Bone Remodeling

Cortical Bone Anatomy for Remodeling

Structural organization:

• Haversian systems (osteons): Concentric lamellae (3-7 layers) surrounding central Haversian canal (contains capillary, nerve)
• Volkmann's canals: Transverse channels connecting adjacent Haversian canals, allowing vascular communication
• Interstitial lamellae: Remnants of old osteons between intact osteons (result of previous remodeling cycles)
• Cement lines: Basophilic lines marking boundaries between old and new bone (scalloped border of previous resorption cavity)

BMU anatomy in cortical bone (cutting cone):

• Leading edge: Osteoclasts (20-50 cells) form cutting head, resorb longitudinal tunnel (200 μm diameter, advance 20-40 μm/day)
• Reversal zone: 50-100 μm behind cutting head, mononuclear cells clean debris, prepare surface for formation
• Closing cone: Osteoblasts deposit concentric lamellae from outside inward (closing cone), filling 80-90% of resorbed tunnel
• Haversian canal: Unfilled central space (10-20 μm diameter) contains capillary, nerve; provides nutrient supply for osteocytes in surrounding lamellae
• Vascular supply: Capillary advances with cutting cone, supplied from periosteum/endosteum via Volkmann's canals

Dimensions:

• Cutting cone length: 1-2 mm
• Lifespan of single cortical BMU: 4-6 months
• Resorption phase: 2-3 weeks; formation phase: 3 months
• Result: New secondary osteon (Haversian system) replaces old bone

Clinical pearl: Excessive cortical remodeling (hyperparathyroidism, Paget disease) increases cortical porosity by creating more Haversian canals. Porosity greater than 20% significantly weakens bone (normal 5-10%). This explains why primary hyperparathyroidism causes cortical bone loss at radius more than trabecular bone loss at spine.

Trabecular Bone Anatomy for Remodeling

Structural organization:

• Trabeculae: Interconnected network of plates and rods (100-200 μm thick)
• Marrow spaces: 300-600 μm diameter, filled with hematopoietic or fatty marrow
• Surface-to-volume ratio: 20-30 m²/L (10-fold higher than cortical), providing large area for remodeling
• Architectural types: Plate-like (spine, ilium) vs rod-like (greater trochanter); plates stronger than rods

BMU anatomy in trabecular bone (resorption cavity):

• Resorption phase: Osteoclasts (5-10 cells) excavate scalloped cavity on trabecular surface (Howship's lacuna, 40-60 μm deep)
• Reversal phase: Cavity depth reaches maximum, mononuclear cells deposit cement line (basophilic, scalloped border)
• Formation phase: Osteoblasts fill cavity from bottom upward, depositing layers until surface restored (partial or complete filling)
• Result: Hemi-osteon (trabecular packet) with concave scalloped cement line at base

Dimensions:

• Resorption cavity diameter: ~1 mm
• Depth: 40-60 μm (can reach 100 μm in high-turnover states)
• Formation layers: 4-5 lamellae (each 5 μm thick)
• Lifespan of single trabecular BMU: 3-6 months

Critical anatomical risk:

• Trabecular perforation: When resorption cavity depth exceeds trabecula thickness (typically when cavity greater than 60 μm and trabecula less than 100 μm)
• Mechanism: Osteoclasts tunnel completely through trabecula, breaking connectivity
• Consequence: Irreversible microarchitectural damage (osteoblasts cannot rebuild trabecular strut across empty space)
• Clinical significance: Contributes to disproportionate bone weakness in osteoporosis beyond what BMD loss alone predicts

Clinical pearl: Postmenopausal osteoporosis preferentially affects trabecular bone because estrogen deficiency increases remodeling rate. With surface-to-volume ratio 10-fold higher than cortical, trabecular bone has more remodeling sites. Elevated remodeling increases risk of trabecular perforation. This explains why vertebral compression fractures (70% trabecular) occur 5-10 years before hip fractures (50% trabecular).

Classification Overview

Bone remodeling can be classified by turnover state, coupling status, and pathological pattern. Understanding these classifications helps guide diagnosis and treatment.

