combined with an aqueous liquid, wherein at least one of the powder or aqueous liquid is mixed with a radiopaque material before being combined with cement. The formulation of claim 1 further comprising a dispersibility enhancing additive to improve the dispersibility of the cement formulation after being combined with an aqueous liquid. The formulation of claim 1, wherein the mixed additive is combined with the calcium phosphate containing powder composition such that the curing properties of the cement formulation and / or the mechanical properties of the cured product are not inherently deteriorated. The formulation of claim 1, wherein the radiopaque material comprises a barium salt. The formulation of claim 4 wherein the barium salt is selected from the group consisting of barium sulfate, tribarium phosphate, barium iodide, barium zirconate and barium manganese barium wolframate. The method of claim 1, wherein at least one of the metal, the inorganic metal compound and the metal organic compound is mixed as an additive, and the metal or metal compound is iron, titanium, tantalum, gold, silver, rare earth elements, yttrium, ytterbium, zirconium, A formulation based on any metal element selected from the group consisting of niobium, molybdenum, ruthenium, rhodium, palladium and tungsten. 7. The formulation of claim 6, wherein the metal compound is selected from the group consisting of iron phosphates, iron oxides, iron hydroxides and iron compounds with organic acids. The formulation of claim 1 wherein the additive comprises a compound of an element selected from the group of rare earth elements. The formulation of claim 1 wherein the iodine compound is mixed as an additive. 10. The formulation according to claim 9, wherein the iodine compound is an ionic or nonionic organic iodine compound, preferably ditricoate, iodaldamate, iotamidol, iohexole or iosaglate, or mixtures thereof. The formulation of claim 1 wherein the mixed additive is a water soluble compound to be mixed with the aqueous liquid component. The formulation of claim 11, wherein the metal or metal oxide is mixed as an additive in particulate form. The formulation according to claim 1, wherein the sintered material, preferably sintered hydroxyapatite and / or sintered tricalcium phosphate, is mixed as an additive. The formulation of claim 1, wherein the additive for enhancing X-ray contrast is mixed in an amount of about 2.5% to about 50% by weight relative to the total amount of cement formulation. The formulation of claim 1 comprising calcium, magnesium and orthophosphate, and optionally other salts of orthophosphoric acid as a component of the composition. The formulation of claim 15 further comprising an ammonium salt, preferably in the form of ammonium phosphate and / or ammonium hydrogen phosphate in the aqueous liquid component. The formulation according to claim 1, wherein the formulation can provide a cured cement comprising at least one of structural components selected from the group consisting of apatite structure, hydroxyapatite structure, struvite structure, and tribarium phosphate structure together with an aqueous liquid. . A cement formulation comprising a powder component comprising a salt mixture of calcium, magnesium and ortho phosphate to be mixed with the aqueous liquid component and further comprising at least one X-ray contrast enhancing additive selected from the group consisting of: Barium salts; Metals, and inorganic and organometallic compounds, preferably metal oxides, wherein the metal is iron, titanium, tantalum, gold, silver, rare earth elements, yttrium, ytterbium, zirconium, niobium, molybdenum, ruthenium, rhodium, palladium and tungsten Selected from the group consisting of; Rare earth elements, preferably compounds of gadolinium or cerium; Inorganic or organic iodine compounds; And Sintered hydroxyapatite and sintered tricalcium phosphate. 19. The cement formulation of claim 18, wherein said additive is mixed in powder form with the powder component of the cement formulation. 19. The cement formulation of claim 18, wherein said additive is a water soluble compound and mixed with the water or aqueous liquid component of the cement formulation. 19. The cement preparation of claim 18 further comprising a strontium salt in the powder component. 19. The method of claim 18, wherein the additive is a barium salt selected from the group consisting of barium sulfate, tribarium phosphate, barium iodide, barium zirconate and barium iron manganese barite and / or the metal compound is iron phosphate, iron oxide, iron Cement formulations selected from the group consisting of iron compounds with hydroxides and organic acids. 19. The cement formulation of claim 1 or 18, wherein the pharmaceutical and / or biologically active substance is further mixed. Cured bone substitute material obtained from the cement preparation of claim 1. The cured bone substitute material of claim 24, wherein the cured cement comprises at least one of structural components selected from the group consisting of apatite structures, hydroxyapatite structures, struvite structures, and tribarium phosphate structures. Use of the cured bone substitute material of claim 24 as a bone graft, bone filler, bone cement or bone adhesive, or as a therapeutic for the treatment of bone defects or osteoporosis. A method of treating a bone defect or disease state of a bone system, comprising applying the cement preparation of claim 1 to a bone defect site or to a skeletal part of a patient in need thereof. The method of claim 27, wherein the bone defect is applied to the spinal agent of the patient. Mixing the powder and liquid components of the cement formulation as defined in claim 1; And Curing the obtained mixture Comprising, calcium phosphate-containing cement production method.