CALCIUM SULFATE– AND CALCIUM PHOSPHATE–BASED BONE SUBSTITUTES

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CALCIUM SULFATE- AND CALCIUM PHOSPHATE-BASED BONE SUBSTITUTES Mimicry of the Mineral Phase of Bone Bobby K. B. Tay, MD, Vikas V. Patel, MD, and David S. Bradford, MD

Each year in the United States, 6.2 million fractures occur. Of these, 5%to 10%exhibit delayed healing or nonunion. Autogenous bone graft from the iliac crest or local sources has been the material of choice for the treatment of significant bone loss, delayed unions, and nonunions. Autogenous bone grafting, however, has been limited by the finite amount of bone available and the possibility of significant donor site morbidity, which can approach 30%. These two limitations of autogenous bone grafting have prompted the development of materials to replace or reduce the need for autograft bone. As knowledge of the material, chemical, and biologic properties of living bone increases, clinicians become increasingly able to design and develop materials that mimic the properties of bone graft. Although most, if not all, of the materials introduced into the market thus far have been osteoconductive, the osteogenic nature of cancellous autograft sets the gold standard that clinicians strive to replicate. The ideal bone-graft substitute is (1) osteogenic, (2) biocompatible, (3) bioabsorbable, (4)able to provide structural support, (5)easy to use clinically, and (6) cost-effective. Practically, however, depending on where it is used, one or

more of these properties may be more desirable than the others. For instance, the requirements for a material used to fill a bony defect at a metaphyseal site is much different biologically and mechanically from a material used in the treatment of a bony nonunion. In the former case, a purely osteoconductivematerial in concert with internal or external fixation may suffice to provide a transient scaffold on which the patient’s natural healing process can deposit bone. Treatment of nonunion, however, requires stimulation of bone growth beyond that of simple osteoconduction. To evaluate critically the compounds that are being rapidly introduced into the market, it is essential to understand the structure, composition, and behavior of living bone. Bone is a composite material that comprises organic and inorganic components. The inorganic phase, comprising 60% to 70% of the total dry weight, is composed of apatitic calcium phosphate containing carbonate and small amounts of sodium, magnesium, and trace components. The main constituent of the organic phase is collagen I, with cellular elements composing the remainder of the organic phase.3 The structural integrity of bone, especially its compressive strength, directly depends on

From the Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California ORTHOPEDIC CLINICS OF NORTH AMERICA

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the state of the mineral phase. In living bone, this mineral phase is in a constant state of deposition and turnover. Normally the rate of dissolution of the mineral is equivalent to the rate of new bone formation. This equivalence creates a dynamic structural support for load transmission and load bearing that is able to adapt to environmental cues-a biologic expression of Wolff’s law. The pursuit of the perfect bone substitute has over the twentieth century begun with the use of gypsum, the primary component of plaster of Paris, to fill bony defects. In the 1990s, better understanding of the mechanical and cellular properties of bone resulted in the introduction and popular application of ceramic hydroxyapatite for use in segmental long bone defects and bony voids. Sintered hydroxyapatite in these situations, however, has been limited by its extremely slow resorption. Composite materials of collagen and soluble hydroxyapatite (Healos) as well as preparations of demineralized bone matrix have been designed to address this problem. The addition of osteoinductive agents (rhBMP-2, GDF-5, BMP-7) to these matrices to form an osteogenic composite is clearly the next step; however, in an environment where cost containment becomes an issue in patient care, the use of these powerful compounds with their high-technology carriers in any significant amount may become prohibitive. Paralleling the introduction of these highly designed materials has been the reintroduction of simple compounds that substitute just the mineral phase of bone. These compounds, composed of calcium sulfate and calcium phosphate, are purely osteoconductive.Their main advantage is that the resorption profile of newer calcium sulfate or calcium phosphate materials closely matches the rate at which new bone is deposited. Thus, clinical use is limited to the filling of large bony defects in which the surrounding host environment is conducive to bony healing. HISTORY OF PLASTER OF PARIS AND CALCIUM PHOSPHATE COMPOUNDS

