Clinical use of bone morphogenetic proteins BMP-2 and BMP-7: analysis of current clinical trials

Abstract

Bone morphogenetic proteins have been used in clinical practice in orthopedics, spine surgery, and maxillofacial surgery for nearly a decade. According to research findings, in most cases the frequency of coalescence when using bone morphogenetic proteins is comparable to or higer that the corresponding indicator when using an autograft. To date, BMP-2 and BMP-7 are commercially available for clinical use and have shown efficacy equal to that of autograft in bone defect replacement.

This study analyzes existing clinical trials registered on the clinicaltirals.gov website for the therapeutic use of BMP-2 and BMP-7 in pathologies of the musculoskeletal system.

The search strategy was to use the material from the clinicaltrials.gov website, which focuses on key terms such as bonemorphogenetic protein 2 or BMP-2, bone morphogenetic protein 7 or BMP-7, recombinant bone morphogenetic protein 2 or rhBMP-2”, “recombinant bone morphogenetic protein 7 or rhBMP-7”, “InductOs”, “Op1”, “bone” and “diseases of the musculoskeletal system”. The inclusion and exclusion criteria were divided into two stages.

By October 2022, about 85 clinical trials had been registered using BMP-2 and about 12 using BMP-7. Most of the studies are in Phase 2, Phase 2–3, or Phase 4. Most of them focus on areas such as tibial trauma therapy and spinal surgery. However, only 12 clinical trials using BMP-2 provide meaningful results. All the clinical trials have similar preparation methods, and 12 clinical trials have provided positive results without serious side effects.

There is a wide potential for clinical use of BMP-2. Many preclinical and clinical studies on the use of BMP-2 and BMP-7 are currently underway; their future results will further explore their therapeutic potential in treating musculoskeletal diseases.

Keywords

bone morphogenetic protein / BMP-2 / BMP-7 / diseases of the musculoskeletal system / therapy / analysis / clinical trials

References

[1] Sampath TK, Reddi AH. Discovery of bone morphogenetic proteins — A historical perspective. Bone. 2020;140:115548. DOI: 10.1016/j.bone.2020.115548

[2] Sampath T.K., Reddi A.H. Discovery of bone morphogenetic proteins — a historical perspective // Bone. 2020. Vol. 140. P. 115548. DOI: 10.1016/j.bone.2020.115548

[3] Gomez-Puerto MC, Iyengar PV, García de Vinuesa A, et al. Bone morphogenetic protein receptor signal transduction in human disease. J Pathol. 2019;247(1):9–20. DOI: 10.1002/path.5170

[4] Gomez-Puerto M.C., Iyengar P.V., García de Vinuesa A. et al. Bone morphogenetic protein receptor signal transduction in human disease // J. Pathol. 2019. Vol. 247, No. 1. P. 9–20. DOI: 10.1002/path.5170

[5] Mukhametov UF, Lyulin SV, Borzunov DY, Gareev IF. Stimulation of bone regeneration using bone morphogenetic proteins: modern concepts. Herald of North-Western State Medical University named after I.I. Mechnikov. 2021;13(4):15–30. (In Russ.) DOI: 10.17816/mechnikov82711

[6] Мухаметов У.Ф., Люлин С.В., Борзунов Д.Ю., Гареев И.Ф. Стимуляция регенерации костной ткани с использованием костных морфогенетических белков: современные концепции // Вестник Северо-Западного государственного медицинского университета им. И.И. Мечникова. 2021. Т. 13, № 4. С. 15–30. DOI: 10.17816/mechnikov82711

[7] Mukhametov U, Lyulin S, Borzunov D, et al. Functions of the bone morphogenetic protein signaling pathway through non-coding RNAs. Noncoding RNA Res. 2022;7(3):178–183. DOI: 10.1016/j.ncrna.2022.07.002

[8] Mukhametov U., Lyulin S., Borzunov D. et al. Functions of the bone morphogenetic protein signaling pathway through non-coding RNAs // Noncoding RNA Res. 2022. Vol. 7, No. 3. P. 178–183. DOI: 10.1016/j.ncrna.2022.07.002

[9] Jain AP, Pundir S, Sharma A. Bone morphogenetic proteins: The anomalous molecules. J Indian Soc Periodontol. 2013;17(5):583–586. DOI: 10.4103/0972-124X.119275

[10] Jain A.P., Pundir S., Sharma A. Bone morphogenetic proteins: The anomalous molecules // J. Indian Soc. Periodontol. 2013. Vol. 17, No. 5. P. 583–586. DOI: 10.4103/0972-124X.119275

