WO2009019323A2

WO2009019323A2 - Use of bioactive glass

Info

Publication number: WO2009019323A2
Application number: PCT/FI2008/050449
Authority: WO
Inventors: Ilkka Kangasniemi; Jouni HEIKKILÄ; Allan Aho
Original assignee: Vivoxid Oy
Current assignee: Vivoxid Oy
Priority date: 2007-08-03
Filing date: 2008-08-01
Publication date: 2009-02-12
Anticipated expiration: 2010-02-03
Also published as: WO2009019323A3

Abstract

The present invention relates to a method of using silica containing bioactive ceramic material for the treatment and prevention of bone resorption, especially when associated with osteoporosis or metallic permanent implants.

Description

USE OF BIOACTIVE GLASS

FIELD OF THE INVENTION

The present invention relates to a method for the treatment and prevention of bone resorption, especially when associated with osteoporosis or metallic permanent implants.

BACKGROUND

Bone fractures, bone defects and disease caused deficiencies may cause incurable states for a patient. Recurring fractures, bone resorption around implants and local bone loss leading to fractures and collapses of the bone structure are common phenomena especially amongst elderly and are typically caused by osteoporosis. Osteoporosis is a disease of bone in which the bone mineral density is reduced, bone micro architecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Typical fractures occur in the vertebral column, hip and wrist.

The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. Either bone resorption is excessive, and/or bone formation is diminished. Bone matrix is manufactured by the osteoblast cells, whereas bone resorption is accomplished by osteoclast cells.

Bone fractures and defects have been treated by using autologous (patients own) bone, allogenous bone (cadaver derived), growth factors, demineralized bone matrices, blood platelet derivatives or synthetic fillers as bone substitutes. These organic or synthetic materials aid the bone formation by providing a suitable substrate for bone cells to grow on, by stimulating the bone growth through their chemistry and even by stimulating the differentiation of bone cells from the stem cells.

Clinically the various materials have been used to stimulate the bone growth in short term, i.e. during the healing period of the actual cavity, fracture or other defect. Once the bone has healed itself the filler material is considered merely as a nuisance because it may interfere with the future X-ray analysis of the site, thus making it more difficult to analyse whether the site has properly healed or not. Most bone fillers are also brittle materials by nature and therefore do not contribute to the mechanical strength of the bone by themselves. Typically the healing period of bone has been considered as 16-24 weeks. The healing time may vary considerably even beyond 24 weeks and some times not healing at all depending on many variables such as age, general health, smoking habits, size and severity of defect, type of disease etc. However, the general consensus has been that the bone filling materials should preferably disappear during the first year after implantation.

Different solutions have been proposed for enhancing bone formation. For example, in WO 96/00536, particles of bioactive glass in a size range of from about 200 micrometers to about 300 micrometers are implanted in bone tissue. The particles are made from about 40 % to about 58 % silicon dioxide, from about 10 % to about 30 % sodium oxide, from about 10 % to about 30 % calcium oxide, and up to about 10 % phosphorous pentoxide, by weight. The size range of the particles is selected such that the bioactive glass particles will become excavated from inside and degrade totally rapidly and therefore rapidly become replaced by bone. These particles are thus not meant to have a long term effect. No information is given that these glasses could exhibit a long term bone supporting function in a prophylactic manner, inhibiting renewed resorption of the bone at the implantation site.

Document WO 2003/103734 presents a calcium -strontium - hydroxyphosphate cement preparation (I) comprising (1 ) powdered mixture containing calcium, strontium and orthophosphate at molar ratios of Ca/P = 1.00-1.50 (excluding 1.00) and Sr/P = 0-1.50 (excluding 0 and 1.50); (2) alkali metal or ammonium orthophosphate salt; and (3) water and/or an aqueous solution.

Document WO 2001/049327 describes bioactive bone cement compositions (1 ) comprising a powder component including (a) strontium containing hydroxyapatite; and a liquid component including (b) bisphenol A diglycidylether dimethacrylate resin, (a) and (b) being formulated to create a settable fluid substance when mixed together.