Gypsum, also referred to as plaster of Paris, owes its name to a village just north of Paris known today as Montmartre. The compound itself dates back to the ancient Egyptians,where it was used to cover the bandages in which mummies were wrapped, and its medical use

dates back to the twelfth century, when it was the key element in the creation of hard setting bandages. The use of gypsum to treat fractures was first reported by Eton in Medicul Commentaries in 1794. He described an Arabian technique in which fractures were immobilized by a cast created from pouring a gypsum solution over the broken extremity. Although Hendrksz in 1814 was the first Western medical practitioner to make systematic use of plaster casts for the treatment of fractures, Mathijsen, who published his work in Het Repertorium in 1852, is credited with the invention of the plaster bandage. He impregnated cotton bandages with gypsum powder and wrapped the wet plaster bandages around the fractured limbs. Although its external use dates back to the seventeenth century, the first internal use of gypsum to fill in bony defects was reported in 1892 by Dreesmann9while he worked at Trendelenburg’s clinic in Bonn. He filled bony defects in eight patients with slurry of plaster of He found that six of the Paris and 5% eight patients treated in this fashion had bony ingrowth into the plaster-filled defects. Anachronistically, 2 years later, the first animal experiments using plaster of Paris as a bone void filler were reported by Martin, who used it to fill bony cavities in dogs. The application of plaster of Paris as a bone void filler was then forgotten until 1925, when Kofmann of Odessa reported a favorable 13-year follow-up of a patient with bone loss from osteomyelitis whose cavity was filled with plaster of Paris.32In 1928, Petrova from the Institute for Traumatology in Leningrad reported good results in dogs in which antibiotic-impregnated plaster of Paris was used to fill infected and noninfected bony cavities. The use of antibioticladen plaster in the treatment of infected bony defects was also supported by clinical studies performed by Nystrom and Edberg3I In 1952, Hauptli reported his series of 16 patients who were treated with plaster of Paris as bone void He noted that the material was both efficacious and safe. Kovacevic then used plaster of Paris impregnated with penicillin and sulfonamide in the treatment of acute osteomyelitis after diaphysectomy. Finally, during the Vietnam War, trauma surgeons used the compound as a space filler for the management of craniofacial bone loss. The application of calcium sulfate as a bone void filler was then supplanted by a similar compound, calcium phosphate, which was thought to be more similar to the true mineral phase of bone. In contrast to calcium sulfate,

