BONE MORPHOGENETIC PROTEINS
TGF-beta Superfamily | Osteoinduction | Smad Signaling | Clinical Applications
CLINICAL BMPs
Critical Must-Knows
- BMPs are secreted growth factors in the TGF-beta superfamily
- BMP-2 and BMP-7 are osteoinductive - induce bone formation in non-skeletal sites
- Signaling via Smad pathway: BMP binds type I/II receptors, activates Smad1/5/8, induces Runx2
- Clinical use: spinal fusion, long bone nonunion, critical-size defects
- Complications: ectopic bone, inflammatory swelling, osteolysis, cost
Examiner's Pearls
- "Urist 1965 discovered BMPs by implanting demineralized bone matrix subcutaneously
- "BMP-2 is more osteogenic than BMP-7 but has higher complication risk
- "Supraphysiologic doses used clinically (mg amounts vs ng in normal healing)
- "Carrier scaffold critical - absorbable collagen sponge standard
Clinical Imaging
BMP Signaling in Bone Remodeling
Critical BMP Exam Points
Osteoinduction Definition
BMPs induce bone formation in non-skeletal sites (ectopic ossification). This distinguishes osteoinduction from osteoconduction (scaffold for bone growth) and osteogenesis (direct bone formation by osteoblasts).
Smad Signaling Pathway
Canonical BMP signaling: BMP binds type I and II serine/threonine kinase receptors, phosphorylates receptor-Smads (Smad1/5/8), complex with Smad4, translocates to nucleus, activates Runx2 and osterix transcription.
Clinical Applications
FDA-approved uses: BMP-2 for anterior lumbar interbody fusion (ALIF) and tibial nonunion. BMP-7 (OP-1) humanitarian device exemption for recalcitrant long bone nonunion. Off-label use common but controversial.
Complications
Dose-dependent adverse effects: Ectopic bone formation, inflammatory swelling (especially cervical spine), osteolysis, heterotopic ossification. Supraphysiologic dosing (1000x normal levels) contributes to complications.
At a Glance
Bone morphogenetic proteins (BMPs) are secreted growth factors in the TGF-β superfamily that are osteoinductive—capable of inducing bone formation in non-skeletal sites, as demonstrated by Urist in 1965. BMP signaling occurs via the Smad pathway: BMP binds type I/II serine-threonine kinase receptors, phosphorylates Smad1/5/8, which translocates to the nucleus and activates Runx2 transcription for osteoblast differentiation. FDA-approved applications include rhBMP-2 for ALIF and tibial nonunion, and BMP-7 (OP-1) for recalcitrant nonunion. Clinical use requires supraphysiologic doses (1000× normal levels) delivered on absorbable collagen sponge carriers. Complications include ectopic bone formation, inflammatory swelling (life-threatening in cervical spine), osteolysis, and significant cost.
BMPBMP - Key Functions
Memory Hook:BMP induces Bone formation via Mesenchymal stem cells through Smad Pathway
SMADSMAD - BMP Signaling Cascade
Memory Hook:SMAD pathway: Serine kinase receptors, MAD proteins, Activate Runx2, Differentiation
ECHOESBMP Clinical Complications
Memory Hook:BMP complications ECHO through treatment: Ectopic bone, Cost, Hematoma, Osteolysis, Edema, Subsidence
Overview
Bone morphogenetic proteins (BMPs) are secreted signaling molecules in the transforming growth factor-beta (TGF-beta) superfamily that induce bone and cartilage formation. Marshall Urist discovered BMPs in 1965 by demonstrating that demineralized bone matrix implanted subcutaneously in rabbits induced ectopic bone formation.
Why BMPs matter clinically:
Biological Enhancement
BMPs provide osteoinductive capacity to bone grafts and synthetic scaffolds. Unlike autograft (osteoconductive and osteogenic) or allograft (osteoconductive only), BMPs actively recruit mesenchymal stem cells and induce osteoblast differentiation.