Hydroxyapatite as a bone filler has in itself not been shown to exhibit a long term effect as a bone producing agent. Adding strontium into it increases the bone producing effect in osteoporotic defects by adjusting the activity of both osteoclast and osteoblast cells. Combining these with acrylic cement would make the material partially inert, while still having a limited amount of bioactivity as a suitable substrate for osteoblastic cells to adhere to and by releasing slowly strontium ions into the surrounding tissues. The effect of the material is taught to be cement that increases bone growth onto its surface. This material can also be used in treatment of osteoporotic defects. The function of the material is also to repair the defect rather than prophylactically prevent a reoccurhng osteoporosis. Furthermore the document does not mention the use of bioactive glass or silica based or silica containing substances in this purpose.

Publication WO 2001/074410 presents an artificial bone comprising calcium phosphate artificial bone cement and a polyphosphate. The artificial bone is used as osteoconductive and osteoinductive biodegradable substitute for conventional bone cements, allografts, and autografts. It can be used for the treatment of defects and fractures in every bone of the body, as cure for osteoporosis, as fillers of implant for dental surgery, as bone substitute for plastic surgery, and as substitution of defected bones in the operation of joints (e.g., hip joint, knee joint and shoulder joint) and the operation of vertebra. It can also be used as filler, reinforcement, and support for vertebra plasty and oral graft operation. The described artificial bone is non-toxic to the body and chemically stable, and promotes biocompatible osteoanagenesis. Neither prophylactic long term effect nor silica based materials are described.

Document WO 2003/02431 shows a bone precursor composition comprising cement mixture or solid cement and a pore-forming agent. The pore-forming agent has a particle size of 20 - 500 microM. Neither prophylactic long term effect nor silica based materials or bioactive glass are described. In WO 2003/045454 a biomatehal (A1 ) comprising a bone compatible matrix material (a1 ) and an inhibitor of cell mediated acidification (b) is described. This is a combination of CaP cement and an inhibitor of cell mediated acidification that may be useful in the treatment of osteoporotic defects. However, neither prophylactic long term effect nor silica based materials are described.

Document WO 2002/068009 presents an orthopaedic composition comprising a homogeneous mixture of a biocompatible polymer and a bioactive particulate ceramic. The ceramic has an average particle size of not more than 500 nm. This composition can be used for forming a shaped article (e.g., bone plate, bone screws and load bearing intervertebral disc implant), and a bone cement for orthopaedic applications; for stabilizing a spine by associating with vertebrae of the spine, a shaped load bearing article formed from the composition; and for correcting bone defect by applying the composition to the bone defect. It can be used to form various spinal implants including various spinal spacers and cages, as well as the bone plates and the bone screws. It can also be used for promoting fusion of adjacent vertebrae.

The composition has mechanical and biological properties. When a polymer is combined with a particulate ceramic (e.g. hydroxyapatite in combination with other forms of calcium phosphate), the ceramic may advantageously promote bone apposition. Although the cages may be strong due to the biphasic reinforcement structure, the cages may gradually lose their strength upon in vivo degradation and eventual resorption. Further, the cages formed of hydroxyapatite and/or other form of calcium phosphate in combination with the resorbable polymer, the nanoparticles of the ceramic may buffer the acidic degradation products of the resorbable polymer. Additionally, the cages can be located in vivo radiographically due to the presence of hydroxyapatite and/or other calcium phosphates. Further, the ceramic may advantageously act as a support structure to enhance bone ingrowth in the composition, and in other forms, may act to reinforce the polymer it is combined with. The nanometer-sized ceramic particles may be more beneficial in promoting bone ingrowth than larger particles, including those greater than 1 mum.

The use of very small particles of bioactive glass or CaP ceramic in a biodegradable/nonbiodegradable polymer for achieving a bioactive composite material is thus described. The size of the particles ensures that they will dissolve from the composite almost as soon as they come into contact with the body fluids, i.e. water. Polymers generally absorb water within the first weeks after implantation of the order of a few weight percentages of their dry weight or in case of biodegradable polymers more in time due to their biodegradation process which is usually selected to occur within a year. In the latter case it is clear that this material cannot have a long term effect. In the former case the presence may or may not be long term depending on the polymer component of the composite. However, again no mention has been made to the potential long term prophylactic effect of silica release.