Classification by Remodeling Turnover State

Classification by Coupling Status

Advanced Classification Systems

Classification by Histomorphometric Parameters

Classification by Bone Turnover Marker Patterns

Classification by Disease-Specific Remodeling Patterns

Growth Factors Released from Bone Matrix

During resorption, osteoclasts release growth factors that were stored in mineralized bone matrix:

Transforming Growth Factor-beta (TGF-β):

• Most abundant growth factor in bone matrix (concentration 200 micrograms per kilogram)
• Released during osteoclastic resorption
• Chemoattractant for osteoblast precursors
• Promotes osteoprogenitor migration to resorption site
• Stimulates preosteoblast proliferation but inhibits terminal differentiation

Insulin-like Growth Factors (IGF-I and IGF-II):

• Stored in bone matrix as IGF-binding protein complexes
• Released and activated during resorption
• Stimulate osteoblast proliferation and collagen synthesis
• Enhance osteoblast differentiation and function

Bone Morphogenetic Proteins (BMPs):

• BMP-2, BMP-4, BMP-6, BMP-7 present in matrix
• Potent osteoinductive factors
• Promote MSC differentiation to osteoblasts
• Activate Runx2 transcription factor

Matrix-derived coupling explains anatomical precision of remodeling.

Direct Osteoclast-Osteoblast Communication

Ephrin-Eph receptor system:

• Forward signaling: EphrinB2 on osteoclasts binds EphB4 on osteoblasts, stimulating osteoblast differentiation
• Reverse signaling: EphB4 binding back-signals to osteoclasts, inhibiting osteoclast differentiation (negative feedback)
• Bidirectional coupling mechanism

RANKL-RANK interaction:

• Osteoblasts express membrane-bound RANKL
• Direct contact with RANK on osteoclast precursors
• Not only activates osteoclasts but also provides spatial information

Semaphorin signaling:

• Semaphorin 3A from osteoblasts inhibits osteoclast formation
• Semaphorin 4D from osteoclasts inhibits osteoblast differentiation
• Balance regulates coupling

Cell-cell signaling provides real-time feedback regulation of coupling.

Anatomical and Spatial Mechanisms

BMU anatomical organization:

• Osteoclasts and osteoblasts physically colocalized within BMU
• Shared blood supply delivers precursors to same location
• Canopy structure isolates microenvironment
• Proximity ensures osteoblasts arrive at resorption site

Cement line as template:

• Reversal cells deposit cement line (glycosaminoglycan-rich)
• Provides attachment surface for osteoblasts
• Signals stop resorption and start formation transition

Bone surface geometry:

• Resorption creates cavity that osteoblasts must fill
• Physical constraint guides bone deposition
• Concave resorption surface favors osteoblast attachment

Physical coupling ensures anatomical precision and efficiency of remodeling.

How Osteocytes Sense Mechanical Load

Mechanical stimulus:

1. Bone deformation under load creates matrix strain
2. Fluid flow in lacunar-canalicular network (osteocyte processes in canaliculi)
3. Shear stress on osteocyte cell membrane and processes

Sensing mechanisms:

• Primary cilium: Mechanosensitive organelle detects fluid flow
• Integrins: Connect cytoskeleton to matrix, sense deformation
• Gap junctions: Connexin 43 channels coordinate osteocyte network
• Ion channels: Mechanosensitive channels (calcium influx)

Signal transduction:

• Calcium influx triggers intracellular signaling
• Prostaglandin E2 (PGE2) production
• Nitric oxide (NO) release
• Changes in gene expression (sclerostin, RANKL, OPG)

Fluid flow amplifies mechanical strain signals, making osteocytes exquisitely sensitive mechanosensors.

Sclerostin - The Loading-Responsive Brake on Bone Formation

Sclerostin biology:

• Product of SOST gene, expressed exclusively by osteocytes
• Glycoprotein secreted into lacunar-canalicular network
• Binds LRP5/6 co-receptors on osteoblasts
• Inhibits Wnt/β-catenin signaling, reducing bone formation

Mechanical regulation:

• Mechanical loading reduces SOST gene expression
• Less sclerostin leads to less Wnt inhibition and more bone formation
• Unloading/immobilization increases SOST expression
• More sclerostin leads to more Wnt inhibition and less formation, resulting in bone loss

Clinical correlations:

• Exercise and loading: Decrease sclerostin, increase bone mass
• Bed rest and immobilization: Increase sclerostin, cause bone loss
• Spaceflight: Microgravity increases sclerostin, rapid bone loss
• Sclerosteosis: SOST mutation (no sclerostin), very high bone mass

Sclerostin regulation is the key mechanism translating mechanical signals to changes in bone formation.

