submit to the journals

A Comparison of Mineral Bone Graft Substitutes for Bone Defects

US Oncology & Hematology, 2011;7(1):38-49 DOI:


Synthetic bone graft substitutes have evolved in response to the downsides of autograft and allograft. This article consolidates the literature regarding the use of mineral bone graft substitutes in the treatment of cavitary bone defects. No level I studies regarding their use in the treatment of bone tumors have been performed, but the clinical studies that have been published indicate that calcium sulfate resorbs too quickly and incites inflammatory reaction and hydroxyapatite resorbs too slowly and blocks new bone ingrowth; tricalcium phosphate and mineral bone graft composites have the biochemical profile that is most compatible with new bone formation. These studies also indicate that mineral bone grafts are safe and may be as effective as other graft options; however, radiographic interpretation may be inaccurate and no evidence exists to suggest that mineral bone graft substitutes are superior to no graft at all. The trauma literature has yielded numerous level I studies that indicate that calcium phosphate cements result in increased metaphyseal fracture stability, but have not yet detected any improvement in healing. Prospective randomized clinical trials in the treatment of bone tumors are necessary to properly delineate the real indications for bone grafting and to demonstrate the graft’s efficacy in this regard.
Keywords: Mineral ceramic bone graft substitute, bone defect, bone void
Disclosure: The authors have no conflicts of interest to declare.
Received: March 22, 2010 Accepted: January 29, 2011
Correspondence: Daniel C Allison, MD, MBA, Assistant Professor and Attending Surgeon, Assistant Director of USC Center for Orthopedic Oncology, University of Southern California and Los Angeles County Medical Center, 1200 N State St, Suite 3900, Los Angeles, CA, 90033. E

Cavitary bone defects are created in the curettage or debridement of benign bone tumors, infections, or low-grade malignancies. In order for new bone to fill these defects, the material that resides within must be osteoconductive, or an appropriate scaffolding that prevents non-osseous (fibrous) tissue infiltration, supports the attachment of new osteoblasts and osteoprogenitor cells, and sustains an interconnected structure through which new cells can migrate and new vessels can form.1 The subsequent substance that develops through this osteoconductive step must also be osteoinductive (facilitate the travel of factors and materials for cellular differentiation) and osteogenic (cause the cellular production of new bone) for new bone to form.1 Current US consensus dictates that in order for this cascade to develop in a bone defect, a graft must be used. In fact, over 500,000 bone graft procedures are performed annually in the US.2 In order to meet the first and crucial step of osteoconductivity, the graft must fill the void and provide a scaffolding on which stem cells can attach; in order to facilitate the next two critical steps, the graft must be non-inflammatory and non-toxic and resorb at a rate roughly equal to that of bone formation.1,3

Grafts that have been used to meet the aforementioned steps include autograft, allograft, and synthetic substitutes. Bone grafts constitute a large economic market, with over $1.5 billion in sales in 2007 in the US alone.2 Autograft has long been the gold standard of bone grafts and is the only graft option that has osteoconductive, osteoinductive, and osteogenic properties.2,4 Autologous bone grafting carries the disadvantages of pain at the donor site, variable quality, limited quantity, increased hospital stay, and a 15.8–29.2% complication rate. Complications include, but are not limited to, lateral femoral cutaneous or cluneal nerve injury, superior gluteal artery injury, wound problems, infection, need for further surgery, pelvic fracture, hematoma, and gait disturbances.4–8 Allogenic bone graft is the most commonly used bone graft material. It has osteoconductive and osteoinductive properties and no donor site morbidity, and is relatively low-cost. Allografts have the disadvantages of limited supply, potential antigenic response, lack of uniformity, and potential disease transmission—the most concerning being the documented instances of HIV and hepatitis C virus (HCV) transmission with fresh-frozen tendon and bone allografts.4,5,9–12 No consensus on the actual rate of disease transmission with bone allograft exists, though one study estimates the ‘viral transmission risk’ associated with bone allografting to be one in 1.6 million;13 there have, however, been no documented instances of HIV or HCV transmission through irradiated bone.14
  1. Brinker MR, O’Connor, DP, Basic Sciences In: Miller, M (ed.), Review of Orthopedics, 4th ed, Philadelphia PA, Saunders, 2004;1–153.