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hydroxyapatite led to the creation of a hywhich was originally used in the orthopedic droxyapatite cement. The material was develarena, calcium phosphate compounds were oped at the Paffenburger Research Center of applied initially in craniofacial and dental surthe American Dental Association Health Foungery as early as the 1970s.11,18,19,22,u,34,39 dation and is applied to the defect as a dense Calcium phosphate was fashioned by various processing methods into materials that paste.2 The compound sets in vivo to microporous hydroxyapatite within 15 minutes and were close to cancellous bone in porosity and structure. In addition, solubility characteristics at a relatively neutral pH. It consists of tetracould be manipulated by altering the basic calcium phosphate and anhydrous dicalcium chemistry of the compounds. There have been phosphate, which, when mixed with water, ismany preparations of calcium phosphate for othermically forms hydroxyapatite at physiouse as bone-graft extenders or bone void fiI1logic pH. ers, the most widely used of which is hydroxyCa,(PO,), + CaHPO, apatite. Hydroxyapatite is a compound that is similar in stoichiometric composition to bone + H,O + Ca,(PO,),OH mineral and to tooth enamel. It shares the forThe hydroxyapatite forms after setting of the mula Ca,,(PO,),OH,, and it is a part of a larger cement. Calcium phosphate salts supersatuclass of compounds identified as apatites that rate the water within the set cement, and hyare characterized by the formula M,,(XO,)Z,. droxyapatite precipitates in situ over the next The crystal lattice of hydroxyapatite is hexag4 to 6 hours. The material has a pore diameter onal or pseudohexagonal.8 Its porosity and from 2 to 5 nm and has a compressive strength crystalline structure can be changed by manipof 380 kg/cm2. Animal studies indicate that ulation of the calcium-to-phosphate ratio, the content of carbonate, and the presence of imthe implant remains stable for more than 12 months, and 77% of the implant is replaced by purities such as fluorine in the lattice. In genliving bone. Another malleable form of hyeral, the higher the carbonate content, the droxyapatite, Bone Source (Orthofix, Winstonhigher the calcium-to-phosphateratio, and the Salem, NC), is composed of tetracalcium phosmore fluourine in the lattice, the more stable phate and dicalcium dihydrate. When these the biologic precipitate in calcified t i s s ~ e s . 8 , ~ ~ two compounds are mixed together with waThe ceramics that are most interesting from a ter, an isothermic reaction occurs, that causes biologic perspective share a calcium-to-phosphate ratio close to 1.67 or 1.5. the cement to set in 10 to 15 minutes.2 Tricalcium phosphate (Ca,[PO,],) has also Early formulations of hydroxyapatite used been used as a bone void filler. It shares similar as bone void fillers were sintered by heating advantages to hydroxyapatite because it is biothe precipitate at temperatures reaching or excompatible and bioabs~rbable.~,'~ It is brittle, ceeding 1100°C. These products include Prohowever, and has low impact resistance. PoOsteon and Interpore (Interpore In'tl, Irvine, rous tricalcium phosphate containing microCA) ,which are hydroxyapatite lattices created pores 3 to 5 nm in diameter has a compressive from a coralline scaffold. The products are creand tensile strength similar to, but lower than, ated by heating the calcium carbonate skeleton of the coral at elevated temperatures in the cancellous boneF2 Tricalcium phosphate dispresence of an aqueous phosphate solution solves more rapidly than hydroxyapatite, esthat drives the exchange of the calcium carpecially in an acidic milieu. bonate of the coral with a calcium phosphate Tricalcium phosphate has also been comreplica. The coral species Porites astreoides was bined with hydroxyapatite and type I collagen, chosen because of its theoretically ideal pore and the resultant material is marketed as Colsize for the ingrowth of bone. A classic study lagraft (Zimmer, Warsaw, IN). Although the by Klawitter and Hulbert2*showed that 100 material shows promise in the treatment of pm is the minimum pore size required for eflong bone fractures, its use in spinal fusion fective bony ingrowth. On electron micromodels has not shown any greater efficacy as scopic examination, the average pore size of compared to autogenous b ~ n e . ~ , ~ O Porites astreoides was found to be 153.95 2 Over the past 5 years, three products have 25.36 pm.% emerged that take advantage of the flexibility The utility of the sintered form of hydroxyof calcium sulfate or calcium phosphate to creapatite has been diminished by its poor bioate compounds that closely mimic the mineral resorbability and poor handling characterisphase of bone: OsteoSet (Wright Bio-Orthotics. This need for a more moldable form of pedics, Arlington, TN), Norian SRS (Norion

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Core, Cupertino, CAI, and ETEX a-BSM (ETEX, Cambridge, MA). OsteoSet, a calcium sulfate product from Wright, received U.S. Food and Drug Administration (FDA) clearance in June 1996. Norian SRS, produced by the Norian corporation, is an injectable calcium phosphate material that is currently under investigational status in the United States. A premarket approval application has been filed with the FDA for orthopedic application. ETEX a-BSM is an injectable calcium phosphate paste that is currently marketed for dental applications as a bone void filler. Its efficacy as a bone void filler in orthopedic applications is currently under investigation. The remainder of this article focuses on the basic science behind these three materials. OSTEOSET

