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Bone morphogenetic protein

Bone morphogenetic proteins (BMPs) constitute a subfamily of signaling molecules within the transforming growth factor-β (TGF-β) superfamily, characterized by their capacity to induce ectopic bone and cartilage formation through the regulation of cellular differentiation, proliferation, and apoptosis.^[1] First identified in 1965 by Marshall R. Urist, who demonstrated that demineralized bone matrix implanted in extraskeletal sites could stimulate osteogenesis via soluble proteinaceous factors, BMPs were later purified and cloned in the 1980s and 1990s, revealing over 20 distinct members with pleiotropic functions in embryonic development, tissue homeostasis, and repair.^[2]^[3] In developmental biology, BMPs orchestrate key processes such as dorsoventral axis formation, limb bud patterning, and organogenesis by binding to type I and type II serine/threonine kinase receptors, activating intracellular SMAD-dependent and non-SMAD pathways that modulate gene expression.^[4] Beyond skeletogenesis, they influence vascularization, immune responses, and neural stem cell fate, underscoring their broad regulatory roles across physiological systems.^[5] Clinically, recombinant human BMP-2 (rhBMP-2) and BMP-7 (rhBMP-7) have been approved for applications in spinal fusion, long bone non-unions, and oral-maxillofacial reconstruction, offering alternatives to autografts by enhancing fusion rates and reducing donor-site morbidity, though evidence from randomized trials indicates variable efficacy dependent on carrier systems and dosing.^[6]^[7] Despite these advances, BMP use has generated controversies, particularly with rhBMP-2 in anterior cervical spine procedures, where post-marketing surveillance revealed elevated risks of adverse events including retrograde ejaculation, dysphagia, and heterotopic ossification, prompting FDA warnings and refined indications to mitigate off-label overuse driven by industry promotion.^[6]^[8] Ongoing research emphasizes dose optimization, biomaterial carriers, and combination therapies to balance osteoinductive potency against tumorigenic potential and inflammatory responses observed in preclinical models.^[5]

Discovery and History

Initial Identification and Characterization

In 1965, orthopedic surgeon Marshall R. Urist conducted experiments implanting demineralized bone matrix (DBM)—prepared by acid extraction to remove minerals—into ectopic sites such as rodent muscle pouches and subcutaneous tissues, resulting in the induction of heterotopic cartilage and bone formation from host mesenchymal cells.^[9] This demonstrated that non-collagenous, thermostable protein components within the bone matrix possessed osteoinductive properties, capable of recruiting and differentiating local cells into chondro-osseous tissues without prior osteogenic potential in those sites.^[10] Urist termed these factors "bone morphogenetic protein" (BMP), establishing through serial extractions and bioassays that the activity resisted collagenase digestion but was sensitive to proteases, confirming its proteinaceous nature.^[11] Purification efforts in the 1970s and 1980s proved challenging due to the trace quantities of BMPs (nanogram levels per kilogram of bone) amid complex matrix proteins, necessitating iterative biochemical fractionation techniques including guanidine hydrochloride extraction, gel filtration, ion-exchange chromatography, and hydroxyapatite adsorption, guided by ectopic implantation bioassays in rodents to track osteoinductive potency.^[12] These methods yielded partially purified fractions enriched for activity, often in the 15-30 kDa range, but full isolation remained elusive owing to heterogeneity, aggregation, and loss of bioactivity during processing, with yields as low as 0.1-1% recovery.^[13] By the mid-1980s, such preparations confirmed multiple BMP species via dissociable subunits and dose-response curves in assays measuring alkaline phosphatase induction and mineralized nodule formation.^[14] The molecular characterization advanced in the late 1980s through genomic approaches; in 1988, John Wozney's group at Genetics Institute isolated cDNAs encoding BMP-2 (initially termed BMP-2A and BMP-2B, later unified as BMP-2 and BMP-4 variants) from a bovine bone matrix-derived library, using oligonucleotide probes based on partial N-terminal sequences from purified fractions and expression in mammalian cells to verify osteoinductive function. Sequence analysis revealed seven conserved cysteine residues and structural homology to the transforming growth factor-β (TGF-β) superfamily, positioning BMPs as dimeric signaling molecules with a TGF-β-like fold, distinct from earlier assumptions of simple matrix-bound factors.^[15] Concurrently, BMP-7 (also known as osteogenic protein-1 or OP-1) was cloned via similar strategies from human and rodent sources, exhibiting comparable inductive potency in ectopic assays and reinforcing the superfamily linkage through shared receptor-binding motifs.^[16] These findings shifted focus from empirical fractionation to genetic definition, enabling targeted functional studies.^[17]

Development of Recombinant Forms

Advancements in recombinant DNA technology during the 1990s enabled the cloning and expression of human BMP genes, facilitating the production of recombinant human BMPs (rhBMPs) in Chinese hamster ovary (CHO) cells to yield sufficient quantities of purified proteins free from the impurities and variability inherent in bone-derived extracts.^[18]^[19] Genetics Institute (later acquired by Wyeth and then Pfizer) developed rhBMP-2, while Creative BioMolecules advanced rhBMP-7, marking a shift toward scalable, human-sequence proteins for therapeutic applications.^[20] These efforts culminated in regulatory milestones, with rhBMP-7 (OP-1 Putty) receiving U.S. Food and Drug Administration (FDA) approval through a Humanitarian Device Exemption on April 27, 2001, for use in recalcitrant long bone nonunions as an alternative to autograft.^[21] Similarly, rhBMP-2 (INFUSE Bone Graft) gained FDA premarket approval on July 2, 2002, for anterior lumbar interbody fusion procedures, allowing it to serve as a bone graft substitute in spinal surgery.^[22] Expansion into dental indications followed, with rhBMP-2 (INFUSE) receiving FDA approval on March 9, 2007, for maxillary sinus augmentation to increase bone volume prior to implant placement, demonstrating the versatility of recombinant forms in augmenting deficient alveolar ridges without donor-site morbidity.^[23]^[24] These approvals underscored the biotechnological progress in engineering BMPs for precise clinical dosing and reduced risks compared to heterogeneous natural preparations.^[25]