  2. Greenwald AS, Boden SD, Goldberg VM, et al., Bone graft substitutes: facts, fictions, and applications. Orthoepdic Device Forum. 68th Annual Meeting of American Academy of Orthopedic Surgeons, February 28 – March 2, 2008, San Francisco CA. Available at: 2001/bone_graft01.pdf (accessed June 7, 2010).
  3. Peltier LF, The use of plaster of Paris to fill large defects in bone. A preliminary report, Am J Surg, 1959;97:311–5.
  4. Gazdag AR, Lane JM, Glaser D, et al., Alternatives to autogenous bone graft: efficacy and indications, J Am Acad Orthop Surg, 1995;3:1–8.
  5. Hak DJ, The use of osteoconductive bone graft substitutes in orthopaedic trauma, J Am Acad Orthop Surg, 2007;15:525–36.
  6. Fowler BL, Dall BE, Rowe DE, Complications associated with harvesting autogenous iliac bone, Am J Orthop, 1995;24:895–903.
  7. Younger EM, Chapman MW, Morbidity at bone graft donor sites, J Orthop Trauma, 1989;3:192–5.
  8. Arrington ED, Smith WJ, Chambers HG, et al., Complications of iliac crest bone graft harvesting, Clin Orthop Relat Res, 1996(329): 300–9.
  9. McLean VA, American Association of Tissue Banks, AATB Information Alert, 1993;3(6).
  10. Centers for Disease Control and Prevention (CDC), Hepatitis C virus transmission from an antibody-negative organ and tissue donor—United States, 2000–2002, MMWR Morb Mortal Wkly Rep, 2003;52:273–74, 76.
  11. Tomford WW, Transmission of disease through transplantation of musculoskeletal allografts, J Bone Joint Surg Am, 1995;77: 1742–54.
  12. Boyce T, Edwards J, Scarborough N, Allograft bone. The influence of processing on safety and performance, Orthop Clin North Am, 1999;30(4):571–81.
  13. Buck BE, Alininm TM, Brown MD, Bone transplantation and human immunodeficiency virus. An estimate of risk of acquired immunodeficiency syndrome (AIDS), Clin Orthop Rel Res, 1986;240:129–36.
  14. Vangsness CT, Wagner PP, Moore T, et al., Overview of safety issues concerning the preparation and processing of softtissue allografts, Arthroscopy, 2006; 22(12):1351–8.
  15. Rougraff BT, Bone graft alternatives in the treatment of benign bone tumors, Instr Course Lect, 2005;54:505–12.
  16. Khan SN, Tomin E, Lane JM, Clinical applications of bone graft substitutes, Orthop Clin N Am, 2000;31(3):389–98.
  17. Bauer TW, Muschler GF, Bone graft materials: An overview of the basic science, Clin Orthop Rel Res, 2000;371:10–27.
  18. Albee FH, Morrison HF, Studies in bone growth: Triple calcium phosphate as a stimulus to osteogenesis, Ann Surg, 1920;71:32–6.
  19. Dreesmann H, Ueber Knochenplombierung, Bietr Klin Chir, 1892;9:804–10.
  20. Perry CR, Bone repair techniques, bone graft, and bone graft substitutes, Clin Orthop Rel Res, 1999;360:71–86.
  21. Peltier LF, Jones RH, Treatment of unicameral bone cysts by curettage and packing with plaster-of-Paris pellets, J Bone Joint Surg Am, 1978;60:820–2.
  22. Russel TA, Making sense of bone graft alternatives—calcium phosphate cements and calcium sulfates, AAOS annual meeting ICL, New Orleans, LA, March 9–13, 2010.
  23. Sidqui M, Collin P, Vitte C, et al., Osteoblast adherence and resorption activity of isolated osteoclasts on calcium sulphate hemihydrate, Biomaterials, 1995;16:1327–32.
  24. Walsh WR, Morberg P, Yu Y, et al., Response of a calcium sulfate bone graft substitute in a confined cancellous defect, Clin Orthop Rel Res, 2003;406:228–36.
  25. Turner TM, Urban RM, Gitelis S, et al., Resorption evaluation of a large bolus of calcium sulfate in a canine medullary defect, Orthopedics, 2003;26(5 Suppl.):s577–9.