[11] Indjeian VB, Kingman GA, Jones FC, et al. Evolving new skeletal traits by cis-regulatory changes in bone morphogenetic proteins. Cell. 2016;164(1–2):45–56. DOI: 10.1016/j.cell.2015.12.007

[12] Indjeian V.B., Kingman G.A., Jones F.C. et al. Evolving new skeletal traits by cis-regulatory changes in bone morphogenetic proteins // Cell. 2016. Vol. 164, No. 1–2. P. 45–56. DOI: 10.1016/j.cell.2015.12.007

[13] Dumic-Cule I, Peric M, Kucko L, et al. Bone morphogenetic proteins in fracture repair. Int Orthop. 2018;42(11):2619–2626. DOI: 10.1007/s00264-018-4153-y

[14] Dumic-Cule I., Peric M., Kucko L. et al. Bone morphogenetic proteins in fracture repair // Int. Orthop. 2018. Vol. 42, No. 11. P. 2619–2626. DOI: 10.1007/s00264-018-4153-y

[15] Hinsenkamp M, Collard JF. Growth factors in orthopaedic surgery: demineralized bone matrix versus recombinant bone morphogenetic proteins. Int Orthop. 2015;39(1):137–147. DOI: 10.1007/s00264-014-2562-0

[16] Hinsenkamp M., Collard J.F. Growth factors in orthopaedic surgery: demineralized bone matrix versus recombinant bone morphogenetic proteins // Int. Orthop. 2015. Vol. 39, No. 1. P. 137–147. DOI: 10.1007/s00264-014-2562-0

[17] Son HJ, Lee MN, Kim Y, et al. Bone generation following repeated administration of recombinant bone morphogenetic protein 2. Tissue Eng Regen Med. 2021;18(1):155–164. DOI: 10.1007/s13770-020-00290-4

[18] Son H.J., Lee M.N., Kim Y. et al. Bone generation following repeated administration of recombinant bone morphogenetic protein 2 // Tissue Eng. Regen. Med. 2021. Vol. 18, No. 1. P. 155–164. DOI: 10.1007/s13770-020-00290-4

[19] Von Rüden C, Morgenstern M, Hierholzer C, et al. The missing effect of human recombinant Bone Morphogenetic Proteins BMP-2 and BMP-7 in surgical treatment of aseptic forearm nonunion. Injury. 2016;47(4):919–924. DOI: 10.1016/j.injury.2015.11.038

[20] Von Rüden C., Morgenstern M., Hierholzer C. et al. The missing effect of human recombinant Bone Morphogenetic Proteins BMP-2 and BMP-7 in surgical treatment of aseptic forearm nonunion // Injury. 2016. Vol. 47, No. 4. P. 919–924. DOI: 10.1016/j.injury.2015.11.038

[21] Poynton AR, Lane JM. Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine (Phila Pa 1976). 2002;27(16 Suppl 1):S40–48. DOI: 10.1097/00007632-200208151-00010

[22] Poynton A.R., Lane J.M. Safety profile for the clinical use of bone morphogenetic proteins in the spine // Spine (Phila Pa 1976). 2002. Vol. 27, No. 16 Suppl 1. P. S40–48. DOI: 10.1097/00007632-200208151-00010

[23] Bannwarth M, Smith JS, Bess S, et al. Use of rhBMP-2 for adult spinal deformity surgery: patterns of usage and changes over the past decade. Neurosurg Focus. 2021;50(6):E4. DOI: 10.3171/2021.3.FOCUS2164

[24] Bannwarth M., Smith J.S., Bess S. et al. Use of rhBMP-2 for adult spinal deformity surgery: patterns of usage and changes over the past decade // Neurosurg. Focus. 2021. Vol. 50, No. 6. P. E4. DOI: 10.3171/2021.3.FOCUS2164

[25] Papanagiotou M, Dailiana ZH, Karachalios T, et al. RhBMP-7 for the treatment of nonunion of fractures of long bones. Bone Joint J. 2015;97–B(7):997–1003. DOI: 10.1302/0301-620X.97B7.35089

[26] Papanagiotou M., Dailiana Z.H., Karachalios T. et al. RhBMP-7 for the treatment of nonunion of fractures of long bones // Bone Joint J. 2015. Vol. 97–B, No. 7. P. 997–1003. DOI: 10.1302/0301-620X.97B7.35089

[27] Mukhametov UF, Lyulin SV, Borzunov DYu, et al. Heterotopic ossification as a side effect of the use of recombinant human bone morphogenetic proteins. Orthopaedic Genius. 2022;28(1):123–132. (In Russ.) DOI: 10.18019/1028-4427-2022-28-1-123-132