Calcium sulfate (CaSO,) has long been used in its partially hydrated form of plaster of Paris (CaS04-2H,0).This material is produced commercially by heating the purified, hydrated form of calcium sulfate: CaS0,-2H,O

+ Heat + CaS0,-1/2H20

Calcium sulfate dihydrate has also long been used in vivo and shown to be biocompatible. PeltieP examined implants and found no increase in inflammation reaction than is normally present in similar fractures without implants. PeltieP stated that in no sections were foreign body giant cells observed, as have often been observed with other inert but nonresorbable materials. More recently, Sidqui et a137found that osteoblasts can attach to the material. In addition, osteoclasts can actively resorb the calcium sulfate, forming lacunae in a manner similar to natural bone. The dissolution of calcium sulfate produces an acidic microenvironment (pH 5.6) that may help limit bacterial activity. Despite this local dissolution, on a systemic level, the breakdown of the graft material does not lead to any appreciable increase in serum calcium levels.32 Mixing the gypsum powder with water initiates an exothermic reaction that leads to recrystallization of the calcium sulfate into the solid form of plaster. The problem with this reaction, however, is that the recrystallization proceeds randomly producing crystals of varying size and shape as well as multiple defects within the crystalline structure. This variability in the crystalline structure causes significant variability in solubility, mechanical

properties, and porosity. Thus, the preparation is too heterogeneous to provide the consistent results required for widespread use. In addition, non-medical grade calcium sulfate may resorb too rapidly leading to fibrous ingrowth instead of bony substitution. Newer forms of calcium sulfate are crystallized in highly controlled microenvironments producing regularly shaped crystals of similar size and shape (Fig. 1). The material that is produced possesses a slower, more predictable solubility and resorption. One such material is OsteoSet, a patented medical grade calcium sulfate bone-graft substitute and bone void filler. The material comes in the form of pellets and functions as a bone void filler providing an osteoconductive matrix for bony substitution. The cylindrical pellets are available in two sizes, 4.8 X 3.3 mm and 3 mm X 2.5 mm, for application in larger or smaller defects. Stringent processing methods produce a highly consistent material that typically dissolves in vivo within 30 to 60 days depending on the volume and location. Preclinical testing has shown that OsteoSet is biocompatible.The pellets are packaged in vials and are sterilized by gamma irradiation. Before human application, numerous animal studies have shown the material's efficacy as a bone void filler. Huff and GrisoniZ0 showed that in a rat femoral defect model, the calcium sulfate pellets were comparable to fresh-frozen corticocancellous allograft in healing rates and mechanical strength at 2,4, and 5 weeks. Canine humeral cavitary defects packed with OsteoSet show equal healing rates as compared to autograft bone (Tm Turner, et al, unpublished data). Cunningham et a16 showed that OsteoSet is comparable to autograft in a sheep posterolateral spinal fusion model. CALCIUM PHOSPHATE

The mineral phase of bone comprises approximately 60% to 70% of its dry This carbonated, calcium phosphate apatite mineral, termed dahllite, contains 4% to 6%carbonate by weight and small amounts of sodium, magnesium, and other trace elements.% Ideally a bone-graft substitute would have a similar mineral composition and structure. The earliest application of calcium phosphate salts was in the form of powders. Albee' used triple calcium phosphate (Ca,(PO,),) as a stimulus to osteogenesis in rabbit bone with a

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Figure 1. A and 6,High and low magnificationviews of regular calcium sulfate showing variability in crystal size and shape. C andD, High and low magnificationviews of OsteoSet material. OsteoSetbone void filler is composed of medical grade calcium sulfate with uniform size and crystalline structure. (Courtesy of Wright Bio-Orthopaedics, Arlington, TN.)