Molecular Structure and Classification

Structural Features

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β (TGF-β) superfamily and are secreted as disulfide-linked homo- or heterodimers, with the mature dimer exhibiting a molecular weight of approximately 30 kDa.^[4] Each monomer adopts a compact fold stabilized by a characteristic cysteine-knot motif, wherein six conserved cysteine residues form three intramolecular disulfide bonds that interlock β-strands into a rigid cystine-knot core.^[26] This motif, evolutionarily conserved across the TGF-β superfamily, ensures structural integrity against proteolytic degradation and maintains the bioactive conformation necessary for receptor engagement.^[27] BMPs are initially synthesized as inactive proproteins, comprising an N-terminal pro-domain and a C-terminal mature domain, with the pro-domain facilitating proper folding, dimerization, and intracellular trafficking.^[28] Proteolytic cleavage by furin-like proprotein convertases occurs at a consensus site (RXXR) adjacent to the mature domain, releasing the active dimer while the pro-domain may remain non-covalently associated in some cases to regulate latency or bioavailability.^[29] Variations in cleavage efficiency or sites can yield distinct ligand forms with altered receptor affinities, underscoring the pro-domain's role in modulating maturation precision.^[30] Post-translational modifications, such as N-linked glycosylation predominantly in the pro-domain, influence processing kinetics and dimer stability, though the mature domain typically lacks extensive glycosylation to preserve receptor-binding epitopes.^[31] Crystal structures, exemplified by human BMP-2 resolved at 2.7 Å resolution in 1999, delineate the dimeric architecture as an open "butterfly" shape with a central intermolecular disulfide bond and exposed convex surfaces. These structures highlight distinct epitopes—the "wrist" region for type II receptor interaction and the "knuckle" (or finger) region for type I receptor binding—facilitating high-affinity heterotetrameric complex formation without delving into downstream signaling.^[32]

Types and Subfamilies

Bone morphogenetic proteins (BMPs) form a subgroup within the transforming growth factor-β (TGF-β) superfamily, with approximately 20 members in mammals identified based on structural and functional similarities.^[33] These proteins are classified into distinct subfamilies primarily by amino acid sequence homology, which correlates with shared receptor binding preferences and biological roles.^[34] The major subfamilies include BMP-2/4, BMP-5/6/7/8, BMP-9/10, and growth differentiation factors (GDFs) such as GDF-5/6/7 (also denoted as BMP-14/12/13).^[35] The BMP-2/4 subfamily exhibits about 80% sequence identity and is notable for its potent osteoinductive properties, promoting bone formation in experimental models.^[36] In contrast, the BMP-5/6/7/8 group shares around 90% homology among BMP-5, -6, and -7, and is associated with chondrogenesis and cartilage maintenance.^[37] The BMP-9/10 subfamily demonstrates roles in vascular development and homeostasis, while GDF-5/6/7 members contribute to skeletal joint formation, though some GDFs exhibit context-dependent inhibitory effects on certain BMP signaling pathways.^[38] These groupings reflect evolutionary conservation, with human BMP-2/4 serving as orthologs to decapentaplegic (dpp) in Drosophila melanogaster, which regulates patterning in fly embryogenesis and imaginal discs.^[39] Expression patterns further distinguish subfamily members, underscoring tissue-specific functions. BMP-2 is predominantly expressed in osteoblasts, supporting bone matrix production and mineralization.^[40] BMP-7, conversely, shows highest expression in the kidney among adult tissues, influencing renal development and repair processes.^[41] Such differential localization highlights the subfamilies' specialized contributions to developmental and homeostatic processes across vertebrates.^[42]

Biological Functions and Mechanisms

Signaling Pathways

Bone morphogenetic proteins (BMPs) primarily transduce signals through heteromeric receptor complexes consisting of type I and type II serine/threonine kinase receptors.^[1] Type II receptors, such as BMPR-II, ActR-IIA, and ActR-IIB, exhibit constitutive kinase activity and initially bind BMP ligands with low affinity; this binding recruits and activates type I receptors, including ALK1, ALK2, ALK3, and ALK6, which are specific to BMP signaling.^[43] Upon ligand-induced oligomerization, the type II receptor phosphorylates the type I receptor's glycine-serine (GS) domain, relieving autoinhibition and enabling the type I kinase to phosphorylate receptor-regulated SMAD proteins (R-SMADs), particularly SMAD1, SMAD5, and SMAD8.^[44] Phosphorylated R-SMADs then form heteromeric complexes with the common mediator SMAD4, translocating to the nucleus to regulate transcription of target genes, such as Runx2 in osteogenic differentiation contexts.^[45] This canonical SMAD-dependent pathway has been empirically validated through receptor binding assays and SMAD phosphorylation studies in cell models, as well as knockout phenotypes in mice demonstrating disrupted BMP-responsive gene expression.^[1] In addition to the canonical pathway, BMPs activate non-canonical signaling cascades independent of SMADs, often modulating cell proliferation, migration, and cytoskeletal dynamics.^[46] These include activation of the MAPK/ERK pathway via receptor recruitment of TRAF6 and TAK1, leading to downstream phosphorylation of ERK1/2, which influences cellular differentiation versus proliferation balance.^[47] Parallel non-canonical routes involve PI3K/AKT signaling, where BMP receptor complexes stimulate PI3K to produce PIP3, activating AKT and promoting survival or anti-apoptotic effects, as observed in mesenchymal cell lines.^[46] Evidence from phosphoproteomic analyses and inhibitor studies confirms these pathways' roles, with MAPK inhibition altering BMP-induced responses in regeneration models without affecting SMAD nuclear translocation.^[48] Extracellular regulation of BMP signaling occurs via antagonists such as noggin and chordin, which directly bind BMP ligands with high affinity, preventing receptor interaction and gradient formation critical for spatial patterning.^[49] Noggin inhibits BMP2 and BMP4 by mimicking receptor epitopes to sequester dimers extracellularly, as structurally resolved by crystallography showing 1:1 or 2:1 stoichiometries.^[50] Chordin similarly antagonizes BMPs through its von Willebrand factor C domains, with cleavage by BMP1/tolloid proteases releasing bound BMPs to fine-tune signaling thresholds, a mechanism disrupted in antagonist knockout models exhibiting ectopic BMP activity.^[51] These interactions, studied via binding kinetics and embryonic patterning assays, underscore antagonists' role in modulating ligand availability without altering intracellular cascades directly.^[49]