  26. Turner TM, Urban RM, Gitelis S, et al., Radiographic and histologic assessment of calcium sulfate in experimental animal models and clinical use as a resorbable bone-graft substitute, a bone-graft expander, and a method for local antibiotic delivery, J Bone Joint Surg Am, 2001;83-A (Suppl. 2 Pt 1):8–18.
  27. Urban RM, Turner TM, Hall DJ, et al., Healing of large defects treated with calcium sulfate pellets containing demineralized bone matrix particles, Orthopedics, 2003;26(5 Suppl.):s581–5.
  28. Urban RM, Turner TM, Hall DJ, et al., Effects of altered crystalline structure and increased initial compressive strength of calcium sulfate bone graft substitute pellets on new bone formation, Orthopedics, 2004;27(1 Suppl.):s113–8.
  29. Borelli J, Prickett WD, Ricci WM, Treatment of nonunions and osseous defects with bone graft and calcium sulfate, Clin Orthop Relat Res, 2003;411:245–54.
  30. McKee MD, Wild LM, Schemitsch EH, et al., The use of an antibiotic-impregnanted, osteoconductive, bioabsorbable bone subtitutes in the treatment of infected long bone defects: Early results of a prospective trial, J Orthop Trauma, 2002;16(9):622–7.
  31. Helgeson MD, Potter BK, Tucker CJ, et al., Antibioticimpregnated calcium sulfate use in combat-related open fractures, Orthopedics, 2009;32(5):323.
  32. Mirzayan R, Panossian V, Avedian R, et al., The use of calcium sulfate in the treatment of benign bone lesions: a preliminary report, J Bone Joint Surg Am, 2001;83:355–8.
  33. Gitelis S, Piasecki P, Turner T, et al., Use of a calcium sulfatebased bone graft substitute for benign bone lesions, Orthopedics, 2001;24(2):162–6.
  34. Gitelis S, Virkus W, Anderson D, et al., Functional outcome of bone graft substitutes for benign bone lesions, Orthopedics, 2004;27(1):S141–4.
  35. Kelly CM, Wilkins RM, Treatment of benign bone lesions with an injectable calcium sulfate-based bone graft substitute, Orthopedics, 2004;27(Suppl. 1):s131–5.
  36. Dormans JP, Sankar WN, Moroz L, et al., Percutaneous intramedullary decompression, curettage, and grafting with medical-grade calcium sulfate pellets for unicameral bone cysts in children, J Pediatr Orthop, 2005;25:804–11.
  37. Mik G, Arkader A, Manteghi A, et al., Results of a minimally invasive technique for treatment of unicameral bone cysts, Clin Orthop Rel Res, 2009;467:2949–54.
  38. Robinson D, Alk D, Sandbank J, et al., Inflammatory reactions associated with a calcium sulfate bone substitute, Ann Transplant, 1999;4(3-4):91–7.
  39. Lee GH, Khoury JG, Bell JE, et al., Adverse reactions to OsteoSet bone graft substitute, the incidence in a consecutive series, Iowa Orthop J, 2002;22:35–8.
  40. Nystron L, Raw R, Buckwalter J, et al., Acute intraoperative reactions during the injection of calcium sulfate bone cement for the treatment of unicameral bone cysts: a review of four cases, Iowa Orthop J, 2008;28:81–4.
  41. Wright JG, Swiontkowski, MF, Heckman JD, Introducing levels of evidence to the journal, J Bone Joint Surg Am, 2003;85-A:1–3.
  42. Kelly CM, Wilkins RM, Gitelis S, et al., The use of surgical grade calcium sulfat as a bone graft substitute: Results of multicenter trial, Clin Orthop Rela Res, 2001;382:42–50.
  43. Petruskevicius J, Nielsen S, Kaalund S, et al., No effect of Osteoset ®, a bone graft substitute, on bone healing in humans: A prospective randomized double-blind study, Acta Orthop Scand, 2002;73(5):575–8.
  44. Bucholz RW, Nonallograft osteoconductive bone graft substitutes, Clin Orthop Rel Res, 2002;395:44–52.
  45. Holmes R, Mooney V, Bucholz R, et al., A coralline hydroxyapatite bone graft substitute: Preliminary report, Clin Orthop Relat Res, 1984;188:252–62.