Clinical Applications
FDA-approved BMP-2 (InFuse, Medtronic) for anterior lumbar interbody fusion and tibial nonunion. BMP-7/OP-1 (Stryker) has humanitarian device exemption for recalcitrant long bone nonunions. Off-label use in posterior spinal fusion, fracture nonunion, and revision arthroplasty is common but controversial.
Osteoinduction vs Osteoconduction
Osteoinduction is the process by which primitive mesenchymal cells are recruited and induced to differentiate into bone-forming osteoblasts. BMPs are osteoinductive. Osteoconduction is passive scaffold support for bone growth from existing bone. Allograft and synthetic scaffolds are osteoconductive but not osteoinductive unless combined with BMPs.
Understanding BMP biology is essential for basic science vivas and explaining clinical decision-making regarding biologics use.
BMP Biology and Classification
BMP Superfamily
The BMP family contains over 20 members, divided into subgroups based on structure and function.
Major BMP Subgroups and Functions
| BMP Subgroup | Key Members | Primary Function | Clinical Relevance |
|---|---|---|---|
| Osteogenic BMPs | BMP-2, BMP-4, BMP-6, BMP-7 | Bone and cartilage induction | BMP-2 and BMP-7 FDA-approved for clinical use |
| TGF-beta-like BMPs | BMP-3 (Osteogenin) | Negative regulator of bone formation | Inhibits osteogenesis (opposite effect) |
| GDF Group | GDF-5, GDF-6, GDF-7 | Joint and tendon development | Experimental tendon/ligament healing |
| Decapentaplegic Group | BMP-5, BMP-8 | Embryonic development | Limited orthopaedic application |
BMP-2 and BMP-7 are the most osteogenic and have been developed for clinical use. BMP-2 shows greater osteoinductive potency but higher complication rates compared to BMP-7.
BMP-2 (Recombinant Human BMP-2, rhBMP-2)
Commercial name: InFuse Bone Graft (Medtronic)
Structure:
- Homodimer of two identical 114 amino acid chains
- Molecular weight: 26 kDa
- Requires dimerization for receptor binding
FDA-approved indications:
- Anterior lumbar interbody fusion (ALIF) single-level L4-S1
- Open tibial shaft fractures (acute fracture, not nonunion initially)
- Oral maxillofacial reconstruction (sinus augmentation, ridge preservation)
Off-label uses (controversial):
- Posterior lumbar fusion
- Cervical fusion (BLACK BOX WARNING - airway swelling risk)
- Long bone nonunion
- Revision arthroplasty with bone loss
Clinical dosing:
- ALIF: 12 mg total (1.5 mg/mL on absorbable collagen sponge)
- Posterolateral fusion: 12-24 mg per level (off-label)
- Nonunion: 6-12 mg depending on defect size
Doses are 100-1000 times higher than physiologic levels during normal fracture healing, contributing to adverse effects.
BMP Signaling Pathways
BMPs exert their effects through cell surface receptor binding and intracellular signal transduction.
Canonical BMP-Smad Signaling
The primary BMP signaling mechanism involves Smad proteins (mothers against decapentaplegic homologs).
BMP-Smad Signaling Cascade
BMP ligand (homodimer) binds to type II serine/threonine kinase receptor (BMPR-II, ActR-II) on cell surface. Type II receptor is constitutively active.
Type II receptor recruits and phosphorylates type I receptor (ALK-2, ALK-3, ALK-6). Type I receptor becomes activated kinase.
Activated type I receptor phosphorylates receptor-regulated Smads (R-Smads): Smad1, Smad5, Smad8 at C-terminal serine residues.
Phosphorylated Smad1/5/8 dissociates from receptor, binds to common mediator Smad4 (Co-Smad), forming heteromeric complex.
Smad1/5/8-Smad4 complex translocates to nucleus via importin proteins.
Smad complex binds DNA at Smad-binding elements (SBEs), recruits co-activators (p300, CBP), activates target gene transcription: Runx2, Osterix, Osteocalcin, Alkaline phosphatase.