Roles in Development and Tissue Homeostasis

Bone morphogenetic proteins (BMPs) establish gradients along the dorsoventral axis of the neural tube, directing the specification of dorsal neuronal identities through concentration-dependent signaling. In chick and mouse embryos, BMPs secreted from the roof plate and non-neural ectoderm create a ventral-to-dorsal gradient that promotes the differentiation of dorsal interneurons and roof plate cells, as evidenced by loss-of-function experiments where BMP inhibition leads to ventralization of dorsal neural progenitors.^[52]^[53] Genetic ablation of BMP receptors in mice disrupts this patterning, resulting in expanded ventral cell types and reduced dorsal populations, confirming BMPs' causal role in axis specification.^[54] In limb development, BMPs mediate interdigital apoptosis to sculpt digit separation. BMP-2, BMP-4, and BMP-7 are expressed in the interdigital mesenchyme and apical ectodermal ridge, where they induce programmed cell death by upregulating apoptotic pathways; conditional knockout of BMP signaling in mouse limb buds impairs this process, leading to soft-tissue syndactyly.^[55]^[56] These gradients oppose fibroblast growth factor (FGF) signals from the ectoderm, with BMP dominance in interdigital regions enforcing mesenchymal cell elimination, as shown in explant cultures where exogenous BMPs trigger apoptosis independently of AER-FGFs.^[57] BMP-2 and BMP-7 drive osteogenesis by committing mesenchymal stem cells (MSCs) to chondrogenic and osteogenic lineages. In vitro studies demonstrate that BMP-2 treatment of human bone marrow-derived MSCs upregulates alkaline phosphatase (ALP) activity within 7 days, a marker of early osteoblast differentiation, followed by mineralization via RUNX2 and osterix expression.^[58] BMP-7 similarly induces ALP in MSCs, promoting hypertrophy in chondroprogenitors, with knockout mice exhibiting delayed endochondral ossification and reduced trabecular bone formation.^[59]^[60] In adult kidney homeostasis, BMP-7 maintains glomerular integrity by counteracting fibrotic tendencies, preserving podocyte function and extracellular matrix balance. Endogenous BMP-7 expression in tubular epithelium inhibits TGF-β-induced epithelial-mesenchymal transition, as loss-of-function models show progressive glomerulosclerosis due to unchecked matrix deposition.^[61]^[62] BMP-6 regulates systemic iron homeostasis via hepatic hepcidin induction. Liver-specific BMP-6 expression responds to iron stores, activating SMAD signaling in hepatocytes to transcriptionally upregulate hepcidin, which suppresses ferroportin-mediated iron export; ablation studies in mice reveal hypoferremia and hepcidin deficiency, underscoring BMP-6's necessity for iron sensing and balance.^[63]^[64]

Clinical Applications

Approved Uses in Orthopedics and Dentistry

Recombinant human bone morphogenetic protein 2 (rhBMP-2), delivered via an absorbable collagen sponge (ACS) carrier as INFUSE Bone Graft, received U.S. Food and Drug Administration (FDA) approval in 2002 for use as an autograft replacement in single-level anterior lumbar interbody fusion (ALIF) procedures.^[23] Pivotal randomized controlled trials supporting this approval demonstrated radiographic fusion rates of approximately 94% at 6 months post-surgery with rhBMP-2/ACS, compared to 88% with iliac crest bone graft (ICBG) autograft, with similar clinical outcomes in pain reduction and function restoration.^[24] In 2004, the FDA expanded approval for rhBMP-2/ACS in treating acute, open tibial shaft fractures stabilized by intramedullary nailing, where randomized trials showed accelerated radiographic healing (90% union by 9 months versus 81% with standard care) without routine autograft harvest.^[65]^[66] Recombinant human bone morphogenetic protein 7 (rhBMP-7), formulated as OP-1 Implant or Putty, obtained FDA Humanitarian Device Exemption approval in 2001 for recalcitrant long bone nonunions as an alternative to autograft when autograft use is unfeasible due to patient morbidity risks.^[67] Supporting studies under this exemption reported healing rates comparable to autograft controls, with approximately 80-90% successful union in nonunions refractory to prior interventions, emphasizing its role in cases where repeat autograft harvest would be contraindicated.^[68] In dentistry, rhBMP-2/ACS gained FDA approval in 2007 for maxillary sinus floor augmentation to increase bone height for dental implant placement and for localized alveolar ridge augmentation following multiple tooth extractions, enabling implant-supported prostheses.^[69] Clinical trials for these indications confirmed new bone formation sufficient for implant stability, often reducing the volume of additional grafting materials required compared to traditional allogeneic or autogenous approaches, with implant success rates exceeding 90% at 1-year follow-up.^[25]

Off-Label and Experimental Applications

Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been used off-label in posterior spinal fusion procedures, such as transforaminal lumbar interbody fusion (TLIF), where meta-analyses indicate minimal overall improvement in fusion rates compared to standard bone grafts, though higher doses correlate with increased complication rates including radiculitis and ectopic bone formation.^[70] In posterior cervical fusions, off-label rhBMP-2 application shows no early increase in complication rates and yields similar clinical outcomes to non-BMP approaches, with fusion success rates around 85% in cohorts followed for at least one year, but prospective data highlight risks of wound complications when doses exceed 1.05 mg per level.^[71] ^[72] These uses persist despite FDA warnings on off-label risks, as some surgeons cite improved pseudarthrosis prevention in high-risk patients, though systematic reviews question net clinical benefits due to adverse events like retrograde ejaculation in lumbar cases.^[73] For cervical procedures, low-dose rhBMP-2 in anterior cervical discectomy and fusion (ACDF) has demonstrated fusion rates of 92-100% at 12 months in select studies, outperforming controls in multilevel cases, but with elevated dysphagia and hematoma risks prompting dose reductions to mitigate morbidity.^[74] Meta-analyses of two-level ACDF report rhBMP-2 enhancing fusion without significant complication differences at optimized doses, yet overall evidence from randomized trials underscores variable efficacy and harms, including soft-tissue swelling, leading to cautious adoption limited to pseudarthrosis-prone individuals.^[75] Experimental applications of BMPs extend to wound healing, where rhBMP-7 accelerates closure in diabetic mouse models by reducing inflammation and oxidative stress, achieving 20-30% faster re-epithelialization compared to controls, though human translation remains preclinical.^[76] In osteoarthritis cartilage repair, intra-articular BMP-7 shows safety in phase I trials with no serious adverse events and preliminary chondroprotective effects, while sustained-delivery formulations of BMP-2 and BMP-7 promote hyaline-like matrix in ex vivo models, but phase II data indicate modest pain relief without structural reversal in moderate knee OA.^[77] Periodontal regeneration studies demonstrate BMP-2 enhancing alveolar bone and cementum formation in defect models, with rhBMP-2 scaffolds yielding 1.5-2-fold greater defect fill than guided tissue regeneration alone in canine and rodent assays, positioning it as a candidate for intrabony defects despite limited randomized human evidence.^[78] ^[79] Market projections for BMP products, driven by rising spinal trauma incidence (projected 15% annual increase in aging populations) and demand for biologics in non-union cases, estimate global revenue reaching $2.11 billion by 2030 from $1.25 billion in 2024, reflecting expanded off-label exploration amid autograft shortages.^[80]