Mechanically-Directed Remodeling

High strain regions:

• Osteocytes sense high strain
• Decrease sclerostin, increase Wnt signaling
• Increase OPG, decrease RANKL (less resorption)
• Net effect: Bone formation increased, resorption suppressed, mass increases

Low strain regions (disuse):

• Osteocytes sense low strain
• Increase sclerostin, decrease Wnt signaling
• Decrease OPG, increase RANKL (more resorption)
• Net effect: Bone formation decreased, resorption increased, mass decreases

Microdamage accumulation:

• Fatigue loading creates microcracks
• Osteocyte apoptosis at damage sites
• Dead osteocytes signal nearby cells
• Targeted remodeling activated to remove damaged bone

Mechanical regulation optimizes bone structure for functional demands, minimizing weight while maximizing strength.

Management Overview

Management of abnormal bone remodeling targets the underlying turnover state: Suppress excessive resorption in high-turnover states, stimulate formation in low-turnover states, and address underlying causes (vitamin D deficiency, hormonal abnormalities).

Management Based on Remodeling State

Antiresorptive Therapy

Anabolic Therapy

Non-Pharmacological Management

Advanced Management Strategies

Disease-Specific Management

Drug Holiday Strategies

Treatment Failure and Alternative Strategies

Combination and Sequential Therapy

Transiliac Bone Biopsy for Remodeling Assessment

Transiliac bone biopsy is the gold standard for assessing bone remodeling when diagnosis cannot be made by biochemical or radiological means. The procedure obtains intact trabecular bone core from iliac crest for histomorphometric analysis.

Indications for Bone Biopsy

Tetracycline Double-Labeling Protocol

Tetracycline labeling is MANDATORY for dynamic histomorphometry (MAR, BFR/BS calculation). Without labeling, only static parameters available (cannot assess remodeling rate).

Give tetracycline 250 mg orally four times daily (or doxycycline 100 mg twice daily) for 3 days.

Mechanism: Tetracycline binds calcium at mineralizing bone surfaces (forming osteoid being mineralized). Creates fluorescent yellow-green label visible on UV microscopy (unstained sections).

Alternative fluorochromes (if tetracycline contraindicated): Calcein green (15 mg/kg IV), alizarin red (20 mg/kg IV). Tetracycline preferred (oral, widely available, strong fluorescence).

Wait 10-14 days (typically 12 days) between first and second tetracycline courses.

Rationale: This interval allows sufficient new bone to mineralize, creating measurable separation between the two tetracycline labels. Distance between labels divided by interval (12 days) equals MAR (μm/day).

Critical: Interval must be known precisely (record dates). If interval incorrect, MAR calculation invalid.

Give second course tetracycline 250 mg orally four times daily for 3 days.

Timing: Start exactly 10-14 days after completing first course.

Result: Second fluorescent label forms at current mineralization front. Distance between two labels reflects bone deposited during interval.

Wait 3-5 days after completing second tetracycline course before performing biopsy.

Total timeline: First tetracycline day 0-3, drug-free day 4-15, second tetracycline day 16-19, biopsy day 19-24. Total 16-24 days from first tetracycline dose to biopsy.

Rationale: 3-5 day delay allows second label to fully form (mineralization continues for several days after tetracycline administration).

Surgical Technique - Step by Step

Position: Lateral decubitus, biopsy side up. Hips and knees flexed 90 degrees (relaxes abdominal muscles, improves access to iliac crest).

Site: Anterior iliac crest, 2 cm posterior and 2 cm inferior to anterior superior iliac spine (ASIS). Mark with surgical marker.

Rationale: This site targets trabecular-rich iliac bone (high remodeling rate, representative of axial skeleton). Avoid too anterior (dense cortical bone, difficult to penetrate) or too posterior (risk of superior gluteal vessels).

Laterality: Either side acceptable. If previous biopsy or surgery, use contralateral side. If Paget disease, biopsy affected bone (if unilateral) or representative site (if polyostotic).

Local anesthesia (most common): Lidocaine 1% with epinephrine (reduce bleeding). Infiltrate skin, subcutaneous tissue, periosteum (15-20 mL total). Wait 5-10 minutes for full effect.

Conscious sedation (optional): Midazolam 1-2 mg IV, fentanyl 50-100 μg IV. Monitor oxygen saturation, respiratory rate. Have reversal agents available (flumazenil, naloxone).

General anesthesia (if severe anxiety, patient preference, or pediatric): Propofol-based or inhalational. Short procedure (20-30 minutes), rapid recovery.

Post-biopsy analgesia: NSAIDs (ibuprofen 400 mg every 6-8 hours) or acetaminophen (1000 mg every 6 hours) for 24-48 hours. Opioids rarely needed.