Runx2 - Master Osteoblast Transcription Factor
Runx2 (Cbfa1) is the master transcription factor for osteoblast differentiation. BMP-Smad signaling directly activates Runx2 gene expression. Runx2 then induces downstream osteoblast genes (Osterix, Osteocalcin, Bone sialoprotein, Collagen type I). Runx2 mutations cause cleidocranial dysplasia (absent clavicles, delayed skull ossification).
The Smad pathway is the canonical and most important BMP signaling route for osteogenesis.
Anatomy
BMP Molecular Structure
BMP Protein Structure
Molecular architecture:
- Secreted polypeptide growth factors
- Active form is homodimer (two identical chains)
- Cysteine-rich domain for dimerization
- BMP-2: 114 amino acids per chain, 26 kDa dimer
- BMP-7: 139 amino acids per chain, 35 kDa dimer
TGF-beta Superfamily
Family relationships:
- BMPs belong to TGF-beta superfamily
- Share cysteine knot motif structure
- Conserved receptor binding domains
- Over 20 BMP subtypes identified
- BMP-2, 4, 5, 6, 7 most osteogenic
Dimeric Structure Requirement
BMPs must form dimers to be biologically active. The active BMP ligand consists of two polypeptide chains joined by disulfide bonds. This dimeric structure is essential for binding to type I and type II receptors on cell surfaces. Monomeric BMP has no biological activity.
Classification
BMP Classification by Function
Functional Classification of BMPs
| Category | BMP Members | Primary Function | Clinical Status |
|---|---|---|---|
| Osteogenic BMPs | BMP-2, BMP-4, BMP-6, BMP-7, BMP-9 | Bone and cartilage induction | BMP-2: FDA approved; BMP-7: HDE |
| Inhibitory BMPs | BMP-3 (Osteogenin) | Negative regulator of bone formation | Not for clinical osteoinduction |
| GDF/Tendon BMPs | GDF-5 (BMP-14), GDF-6, GDF-7 | Tendon, ligament, joint development | Experimental tendon repair |
| Developmental BMPs | BMP-5, BMP-8, BMP-10 | Embryonic patterning, heart | Limited orthopaedic use |
Clinical BMPs
FDA-approved or HDE:
- BMP-2 (InFuse): Most widely used
- BMP-7 (OP-1): Limited availability
Approved indications:
- ALIF L4-S1 (BMP-2)
- Open tibial fractures (BMP-2)
- Recalcitrant nonunion (BMP-7 HDE)
Research BMPs
Under investigation:
- BMP-9: Most potent in vitro
- BMP-6: Strong osteogenic capacity
- GDF-5: Tendon/ligament applications
No clinical approval for these BMPs yet due to manufacturing, cost, and regulatory hurdles.
Clinical Applications
BMP-2 is the most widely used osteobiologic in orthopaedic surgery, despite controversies regarding safety and off-label use.
BMP in Spinal Fusion
FDA-approved indication: Anterior lumbar interbody fusion (ALIF), single-level L4-S1
Evidence for ALIF:
- Fusion rates: BMP-2 (95%) vs autograft iliac crest (85%) at 2 years
- Eliminates donor site morbidity (10-20% chronic pain with iliac crest harvest)
- Shorter operative time
- Equivalent clinical outcomes (ODI, VAS)
Off-label use in posterolateral fusion (controversial):
- Not FDA-approved for posterior approach
- Higher doses used (12-24 mg per level)
- Complications: ectopic bone (nerve root compression), osteolysis (screw loosening), radiculitis
- Mixed evidence on fusion rates vs autograft
Cervical spine (BLACK BOX WARNING):
- NOT approved for anterior cervical fusion
- Life-threatening complications: airway edema, hematoma, dysphagia, dysphonia
- Enclosed anterior cervical space amplifies inflammatory swelling
- Case reports of intubation, tracheostomy, death
BMP-2 Contraindicated in Cervical Spine
FDA black box warning: Do NOT use BMP-2 in anterior cervical spine fusion. Soft tissue swelling in the confined prevertebral space can cause life-threatening airway obstruction. Multiple case reports of respiratory compromise requiring prolonged intubation or emergency tracheostomy.