Safety and Risks

Observed Adverse Effects

Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been associated with ectopic bone formation in spinal fusion procedures, particularly in off-label posterior lumbar interbody fusion (PLIF) applications, where incidence rates reached 70.1% compared to 12.9% in controls without rhBMP-2.^[81] This ectopic bone can compress neural structures, resulting in radiculopathy or, in anterior cervical fusions, dysphagia due to soft tissue swelling and ossification.^[82] Heterotopic ossification, a related complication, occurs in up to 71% of rhBMP-2 cases versus 12% in iliac crest bone graft controls in select randomized controlled trials (RCTs).^[73] Inflammatory responses, including seroma and edema, are documented in post-marketing surveillance and RCTs, with sterile seroma formation reported at 1.2% in rhBMP-2 patients versus 0% in controls.^[81] Local edema with or without seroma collections affects 10-50% of cases across spinal approaches, often resolving spontaneously but contributing to transient radiculitis.^[83] Overall complication rates from rhBMP-2 in spinal fusions range from 10.7% in longitudinal assessments of over 1,200 patients to higher figures in systematic reviews estimating 10-50% depending on surgical technique.^[83] Dose-dependent risks are evident, with higher rhBMP-2 concentrations (e.g., 1.5 mg/mL) correlating with increased ectopic bone and inflammation compared to lower doses (e.g., 0.75 mg/mL).^[81] Retrograde ejaculation following anterior lumbar interbody fusion shows a sixfold increase, with rates of 7.2% versus 0.6% in non-rhBMP-2 cohorts.^[81] Osteolysis, including endplate resorption in 68-82% of affected cases, is linked to elevated doses and early graft subsidence.^[81] These effects stem from rhBMP-2's potent osteoinductive properties, which can extend beyond the implant site when dosing exceeds FDA-approved levels for on-label uses.^[73]

Contraindications and Patient Selection

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is contraindicated in patients with known hypersensitivity to rhBMP-2, bovine Type I collagen, or other formulation components, as this can precipitate allergic reactions.^[84] It is also absolutely contraindicated during pregnancy, based on animal studies demonstrating teratogenic effects including ectopic bone formation and skeletal abnormalities in fetuses exposed to rhBMP-2.^[22] Use is prohibited in skeletally immature patients under 18 years, due to insufficient long-term safety data and potential disruption of normal growth plate function from osteoinductive activity.^[85] Active or suspected malignancy represents an absolute contraindication, given evidence of BMP receptors on tumor cells and preclinical data suggesting rhBMP-2 may promote neoplastic growth via enhanced angiogenesis and proliferation signaling.^[86] ^[87] Relative contraindications include posterior approaches in the cervical spine, where proximity to neural and vascular structures heightens risks of compressive edema or heterotopic ossification, as observed in clinical reports of postoperative airway compromise and radiculopathy.^[88] Active infection at the surgical site is similarly cautioned against, owing to potential exacerbation of inflammatory cascades despite theoretical antibacterial properties of BMPs in vitro.^[86] Patient selection prioritizes skeletally mature adults without these comorbidities, with careful pharmacokinetic consideration of rhBMP-2's localized release profile to avoid systemic dissemination; doses exceeding 12 mg per spinal level correlate with elevated complication rates from overdose-induced inflammation.^[89] Recent guidelines advocate lower dosing regimens, such as 1.3–4.2 mg per level for anterior lumbar fusions, to balance osteoinduction efficacy against iatrogenic harm in comorbid profiles like obesity or vascular insufficiency, which may prolong carrier resorption and amplify off-target effects.^[74] Pre-surgical screening for malignancy history via imaging and biomarkers, alongside allergy testing, informs exclusion to minimize causal risks of unintended tissue overgrowth.^[87]

Controversies and Debates

Efficacy Challenges in Spinal Fusion

Recombinant human bone morphogenetic protein-2 (rhBMP-2) showed superior radiographic fusion rates to iliac crest bone graft (ICBG) in the pivotal 2002 Investigational Device Exemption trial for single-level anterior lumbar interbody fusion using threaded titanium cages, achieving 94.5% fusion at 24 months compared to 88.7% with autograft, alongside comparable clinical success rates but reduced donor-site morbidity.^[89] This supported FDA approval for that specific indication in 2002. However, extension to posterior lumbar interbody fusion (PLIF), transforaminal lumbar interbody fusion (TLIF), or multilevel procedures has yielded inconsistent results, with multiple randomized trials and meta-analyses demonstrating noninferiority at best and no overall clinical superiority to autograft in pain relief, function, or return to work.^[73] A 2013 systematic review of 13 randomized controlled trials encompassing over 1,000 patients found rhBMP-2 fusion rates ranging from 86% to 100% versus 70% to 90% for ICBG, yet no significant differences in patient-reported outcomes or secondary surgeries, attributing apparent radiographic edges to short-term assessments prone to selection bias in industry-sponsored studies favoring anterior approaches.^[73] In posterior and multilevel contexts, 2010s meta-analyses similarly reported equivalent fusion success (e.g., 93-96% with rhBMP-2 vs. 89-92% without in PLIF/TLIF at 24 months) but highlighted overstatement risks from trial designs excluding high-risk patients, such as smokers or those with comorbidities, which real-world registries later exposed as inflating efficacy.^[90] Medicare claims data from 2003-2008, analyzing over 400,000 fusions, indicated off-label rhBMP-2 use in 83% of cases (predominantly posterior or multilevel), with utilization peaking at 28% before declining amid scrutiny, yet no reduction in reoperations for pseudarthrosis (rates ~5-10% across groups) and higher adjusted hospital charges ($12,000 more per case) without proportional outcome gains over autograft controls.^[91] These discrepancies underscore selection bias in pivotal trials, where idealized anterior single-level cohorts underrepresented posterior complexities like hardware stress or multilevel nonunion risks (up to 20-30% without biologics), leading to overstated generalizability. FDA scrutiny of promotional materials has addressed pseudoscientific assertions of universal superiority, issuing public health notifications in 2008-2009 warning against off-label dissemination implying broad efficacy without evidence, particularly for posterior or cervical applications where complications outweighed unproven benefits; this followed Senate probes into industry influence on trial reporting and marketing, revealing undisclosed payments potentially biasing efficacy claims beyond empirical data.^[21]