  46. Holmes RE, Bucholz RW, Mooney V, Porous hydroxyapatite as a bone-graft substitute in metaphyseal defects: A histometric study, J Bone Joint Surg Am, 1986;68:904–11.
  47. Martin RB, Chapman MW, Sharkey NA, et al., Bone ingrowth and mechanical properties of coralline hydroxyapatite one year after implantation, Biomaterials, 1993;14:341–7.
  48. Shors E, Holmes R, Bone formation in porous hydroxyapatite obtained from human biopsies, Bioceramics, 1993;6:375–9.
  49. Inoue O, Ibaraki K, Shimabukuro H, et al., Packing with highporosity hydroxyapatite cubes alone for the treatment of simple bone cyst, Clin Orthop Relat Res, 1993;293:287–92.
  50. Natarajan M, Dhanapal R, Kumaravel S, et al., The use of bovine calcium-hydroxy-apatite in filling defects following curettage of benign bone tumours, Indian J Orthop, 2003;37:192–4.
  51. Reddy R, Swamy M, The use of hydroxyapatite as a bone graft substitute in orthopaedic conditions, Indian J Orthop, 2005;39:52–4.
  52. Uchida A, Araki N, Shinto Y, et al., The use of calcium hydroxyapatite ceramic in bone joint tumour surgery, J Bone Joint Surg (Br), 1990;72:298–302.
  53. Matsumine A, Myoui A, Kusuzaki K, et al., Calcium hydroxyapatite ceramic implants in bone tumour surgery. A long-term follow-up study, J Bone Joint Surg Br, 2004;86(5): 719–25.
  54. Irwin RB, Bernhard M, Biddinger A, Coralline hydroxyapatite as bone substitute in orthopedic oncology, Am J Orthop (Belle Mead NJ), 2001;30(7):544–50.
  55. Bucholz, RW, Carlton A, Holmes R, Interporous hydroxyapatite as a bone graft substitute in tibial plateau fractures, Clin Orthop Rel Res, 1989;240:53–62.
  56. Dickson KF, Freidman J, Bucholz JG, et al., The use of BoneSource hydroxyapatite cement for traumatic metaphyseal bone void filling, J Trauma, 2002;53:1103–8.
  57. Wiltfang J, Merten MA, Schlegel KA, et al., Degradation characteristics of alpha and beta tri-calcium-phosphate (TCP) in minipigs, J Biomed Mater Res, 2002;63:115–21.
  58. Jarcho M, Calcium phosphate ceramics as hard tissue prosthetics, Clin Orthop, 1981;157:259–78.
  59. Ducheyne P, Radin S, King L, The effect of calcium phosphate ceramic composition and structure on in vitro behavior. I. Dissolution, J Biomed Mater Res, 1993;27:25–34.
  60. Klein CPAT, de Blieck-Hogervorst JMA, Wolke JGC, et al., Studies of the solubility of different calcium phosphate ceramic particles in vitro, Biomaterials, 1990;11:509–12.
  61. LeGeros RZ, Biodegradation and bioresorption of calcium phosphate ceramics, Clin Mater, 1993;14:65–88.
  62. Moore WR, Graves SE, Bain GI, Synthetic bone graft substitutes, ANZ J Surg, 2001;71:354–61.
  63. Uchida A, Nade S, McCartney ER, et al., The use of ceramics for bone replacement. A comparative study of three different porous ceramics, J Bone Joint Surg (Br), 1984:66:269–75.
  64. Fredericks DC, Bobst JA, Petersen EB, et al., Cellular interactions and bone healing responses to a novel porous tricalcium phosphate bone graft material, Orthopedics, 2004;27(1 Suppl.):s167–73
  65. Bucholz RW, Carlton A, Holmes RE, Hydroxyapatite and tricalcium phosphate bone graft substitutes, Orthop Clin North Am, 1987;18(2):323–34.
  66. Altermatt S, Schwöbel M, Pochon JP, Operative treatment of solitary bone cysts with tricalcium phosphate ceramic. A 1 to 7 year follow-up, Eur J Pediatr Surg, 1992;2(3):180–2.