BMP-2 in ALIF is well-established, but off-label use requires careful risk-benefit consideration.
Investigations
Assessing BMP Response and Bone Healing
Radiographic Assessment
Plain radiographs:
- Serial X-rays at 6, 12, 24 weeks post-BMP
- Look for bridging bone formation
- Assess fusion mass in spinal surgery
- Monitor for ectopic bone formation
CT scan:
- Gold standard for assessing fusion
- 3D reconstruction for complex anatomy
- Detect trabecular bridging across fusion
Clinical Assessment
Healing indicators:
- Pain reduction at fracture/fusion site
- Stability on clinical examination
- Return of weight-bearing capacity
Complication monitoring:
- Soft tissue swelling assessment
- Neurological examination (ectopic bone)
- Dysphagia screening (cervical - contraindicated)
CT vs X-ray for Fusion Assessment
CT scan is superior to plain radiographs for assessing spinal fusion. CT can detect fine trabecular bridging and cortical continuity that plain films miss. Fusion assessment by CT shows 20-30% lower fusion rates compared to X-ray alone, suggesting plain films overestimate fusion success.
Management
Clinical Decision Making for BMP Use
When to Consider BMP
Appropriate indications:
- ALIF L4-S1 (FDA-approved)
- Severe open tibial fractures (Gustilo IIIA/B)
- Recalcitrant nonunion (after failed autograft)
- High-risk fusion patients (smokers, revision surgery)
Patient factors favoring BMP:
- Inadequate autograft quantity
- Donor site morbidity concerns
- Metabolic bone disease
When to Avoid BMP
Absolute contraindications:
- Anterior cervical spine (BLACK BOX)
- Active malignancy
- Pregnancy or breastfeeding
- Known hypersensitivity to BMP or bovine collagen
Relative contraindications:
- Active infection
- Recent cancer history
- Immunocompromised patients
Cervical Spine Contraindication
BMP-2 is absolutely contraindicated in anterior cervical spine surgery. The confined prevertebral space amplifies inflammatory swelling, causing life-threatening airway obstruction. Case reports include prolonged intubation, emergency tracheostomy, and death. This is an FDA BLACK BOX warning.
Surgical Technique
BMP Application Techniques
BMP Preparation and Application
- Open BMP kit sterilely
- Add sterile water to lyophilized BMP vial
- Allow to dissolve completely (do not shake)
- Final concentration: 1.5 mg/mL for BMP-2
- Remove absorbable collagen sponge from kit
- Pour BMP solution evenly over sponge
- Allow to absorb for minimum 15 minutes
- Do not wring, squeeze, or manipulate excessively
- Prepare fusion bed or fracture site
- Decorticate surfaces if applicable
- Ensure hemostasis before placement
- Clear soft tissue from target area
- Place BMP-soaked sponge at target site
- Position within cage for ALIF
- Pack into nonunion site for fractures
- Avoid contact with dura, neural elements, vessels
- Meticulous hemostasis
- Layer closure without excess tension
- Drain placement controversial (may remove BMP)
- Monitor for swelling postoperatively
ALIF Application
Technique for anterior lumbar fusion:
- Place BMP-soaked sponge inside interbody cage
- Or place sponge anterior/lateral to cage
- Total dose: 12 mg (small kit) or 4.2 mg (XS)
- Sponge dimensions matched to cage size
Posterolateral Application
Technique for posterior fusion (off-label):
- Place BMP sponge over transverse processes
- May combine with local bone or allograft
- Higher doses: 12-24 mg per level
- Contained within paraspinal gutters
Complications and Controversies
Supraphysiologic BMP dosing and off-label use have led to recognized complications and ongoing controversies.