positive influence on healing. This material, however, was limited by a lack of structural integrity until the 1960s, when the ceramic form first became a~ailab1e.I~ Since then, the most commonly used calcium phosphate ceramics are hydroxyapatite and tricalcium phosphate used ex vivo in the form of implant coatings and defect fillers. These materials require high temperature and often high-pressure processing to produce dense, highly crystalline, bioinert ceramics, which are not moldable intraoperatively and have poor fatigue characteristics. In situ setting calcium phosphate cements have become commercially available or are in the final stages of FDA approval. They have the advantage of excellent biocompatibility as well as in situ setting without heat generation or shrinkage. NORIAN SKELETAL REPAIR SYSTEM (SRS)

A biocompatible and resorbable calcium phosphate cement has been introduced for augmentation of fracture repair. It is a combi-

nation of monocalcium phosphate, tricalcium phosphate, calcium carbonate, and a sodium phosphate solution mixed into an injectable paste. Under physiologic conditions, the material hardens within minutes into a dahllite (carbonated hydroxyapatite) in a nonexothermic reaction with the following approximate stoichiometry: Ca,,(HP0,),7(P0,),,(C0,),7 (OH),,. It reaches 85% to 95% of completion within 12 hours and has a final compressive strength of 55 mPa.21Ison et alZ1also showed that the chemical composition and crystallinity of the material are similar to that of the mineral phase of bone. Finally, this biocompatible and osteoconductive material appears to undergo the same in vivo remodeling as normal bone; it undergoes cell-mediated osteoclast resorption and replacement with osteoblast-mediated mineralized tissue formation to reestablish bone morphology and strength.I3 This material appears to offer significant mechanical integrity for the augmentation of fixation during the healing process as noted in increased strength when used with sliding hip screw fixation, pedicle screw fixation, and femoral neck fracture^.'^,^^,^^

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ETEX a-BSM

This novel substance appears quite well suited to incorporation of antibiotics or other proteins, such as bone morphogenetic proteins. The setting reaction of a-BSM takes place at relatively neutral pH and is compatible with a variety of buffers, including human serum. The lack of significant heat generation also minimizes denaturing of protein structure, and unconfirmed proprietary studies have verified the maintenance of incorporated protein bioactivity.

Calcium orthophosphate cements, produced from calcium phosphates, are solids between 20°C and - 40°C and include dicalcium phosphate dihydrate, octocalcium phosphate, and many precipitated apatites, including carbonated and calcium-deficient apatites.l0Their development has evolved to mimic more closely the poorly crystalline apatitic structure of natural bone, providing superior resorption and osseointegration (Fig. 2)?,14J5Even with these materials, residues of the cements can be found within bone up to a year after implanINCORPORATIONOF ANTIBIOTICS tation. AND GROWTH FACTORS a-BSM has been introduced to provide a poorly crystalline calcium phosphate apatite Another advantage in the use of simple mawith favorable absorption characteristics and terials, such as calcium sulfate or calcium easy intraoperative handling chara~teristics.2~ phosphate, as bone void fillers is uniform and predictable elution kinetics. The materials can It is composed of a calcium phosphate material be manufactured to contain antibiotics, which that can be hydrated with saline to form a during resorption create a locally bactericidal workable paste (Fig. 3). This paste remains environment around the implant for up to 3 formable for hours at room temperature but hardens within 20 minutes at physiologic week^.^,^^ In addition, by filling in the dead body temperature (37°C) and can be prepared space, the materials physically ablate voids to harden to a variety of compressive strengths where infection would collect and be protected (5 to 40 mPa). The setting reaction is also enfrom the host immune system. Because the caldothermic, avoiding the thermal damage seen cium sulfate is bioabsorbable, it has inherent with exothermic cements, such as polymethyl advantages over other antibiotic carriers, such methacrylate. The poorly crystalline nature of as polymethyl methacrylate, which become a the cement also closely mimics the mineral nidus for further infection after elution of the phase of bone, thus providing an excellent osantibiotics, thus requiring a separate operation for removal from the surgical site. In contrast, teoconductive scaffold for cell-mediated abcalcium sulfate pellets become resorbed by the sorption and remodeling into natural host host or in the presence of active infection, liqbone (Fig. 4).