Incision: 5-8 mm stab incision with #11 blade, perpendicular to skin. Deepen through subcutaneous fat to periosteum.

Periosteal dissection: Use periosteal elevator to clear soft tissue from outer cortex (1-2 cm diameter circle). Expose bone surface.

Cortical window (optional, if trephine cannot penetrate intact cortex): Use 3-4 mm drill bit to create pilot hole through outer cortex. Widen to 7-8 mm with larger drill or rongeur. Facilitates trephine passage.

Alternative - direct trephine advancement: If osteoporotic bone (thin cortex), may advance trephine directly without pre-drilling. Rotate trephine with firm steady pressure (avoid forceful jabbing, may fracture cortex).

Trephine needle: Jamshidi needle (7-8 mm internal diameter, 10-15 cm length) most common. Alternative: Minnesota bone biopsy needle, Islam needle.

Advancement: Rotate trephine clockwise with downward pressure, advancing through outer cortex → trabecular bone → inner cortex. Maintain perpendicular angle to bone surface (avoid angling, may exit lateral cortex).

Depth: Advance until both cortices penetrated (feel "give" as inner cortex breached). Total core length 1-2 cm (includes both cortices and intervening trabecular bone).

Core harvest: Rotate trephine 360 degrees to shear bone core at base. Withdraw trephine. Extract core from trephine lumen using obturator or probe (push from proximal end, core exits distal end).

Specimen handling: Place core immediately in fixative (70% ethanol preferred for histomorphometry; formalin acceptable). DO NOT allow to dry (artifact). Label with patient ID, side (left/right ilium), orientation (mark anterior/superior end with suture or ink).

Hemostasis and Wound Closure

Direct pressure: Apply gauze soaked with 1:1000 epinephrine to biopsy site. Hold firm pressure 5-10 minutes.

Bone wax (if bleeding from cortical bone edges): Apply small amount (pea-sized) to exposed cortical surfaces. Press into bone to seal vascular channels.

Gelfoam or thrombin-soaked gauze: Pack into biopsy cavity if persistent oozing. Leave in situ (absorbed over days-weeks).

Reassess: Remove pressure, observe for 1-2 minutes. If no active bleeding, proceed to closure. If bleeding continues, re-apply pressure or add hemostatic agent.

Skin closure: Single interrupted 3-0 or 4-0 nylon suture (stab incision small, one suture usually sufficient). Alternative: Skin glue (Dermabond), adhesive strips (Steri-Strips).

Subcutaneous closure: Not required for small incision (5-8 mm).

Dressing: Sterile gauze and adhesive tape (Tegaderm, Opsite). Compression dressing (elastic bandage wrapped around pelvis) for 4-6 hours (reduce hematoma risk).

Suture removal: 7-10 days (outpatient). If skin glue used, no removal needed (sloughs in 7-14 days).

Immediate: Observe 30-60 minutes for bleeding, hematoma. Check dressing, vital signs. Ensure patient can ambulate safely (avoid syncope from sedation or vasovagal response).

Activity: Avoid strenuous activity 24-48 hours (heavy lifting, running, jumping). Walking and light activities acceptable.

Analgesia: NSAIDs or acetaminophen as needed. Ice pack to site 20 minutes every 2-3 hours for 24 hours (reduce swelling, pain).

Warning signs: Contact provider if excessive pain, expanding hematoma (greater than 5 cm diameter), wound dehiscence, signs of infection (fever, purulent drainage, erythema). Infection rate less than 1% with sterile technique.

Histomorphometric Processing and Analysis

Specimen Processing - Undecalcified Bone

Staining and Microscopy

Histomorphometric Interpretation

Complications of Abnormal Bone Remodeling

Complications categorized by remodeling state:

Medication-Related Complications of Remodeling Therapies

Systemic and Metabolic Complications of Abnormal Remodeling

Rare Complications and Long-Term Sequelae

Rare (less than 1% of Paget patients) but devastating complication: Pagetic bone undergoes malignant transformation to osteosarcoma, fibrosarcoma, or chondrosarcoma.

Risk factors: Long-standing polyostotic Paget disease (greater than 10 years duration), extensive skeletal involvement, skull or facial bone Paget.

Clinical presentation: New onset severe bone pain in previously stable pagetic bone. Rapidly enlarging soft tissue mass. Pathological fracture through pagetic bone. Constitutional symptoms (weight loss, fatigue).