BMP-2 Complications by Anatomical Site
| Complication | Incidence | Mechanism | Management |
|---|---|---|---|
| Ectopic bone formation | 10-30% posterior fusion | BMP diffusion into surrounding soft tissues | Observation if asymptomatic, excision if nerve compression |
| Inflammatory swelling | 10-50% anterior cervical (CONTRAINDICATED) | Cytokine release, edema in confined space | Airway monitoring, intubation if severe |
| Radiculitis | 3-8% ALIF | Inflammation, ectopic bone near nerve roots | NSAIDs, neuropathic agents, decompression if severe |
| Osteolysis/cyst formation | 5-15% spinal fusion | Inflammatory osteoclast activation | Observation, revision if structural concern |
| Heterotopic ossification | Variable | Ectopic induction in muscle/soft tissue | Prophylaxis with NSAIDs (if used), excision if symptomatic |
| Seroma | 5-10% | Fluid accumulation at BMP site | Aspiration if large, observation |
Supraphysiologic Dosing Drives Complications
Clinical BMP doses are 100-1000 times physiologic levels. Normal fracture healing involves nanogram amounts; clinical use involves milligrams (12 mg = 12,000,000 nanograms). This massive excess causes off-target effects: inflammation, ectopic bone, osteolysis. Dose-reduction strategies under investigation but not yet validated.
Controversies:
Off-Label Use Rate
Studies suggest over 50% of BMP use is off-label (posterior fusion, cervical spine, nonunion). Lack of FDA approval for these indications creates medico-legal exposure. Evidence quality variable. Industry-sponsored trials dominate literature.
Cost-Effectiveness
BMP costs thousands of dollars per dose. Cost-effectiveness compared to autograft is debatable. Savings from avoiding donor site morbidity offset by BMP cost. Higher complication management costs. QALY analyses show marginal benefit at best.
Cancer Risk Debate
Early retrospective studies suggested increased cancer risk with BMP. Subsequent analyses showed no causal link. Theoretical concern: BMPs stimulate cell proliferation. Current consensus: no proven cancer risk, but avoid in active malignancy or recent cancer history.
Industry Influence
Most BMP research funded by manufacturers. Concerns about publication bias, ghostwriting, selective outcome reporting. Independent studies show less favorable results. Regulatory scrutiny of manufacturer marketing practices.
Understanding complications and controversies is essential for informed clinical decision-making and exam discussions.
Postoperative Care
Post-BMP Monitoring Protocol
Postoperative Care Timeline
- Monitor for soft tissue swelling
- Neurological assessment if spinal procedure
- Wound inspection for hematoma
- Pain management per protocol
- Wound check at 2 weeks
- Assess for radiculitis symptoms
- Monitor inflammatory markers if concerns
- Mobilization per surgical protocol
- First radiographs to assess fusion/healing
- Continue activity restrictions
- Physical therapy as appropriate
- Assess for ectopic bone symptoms
- CT scan to confirm fusion (spinal cases)
- Progressive return to activities
- Final radiographs at 12 months
- Discharge if healed
Fusion Assessment
Radiographic follow-up:
- X-rays at 6, 12, 24 weeks
- CT scan for definitive fusion assessment
- Look for bridging bone, no lucency
Clinical correlation:
- Pain improvement
- Mechanical stability
- Return to function
Complication Monitoring
Watch for:
- Radiculitis (leg pain, numbness)
- Wound swelling or seroma
- New neurological symptoms
- Persistent inflammatory pain
Action:
- Early imaging if symptoms
- Neurological examination
- Consider decompression if nerve compression
Outcomes
BMP Clinical Outcomes Summary
Spinal Fusion Outcomes
ALIF (FDA-approved):
- Fusion rate: 94-100%
- Superior to autograft (85-90%)
- Eliminates donor site morbidity
Posterolateral (off-label):
- Fusion rate: 85-95% (variable)
- Mixed evidence vs autograft
- Higher complication rates
Fracture/Nonunion Outcomes
Open tibial fractures:
- 36% reduction in infection (IIIA/B)
- Faster union times
- Fewer secondary interventions
Established nonunion:
- 75-85% union rate
- Comparable to autograft
- Avoids donor site morbidity
Key Outcome Studies
Landmark BMP trials:
- Burkus 2002: ALIF RCT - BMP-2 94.5% fusion vs autograft 88.7%
- Govender 2002: Open tibial fractures - 36% infection reduction with BMP-2
- Vaccaro 2008: Posterolateral fusion - mixed results, more complications
BMP-2 is most effective for ALIF (FDA-approved) and open tibial fractures. Off-label use has less robust evidence.