Cancer Risk Assessments

Bone morphogenetic proteins (BMPs), particularly recombinant human BMP-2 (rhBMP-2), have raised theoretical concerns for oncogenicity due to their role in promoting cell proliferation and differentiation via BMP receptors expressed on various tumor cells, potentially exerting mitogenic effects that could accelerate latent malignancies.^[73] However, empirical data from large-scale human cohort studies have not substantiated an increased cancer risk. A 2023 analysis of over 100,000 patients undergoing thoracolumbar spinal fusion found that BMP exposure was associated with a relative risk (RR) of 0.89 (95% CI 0.81-0.98, p=0.02) for developing solid organ malignancies and no elevated risk for hematopoietic cancers, indicating no causal link to oncogenesis.^[92] Similarly, a 2016 case-cohort study using the SEER-Medicare database examined 15,445 elderly patients undergoing lumbar arthrodesis and reported no association between BMP use and subsequent cancer incidence or cancer-specific mortality after multivariable adjustments for confounders such as age, comorbidities, and prior malignancy.^[93] Earlier randomized controlled trial (RCT) data presented mixed signals, with a 2013 systematic review noting a short-term hazard ratio exceeding 1 for cancer events in BMP-treated groups, prompting safety scrutiny.^[73] These findings, however, were limited by small sample sizes, short follow-up periods, and potential confounding by indication, and subsequent large-database analyses with longer observation windows and risk adjustments have consistently failed to replicate an association, suggesting overinterpretation of early signals.^[93] Animal models further support a favorable profile, showing no tumorigenicity in rodents or nonhuman primates at doses equivalent to or exceeding clinical human exposures (e.g., 1.5 mg/mL rhBMP-2), with some preclinical evidence indicating BMP-2 may even suppress tumor growth in certain contexts by inducing differentiation or apoptosis in cancer stem cells.^[94] Long-term human surveillance remains essential given the latency of many cancers, but cumulative evidence from registries and cohort studies spanning over a decade post-exposure favors no clinically meaningful oncogenic risk attributable to BMPs in orthopedic applications.^[95] Ongoing pharmacovigilance through databases like Medicare and professional society registries continues to monitor for rare events, prioritizing causal inference via propensity-matched designs to distinguish BMP effects from baseline population risks.^[92]

Research Ethics and Industry Involvement

In 2011, the U.S. Senate Finance Committee, led by Senators Max Baucus and Chuck Grassley, initiated an investigation into Medtronic's recombinant human bone morphogenetic protein-2 (rhBMP-2) product Infuse, uncovering substantial financial ties between the company and clinical trial investigators.^[96] The probe revealed that Medtronic had paid approximately $210 million in consulting fees, royalties, and other compensation to 13 key physician authors involved in studies supporting Infuse's approval and promotion, with some individual surgeons receiving multimillion-dollar sums over the period.^[97] These payments raised concerns about potential conflicts of interest influencing trial reporting, as investigators with direct financial stakes in the product's success may have underemphasized adverse events such as ectopic bone formation and inflammation.^[98] The investigation further documented instances of ghostwriting, where Medtronic employees, including marketing staff, drafted or substantially edited manuscripts for peer-reviewed journals to portray Infuse favorably, before submitting them under the names of ostensibly independent physician authors.^[99] For example, internal company documents showed Medtronic personnel shaping study conclusions to highlight efficacy while minimizing risks, which were then published without disclosing the extent of corporate involvement.^[100] This practice compromised the integrity of the scientific literature used for FDA approvals and clinical guidelines, prompting calls for greater transparency in industry-sponsored research.^[101] In response to emerging safety signals from post-market surveillance, the FDA mandated label updates for Infuse in 2008, issuing a public health warning about severe complications associated with off-label use in anterior cervical spine fusions, including life-threatening airway swelling and soft tissue edema not adequately captured in pre-approval trials.^[102] Pivotal trials had underreported these events, partly attributable to industry-influenced designs that prioritized fusion rates over comprehensive adverse event tracking, leading to FDA requirements for enhanced warnings on ectopic bone growth and cancer risks in labeling revisions through 2011.^[103] Reproducibility challenges in BMP research have been highlighted by retractions of key studies, such as a 2020 meta-analysis comparing BMP to autologous grafting for long bone nonunion, which was retracted in 2021 due to unverifiable data and methodological flaws in included trials, many of which were industry-funded.^[104]^[105] This retraction exemplifies broader issues in the field, where selective reporting in sponsored studies has hindered reliable assessment of BMP's risks versus benefits, underscoring the need for independent verification of trial outcomes.^[106]