Publication WO 94/04657 describes a bioactive material for in vitro inoculation of cells capable of attaining an osteoblastic phenotype, comprising a substrate with a surface capable of leaching ions, into a tissue culture medium. The surface is treated prior to inoculation under aqueous conditioning to render the substrate incapable of raising the pH of a tissue culture medium above physiological pH upon inoculation. It also describes implantable bone replacement comprising said substrate and bone tissue formed on the substrate in vitro by inoculation with cells capable of attaining an osteoblastic phenotype. It further describes forming a porous glass substrate for use in an implantable bone replacement comprising: (a) melting an admixture of SiO2, Na2O, CaO and P2O5; (b) quenching the method admixed to create a glass frit; (c) forming a glass powder from the glass frit; and (d) forming a porous glass substrate from the powder. The porous glass thus formed exhibits no crystals.

Preferably the bioactive material is a glass with the composition of Siθ2 (40-50 weight-%), CaO (20-30 weight-%), Na₂O (5-30 weight-%) and P₂O₅ (0-12 weight- %). The material is porous and has a porosity of 10-80 %. The pore size is less than 800 μm. The materials can be inserted into all areas of the body which exhibit increased risk of fracture and a decreased potential for bone tissue formation, e.g., as a result of osteoporosis.

This document thus describes a bioactive glass product that may have compositions and particle sizes capable of staying in the body for extended periods of time. In addition in the in vitro phase of the treatment bone cells are differentiated in culture as a result of the ions leaching from the glass. The combination of cells and glass scaffold is intended for high formation rates of extra cellular material to quickly heal the diseased bone. No mention is however made on the potential long term effect of the material in prophylactic prevention of osteoporosis as a result of the leaching ions from the material. After the bone has healed, i.e. it retains its more or less original shape, thickness and strength, the document does not mention any further benefit for the material.

Bone healing involves first osteoclast activity that leads to partial resorption of the damaged bone, followed by new bone formation that produces a slight excess amount of bone, which is not as well organised and dense as mature bone. Typically the last phase of bone healing involves a remodeling phase where bone cells slowly replace the newly formed bone with more organised and densely mineralised bone.

Autologous bonegraft as a bone filler experiences this osteoclast activity and remodeling action and results in a total loss of the autologous bone chips within a year from the implantation site. Simultaneously also the implantation site volume may experience a relapse due to the volume reduction of the bone graft and the support they have provided for the newly formed bone structure. The in vivo studies in goat sinuses by Tia Turunen showed that when adding bioactive glass S53P4 to the same site the bone volume was upheld after the period when autologous bone had already disappeared.

In an in vitro study by Radin et al. it was concluded that "in the presence of bioactive glass, elevated levels of calcium and silicon in the culture medium were observed throughout the 7-day culture period, suggesting a continuous dissolution of surface-modified bioactive glass and resulting release of bioactive glass dissolution products. The data suggest that both surface- and solution-mediated events play a role in the osteogenic effect of bioactive glass." Similar results have also been reported by V. Valimaki et al., showing in vivo measured heightened levels of type 1 , 2 and 3 collagen, osteonectin, osteopontin, MMP-9 and cathepsin during the 8 week study period. They also suggested the use of glass to treatment of osteoporotic fractures based on these short term results.

Allan Aho has published a long term case study of a fibrous dysplacia patient with a severely resorbed tibia. The tibia was implanted with a mixture of CaP ceramic and a glass composition of potential bioactivity. This publication reports the first long term case with a potentially bioactive glass composition. The resulting bone is clearly thicker on the treated side than on the healthy side. Although it is known that CaP ceramics do not have a long term effect on their own, it is not possible to conclude from this single patient case that the glass would have been the sole cause of the bone thickening.

Another effect of the glass as an implantation material is that it mineralizes the surrounding bony tissues. An earlier patent application on mineralisation of dental bony structures (teeth) describes this clinical effect (WO 96/10985 EP 804136 US 5,891 ,233). OBJECTS AND SUMMARY OF THE INVENTION

In view of the above-mentioned, there still exists a need for a prophylactic treatment of osteoporosis, and a need for strengthening the once injured bone.

An object of the present invention is to provide a material suitable for the treatment and prevention of bone resorption.

The present invention relates to a method of using bioactive ceramic material for the treatment and prevention of bone resorption. DETAILED DESCRIPTION OF THE INVENTION

The present inventors have performed bone tumour filling studies in which the cavity created by the tumour surgery was filled with either autologous bone or bioactive glass S53P4. The glass-side showed in three year follow up a higher bone thickness than the autologous bone side. In contrast the autologous bone produced faster bone growth initially than the glass.