  67. Saikia K, Bhattacharya T, Bhuyan S, et al., Calcium phosphate ceramics as bone graft substitutes in filling bone tumor defects, Indian J Orthop, 2008;42(2):169–72.
  68. Nicholas RW, Lange TA, Granular tricalcium psphate grafting in cavitary lesions in human bone, Clin Orthop Rel Res, 1994;306:197–203.
  69. Hirata M, Murata H, Takeshita H, et al., Use of purified betatricalcium phosphate for filling defects after curettage of benign bone tumours, Int Orthop, 2006;30:510–3.
  70. Galois L, Mainard D, Delagoutte JP, Beta-tricalcium phosphate ceramic as a bone substitute in orthopaedic surgery, Int Orthop, 2002;26:109–15.
  71. Ogose A, Hotta T, Kawashima H, et al., Comparison of hydroxyapatite and beta tricalcium phosphate as bone substitute after excision of bone tumors, J Biomed Mater Res B Appl Biomater, 2005;72:94–101.
  72. Hinz P, Wolf E, Schwesinger G, et al., A new resorbable bone void filler in trauma: Early clinical experience and histologic evaluation, Orthopedics, 2002;25(5):s597–600.
  73. Siegel HJ, Baird RC 3rd, Hall J, et al., The outcome of composite bone graft substitute used to treat cavitary bone defects, Orthopedics, 2008;31(8):754.
  74. Anker CJ, Holdridge SP, Baird B, et al., Ultraporous betatricalcium phosphate is well incorporated in small cavitary defects, Clin Orthop Relat Res, 2005;434:251–7.
  75. Saini S, Muschler G, McGlohorn J, The Effect of Bone Graft Architecture on Bone Formation in a Canine Defect Model, Orthopaedic Research Society, Chicago, IL, 2006.
  76. Hyer CF, Philbin TM, Berlet GC, et al., Bone void filler in hindfoot and ankle arthrodesis procedures: A prospective study of 18 fusions, American Orthopedic Foot and Ankle Society Summer Meeting, Boston, MA, July 15–17, 2005.
  77. Jansen J, Ooms E, Verdonschot N, et al., Injectable calcium phosphate cement for bone repair and implant fixation, Orthop Clin N Am, 2005;36:89–95.
  78. Goodman SB, Bauer TW, Carter D, et al., Norian SRS cement augmentation in hip fracture treatment: laboratory and initial clinical results, Clin Orthop, 1998;348:42–50.
  79. Frankenburg EP, Goldstein SA, Bauer TW, et al., Biomechanical and histological evaluation of calcium phosphate cement, J Bone Joint Surg Am, 1998;80:1112–24.
  80. Trenholm A, Landry S, McLaughlin K, et al., Comparative fixation of tibial plateau fractures using a-BSM, a calcium phosphate cement, versus cancellous bone graft, J Orthop Trauma, 2005;19:698–702.
  81. Cassidy C, Jupiter JB, Cohen M, et al., Norian SRS cement compared with conventional fixation in distal radius fractures: A randomized study, J Bone Joint Surg Am, 2003;85-A(11):2127–37.
  82. Sanchez-Sotelo J, Munuera L, Madero R, Treatment of fractures of the distal radius with a remodellable bone cement: A prospective, randomized study using Norian SRS, J Bone Joint Surg (Br), 2000;82:856–63.
  83. Schildhauer TA, Bauer TW, Josten C, et al., Open reduction and augmentation of internal fixation with an injectable skeletal cement for the treatment of complex calcaneal fractures, J Orthop Trauma, 2000;14:309–17.
  84. Lobenhoffer P, Gerich T, Witte F, et al., Use of injectable calcium phosphate cement in the treatment of tibial plateau fractures: A prospective study of twenty-six cases with twenty month mean follow-up, J Orthop Trauma, 2002;16:143–9.
  85. Mattsson P, Larsson S, Calcium phosphate cement for augmentation did not improve results after internal fixation of displaced femoral neck fractures: a randomized study of 118 patients, Acta Orthop, 2006;77(2):251–6.