Investigations: Radiograph shows aggressive lytic destruction of pagetic bone with soft tissue mass, cortical breakthrough, sunburst periosteal reaction (osteosarcoma). BSAP: May increase further above baseline pagetic level. MRI: Large soft tissue mass with bone marrow replacement, enhancing tumor. Biopsy: Malignant spindle cells (osteosarcoma), malignant cartilage (chondrosarcoma), or malignant fibrous tissue (fibrosarcoma) arising from pagetic bone.

Prognosis: Very poor, 5-year survival less than 10%. Metastasize early (lung).

Management: Wide resection if feasible (limb salvage or amputation), neoadjuvant chemotherapy (MAP protocol: methotrexate, doxorubicin, cisplatin, same as primary osteosarcoma), adjuvant chemotherapy, palliative radiotherapy if unresectable. Control underlying Paget with bisphosphonates (reduce bone turnover in non-transformed areas).

Pathophysiology: Immobilization (bedrest, spinal cord injury, prolonged casting) causes disuse osteoporosis with increased bone resorption and decreased formation (uncoupled remodeling). In patients with pre-existing high-turnover remodeling (Paget, hyperthyroidism, adolescents with rapid bone growth), immobilization superimposes further resorption, causing hypercalcemia.

Clinical scenario: Adolescent with femur fracture treated with traction/casting, develops nausea, confusion, polyuria 2-3 weeks post-injury. Or: Paget patient with hip fracture, bedbound post-surgery, develops symptomatic hypercalcemia.

Investigation: Calcium greater than 2.75 mmol/L (greater than 11 mg/dL). PTH suppressed. CTX markedly elevated (reflects combined immobilization and pre-existing high turnover). Ionized calcium elevated (confirms true hypercalcemia).

Management: IV hydration (restore volume, increase renal calcium excretion). Mobilization as soon as possible (most effective treatment, mechanical loading suppresses resorption). Bisphosphonate: Pamidronate 60-90 mg IV or zoledronate 4 mg IV (if severe hypercalcemia, greater than 3.0 mmol/L, or immobilization expected to continue). Calcitonin: Bridge therapy for rapid effect. Avoid thiazide diuretics (reduce renal calcium excretion, worsen hypercalcemia). Loop diuretics (furosemide) only after adequate hydration (prevent volume depletion).

Prevention: Early mobilization post-fracture/surgery. Adequate hydration in immobilized patients. Consider prophylactic bisphosphonate in high-risk patients (Paget, adolescents with expected prolonged immobilization).

Paradox: Teriparatide increases bone formation and BMD, but early in treatment (first 3-6 months), transient increase in stress fracture risk reported in some studies.

Proposed mechanism: Teriparatide increases bone remodeling (both formation and resorption, though net balance favors formation). Increased remodeling space transiently weakens bone (remodeling space is areas of active resorption/formation, mechanically weaker than quiescent bone). After 6-12 months, new bone formation fills remodeling space, strength increases.

Clinical evidence: Conflicting data. Some RCTs show small increase in stress fractures in first 6 months (relative risk 1.5-2.0), others show no increase. Fracture risk overall decreases with teriparatide (vertebral fracture risk reduction 65% vs placebo).

Clinical approach: Warn patients of theoretical transient stress fracture risk. Avoid high-impact activities in first 3 months of teriparatide (allow bone formation to catch up). Monitor for new bone pain (may indicate stress reaction). If stress fracture occurs during teriparatide, continue therapy (promotes healing, do not stop). Overall benefit outweighs transient risk.

Recognition and Prevention of Complications

Monitoring Patients on Remodeling-Modulating Therapies

General principles:

• Regular monitoring ensures treatment efficacy, identifies non-responders, detects complications early
• Monitoring frequency depends on drug type, baseline fracture risk, comorbidities
• Key parameters: Bone mineral density (DEXA), bone turnover markers (BTMs), calcium and vitamin D levels, clinical fractures, adverse events

Monitoring Antiresorptive Therapy (Bisphosphonates, Denosumab)

Monitoring Anabolic Therapy (Teriparatide, Romosozumab)

Management of Specific Monitoring Scenarios

Higher risk than oral bisphosphonates due to rapid, potent suppression of bone resorption.

Risk factors: Vitamin D deficiency (25-OH vitamin D less than 30 nmol/L), chronic kidney disease (eGFR less than 45, impaired vitamin D activation), hypoparathyroidism, malabsorption, prior parathyroidectomy.