Figure 2. High magnificationviews of wBSM calcium phosphatecement after setting has taken place. (Courtesy of ETEX Corporation, Cambridge, MA.)

CALCIUM SULFATE- AND CALCILJM PHOSPHATE-BASED BONE SUBSTITUTES

Figure 3. The a-BSM is activated by mixing with saline solution. The slurry solidifies at body temperature. (Courtesy of ETEX Corporation, Cambridge, MA.)

uefy, and drain out with the pus.32In vitro studies show that 6- X 4-mm cylindrical pellets of calcium sulfate released 17%of their tobramycin load at 24 hours, but the amount of antibiotic released over time is dependent on the specific antibiotic used.26 Aminoglycosides, amoxicillin, and glycopeptides were released out over 3 weeks, whereas cephalosporins and sodium amoxicillin were completely released after 2 to 3 days. In addition, the bactericidal activity of the antibiotics can be altered by the incorporation process. Cephalosporins and penicillins were unstable, but aminoglycosides remain fully stable with 100% activity after 2 weeks. About 60% of the initial bactericidal activity of quinolone, glycopeptides, and fusidate sodium were still detectable after 2 ~ e e k s . 2 ~

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calcium sulfate or calcium phosphate. Manufacturers have taken advantage of the basic chemistry of calcium sulfate and of calcium phosphate to produce compounds that function quite well as resorbable bone void fillers. Calcium sulfate has shown itself in both animal and human studies to be an effective void filler in the treatment of bony defects in which the host bed is conducive to bony healing. The calcium sulfate bone void fillers provide an inert, biodegradable scaffold on which preexisting host osteoblasts can direct the deposition of new bone. The medical grade calcium sulfate that composes OsteoSet takes advantage of high-technology processing to create a compound that not only retains all of the biologic advantages of calcium sulfate, but also possesses more consistent mechanical properties and resorption profiles. The material can provide structural support and is bioabsorbable and biocompatible. Most importantly, its resorption profile closely matches the rate at which the host environment can lay down bone around the compound itself.

DISCUSSION

The design and manufacture of bone-graft substitutes have rapidly advanced over the last 10 years. The creation of highly osteogenic materials from the pairing of osteoconductive matrices and osteoinductive growth factors is the fruit of a decade of basic research in bone biology. A complex and high-technology solution is, however, seldom required in the treatment of one of the most common problems in orthopedics-the filling of an osseous defect. In this particular situation, materials that show promise as bone-graft substitutes are compounds that are able to mimic the mineral phase of bone. The main constituent of the three products that lead the market are either

Figure 4. Low (A) and high magnification (6)histologic section of femoral slot defects filled with a-BSM. (Courtesy of ETEX Corporation, Cambridge,MA.)

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Another advantage of the OsteoSet material is the ability to incorporate antibiotics into the calcium sulfate. Aminoglycosides are the ideal antibiotic because of their prolonged elution characteristics. When this is combined with the eradication of dead space and the acidic environment created during resorption, the compound can be an extremely effective treatment for acute bony infections with bone loss. The new calcium phosphate-based compounds, Norian SRS and ETEX a-BSM, are complementary to the calcium sulfate products. These calcium phosphate-based materials are injectable cements that were designed for different applications. Similar to calcium sulfate, the calcium phosphate cements are replaced by creeping substitution over time with host bone. In addition, both of these compounds have the potential for antibiotic incorporation and may be effective carriers for growth factors. The knowledge of bone biology has led to two rational but divergent pathways to address the problem of filling in a bony defect. One pathway is the creation of composite materials containing growth factors in specially designed carrier matrices in an attempt to create material that may surpass autogenous bone graft in osteogenic potential. The other pathway, the mimicry of the mineral phase of bone, although simpler, certainly shows as much promise. At this point, the application of these materials requires a thorough understanding of the host bed. Animal testing and limited numbers of human case reports have touted the efficacy of these compounds, but large controlled human clinical studies are necessary to evaluate fully the theoretical advantages of these new calcium sulfate and calcium phosphate compounds. In addition, despite the large amount of data that exist showing initial material properties and resorption characteristics of these materials, relatively little is known about how these material properties change in vivo as the compounds are gradually replaced by host bone. Many of these questions are likely to be answered over the next few years, but until then the application of these new compounds should be approached with an understanding of their limitations. References 1. Albee FH: Studies in bone growth triple calcium phosphate as a stimulus to osteogenesis. Ann Surg 71:32, 1920

