Published 12/1/2014
Ivan Cheng, MD; Stuart B. Goodman, MD, PhD; Philipp Leucht, MD, PhD

If Not BMP, Then What?

The safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) has recently been called into question due to concerns regarding postoperative soft-tissue swelling, the potential increased risk of retrograde ejaculation with its use in the anterior lumbar spine, and possibly an increased cancer risk.

In response to these concerns, the Yale University Open Data Access (YODA) Project recently published two independent systematic reviews on rhBMP-2. Neither group found a clinically significant difference in outcomes or complication rates between rhBMP-2 and iliac crest bone graft (ICBG) in the spine with the exception of increased immediate postoperative pain in patients receiving rhBMP-2. Cancer risk was slightly increased in patients receiving rhBMP-2 at 2 years, but the difference seemed to disappear at 4 years.

One of the YODA papers concluded that “rhBMP-2 provided little or no benefit compared to bone graft and may be associated with more harms, possibly including cancer.” The other paper concurred, noting that rhBMP-2 did not decrease pain or improve function compared to ICBG, but did increase adverse events.

Autografts and allografts
Orthopaedic surgeons need to understand all bone graft options and to present patients with these options, including the optimal one for their particular circumstances. Although ICBG represents the current “gold standard” for bone grafting, recent technological developments and a more comprehensive understanding of the biology of bone healing have provided today’s surgeons with a myriad of bone graft options.

ICBG possesses all the properties desired in a bone graft option, namely osteoconductivity, osteoinductivity, osteogenesis, and potential mechanical strength if the cortex is harvested as well. Recently, however, a multivariate analysis of the data from the American College of Surgeons National Surgical Quality Improvement Project 2010–2012 database confirmed that harvesting ICBG was associated with the need for postoperative blood transfusion (odds ratio, 1.5), extended surgical time (+ 22.0 minutes, and increased length of stay (+ 0.2 days).

Allograft bone remains an often-used bone graft substitute/extender and is second only to blood as the most commonly transplanted tissue. Allograft bone has many advantages; one of the most important is its common availability in large quantities. It can be used alone or as an adjunct to autograft bone. Further, it saves surgical time and avoids donor site morbidity as described with ICBG.

Fresh-frozen allograft bone has been used successfully in a variety of circumstances, including osteoarticular reconstruction, intercalary reconstruction, management of bone loss in total joint reconstruction, and spinal fusion.

Demineralized bone matrix (DBM) is allograft bone that has had its mineral phase removed. What remains is the organic phase, an osteoconductive composite matrix of collagen and noncollagenous proteins. Growth factors are found within this organic phase, thereby providing osteoinductive potential. DBM is available in multiple forms, including putty, gel, flexible sheets, or mixed with cortical chips.

The quantity of BMP in DBM, however, is questionable. High variability in BMP-2, BMP-7, and BMP-4 content has been found among different manufacturers and even among different lots of DBM from the same manufacturer. In addition, the absolute quantity of growth factor was on the order of 1 × 10-9 gram BMP per gram of DBM. Although prospective literature is sparse, the use of DBM has been described in hand surgery, distal radius fractures, foot and ankle arthrodesis, spinal fusion, and a variety of other orthopaedic indications.

Ceramics and CBMs
Another category of bone graft material is ceramics. Composed of tricalcium phosphate, calcium sulfate, and hydroxyapatite, or a combination thereof, ceramics have the following four characteristics:

  • tissue and mechanical compatibility
  • stability in body fluids
  • ability to withstand sterilization
  • capability to be molded into functional shapes

Although ceramics act as osteoconductive scaffolds when placed next to bone, they are neither osteogenic nor osteoinductive when used alone. Pore sizes typically range between 100 and 500 microns and are critical for the fibrovascular ingrowth of osteoid matrix. Remodeling via multinucleated, giant-cell–like cells follows mineralization of the osteoid.

In a recent meta-analysis of ceramics in lumbar spine fusion, the overall fusion rate for all ceramic products used as bone graft extenders in the lumbar spine was 86.4 percent. When ceramics were used in combination with local autograft, fusion rates were significantly higher compared with all other extenders. Bone marrow aspirate and platelet concentrates, on the other hand, resulted in significantly lower fusion rates.

As an injectable cement, calcium sulfate has been used to treat tibial plateau fractures, metaphyseal fracture defects, osteonecrosis of the femoral head, and benign bone lesions.

The last few years have seen an increased use of allogenic bone grafts containing live mesenchymal stem cells (MSCs), also known as cellular bone matrices (CBMs). In the skeletal system, MSCs are the osteogenic cells required for bone repair, remodeling, and maturation. The currently marketed CBMs bypass the U.S. Food and Drug Administration’s (FDA) premarket review process by claiming to meet FDA criteria under Section 361, 21 CFR Part 1271. (Briefly, the cellular product must be no more than minimally manipulated, must be intended for homologous use, must not be combined with another article, must not have a systemic effect, and must not be dependent on the metabolic activity of living cells for its primary function.) As a result, they are not required to undergo clinical trials to establish their safety.