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Oct 1, 2007 · In North America, this effort was initially led by 2 biotechnology companies: Genetics Institute Inc (Boston, Mass), which developed rhBMP-2, ...
[21]
On Label and Off-Label Use of Bone Morphogenetic Proteins (BMPs)
Summary of FDA Actions on BMPs. Question Reference, Date, Infuse (rhBMP -2), OP-1 (rhBMP -7), Indications. LS, Lumbar Spine Anterior, July 2, 2002, Approved PMA ...<|separator|>
[22]
[PDF] SUMMARY OF SAFETY AND EFFECTIVENESS DATA
Jan 10, 2002 · rhBMP-2 is the active agent in the InFUSE™ Bone Graft component. ... FDA issued an approval order on July 2, 2002. The InFUSE™ Bone Graft ...
[23]
[PDF] INFUSE® Bone Graft - accessdata.fda.gov
Date of Notice of Approval of Application: March 9, 2007. II. ... rhBMP-2 is the active agent in INFUSE® Bone Graft. rhBMP-2 is a disullide-linked.
[24]
A comprehensive clinical review of recombinant human bone ... - NIH
In 2002, INFUSE® Bone Graft was approved by the US Food and Drug Administration (FDA) as a replacement for autogenous bone graft in anterior lumbar interbody ...
[25]
Current Status of Recombinant Human Bone Morphogenetic Protein ...
Aug 24, 2023 · Another noteworthy feature in the history of rhBMP-2 is the development of Escherichia-coli-produced rhBMP-2 (erhBMP-2). The widely used rhBMP-2 ...
[26]
The family of bone morphogenetic proteins - ScienceDirect
Analysis of the crystal structure of two TGF-β family members, TGF-β2 and BMP7, has revealed that the core of the monomer is a cystine knot involving six ...
[27]
Common structural traits for cystine knot domain of the TGFβ ...
Cystine-knot (CK) motif is a spatial feature of the TGFβ superfamily of proteins whereas the extra-cellular domains (ectodomains) of their respective receptors ...
[28]
Cleavages within the Prodomain Direct Intracellular Trafficking ... - NIH
Pro bone morphogenetic protein-4 (BMP-4) is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows ...
[29]
Alternative cleavage of the bone morphogenetic protein (BMP), Gbb ...
Alternative processing of BMP proproteins produces ligands that signal through different receptors and exhibit specific developmental functions.
[30]
Mutations that prevent phosphorylation of the BMP4 prodomain ...
May 29, 2025 · (2024) The prodomain of bone morphogenetic protein 2 promotes dimerization and cleavage of BMP6 homodimers and BMP2/6 heterodimers. The ...
[31]
Bone Morphogenetic Proteins (BMPs) - R&D Systems
Mature BMP segments are all assumed to form a cysteine knot with six conserved cysteine residues,7, 8, 14 and there may be an additional one to three cysteines.
[32]
3BMP: HUMAN BONE MORPHOGENETIC PROTEIN-2 (BMP-2)
Mar 12, 2000 · We report here the crystal structure of human BMP-2 determined by molecular replacement and refined to an R-value of 24.2 % at 2.7 A resolution.
[33]
Bone Morphogenetic Protein Signaling in Cancer - NIH
The BMP-2/4 group preferentially binds to ALK3 and ALK6, whereas the BMP-5/6/7/8 group mainly binds to ALK2 and ALK6. The GDF-5/6/7 (also known as BMP-12/13 ...
[34]
Relationship between molecular structure and their osteogenic activity
In 1999, Scheufler et al. [17] obtained the crystal structure of BMP-2 at 2.7 Å resolution via X-ray differentiation analysis. The structural basis of ...
[35]
Insights into Bone Morphogenetic Protein—(BMP-) Signaling in ...
Based on amino acid sequences and functional differences, the BMP subfamily is divided into different subgroups: BMP-2/4, BMP-5/6/7/8, BMP-14/13/12 (GDF5/6/7), ...
[36]
Bone morphogenetic proteins: basic concepts
The BMP protein can be broadly classified into three subfamilies.22,24,25 Both BMP-2 and BMP-4 have 80% amino acid sequence homology of molecules. In the ...
[37]
Bone Morphogenetic Protein | BMP 2 | BMP 7 | GDF5 - Prospec Bio
From a high degree of amino acid sequence homology (approximately 90 %), BMP5, BMP6, and BMP7 are recognized as a distinct subfamily of the BMPs. Sequence ...Missing: classification | Show results with:classification
[38]
BMP signaling in vascular diseases - ScienceDirect.com
Jul 4, 2012 · The BMP subfamily can be further subdivided into several subgroups, including BMP-2/4, BMP-5/6/7/8, GDF-5/6/7 and BMP-9/10 [4], [5]. BMPs are ...
[39]
Decapentaplegic - Society for Developmental Biology
Aug 25, 2025 · The Drosophila BMP 2/4 homologue Decapentaplegic (Dpp) acts as a morphogen to regulate diverse developmental processes, including wing morphogenesis.
[40]
The Role Of BMPs in the Regulation of Osteoclasts Resorption and ...
Apr 26, 2022 · It is known that BMP2 and -7 increase osteoblastic differentiation markers (34, 90), and that BMP signaling promotes chondrocyte differentiation ...
[41]
Bone morphogenetic protein-7 expression and activity in the human ...
Aug 2, 2006 · In the adult, BMP-7 is most strongly expressed in the kidney compared to other organs, but the exact expression pattern as well as the function ...
[42]
BMP signaling in telencephalic neural cell specification and ...
BMPs can be further classified into at least four subgroups: BMP-2/4 group, BMP-5/6/7/8 group, growth and differentiation factor-5,-6,-7 (GDF-5/6/7) group, and ...
[43]
Bone morphogenetic protein receptors: Structure, function and ...
Bone morphogenetic proteins (BMPs) are secreted cytokines that control the fate and function of many different cell types. They exert their cellular ...
[44]
Bone morphogenetic protein signaling: the pathway and its regulation
Dec 20, 2023 · At the heart of the BMP/TGF-β pathway explosion in the late 1980–1990s was the willingness of Drosophila researchers and those studying ...
[45]
The Smad Dependent TGF-β and BMP Signaling Pathway in Bone ...
May 4, 2021 · This article aims to review recent advances in this field, summarizing the influence of Smad on osteoblast and osteoclast function, together with Smad ...
[46]
The roles and regulatory mechanisms of TGF-β and BMP signaling ...
Jan 24, 2024 · Noggin is a twelve-membered cystine knot protein and a critical antagonist of BMP ligands in bone. ... β/bone morphogenetic protein superfamily ...Missing: cysteine | Show results with:cysteine
[47]
BMP signaling and its paradoxical effects in tumorigenesis and ... - NIH
In addition to the canonical SMAD pathway, BMPs activate the non-canonical SMAD pathways, such as phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated ...
[48]
Large-scale phosphoproteomics reveals activation of the MAPK ...
Mar 4, 2024 · These BMPs activated a non-canonical transcriptional SMAD-dependent MAPK pathway (MEKK4/P38). We were able to validate this signaling pathway ...
[49]
Noggin-mediated antagonism of BMP signaling is required for ...