Timing: Typically 7-10 days after denosumab or zoledronate administration (nadir of calcium, maximal suppression of resorption).

Clinical features: Asymptomatic (mild, calcium 2.0-2.1 mmol/L) to severe (calcium less than 1.9 mmol/L, symptomatic). Symptoms: Perioral numbness, paresthesias (hands, feet), muscle cramps, tetany (carpopedal spasm), seizures (severe). Chvostek sign (facial twitch with tapping facial nerve), Trousseau sign (carpopedal spasm with BP cuff inflation).

Prevention:

• Measure vitamin D before denosumab or IV bisphosphonate
• If vitamin D less than 50 nmol/L: Supplement BEFORE drug administration (loading dose 50,000 IU weekly x 4-8 weeks until greater than 50 nmol/L)
• Ensure adequate calcium intake (1200 mg/day dietary or supplemental)
• In CKD patients (eGFR less than 45): Consider calcitriol (active vitamin D, 0.25 mcg daily) instead of cholecalciferol (requires renal activation), give 1-2 weeks before denosumab
• After administration: Monitor calcium at 7-10 days (especially high-risk patients)

Management if hypocalcemia occurs:

• Mild asymptomatic (calcium 2.0-2.1 mmol/L): Oral calcium carbonate 1-2 g elemental calcium three times daily, calcitriol 0.5 mcg twice daily, recheck calcium in 3-5 days
• Moderate symptomatic or severe (calcium less than 2.0 mmol/L): IV calcium gluconate 10% 10-20 mL (1-2 g elemental calcium) in 50-100 mL normal saline over 10-20 minutes, then infusion 1-2 mg/kg/hr elemental calcium. Oral calcium and calcitriol. Monitor calcium every 4-6 hours, adjust infusion to maintain calcium 2.0-2.2 mmol/L. Continue IV calcium 24-48 hours, transition to oral. Check magnesium (hypomagnesemia impairs PTH secretion, correct if less than 0.7 mmol/L).
• Do not withhold next denosumab dose (hypocalcemia transient, ensure adequate vitamin D and calcium beforehand).

Incident fragility fracture while on therapy suggests inadequate treatment, though not all fractures are treatment failures.

Assess fracture type and context:

• Low-energy fragility fracture (fall from standing height or less, fracture site: vertebral, hip, distal radius, proximal humerus): Suggests treatment failure, requires escalation.
• High-energy trauma fracture (motor vehicle accident, fall from height): Not treatment failure, continue current therapy.
• First fracture on therapy vs multiple fractures: Single fracture after 6-12 months therapy may be pre-existing microarchitectural damage (treatment needs more time). Multiple fractures or fracture within first 3 months suggests severe disease or non-response.

Investigations after incident fracture:

• DEXA (if not done in last 12 months): Assess BMD change on therapy
• BTMs (CTX, P1NP): Assess biochemical response to current therapy
• Secondary osteoporosis workup (see Basic tab, viva scenario)
• Compliance assessment
• Lateral thoracolumbar radiograph: Detect prevalent vertebral fractures (may have additional asymptomatic fractures indicating high risk)

Management decision algorithm:

• Fracture on oral bisphosphonate, compliant, adequate vitamin D: Switch to more potent antiresorptive (IV zoledronate 5 mg annually or denosumab 60 mg SC every 6 months).
• Fracture on IV bisphosphonate or denosumab, compliant, adequate vitamin D: Switch to anabolic therapy (teriparatide 20 mcg SC daily x 24 months or romosozumab 210 mg SC monthly x 12 months, then transition to denosumab).
• Multiple fractures or very high risk (T-score less than -3.5, prevalent vertebral fractures): Immediate anabolic therapy (teriparatide or romosozumab), then transition to denosumab.
• Fracture due to non-compliance or vitamin D deficiency: Address compliance, optimize vitamin D (target greater than 75 nmol/L), continue or intensify current therapy.
• Fracture due to secondary cause (hyperthyroidism, myeloma, etc.): Treat underlying cause, consider anabolic therapy if high risk.

Systematic approach to early detection in patients on bisphosphonates greater than 5 years or any duration denosumab.