The price for CBMs is comparable with, or exceeds, the price of rhBMP-2. Prospective, non-industry–sponsored studies involving CBMs have not been conducted, and concerns about both safety and efficacy have been voiced.

A plethora of options for bone graft materials exist. Although the most data regarding outcomes pertain to iliac crest autograft, the morbidity of harvesting autograft is a consideration. Allograft continues to be used in abundance. Use of demineralized bone matrices, ceramics, and cellular bone matrices is increasing, but well-designed prospective studies regarding these materials is lacking. The onus remains on healthcare providers to understand the current data and provide patients with appropriate bone graft options for their particular needs.

Ivan Cheng, MD, is an associate professor in orthopaedic surgery at the Stanford University Medical School. Stuart B. Goodman, MD, PhD, chairs the AAOS Biological Implants Committee and is a professor of orthopaedic surgery and bioengineering at Stanford. Philipp Leucht, MD, is a member of the AAOS Biological Implants Committee and is an assistant professor at New York University Hospital for Joint Diseases.

Disclosure information: Dr. Cheng—Nuvasive, Bioventus, Globus Medical, Stryker, Spinal Cyte, Spine Wave, Spine, The Spine Journal, Cervical Spine Research Society; Dr. Goodman—Integra, Accelalox, Biomimedica, DJO, Baxter, National Institutes of Health, Musculoskeletal Tumor Foundation, Coulter Foundation, Clinical Orthopaedics and Related Research, Journal of Orthopaedic Research, Biomaterials, Journal of Arthroplasty, Journal of Biomedical Material Research, Open Orthopaedics Journal, Orthopedics, Society For Biomaterials; Dr. Leucht—no conflicts.

Bottom Line

  • The YODA research has determined that the use of rhBMP-2 offers no significant advantage over the use of iliac crest bone graft.
  • Alternatives to the use of rhBMP-2 include allografts, autografts, demineralized bone matrix, ceramics, calcium sulfate cement, and cellular bone matrices.
  • Orthopaedic surgeons need to understand all bone graft options and to present patients with these options, including the optimal one for their particular circumstances.