In this prospective, in a randomized open clinical study bioactive glass (BG) granules were compared with autogenous bone (AB) as bone filler in benign bone tumour surgery in patients with radiologically diagnosed benign cystic bone tumour. Consecutive 25 patients (11 AB and 14 BG) were operated between 1993 and 1997. The two groups were identical with regard to age, race, type of tumour and location of tumour (big/small). There was a difference between the groups regarding gender, but according to the experts this was without clinical significance and did not affect the comparability of the groups. The evaluation was made using radiological and laboratory analysis.

According to the findings in X-ray and computed tomography the time in which the bone cyst area remodelled to bone was significantly longer in the BG group than in the AB group. In the BG group it took 24 months for small cysts and 36 months for large cysts to achieve the remodellation-level in the AB group, where bone tumour cavities were no longer visible 12 months postoperatively. Even at 36 months postoperatively there were some patients in the BG group whose cyst cavity was still visible (all had large cyst). The cortex of the bone in the BG group seemed to become thicker with time. Radiological findings were similar in adolescent patients. There was no statistical difference between the groups in the serum osteocalcin concentration, neither were there major differences between the groups in the serum alkaline phosphatase.

No differences were found between the groups in the clinical laboratory analyses including blood silicon concentration. No BG related adverse events were reported.

It was concluded that bioactive glass S53P4 can be used as a bone substitute material in the treatment of benign cystic bone tumours, including adolescent patients. Clinically S53P4 was well functioning, safe and well tolerated. The main benefit from using the bioactive glass is that harvesting of the bone grafts can be avoided. The study showed that in "healthy" subjects an effect of the glass can be seen as the thickening of the bone in time. The study does not reveal if any of the patients were simultaneously suffering from osteoporosis.

In this same bone tumour study the surgeons were noting outside the study protocol that the healed bone of the patients on the glass side was harder than on the autologous side. This indicates that also long term mineralisation effect in living tissue conditions with living cells takes place. When compared to the above- mentioned effect on the mineralisation of teeth, it is to be noted that the mineralised part of teeth is essentially non living since the tooth forming cells have long ceased from activity and have greatly reduced in numbers. Thus it is surprising that such an effect occurs also in areas of high metabolism.

The effect of the glass can naturally last only as long as the glass exists in the operated area. Generally it is considered that the glass has its bone growth promoting effect through three mechanisms:

1 ) its ability to transform its own surface into hydroxyl apatite through the chemical reaction with surrounding body fluids,

2) its ability to provide the bone cells with a biocompatible surface to grow and proliferate on, and

3) its ability to induce cell differentiation through silica release into the surrounding body fluids.

Now, since the glass needs to have a certain dissolution rate in order to be bioactive in the first two aspects it means that the glass will also dissolve at a rate enabling these effects. In turn this means that the glass compositions as well as the dissolution rates are limited to certain limits to achieve all three of these effects. The relationship between the composition and the bioactivity has been described at least in three different ways that give the expert sufficient tools to design a bioactive glass. (Hench L. Bioactive ceramics: Theory and clinical applications. Bioceramics 1994;7:3-14).

Another factor influencing the dissolution rate and therefore the total degradation time of the glass particles is the particle size, or the surface area to volume ratio (SaA/). In other words the smaller the particle the higher the SaA/ ratio and the faster dissolution-shorter total degradation time. For example the commercially available glass 45S5/Bioglass is available in size range from 90-700 μm and it is claimed to vanish from the body in less than a year.

What these models do not take into account is the potential long term effect of the glass. As seen now in the clinical study analysis of the inventors there seems to be such an effect. Since the models described by earlier authors have the short term healing of the bone as an efficacy variable they neglect the fact that by reducing the dissolution rate of the glass it is possible to design glasses that have perhaps less of bone forming ability in short term but in contrast by dissolving for a much longer period they have the ability to sustain the bone level and even increase the thickness, density and volume of bone in long term. This of course would be of great importance in conditions where these bone qualities would otherwise be reduced, such as osteoporosis or the surrounding bony tissue around metallic permanent implants.

Thus the present invention describes the use of bioactive glass compositions and particle sizes that are able to retain this long term bioactivity and their use in local treatment of osteoporosis or other bone reducing conditions.

Glass S53P4/BonAlive^® has a chemical composition of 53 weight-% Siθ2- Na2θ 23 weight-%, CaO 20 weight-% and P₂O₅ 4 weight-% that is a clearly slower dissolving glass than the 45S5 glass that has a composition of 45 weight-% SiO₂, 24.5 weight-% Na₂O, 24.5 weight-% CaO, and 6 weight-% P₂O₅.