2. Brown P. A new calcium phosphate water setting cement. In: Cements Research Progress. American Ceramic Society, Westerville, OH, 1986 3. Constantz BR, Ison IC, Fulmer MT, et al: Skeletal repair by in situ formation of the mineral phase of bone [see comments]. Science 2671796-1799,1995 4. Cornell CN, Lane JM, Chapman M, et al: Multicenter trial of Collagraft as bone graft substitute. J Orthop Trauma 5:l-8,1991 5. Costantino PD, Friedman CD, Jones K, et a1 Hydroxyapatite cement: I. Basic chemistry and histologic properties. Arch Otolaryngol Head Neck Surg 117:379384,1991 6. Cunningham BWO, Sefter JC, Buckley R, et al: An investigational study of calcium sulfate for posterolatera1 spinal arthrodesis-an in-vivo animal model. Presented at Scoliosis Research Society Meeting, New York, September 16-19,1998 7. Cutright DE, Bhaskar SN, Brady JM, et a1 Reaction of bone to tricalcium phosphate ceramic pellets. Oral Surg Oral Med Oral Pathol33:850-856,1972 8. Dacquet V, Varlet A, Tandogan RN, et al: Antibioticimpregnated plaster of Paris beads: trials with teicoplanin. Clin Orthop 241-249,1992 9. Dreesmann H. Ueber Knochenplombierung. Beitr Klin Chir 92304-810,1892 10. Driessens FC, Planell JA, Boltong MG, et al: Osteotransductive bone cements. Proc Inst Mech Eng [HI 212427-435,1998 11. el Deeb M, Roszkowski M: Hydroxylapatite granules and blocks as an extracranial augmenting material in rhesus monkeys. J Oral MaxillofacSurg 4633-40,1988 Experimental evaluation of ceramic cal12. Ferraro JW: cium phosphate as a substitute for bone grafts. Plast Reconstr Surg 63:634-640,1979 13. Frankenburg EP, Jiang M, et a1 Mechanical integrity of calcium phosphate cement in in-vivo metaphyseal models over time. Trans Orthop Res SOCp 21,1996 14. Fukase Y, Eanes ED, Takagi S, et al: Setting reactions and compressive strengths of calcium phosphate cements. J Dent Res. 69:1852-1856,1990 15. Fukase Y, Wada S, Uehara H, et al: Basic studies on hydroxy apatite cement: I. Setting reaction. J Oral Sci 40: 71-76,1998 16. Goodman SB, Bauer TW, Carter D, et al: Norian SRS cement augmentation in hip fracture treatment. Laboratory and initial clinical results. Clin Orthop 348:4250,1998 17. Groot K D Bioceramics of Calcium Phosphate. Boca Raton, FL, CRC Press, 1983 18. Harvey WK, Pincock JL, Matukas VJ, et al: Evaluation of a subcutaneously implanted hydroxylapatite-avitene mixture in rabbits. J Oral Maxillofac Surg 43:277280,1985 19. Holmes R, Hagler H: Porous hydroxyapatite as a bone graft substitute in maxillary augmentation. An histometric study. J Craniomaxillofac Surg 16:199-205, 1988 20. Huff W, Grisoni B. Mechanical integrity of rate bone after autograft and calcium sulfate graft. Proceedings of the Fifth World Biomaterials Congress, May 29June 2,1996 21. Ison I, Barr B, et al: Synthesis of Dahllite: The Mineral Phase of Bone. In Yamamuro T (ed): Handbook of Bioactive Ceramics. Boca Raton, FL, CRC Press, 1994 22. Jarcho M: Calcium phosphate ceramics as hard tissue prosthetics. Clin Orthop 259-278,1981 23. Jarcho M, Kay JF, Gumaer KI, et al: Tissue, cellular and subcellular events at a bone-ceramic hydroxylapatite interface. J Bioeng 1:79-92, 1977