Evidence Base
BMP-2 vs Autograft in ALIF - Pivotal Trial
- 143 patients randomized to BMP-2/collagen sponge vs autograft in ALIF
- Fusion rate BMP-2: 94.5% vs autograft: 88.7% at 24 months
- BMP-2 superior outcomes, eliminated iliac crest donor site morbidity
- No significant difference in clinical improvement (ODI, SF-36)
BMP-2 in Open Tibial Fractures
- 450 open tibial fractures randomized to BMP-2 (0.75, 1.5 mg/mL) vs control
- BMP-2 reduced infection risk by 36% in severe injuries (Gustilo IIIA/B)
- Faster fracture healing and fewer secondary interventions with BMP-2
- Dose-dependent effect (1.5 mg/mL superior to 0.75 mg/mL)
Complications of Off-Label BMP Use
- Systematic review of BMP adverse events from FDA MAUDE database and literature
- Increased complications with off-label use (posterior fusion, cervical spine)
- Life-threatening cervical complications (airway swelling, hematoma)
- Ectopic bone, radiculitis, osteolysis in off-label applications
- Concerns about industry-sponsored trial bias and underreporting
MCQ Practice Points
Exam Pearl
Q: What is the mechanism of action of BMP-2 and BMP-7 in bone healing?
A: Osteoinduction - BMPs induce differentiation of mesenchymal stem cells (MSCs) into osteoblasts. They signal through SMAD pathway (receptor binding → SMAD phosphorylation → gene transcription). BMP-2 and BMP-7 are the only clinically approved BMPs. Distinct from osteoconduction (scaffold providing surface for bone growth) and osteogenesis (cells directly forming bone).
Exam Pearl
Q: What are the approved clinical indications for recombinant BMP-2 (rhBMP-2, Infuse)?
A: (1) Anterior lumbar interbody fusion (ALIF) in titanium cage - FDA approved. (2) Open tibial fractures with IM nail - FDA approved. Off-label use in many other applications (posterolateral fusion, nonunion, spinal deformity). Note: NOT approved for posterior cervical spine due to swelling risk (dysphagia, airway compromise). Dose: 1.5mg/mL on absorbable collagen sponge.
Exam Pearl
Q: What are the potential complications of BMP-2 use in spinal surgery?
A: (1) Heterotopic ossification (can cause neural compression), (2) Radiculitis/nerve inflammation, (3) Osteolysis adjacent to cage, (4) Increased cancer risk (controversial - early studies suggested, later refuted), (5) Swelling - especially concerning in anterior cervical spine (dysphagia, airway compromise). Use in posterior cervical spine discouraged. Cost: approximately $5000-$10000 per application.
Exam Pearl
Q: How does BMP-7 (OP-1) differ from BMP-2 in clinical applications?
A: BMP-7 (OP-1, Stryker) was approved for tibial nonunion and posterolateral spinal fusion under Humanitarian Device Exemption (HDE). Lower osteoinductive potency than BMP-2 but possibly fewer inflammatory complications. BMP-7 is no longer commercially available (discontinued 2014). BMP-2 remains the only clinically available recombinant BMP. Research continues on other BMPs and delivery systems.
Exam Pearl
Q: What is the role of the carrier/scaffold in BMP delivery and what carriers are used?
A: The carrier provides: (1) Sustained release of BMP, (2) Localization at target site, (3) Structural support. Absorbable collagen sponge (ACS) is the FDA-approved carrier for BMP-2. Other carriers: DBM, calcium phosphate ceramics, synthetic polymers. The carrier affects release kinetics - initial burst release followed by sustained release. BMP alone without carrier has poor retention at site.