Chordin also antagonizes BMP signaling by directly binding BMP proteins, thereby preventing receptor activation (Piccolo et al. 1996). Follistatin binds to ...
[50]
Nanoscale structure of the BMP antagonist chordin supports ... - PNAS
BMP signaling is regulated by a number of extracellular antagonists, which include noggin (3), the DAN family (4), and chordin (5). During embryogenesis of ...
[51]
BMP antagonists in tissue development and disease - ScienceDirect
Mechanism of BMP inhibition and release by chordin. A: Chordin binds BMP via its first and third von Willebrand factor type C (vWC) domains (orange). Likely ...
[52]
BMP signaling patterns the dorsal and intermediate neural tube via ...
Bone morphogenetic proteins (BMPs) and other transforming growth factor beta (TGFbeta) proteins are expressed by the dorsal-most cells of the neural tube (the ...
[53]
Interplay between electrical activity and bone morphogenetic protein ...
A gradient of bone morphogenetic proteins (BMPs) along the dorsoventral axis of the spinal cord is necessary for the specification of dorsal neurons.
[54]
Bone Morphogenetic Protein signaling is required in the dorsal ...
Bone morphogenetic proteins (BMPs) are a family of secreted ligands that are important regulators of dorsal neural tube development (Liu and Niswander, 2005).
[55]
BMP signals control limb bud interdigital programmed cell death by ...
Jun 15, 2007 · We conclude that during normal embryogenesis, BMP signaling to the AER indirectly regulates interdigit PCD by regulating AER-FGFs, which act as ...
[56]
BMPs are direct triggers of interdigital programmed cell death - PMC
BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling. Development 134, 2359–2368. [DOI] [PubMed] [Google Scholar] ...
[57]
BMP-2/-4 mediate programmed cell death in chicken limb buds
Dec 1, 1996 · The results shown above indicate that BMP-2/-4 function as the apoptotic signal during limb development. We next analyzed the relationship ...
[58]
BMP-2 promotes osteogenic differentiation of mesenchymal stem ...
BMP-2 promotes osteogenic differentiation of MSCs by enhancing mitochondrial activity, which is achieved by up-regulating PGC-1α.
[59]
BMP‐2 Enhances Osteogenic Differentiation of Human Adipose ...
Mar 4, 2022 · BMP2 plays a key role in the expression of osteogenic markers such as alkaline phosphatase (ALP) and osteocalcin (OC) [37, 38]. Furthermore, ...Introduction · Materials and Methods · Results · Discussion
[60]
Role of bone morphogenetic protein-2 in osteogenic differentiation ...
Jun 18, 2015 · To determine whether the early osteogenic differentiation of BMSCs was induced by BMP-2, ALP staining was performed, as previously reported (9).
[61]
Role of bone morphogenetic protein-7 in renal fibrosis - PMC
Mar 26, 2015 · A large variety of evidence shows an anti-fibrotic role of BMP-7 in chronic kidney disease, and this effect is largely mediated via counterbalancing the ...Missing: homeostasis | Show results with:homeostasis
[62]
Bone morphogenetic proteins in development and homeostasis of ...
BMPs are endogenous molecules with important functions in kidney development and postnatal kidney homeostasis. BMP-7 regulates kidney mesenchyme differentiation ...
[63]
Coordination of iron homeostasis by bone morphogenetic proteins
Together, these data suggest that tissue iron content in the liver regulates hepcidin production at least in part by regulating the production of BMP6 and BMP2 ...
[64]
Iron overload induces BMP6 expression in the liver ... - Haematologica
Conclusions Our data strongly support the importance of liver BMP6 for regulation of iron metabolism. Indeed, they demonstrate that intestinal Bmp6 expression ...
[65]
[PDF] INFUSE® Bone Graft - accessdata.fda.gov
Apr 30, 2004 · INFUSE Bone Graft is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate ...
[66]
FDA approves rhBMP-2 for orthopedic trauma patients - Healio
Jun 1, 2004 · FDA approves rhBMP-2 for orthopedic trauma patients ... “Infuse Bone Graft could rapidly become the standard of care in open tibia fractures ...
[67]
[PDF] Summary of Safety and Probable Benefit - accessdata.fda.gov
Oct 17, 2001 · OP-1 Implant is indicated for use as an alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and ...Missing: rhBMP- | Show results with:rhBMP-
[68]
Use of OP-1 (rhBMP-7) in posterolateral lumbar arthrodesis - PMC
Dec 2, 2016 · rhOP-1 has only a Humanitarian Device Exemption approval from the U.S. FDA for use in compromised patients undergoing revision ...
[69]
[PDF] 2.1 Physician Labeling - accessdata.fda.gov
Mar 8, 2007 · INFUSE® Bone Graft is now approved for two oral procedures: in sinus augmentation, and for localized alveolar ridge augmentation following tooth ...<|control11|><|separator|>
[70]
Exploratory meta-analysis on dose-related efficacy and morbidity of ...
Nov 27, 2015 · The rate of complications showed a positive correlation with the BMP dose used. Use of BMP in TLIF had only a minimal impact on fusion rates ( ...
[71]
Off-label usage of RhBMP-2 in posterior cervical fusion is ... - PubMed
Off-label usage of RhBMP-2 in posterior cervical fusion is not associated with early increased complication rate and has similar clinical outcomes. Spine J.
[72]
Off-label usage of RhBMP-2 in posterior cervical fusion is not ...
Clinical Study. Off-label usage of RhBMP-2 in posterior cervical fusion is not associated with early increased complication rate and has similar clinical ...Missing: spine | Show results with:spine
[73]
Effectiveness and Harms of Recombinant Human Bone ...
Jun 18, 2013 · In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms.
[74]
Safety and efficacy of low-dose rhBMP-2 use for anterior cervical ...
The clinical results indicating superior fusion rates using rhBMP-2 has led to increased off-label usage in patients with known risk factors for nonunion such ...
[75]
Exploratory meta-analysis on dose-related efficacy and ...
Feb 18, 2020 · Therefore, our meta-analysis showed that rhBMP-2 increased fusion rate and no significant difference of complication rate on 2-level ACDF.
[76]
Bone Morphogenetic Protein 7 Improves Wound Healing in ... - NIH
Feb 26, 2025 · Our data suggest that BMP7 enhanced skin wound healing in diabetes by decreasing local inflammation and oxidative stress.
[77]
Phase 1 safety and tolerability study of BMP-7 in symptomatic knee ...
There are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular ...
[78]
Bone Morphogenetic Proteins: Periodontal Regeneration - PMC
The aim of this review is to assess the potential role of BMPs, mechanism of action, delivery systems, and their application in the regeneration of periodontal ...