Patient education (proactive at year 5 of bisphosphonates):

• Educate patient about AFF risk (rare, approximately 1 in 1,000 with greater than 5 years therapy)
• Instruct to report new thigh, groin, or hip pain immediately (70% have prodromal pain before complete fracture)
• Explain warning signs: Dull aching thigh pain, bilateral symptoms, pain with weight-bearing

Annual clinical assessment (years 5+):

• Ask specifically: "Any new thigh or groin pain in the past year?"
• If yes: Examine lateral femoral shaft for tenderness, perform single-leg stance test (pain suggests stress reaction), order radiographs entire femur (AP and lateral, hip to knee) bilaterally

Radiographic surveillance (controversial, not standard but consider in high-risk):

• Some experts recommend: Femur radiographs (AP and lateral) at year 5, then every 2-3 years if continuing bisphosphonates
• High-risk for AFF surveillance: Asian ethnicity (higher risk), glucocorticoid use (alters bone quality), bisphosphonate greater than 10 years, bilateral hip geometry (high femoral neck-shaft angle, anterolateral bowing)
• Look for: Lateral cortex thickening, periosteal beaking, lucent line in lateral cortex

If incomplete AFF detected:

• Stop bisphosphonates immediately (drug holiday)
• Orthopaedic referral urgently (same week)
• Protected weight-bearing (crutches, toe-touch only affected side)
• Calcium 1200 mg/day, vitamin D 2000 IU/day
• Teriparatide 20 mcg SC daily (discuss with orthopaedics, may enhance healing, off-label)
• Serial radiographs every 4-6 weeks
• Orthopaedic decision: Prophylactic IM nail vs conservative management (depends on fracture extent, pain severity, patient factors)
• Contralateral femur: If bilateral incomplete AFF, consider prophylactic bilateral nailing
• Do not restart antiresorptive until fracture healed (6-12 months), then if needed, denosumab preferred over bisphosphonates (though AFF reported with denosumab too)

Long-Term Management Decisions

Outcomes of Remodeling-Modulating Therapies

Key outcome measures:

• Fracture risk reduction (primary outcome, clinical benefit)
• BMD improvement (surrogate outcome, correlates with fracture reduction)
• Bone turnover marker suppression or increase (biochemical response)
• Safety and tolerability (adverse events, treatment discontinuation)

Antiresorptive Therapy Outcomes

Anabolic Therapy Outcomes

Comparative Efficacy

Long-Term Outcomes and Durability

Long-term extension trials demonstrate sustained but plateauing benefit.

FLEX trial (FosamaX Long-term Extension):

• Design: Women who completed 5 years alendronate (FIT trial) randomized to continue alendronate (5 or 10 mg daily) vs placebo x 5 more years (total 10 years alendronate vs 5 years alendronate + 5 years placebo).
• BMD findings: Continued alendronate maintained BMD at lumbar spine (stable, no further increase). Discontinuation group lost 2-3% spine BMD over 5 years (but remained above baseline). Hip BMD stable in both groups (bisphosphonate residual effect from first 5 years).
• Fracture findings: Continued alendronate reduced clinical vertebral fractures 55% vs discontinuation group (2.4% vs 5.3%, NNT 34). Non-vertebral fractures: No significant difference (residual effect from first 5 years protects discontinuation group). Morphometric vertebral fractures: No difference (suggests 5 years sufficient for low-risk patients).
• Conclusion: Continue alendronate beyond 5 years if high fracture risk (prior vertebral fracture, very low BMD). Consider drug holiday if low risk (no fractures on therapy, T-score greater than -2.5).

HORIZON extension (zoledronate 6 years vs 3 years):

• Design: Women who completed 3 years zoledronate randomized to 3 more years zoledronate vs placebo (total 6 years vs 3 years).
• BMD: Continued zoledronate maintained spine BMD. Discontinuation group lost 1-2% (less than alendronate discontinuation, zoledronate more potent residual effect).
• Fractures: Morphometric vertebral fractures 50% reduced with continued zoledronate vs placebo (14% vs 25%, NNT 9 in high-risk subset). Non-vertebral fractures: No difference.
• Conclusion: Continue zoledronate 6 years in very high-risk patients (low BMD, prior fractures). May stop at 3 years in lower-risk patients (residual effect provides continued protection).

Key principle: Bisphosphonates accumulate in bone, providing residual anti-fracture effect for 2-5 years after discontinuation (longer half-life drugs like zoledronate have longer residual effect than alendronate). Drug holidays reasonable in low-risk patients after 5 years, but high-risk patients benefit from continued therapy.

FREEDOM extension demonstrates sustained benefit but NO residual effect after stopping.