  1. Gruskay JA, Basques BA, Bohl DD, Webb ML, Grauer JN. Short-term adverse events, length of stay, and readmission after iliac crest bone graft for spinal fusion. Spine (Phila Pa 1976). 2014;39(20):1718-24.
  2. Prolo DJ, Rodrigo JJ. Contemporary bone graft physiology and surgery. Clin Orthop Rel Res. 1985;(200):322-42.
  3. Clohisy DR, Mankin HJ. Osteoarticular allografts for reconstruction after resection of a musculoskeletal tumor in the proximal end of the tibia. J Bone Joint Surg Am. 1994;76(4):549-54.
  4. Gebhardt MC, Roth YF, Mankin HJ. Osteoarticular allografts for reconstruction in the proximal part of the humerus after excision of a musculoskeletal tumor. J Bone Joint Surg Am. 1990;72(3):334-45.
  5. Aponte-Tinao LA, Ayerza MA, Muscolo DL, Farfalli GL. Allograft reconstruction for the treatment of musculoskeletal tumors of the upper extremity. Sarcoma. 2013;2013:925413.
  6. Farfalli GL, Aponte-Tinao L, Lopez-Millan L, Ayerza MA, Muscolo DL. Clinical and functional outcomes of tibial intercalary allografts after tumor resection. Orthopedics. 2012;35(3):e391-6.
  7. Aponte-Tinao L, Farfalli GL, Ritacco LE, Ayerza MA, Muscolo DL. Intercalary femur allografts are an acceptable alternative after tumor resection. Clin Orthop Rel Res. 2012;470(3):728-34.
  8. Sheth NP, Nelson CL, Paprosky WG. Femoral bone loss in revision total hip arthroplasty: evaluation and management. J Amer Acad Ortho Surg. 2013;21(10):601-12.
  9. Sheth NP, Nelson CL, Springer BD, Fehring TK, Paprosky WG. Acetabular bone loss in revision total hip arthroplasty: evaluation and management. J Amer Acad Ortho Surg. 2013;21(3):128-39.
  10. Huten D. Femorotibial bone loss during revision total knee arthroplasty. Orthop Traumatol Surg Res. 2013;99(1 Suppl):S22-33.
  11. Miller LE, Block JE. Safety and effectiveness of bone allografts in anterior cervical discectomy and fusion surgery. Spine (Phila Pa 1976). 2011;36(24):2045-50.
  12. Vaccaro AR, Cirello J. The use of allograft bone and cages in fractures of the cervical, thoracic, and lumbar spine. Clin Orthop Rel Res. 2002;(394):19-26.
  13. Ehrler DM, Vaccaro AR. The use of allograft bone in lumbar spine surgery. Clin Orthop Rel Res. 2000;(371):38-45.
  14. Cheng I, Oshtory R, Wildstein MS. The role of osteobiologics in spinal deformity. Neurosurgery clinics of North America. 2007;18(2):393-401.
  15. Bae H, Zhao L, Zhu D, Kanim LE, Wang JC, Delamarter RB. Variability across ten production lots of a single demineralized bone matrix product. J Bone Joint Surg Am. 2010;92(2):427-35.
  16. Upton J, Glowacki J. Hand reconstruction with allograft demineralized bone: twenty-six implants in twelve patients. J Hand Surg. 1992;17(4):704-13.
  17. Whiteman D, Gropper PT, Wirtz P, Monk P. Demineralized bone powder. Clinical applications for bone defects of the hand. J Hand Surg. 1993;18(4):487-90.
  18. Ladd AL, Pliam NB. The role of bone graft and alternatives in unstable distal radius fracture treatment. The Orthopedic clinics of North America. 2001;32(2):337-51, ix.
  19. Kado KE, Gambetta LA, Perlman MD. Uses of Grafton for reconstructive foot and ankle surgery. J Foot Ankle Surg. 1996;35(1):59-66.
  20. Weinraub GM, Cheung C. Efficacy of allogenic bone implants in a series of consecutive elective foot procedures. J Foot Ankle Surg. 2003;42(2):86-9.
  21. Michelson JD, Curl LA. Use of demineralized bone matrix in hindfoot arthrodesis. Clin Orthop Rel Res. 1996;(325):203-8.
  22. Sassard WR, Eidman DK, Gray PM, et al. Augmenting local bone with Grafton demineralized bone matrix for posterolateral lumbar spine fusion: avoiding second site autologous bone harvest. Orthopedics. 2000;23(10):1059-64; discussion 64-5.
  23. Cammisa FP, Jr., Lowery G, Garfin SR, et al. Two-year fusion rate equivalency between Grafton DBM gel and autograft in posterolateral spine fusion: a prospective controlled trial employing a side-by-side comparison in the same patient. Spine (Phila Pa 1976). 2004;29(6):660-6.
  24. An HS, Simpson JM, Glover JM, Stephany J. Comparison between allograft plus demineralized bone matrix versus autograft in anterior cervical fusion. A prospective multicenter study. Spine (Phila Pa 1976). 1995;20(20):2211-6.
  25. Killian JT, Wilkinson L, White S, Brassard M. Treatment of unicameral bone cyst with demineralized bone matrix. J Ped Orthop. 1998;18(5):621-4.
  26. Geesink RG, Hoefnagels NH, Bulstra SK. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg Br. 1999;81(4):710-8.
  27. Tiedeman JJ, Garvin KL, Kile TA, Connolly JF. The role of a composite, demineralized bone matrix and bone marrow in the treatment of osseous defects. Orthopedics. 1995;18(12):1153-8.
  28. Nickoli MS, Hsu WK. Ceramic-based bone grafts as a bone grafts extender for lumbar spine arthrodesis: a systematic review. Global Spine Journal. 2014;4(3):211-6.
  29. Yu B, Han K, Ma H, et al. Treatment of tibial plateau fractures with high strength injectable calcium sulphate. International Orthopaedics. 2009;33(4):1127-33.
  30. Drosos GI, Ververidis A, Babourda EC, Kakagia D, Verettas DA. Calcium sulfate cement in contained traumatic metaphyseal bone defects. Surgical Technology International. 2012;22:313-9.
  31. Bednarek A, Atras A, Gagala J, Kozak L. Operative technique and results of core decompression and filling with bone grafts in the treatment of osteonecrosis of femoral head. Ortopedia, traumatologia, rehabilitacja. 2010;12(6):511-8.
  32. Mirzayan R, Panossian V, Avedian R, Forrester DM, Menendez LR. The use of calcium sulfate in the treatment of benign bone lesions. A preliminary report. J Bone Joint Surg Am. 2001;83-A(3):355-8.
  33. U.S Food and Drug Administration (2012, April 16). 7341.002. Inspection of human cells, tissues, and cellular and tissue-based products (HCT/Ps). Accessed September 29, 2014.
  34. Skovrlj B, Guzman JZ, Al Maaieh M, Cho SK, Iatridis JC, Qureshi SA. Cellular bone matrices: viable stem cell-containing bone graft substitutes. Spine J. 2014