CALCIUM SULFATE- AND CALCIUM PHOSPHATE-BASED BONE SUBSTITUTES 24. Klawitter JJ, Hulbert S Application of porous ceramics for the attachment of load-bearing orthopadic applications. J. Biomed Mater Res Symp 161,1971 25. Knaack D, Goad ME, Aiolova M, et al: Resorbable calcium phosphate bone substitute [in process citation]. J Biomed Mater Res 43:399-409, 1998 26. Miclau T, Dahners LE, Lindsey RW In vitro pharmacokinetics of antibiotic release from locally implantable materials. J Orthop Res 11:627-632, 1993 27. Moore DC,FE, Goulet JA: Hip screw augmentation with an in-situ setting calcium phosphate ceramic: An in-vitro biomechanical analysis with time. Trans Orthop Res SOC18,1993 28. Mousset B, Benoit MA, Bouillet R, et al: [Plaster of Pans: A carrier for antibiotics in the treatment of bone infections]. Acta Orthop Belg 59:239-248, 1993 29. Mousset B, Benoit MA, Delloye C, et a1 Biodegradable implants for potential use in bone infection. An in vitro study of antibiotic-loaded calcium sulphate. Int Orthop 19:157-161,1995 30. Muschler GF, Negami S, Hyodo A, et a 1 Evaluation of collagen ceramic composite graft materials in a spinal fusion model [see comments]. Clin Orthop 250-260, 1996 31. Nystrom G: Plugging of bone cavities with Rivanolplaster-porridge. Acta Chir Scan 63296,1928

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32. Peltier L: The use of plaster of Paris to fill large defects in bone. Am J Surg 97:311-315,1959 33. Posner AS: The mineral of bone. Clin Orthop 87-99, 1985 34. Rawlings CE, Wilkins RH, Hanker JS, et al: Evaluation in cats of a new material for cranioplasty: A composite of plaster of Paris and hydroxylapatite. J Neurosurg 69:269-275,1988 35. Roudier M, Bouchon C, Rouvillain JL, et al: The resorption of bone-implanted corals varies with porosity but also with the host reaction. J Biomed Mater Res 29:909-915,1995 36. Roufosse AH, Aue WP, Roberts JE, et al: Investigation of the mineral phases of bone by solid-state phosphorus-31 magic angle sample spinning nuclear magnetic resonance. Biochemistry 236115-6120,1984 37. Sidqui M, Collin P, Vitte C, et al: Osteoblast adherence and resorption activity of isolated osteoclasts on calcium sulphate hemihydrate. Biomaterials 1613271332; 1995 38. Stankewich CJ, Swiontkowski MF, Tencer AF, et al: Augmentation of femoral neck fracture fixation with an injectable calcium-phosphate bone mineral cement. J Orthop Res 14:786-793,1996 39. Zide MF, Kent JN, Machado L: Hydroxylapatite cranioplasty directly over dura. J Oral Maxillofac Surg 45:481-486,1987

Address reprint requests to David S. Bradford, MD University of California, San Francisco 500 Parnassus Avenue, MU-320W San Francisco, CA 94143