FREEDOM extension (up to 10 years denosumab):

• Design: Women who completed 3 years denosumab (FREEDOM trial) continued denosumab 60 mg SC every 6 months for up to 7 additional years (total 10 years).
• BMD findings: BMD continued to increase throughout 10 years. Lumbar spine +21% from baseline at 10 years (vs +13% at 3 years, continued linear increase). Total hip +9% at 10 years (vs +6% at 3 years). No plateau effect (unlike bisphosphonates).
• Fracture findings: Fracture rates remained low throughout 10 years (annual vertebral fracture rate 1-2%, non-vertebral 1-3%). No loss of anti-fracture efficacy over time. Suggests continued benefit with long-term use.
• Safety: AFF incidence 0.8 per 10,000 patient-years (rare but present). MRONJ incidence 5.2 per 10,000 patient-years (slightly higher than bisphosphonates). Overall favorable risk-benefit ratio.
• Critical finding - OFF-treatment data: Participants who stopped denosumab after 2-7 years: BMD rapidly decreased (lost 50-100% of BMD gains within 12 months), bone turnover markers rebounded above baseline, multiple vertebral fractures occurred in 10-15% (7-20 months after last dose).

Conclusion: Denosumab provides continued benefit for 10+ years (no plateau). However, stopping denosumab is high-risk (rapid bone loss, rebound vertebral fractures). Transition to bisphosphonate mandatory if discontinuing (see Management section). Denosumab is essentially lifelong therapy unless transitioned to bisphosphonate.

Sequencing matters: Order of therapies affects outcomes.

Teriparatide followed by antiresorptive (correct sequence):

• Design: Patients receive teriparatide 24 months, then transition to alendronate or denosumab.
• Outcomes: BMD increases from teriparatide maintained or further increased with subsequent antiresorptive. Alendronate after teriparatide: Spine BMD stable, hip BMD continues to increase slightly (+1-2% over 2 years). Denosumab after teriparatide: Spine and hip BMD continue to increase (+3-5% over 2 years, denosumab more potent). Fracture protection sustained.
• Conclusion: Effective sequence, BMD gains consolidated.

Bisphosphonate followed by teriparatide (WRONG sequence):

• Design: Patients on bisphosphonates (alendronate) for 1-5 years, then switch to teriparatide.
• Outcomes: Blunted teriparatide response. Patients pre-treated with bisphosphonates have 50% less BMD increase with teriparatide vs bisphosphonate-naive patients (spine +6% vs +12% at 18 months). Mechanism: Bisphosphonates suppress bone turnover profoundly, reducing remodeling space for teriparatide to build new bone. Effect worse with longer bisphosphonate duration and more potent bisphosphonates (zoledronate blunts more than alendronate).
• Recommendation: If patient on bisphosphonates needs escalation to anabolic therapy: (1) Stop bisphosphonate 6-12 months before starting teriparatide (allow remodeling to resume), OR (2) Use romosozumab instead (less affected by prior bisphosphonates than teriparatide).

Romosozumab followed by denosumab (correct sequence):

• Design: FRAME trial - romosozumab 12 months, then denosumab 12 months.
• Outcomes: BMD continues to increase with denosumab after romosozumab. Spine +17% with romosozumab at 12 months, +18% at 24 months (continued increase with denosumab). Fracture reduction maintained and enhanced (cumulative effect).
• Conclusion: Optimal sequence for severe osteoporosis.

Romosozumab followed by alendronate (WRONG sequence):

• Design: ARCH trial - romosozumab 12 months, then alendronate 12 months vs alendronate throughout.
• Outcomes: BMD decreased with alendronate after romosozumab. Spine BMD +13% at 12 months (romosozumab), then decreased to +11% at 24 months (lost 2% after switching to alendronate). Mechanism unknown (possibly romosozumab's antiresorptive effect occupies bisphosphonate binding sites).
• Recommendation: NEVER give bisphosphonate after romosozumab. Only denosumab maintains romosozumab BMD gains.

Combination therapy (teriparatide + denosumab simultaneous):

• Design: DATA trial - teriparatide alone vs denosumab alone vs both together x 24 months.
• Outcomes: Combination superior to either alone. Spine BMD: Teriparatide +10%, denosumab +6%, combination +17% (additive effect). Mechanism: Teriparatide increases formation, denosumab prevents any concomitant resorption increase (uncouples formation from resorption).
• Limitations: Very expensive, no fracture data (BMD surrogate only), not standard practice. Reserved for research or extreme cases (e.g., pregnancy-associated osteoporosis with multiple fractures).

Safety Outcomes and Risk-Benefit Analysis