[79]
The application of bone morphogenetic proteins to periodontal ... - NIH
This review focuses on the various components of BMPs and how they may contribute to the improvement in periodontal regenerative outcomes.
[80]
Bone morphogenetic protein market size ($2.11 billion) 2030
Bone morphogenetic protein (BMP) market valued at $1.25 Bn in 2024, projected to reach $2.11 Bn by 2030 at 7.8% CAGR, says Strategic Market Research.
[81]
A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2
The rate of retrograde ejaculation after anterior lumbar surgery with the use of BMP-2 increases the frequency of retrograde ejaculation by at least sixfold, ...
[82]
Symptomatic ectopic bone formation after off-label use of ... - PubMed
Although previously believed to be only a radiographic finding, the development of ectopic bone following rhBMP-2 use in lumbar fusion can be clinicallyMissing: incidence | Show results with:incidence
[83]
Dose Adjustment Associated Complications of Bone Morphogenetic ...
A 2011 systematic review estimated complication rates of 10%–50% for all spinal fusions with rhBMP-2 depending on the approach. Complications included ...
[84]
[PDF] INFUSE Bone Graft - accessdata.fda.gov
INFUSE Bone Graft is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound ...
[85]
[PDF] AL09-13 February 20, 2009 Page 1of 5
Feb 20, 2009 · Both rhBMPs are contraindicated for all uses in patients who are skeletally immature (<18 years of age) or pregnant, and in those with a known ...
[86]
[PDF] Molina Clinical Policy Recombinant Human Bone Morphogenetic ...
Apr 13, 2022 · The key clinical trial of rhBMP-2 as part of the Food and Drug Administration (FDA) approval process consisted of 279 individuals undergoing ...
[87]
Risk of Cancer Following Lumbar Fusion Surgery With Recombinant ...
However, because BMP receptors are found on cancer cells, there is concern about potential cancer following treatment with rhBMP-2. Data from clinical trials ...
[88]
Complications due to the use of BMP/INFUSE in spine surgery
There is mounting evidence in the spinal literature that utilizing BMP/INFUSE in spinal fusions contributes to major perioperative and postoperative morbidity.FDA APPROVAL OF BMP... · UNREPORTED ADVERSE... · IMPACT OF BMP ON...
[89]
Recombinant human bone morphogenetic protein-2 in spine surgery
A systematic review and meta-analysis of lumbar fusion rates with or without the use of rhBMP-2 found significant improvement in 24-month fusion rates with use ...
[90]
A Systematic Review of Lumbar Fusion Rates with and Without the ...
Aug 6, 2025 · A systematic review further demonstrated that the use of rhBMP-2 significantly enhanced fusion rates in ALIF and PLF procedures, but not in ...<|separator|>
[91]
Prevalence, Complications, and Hospital Charges Associated With ...
Jul 1, 2009 · For anterior cervical fusions, the rate of any complication in cases that used BMP was 7.09%. This was 51.4% higher than the rate of 4.68% in ...
[92]
Bone morphogenetic protein and cancer in spinal fusion - PubMed
Sep 1, 2023 · The relative risk (RR) of developing solid organ malignancy after BMP exposure was 0.89 (95% CI 0.81-0.98, p = 0.02). Among patients without ...Missing: cohort | Show results with:cohort
[93]
Bone Morphogenetic Protein Use and Cancer Risk Among Patients ...
Jul 6, 2016 · In a large population of elderly US adults undergoing lumbar arthrodesis, BMP use was not associated with cancer risk or mortality.
[94]
BMP-2 inhibits the tumorigenicity of cancer stem cells in human ...
BMP-2 suppresses tumor growth by reducing the gene expression of tumorigenic factors and inducing the differentiation of CSCs in osteosarcoma.
[95]
Longer follow-up continues to reveal no increased risk of cancer ...
Clinical Study. Longer follow-up continues to reveal no increased risk of cancer with the use of recombinant human bone morphogenetic protein in spine fusion.
[96]
Baucus, Grassley Question Medtronic about Unreported Side Effects ...
Jun 22, 2011 · The Committee raised concerns over recent media reports that indicate medical researchers in charge of Infuse clinical trials may have been aware of and failed ...Missing: ghostwriting | Show results with:ghostwriting
[97]
Senate Panel Says Medtronic Ghostwrote Positive Medical Journal ...
Oct 25, 2012 · A Senate Finance Committee investigation also alleges that the company paid $210 million to 13 doctors who co-authored the studies.Missing: 2011 BMP
[98]
[2012-10-25] Baucus-Grassley Investigation into Medtronic Reveals ...
Oct 25, 2012 · Washington, DC – Senate Finance Committee Chairman Max Baucus (D-Mont.) and senior member Chuck Grassley (R-Iowa) today released the results ...
[99]
Senate panel says Medtronic workers ghostwrote papers
Oct 24, 2012 · Medtronic marketing employees were secretly involved in drafting and editing favorable medical journal articles about the company's ...
[100]
Senate Investigation Claims Medtronic Edited, Influenced Studies
Oct 25, 2012 · A new report released by the Senate Finance Committee slams medical device manufacturer Medtronic for allegedly ghostwriting studies used to ...Missing: 2011 BMP
[101]
Staff report on Medtronic's influence on INFUSE clinical studies
Background: On June 21, 2011, the US Senate Finance Committee staff initiated an inquiry into whether Medtronic, Inc improperly influenced peer-reviewed ...Missing: surgeons ghostwriting
[102]
Complications due to the use of BMP/INFUSE in spine surgery - NIH
Jul 9, 2013 · The safety and effectiveness of rhBMP in the cervical spine have not been demonstrated, and these products are not approved by the FDA for this ...
[103]
Complications rise along with off-label use of BMP-2 - Medical Xpress
Sep 6, 2010 · Cervical spine fusion: In July 2008, the FDA warned doctors of life-threatening complications with BMP when it was used in unapproved cervical ...Missing: rhBMP- | Show results with:rhBMP-
[104]
RETRACTED ARTICLE: Comparison of bone morphogenetic protein ...
Jul 29, 2020 · The aim of this meta-analysis was to synthetically evaluate the advantages and disadvantages of BMP plus bone grafting (observation group) ...
[105]
Retraction Note: Comparison of bone morphogenetic protein and ...
This retracts the article "Comparison of bone morphogenetic protein and autologous grafting in the treatment of limb long bone nonunion: a systematic review ...Missing: BMP | Show results with:BMP
[106]
Retraction Note: Comparison of bone morphogenetic protein and ...
May 29, 2021 · Meta-analysis of bone morphogenetic protein versus autologous bone grafting for limb long bone nonunion. Chinese Journal of Tissue Engineering ...Missing: BMP | Show results with:BMP