Without wishing to be bound to a theory, it is believed that the present invention is based on the following facts.

1 ) certain glass compositions and particle ranges remain in the body for an extended period of time,

2) dissolution products of the glass may influence the differentiation of cells into osteoblasts,

3) glass dissolution products, mainly silica is capable of mineralizing the surrounding bony tissues, and

4) long term effect of the glass produces more bone than would otherwise exist on the "healthy" side. This fourth fact is not obvious because the reactions of the glasses slow down considerably after implantation and initial CaP surface layer formation. It could not be assumed that even the slowly degradable glasses would have such low rate but yet significant bone producing ability. It is known from the bioactivity models and studies behind them that the slower degrading glass compositions loose their ability to form CaP layer in the body and their bone bonding ability decreases as the silica content increases and the dissolution rate decreases. Approximately 60 weight-% of silica is the limit above which the melt derived glasses can no longer achieve bioactivity of any rate. Between 50-60 weight-% of approximative silica content the melt derived glasses have dissolution rates that allow for the long term implantation and yet still for bone bonding.

The long term bone producing ability is however not dependent of the bone bonding ability and of the CaP surface formation. It is believed from the above four facts that it is the combination of the long term existence, release of silica and differentiation of the stem cells into osteoblasts that allow for the fourth fact. Therefore the fourth fact cannot be considered to be the based on the same invention as the other bioactivity parameters.

Based on the clinical studies, it is also believed that the bioactive glass not only aids the formation of new bone, but also maintains the once formed new bone.

Furthermore, it is commonly believed that the disease, osteoporosis, is stronger that the ability of forming new bone. Therefore, there exists a prejudice against the present invention, among the experts in the art. This belief is confirmed by the fact that at present, all materials for the treatment of osteoporosis are designed to last for a maximum of one year, i.e. it is not desired that the material remains after the first year.

The present invention relates to a method of using silica containing bioactive ceramic material for the treatment and prevention of bone resorption.

An additional benefit of silica as the active agent in the prevention of the osteoporosis is that it is a natural substance rather than foreign substance in the human body.

According to one embodiment of the invention, said bone resorption is caused by osteoporosis, metallic implant, composite implant or trauma. Preferably, said bioactive ceramic material is selected such that the dissolution period is from 1 to 15 years.

According to yet another embodiment, the bioactive ceramic material is capable of releasing silica in amounts resulting in its sustained release for periods of longer than one year.

The bioactive ceramic material may be selected from the group consisting of bioactive glass, silica sol-gel glass, CaP ceramic material doped with Siθ2, CaNaP glass with addition of SiO2, Ti₁Si sol gel material and mixtures thereof.

The bioactive glass has, for example, a composition of

43-65 weight-% of SiO₂, 0-30 weight-% of Na₂O, 0-20 weight-% of CaO and 0-10 weight-% Of P₂O₅.

Said bioactive glass composition may further comprise potassium, magnesium, boron, calcium peroxide or mixtures thereof.

Other possible bioactive glass compositions are for example

Siθ2 in an amount of 53 - 60 wt-%, Na2θ in an amount of 0 - 34 wt-%, K2O in an amount of 1 - 20 wt-%, MgO in an amount of 0 - 5 wt-%,

CaO in an amount of 5 - 25 wt-%, B2O3 in an amount of 0 - 4 wt-%,

P2O5 in an amount of 0.5 - 6 wt-%, provided that Na₂O + K₂O = 16 - 35 wt-%

K₂O + MgO = 5 - 20 wt-%, and MgO + CaO = 10 - 25 wt-%.

This composition has been disclosed in WO 96/21628, the content of which is herein incorporated by reference. According to another embodiment of the invention, the bioactive glass has the composition of

SiO2 is 53 wt-%, Na2θ is 23 wt-%, CaO is 20 wt-% and

P2O5 is 4 wt-%.

According to yet another embodiment of the invention the bioactive glass has the composition of

SiO2 is 51-56 wt-%, Na2θ is 7-9 wt-%,

CaO is 21 -23 wt-%, K₂O is 10-12 wt-%,

MgO is 1 -4 wt-%,

P2O5 is 0.5-1.5 wt-% and B2O3 is 0-1 wt-%,

provided that the total amount of Na₂O and K₂O is 17-20 wt-% of the starting oxides. This composition has been disclosed in WO 2004/031086, the content of which is herein incorporated by reference.