Australian Context
Australian Regulatory and Practice Context
TGA Approval Status
rhBMP-2 (InFuse - Medtronic):
- TGA registered for spinal fusion and tibial fractures
- Similar indications to FDA approval
- Available on ARTG (Australian Register of Therapeutic Goods)
rhBMP-7 (OP-1):
- Limited availability in Australia
- Not widely used, similar to international trends
- Some specialty centers may stock for salvage use
Funding and Reimbursement
Medicare (MBS):
- BMP not separately reimbursed under MBS
- Surgical procedure fees only
- BMP cost absorbed by hospital or patient
Private Insurance:
- Variable coverage by insurers
- May be covered under surgical prosthesis benefits
- Check individual fund policies
Australian Practice Patterns
BMP use in Australia:
- Less common than in USA (cost considerations)
- Most surgeons prefer autograft for primary fusion
- BMP reserved for high-risk cases: revision surgery, smokers, metabolic bone disease
- Major spinal centers have access and expertise
- Off-label use requires careful documentation
Exam Viva Scenarios
Practice these scenarios to excel in your viva examination
Classification Viva Question
"How are BMPs classified and which are used clinically?"
Management Viva Question
"When would you consider using BMP in a patient undergoing spinal fusion?"
Surgical Technique Viva Question
"Describe how you would use BMP-2 in an anterior lumbar interbody fusion."
Outcomes Viva Question
"What is the evidence for BMP-2 use in spinal fusion, and what are the controversies?"
Australian Context Viva Question
"A patient in your public hospital requires spinal fusion. How do you decide whether to use BMP?"
BONE MORPHOGENETIC PROTEINS (BMPs)
High-Yield Exam Summary
BMP Biology Fundamentals
- •BMPs: TGF-beta superfamily, secreted growth factors
- •Over 20 BMP subtypes, BMP-2 and BMP-7 most osteogenic
- •Osteoinductive: induce bone in non-skeletal sites (Urist 1965)
- •BMP-2 more potent than BMP-7 but higher complications
Smad Signaling Pathway
- •Type II receptor (BMPR-II) binds BMP, recruits type I (ALK-2/3/6)
- •Type I phosphorylates Smad1/5/8 (R-Smads) at C-terminus
- •Smad1/5/8 + Smad4 (Co-Smad) complex translocates to nucleus
- •Activates Runx2 (master osteoblast TF) → Osterix, Osteocalcin, BSP, Collagen I
Clinical BMPs
- •BMP-2 (InFuse): FDA-approved ALIF L4-S1, open tibial fractures
- •BMP-7 (OP-1): HDE for recalcitrant long bone nonunion (limited availability)
- •Dosing: 12 mg ALIF, 12-24 mg posterolateral (off-label)
- •Supraphysiologic: 100-1000x normal healing levels
FDA-Approved Indications
- •BMP-2: ALIF single-level L4-S1 (fusion rate 94-100%)
- •BMP-2: Open tibial shaft fractures (reduces infection 36%)
- •BMP-2: Oral maxillofacial (sinus augmentation, ridge preservation)
- •BMP-7: HDE only - recalcitrant nonunion after failed autograft
Complications
- •Ectopic bone: 10-30% posterolateral (nerve compression risk)
- •Osteolysis/cysts: 5-15% (screw loosening concern)
- •Radiculitis: 3-8% ALIF (inflammation near nerve roots)
- •Cervical CONTRAINDICATED: airway edema, life-threatening (BLACK BOX)
Key Exam Points
- •Urist 1965: demineralized bone matrix subcutaneous → ectopic bone
- •Osteoinduction (active MSC recruitment) vs osteoconduction (passive scaffold)
- •Runx2 knockout: cleidocranial dysplasia (absent clavicles)
- •Off-label use over 50%: posterolateral fusion, nonunion, revision surgery