Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients

Axelrad, T. William; Steen, Brandon; Lowenberg, David W.; Creevy, William R.; Einhorn, Thomas A.

doi:10.1302/0301-620x.90b12.20975

Cited by 79 publications

(41 citation statements)

References 58 publications

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“…The classical adverse effects observed and described in our patients (local swelling [18,51], heterotopic calcifications [52][53][54]) are rare, but already reported in children. We observed in one case a severe local inflammatory reaction without complication.…”

Section: Application Of Bmpsupporting

confidence: 59%

Masquelet's procedure and bone morphogenetic protein in congenital pseudarthrosis of the tibia in children: A case series and meta-analysis

Dohin

Köhler²

2012

Journal of Children's Orthopaedics

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Purpose A type 2 recombinant human bone morphogenetic protein (rhBMP2) and Masquelet's procedure were used in three children presenting with congenital pseudarthrosis of the tibia (CPT). Recent studies on CPT suggested the presence in situ of pathologic tissues promoting pseudarthrosis. The authors hypothesized that large segmental resection of pseudarthrosis could improve prognosis of the CPT. Masquelet's procedure and rhBMP2 have been advocated for the treatment of long bone defect. Method The authors report three cases of CPT in children treated with Masquelet's procedure and application of rhBMP2. They analyzed all published cases of CPT similarly treated. Results In the present study, Masquelet's procedure did not improve the results in the treatment of CPT, but segmental bone reconstruction was possible. Bone healing was obtained in three out of the five applications of rhBMP2. In one case, the patient's parents asked for leg amputation. Analysis of the 33 published cases with the application of BMP in CPT points to a 62 % healing rate in this pathology. Conclusion The authors confirmed that segmental bone reconstruction is possible in CPT using Masquelet's procedure. In the literature, the success rate of the application of rhBMP in CPT appears to be lower than the healing rate usually reported without BMP. Nevertheless, the strict selection of patients, limited number of cases, and their heterogeneity make interpreting the results difficult. However, the theoretical risk which the children are exposed to during the use of BMP makes rigorous selection of the indications necessary. Finally, the interest of rhBMP2 application in Masquelet's procedure remained to be proven.

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Section: Application Of Bmpsupporting

confidence: 59%

Masquelet's procedure and bone morphogenetic protein in congenital pseudarthrosis of the tibia in children: A case series and meta-analysis

Dohin

Köhler²

2012

Journal of Children's Orthopaedics

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“…The clinical use of growth factors has been hindered by the significantly large, and hence costly, doses needed in humans. Large doses of exogenous growth factors may cause unexpected physiological effects ranging from bone resorption (Giannoudis et al, 2007) to heterotopic ossification (Wysocki and Cohen, 2007;Axelrad et al, 2008). Hence, alternative methods for effective osteoinduction of MSCs are under investigation Kim et al, 2005;McCullen et al, 2010;Tirkkonen et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture

Tirkkonen¹,

Haimi²,

Huttunen³

et al. 2013

eCM

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Human adipose stem cells (hASCs) have been recently used to treat bone defects in clinical practice. Yet there is a need for more optimal scaffolds and cost-effective approaches to induce osteogenic differentiation of hASCs. Therefore, we compared the efficiency of bone morphogenetic proteins (BMP-2 and BMP-7), vascular endothelial growth factor (VEGF), and osteogenic medium (OM) for the osteoinduction of hASCs in 3D culture. In addition, growth factors were tested in combination with OM. Commercially available bioactive glass scaffolds (BioRestore) and biphasic calcium phosphate granules (BoneCeramic) were evaluated as prospective carriers for hASCs. Both biomaterials supported hASC-viability, but BioRestore resulted in higher cell number than BoneCeramic, whereas BoneCeramic supported more significant collagen production. The most efficient osteo-induction was achieved with plain OM, promoting higher alkaline phosphatase activity and collagen production than growth factors. In fact, treatment with BMP-2 or VEGF did not increase osteogenic differentiation or cell number significantly more than maintenance medium with either biomaterial. Moreover, BMP-7 treatment consistently inhibited proliferation and osteogenic differentiation of hASCs. Interestingly, there was no benefit from growth factors added to OM. This is the first study to demonstrate that OM enhances hASCdifferentiation towards bone-forming cells significantly more than growth factors in 3D culture.

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“…Considering the potential adverse events of BMPs, this systematic review on the treatment of bone fractures, non union, and osteonecrosis, also focused on the literature evidence of complications related to these orthopaedic conditions. The analysis of the comparative studies underlining a higher percentage of complications, showed that the majority of complications after BMPs treatment were related to heterotopic ossification, which were reported in 3 papers on fracture repair [25,29,34], in 2 papers on non union treatment [40,44], and in 1 paper on osteonecrosis [59] involving both rhBMP-2 and 7. Moreover, other described complications were infections [26,55], peripheral oedema, heterotopic ossification/soft-tissues calcification, new or increased pain [26], and the development of distal tibiofibular synostosis (1/52) described with rhBMP-7 for non-union treatment [52].…”

Section: Complicationsmentioning

confidence: 99%

Clinical application of bone morphogenetic proteins for bone healing: a systematic review

Krishnakumar

Roffi

Reale

et al. 2017

International Orthopaedics (SICOT)

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Purpose This paper documents the existing evidence on bone morphogenetic proteins (BMPs) use for the treatment of bone fractures, non-union, and osteonecrosis, through a review of the clinical literature, underlying potential and limitations in terms of cost effectiveness and risk of complications. Methods A systematic review was performed on the PubMed database using the following string: (bone morphogenetic proteins OR BMPs) and (bone repair OR bone regeneration) including papers from 2000 to 2016. The search focused on clinical trials dealing with BMPs application to favor bone regeneration in bone fractures, non-union, and osteonecrosis, in English language, with level of evidence I, II, III, and IV. Relevant data (type of study, number of patients, BMPs delivery material, dose, site, follow-up, outcome, and adverse events) were extracted and analyzed. Results Forty-four articles met the inclusion criteria: 10 randomized controlled trials (RCTs), 7 comparative studies, 18 case series, and 9 case reports. rhBMP-2 was documented mainly for the treatment of fractures, and rhBMP-7 mainly for non-unions and osteonecrosis. Mixed results were found among RCTs and comparative papers: 11 reported positive results for BMPs augmentation, 3 obtained no significant effects, and 2 showed negative results. The only study comparing the two BMPs showed a better outcome with rhBMP-2 for non-union treatment. Conclusion Clinical evidence on BMPs use for the treatment of fractures, non-union, and osteonecrosis is still controversial, with the few available reports being mainly of low quality. While positive findings have been described in many studies, mixed results are still present in the literature in terms of efficacy and adverse events. The difficulties in drawing clear conclusions are also due to the studies heterogeneity, mainly in terms of different BMPs applied, with different concomitant treatments for each bone pathology. Therefore, further research with well-designed studies is needed in order to understand the real potential of this biological approach to favour bone healing.

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Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients

Cited by 79 publications

References 58 publications

Masquelet's procedure and bone morphogenetic protein in congenital pseudarthrosis of the tibia in children: A case series and meta-analysis

Masquelet's procedure and bone morphogenetic protein in congenital pseudarthrosis of the tibia in children: A case series and meta-analysis

Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture

Clinical application of bone morphogenetic proteins for bone healing: a systematic review

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