  86. Mattsson P, Alberts A, Dahlberg G, et al., Resorbable cement for the augmentation of internally-fixed unstable trochanteric fractures. A prospective, randomised multicentre study, J Bone Joint Surg (Br), 2005;87(9):1203–9.
  87. Mattsson P, Larsson S, Unstable trochanteric fractures augmented with calcium phosphate cement. A prospective randomized study using radiostereometry to measure fracture stability, Scand J Surg, 2004;93(3):223–8.
  88. Mattsson P, Larsson S, Stability of internally fixed femoral neck fractures augmented with resorbable cement:A prospective randomized study using radiostereometry, Scand J Surg, 2003;92:215–9.
  89. Dickson KF, Friedman J, Bucholz JG, et al., The use of BoneSource hydroxyapatite cement for traumatic metaphyseal bone void filling, J Trauma, 2002;53:1103–8.
  90. Russell TA, Ross K, Comparison of autogenous bone graft and endothermic calcium cement for defect augmentation in tibial plateau fractures, Bone Joint Surg Am, 2008;90:2057–61.
  91. Johal HS, Buckley RE, Li IL, et al., A prospective randomized controlled trial of a bioresorbable calcium phosphate paste (Alpha-BSM) in displaced intra-articular calcaneal fractures, J Trauma, 2009;67(4):875–82.
  92. Bajammal SS, Zlowodzki M, Lelwica A, et al., The use of calcium phosphate bone cement in fracture treatment. A meta-analysis of randomized trials, J Bone Joint Surg Am, 2008;90(6):1186–96.
  93. Chapman MW, Bucholz R, Cornell C, A randomized clinical trial, J Bone Joint Surg Am, 1997;79(4):495–502.
  94. Pietak AM, Reid JW, Stott MJ, et al., Silicon substitution in the calcium phosphate bioceramics, Biomaterials, 2007;28(28): 4023–32.
  95. Bohner M, Silicon-substituted calcium phosphates – a critical view, Biomaterials, 2009;30(32):6403–6.
  96. Hing KA, Wilson LF, Buckland T, Comparative performance of three ceramic bone graft substitutes, Spine J, 2007;7(4): 475–90.
  97. Fellah BH, Weiss P, Gauthier O, et al., Bone repair using a new injectable self-crosslinkable bone substitute, J Orthop Res, 2006;24(4):628–35.
  98. Urban RM, Turner TM, Hall DJ, et al., An injectable calcium sulfate-based bone graft putty using hydroxypropylmethycellulose as the plasticizer, Orthopedics, 2004:27(1 Suppl.):s155–59.
  99. Moore D, Chapman M, Marske D, The evaluation of a biphasic calcium phosphate ceramic for use in grafting long bone defects, J Orthop Res, 1987;5:356–65.
  100. Urban RM, Turner TM, Hall DJ, et al., Increased bone formation using calcium sulfate-calcium phosphate composite graft, Clin Orthop Relat Res, 2007;459:110–7.
  101. Schindler OS, Cannon SR, Briggs TWR, et al., Composite ceramic bone graft substitute in the treatment of locally aggressive benign bone tumours, J Orthop Surg (Hong Kong), 2008;16(1):66–74.
  102. Yamamoto T, Onga T, Marui T, et al., Use of hydroxyapatite to fill cavities after excision of benign bone tumours. Clinical results, J Bone Joint Surg (Br), 2000;82(8):1117–20.
  103. El-Adl G, Mostafa MF, Enan A, et al., Biphasic ceramic bone substitute mixed with autogenous bone marrow in the treatment of cavitary benign bone lesions, Acta Orthop Belg, 2009;75(1):110–8.
  104. Sartoris DJ, Holmes RE, Resnick D, Coralline hydroxyapatite bone graft substitutes: radiographic evaluation, J Foot Surg, 1992;31(3):301–13.
  105. McAndrew MP, Gorman PW, Lange TA, Tricalcium phosphate as a bone graft substitute in trauma: preliminary report, J Orthop Trauma, 1988;2(4):333–9.
  106. Habibovic P, Kruyt MC, Juhl MV, et al., Comparative in vivo study of six hydroxyapatite-based bone graft substitutes, J Orthop Res, 2008;26:1363-70.
Keywords: Mineral ceramic bone graft substitute, bone defect, bone void