When silica sol-gel glass is used, it may be doped with ions selected from the group consisting of calcium, phosphorus, sodium, magnesium, potassium, boron or mixtures thereof. The silica content of the sol-gel glasses can be up to 100 weight-% and Ti₁Si sol gel materials, the SiO2 content can vary between 0,1-100 weight-%. In case of using CaP ceramic material, it may be selected from the group consisting of hydroxyl phosphates, fluor phosphates, carbonated phosphates, apatite, tricalcium phosphates, amorphous CaP with the Ca/P ratio between 0,5-2,5 and mixtures thereof.

Sodium and potassium are known to influence the degradation rate of the ceramic material, as well as the particle size as mentioned above. Especially in sol-gel materials, the porosity of the material has also an effect on its degradation rate. The material according to the present invention may be in any suitable form, such as particles, granules, fibres, coating, composite, blocks, scaffolds and mats or tissues.

In general, it can be said that the present invention relates to bioactive glass or ceramic particles of such size and compositions resulting in a) sustaining bone levels, b) increasing bone density and c) increasing cortical bone thickness i) after natural healing period, ii) for the entire period of the glass resorption, iii) for periods up to the lifetime of the patient, and iv) for periods up to and over 20 years.

The product according to the present invention may be used for the prevention of bone resorption around metallic and composite implants, in spinal, dental, orthopaedic and cranio maxillo facial injuries and defects as well as in injuries caused by trauma or sport.

The material according to the present invention may be either implanted within the bone in surgery or injected into the bone or near the bone, should surgery be undesirable. It is can thus be used in local treatment. It is believed to be sufficient to inject the material near the bone, as a hole in a bone further decreases its strength and increases the risk of infection, and may thus be undesirable. In case of surgery for treating collapsed vertebrae, the surrounding vertebrae are preferably treated in preventive manner at the same time. The present invention further relates to a method for sustaining bone level, increasing bone density or increasing cortical bone thickness by implanting bioactive ceramic material in the bone or in the vicinity of the bone of a patient. The embodiments and variations presented above apply mutatis mutandis to this method.

The present invention further relates to a bioactive ceramic material capable of releasing silica in amounts resulting in its sustained release for periods of longer than one year. The embodiments and variations presented above apply mutatis mutandis to this material.

Claims

1. Method of using silica containing bioactive ceramic material for the treatment and prevention of bone resorption.

2. Method according to claim 1 , wherein the bone resorption is caused by osteoporosis, metallic implant, composite implant or trauma.

3. Method according to claim 1 , wherein the dissolution period of said material is from 1 to 15 years.

4. Method according to claim 1 , wherein the bioactive ceramic material is capable of releasing silica in amounts resulting in its sustained release for periods of longer than one year.

5. Method according to claim 4, wherein the bioactive ceramic material is selected from the group consisting of bioactive glass, silica sol-gel glass, CaP ceramic material doped with Siθ2, CaNaP glass with addition of SiO2, Ti₁Si sol gel material and mixtures thereof.

6. Method according to claim 5, wherein the bioactive glass has a composition of

7. Method according to claim 6, wherein the bioactive glass composition further comprises potassium, magnesium, boron, calcium peroxide or mixtures thereof.

8. Method according to claim 5, wherein the silica sol-gel glass is doped with ions selected from the group consisting of calcium, phosphorus, sodium, magnesium, potassium, boron or mixtures thereof.

9. Method according to claim 5, wherein the CaP ceramic material is selected from the group consisting of hydroxyl phosphates, fluor phosphates, carbonated phosphates, apatite, tricalcium phosphates, amorphous CaP with the Ca/P ratio between 0,5-2,5 and mixtures thereof.

10. Method according to claim 1 , wherein the bioactive ceramic material is selected from the group consisting of particles, granules, fibres, coating, composite, blocks, scaffolds, mats and tissues.

11. Method for sustaining bone level, increasing bone density or increasing cortical bone thickness by implanting silica containing bioactive ceramic material in the bone or in the vicinity of the bone of a patient.

12. A silica containing bioactive ceramic material capable of releasing silica in amounts resulting in its sustained release for periods of longer than one year.