[28] Мухаметов У.Ф., Люлин С.В., Борзунов Д.Ю. и др. Гетеротопическая оссификация как побочный эффект применения рекомбинантных человеческих костных морфогенетических белков // Гений ортопедии. 2022. Т. 28, № 1. С. 123–132. DOI: 10.18019/1028-4427-2022-28-1-123-132

[29] McGrath M, Feroze AH, Nistal D, et al. Impact of surgeon rhBMP-2 cost awareness on complication rates and health system costs for spinal arthrodesis. Neurosurg Focus. 2021;50(6):E5. DOI: 10.3171/2021.3.FOCUS2152

[30] McGrath M., Feroze A.H., Nistal D. et al. Impact of surgeon rhBMP-2 cost awareness on complication rates and health system costs for spinal arthrodesis // Neurosurg. Focus. 2021. Vol. 50, No. 6. P. E5. DOI: 10.3171/2021.3.FOCUS2152

[31] Nosho S, Ono M, Komori T, et al. Preclinical bioequivalence study of E. coli-derived rhBMP-2/β-TCP and autogenous bone in a canine guided-bone regeneration model. J Prosthodont Res. 2022;66(1):124–130. DOI: 10.2186/jpr.JPR_D_20_00226

[32] Nosho S., Ono M., Komori T. et al. Preclinical bioequivalence study of E. coli-derived rhBMP-2/β-TCP and autogenous bone in a canine guided-bone regeneration model // J. Prosthodont. Res. 2022. Vol. 66, No. 1. P. 124–130. DOI: 10.2186/jpr.JPR_D_20_00226

[33] Chen H, Yu Y, Wang C, et al. The regulatory role of sulfated polysaccharides in facilitating rhBMP-2-induced osteogenesis. Biomater Sci. 2019;7(10):4375–4387. DOI: 10.1039/c9bm00529c

[34] Chen H., Yu Y., Wang C. et al. The regulatory role of sulfated polysaccharides in facilitating rhBMP-2-induced osteogenesis // Biomater. Sci. 2019. Vol. 7, No. 10. P. 4375–4387. DOI: 10.1039/c9bm00529c

[35] Kisiel M, Ventura M, Oommen OP, et al. Critical assessment of rhBMP-2 mediated bone induction: an in vitro and in vivo evaluation. J Control Release. 2012;162(3):646–653. DOI: 10.1016/j.jconre.l.2012.08.004

[36] Kisiel M., Ventura M., Oommen O.P. et al. Critical assessment of rhBMP-2 mediated bone induction: an in vitro and in vivo evaluation // J. Control Release. 2012. Vol. 162, No. 3. P. 646–653. DOI: 10.1016/j.jconre.l.2012.08.004

[37] Khan SN, Lane JM. The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in orthopaedic applications. Expert Opin Biol Ther. 2004;4(5):741–748. DOI: 10.1517/14712598.4.5.741

[38] Khan S.N., Lane J.M. The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in orthopaedic applications // Expert. Opin. Biol. Ther. 2004. Vol. 4, No. 5. P. 741–748. DOI: 10.1517/14712598.4.5.741

[39] Bobyn J, Rasch A, Little DG, Schindeler A. Posterolateral inter-transverse lumbar fusion in a mouse model. J Orthop Surg Res. 2013;8:2. DOI: 10.1186/1749-799X-8-2

[40] Bobyn J., Rasch A., Little D.G., Schindeler A. Posterolateral inter-transverse lumbar fusion in a mouse model // J. Orthop. Surg. Res. 2013. Vol. 8. P. 2. DOI: 10.1186/1749-799X-8-2

[41] Hosseinpour S, Rad MR, Khojasteh A, Zadeh HH. Antibody administration for bone tissue engineering: a systematic review. Curr Stem Cell Res Ther. 2018;13(4):292–315. DOI: 10.2174/1574888X13666180207095314

[42] Hosseinpour S., Rad M.R., Khojasteh A., Zadeh H.H. Antibody administration for bone tissue engineering: a systematic review // Curr. Stem. Cell. Res. Ther. 2018. Vol. 13, No. 4. P. 292–315. DOI: 10.2174/1574888X13666180207095314

[43] Mukhametov UF, Liulin SV, Borzunov DYu, et al. The risk of tumor with the use of recombinant human bone morphogenetic proteins. Orthopaedic Genius. 2022;28(4):592–598. (In Russ.) DOI: 10.18019/1028-4427-2022-28-4-592-598

[44] Мухаметов У.Ф., Люлин С.В., Борзунов Д.Ю. и др. Риск развития опухолей после применения рекомбинантных человеческих костных морфогенетических белков // Гений ортопедии. 2022. Т. 28, № 4. С. 592–598. DOI: 10.18019/1028-44272022-28-4-592-598

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