PAGET'S DISEASE OF BONE
Osteoclast Hyperactivity | Bone Remodeling Disorder | Bisphosphonate Responsive
DISEASE PHASES
Critical Must-Knows
- Pathophysiology: Abnormal osteoclast activity leads to disorganized bone remodeling with woven bone
- Biochemistry: Elevated alkaline phosphatase (ALP) with normal calcium and phosphate
- Radiology triad: Bone expansion, cortical thickening, trabecular coarsening
- First-line treatment: Bisphosphonates (zoledronic acid single dose highly effective)
- Orthopaedic complications: Pathological fracture, deformity, arthritis, sarcomatous change
Examiner's Pearls
- "Normal calcium differentiates from hyperparathyroidism and malignancy
- "Flame-shaped or V-shaped lytic lesions on X-ray are pathognomonic
- "Sarcomatous transformation presents as sudden pain increase with soft tissue mass
- "Prophylactic bisphosphonates reduce perioperative bleeding for elective surgery
Clinical Imaging
Imaging Gallery
Critical Paget's Disease Exam Points
Biochemical Profile Distinguishes
Elevated ALP with normal calcium and phosphate is the hallmark. Calcium elevation suggests immobilization hypercalcemia or malignancy. PTH is normal, distinguishing from hyperparathyroidism.
Three Radiological Phases
Lytic phase (osteoporosis circumscripta in skull), mixed phase (blade of grass in long bones), sclerotic phase (dense cotton wool appearance). Most lesions show mixed pattern.
Bisphosphonates Are First-Line
Zoledronic acid 5mg single IV dose is now standard of care. Reduces bone pain, normalizes ALP in 90% by 6 months. Oral alendronate or risedronate are alternatives. Indications: symptoms, high-risk sites, preoperative.
Sarcomatous Change Is Rare But Devastating
1% lifetime risk but extremely poor prognosis. Suspect with sudden pain increase, soft tissue mass, lytic expansion on X-ray. Most are osteosarcoma. Requires wide resection or amputation with chemotherapy.
At a Glance
Paget's disease of bone is a chronic disorder of excessive and disorganized bone remodeling characterized by elevated alkaline phosphatase with normal calcium and phosphate—distinguishing it from hyperparathyroidism and malignancy. Three radiographic phases exist: lytic (osteoporosis circumscripta in skull), mixed (blade of grass/flame sign in long bones), and sclerotic (cotton wool appearance). Most patients are asymptomatic (70-80%); when symptomatic, zoledronic acid 5mg IV single dose is first-line treatment, normalizing ALP in 90% by 6 months. Orthopaedic complications include pathological transverse stress fractures, secondary arthritis, and sarcomatous transformation (1% risk) presenting as sudden pain increase with soft tissue mass—typically osteosarcoma with extremely poor prognosis.
PAGETPAGET - Key Features of Paget's Disease
Memory Hook:PAGET - elevated Phosphatase, often Asymptomatic, Geographic pattern, bone Expansion, Trabecular changes
FASTCOMPLICATIONS - Orthopaedic Problems in Paget's
Memory Hook:FAST complications require urgent orthopaedic assessment
Overview and Epidemiology
Paget's disease of bone is a chronic disorder of excessive and disorganized bone remodeling. Second most common metabolic bone disease after osteoporosis.
Epidemiology:
- 3-4% prevalence over age 55
- Male predominance (M:F 3:2)
- 70-80% asymptomatic
- High in UK/Australia/NZ, rare in Asia/Africa
- Familial clustering (15-30% have affected relative)
Orthopaedic relevance: Pathological fractures, deformity, secondary arthritis, increased operative bleeding, implant fixation challenges.
Pathophysiology and Bone Biology
Cellular Mechanism
Disease Progression
Excessive osteoclast activity with abnormally large multinucleated osteoclasts (up to 100 nuclei vs normal 3-5). Rapid bone resorption exceeds formation. Radiology shows advancing lytic fronts (flame-shaped or blade-of-grass lesions).
Osteoblasts attempt to repair but lay down disorganized woven bone instead of lamellar bone. Mosaic pattern on histology. Bone is mechanically weak despite increased mass. Most symptomatic disease occurs in this phase.
Osteoblast predominance with dense, sclerotic bone formation. Reduced turnover but bone remains structurally abnormal. Cotton-wool appearance on X-ray. May still have complications despite reduced activity.
The Woven Bone Problem
The disorganized woven bone in Paget's is structurally weaker than normal lamellar bone despite appearing denser on imaging. This creates susceptibility to stress fractures (especially lateral femoral cortex, anterior tibial cortex) and pathological fractures with minimal trauma.
Etiology
Multifactorial: SQSTM1 gene mutations (15-30% familial cases), chromosome 18q abnormalities. Slow virus hypothesis (measles paramyxovirus) not proven. Geographic clustering and declining incidence suggest environmental trigger.
Principles and Core Concepts
The Pathognomonic Triad
Paget's disease is defined by three cardinal features:
1. Biochemical Hallmark: Elevated ALP with Normal Calcium
- Alkaline phosphatase reflects osteoblast activity (10-15x normal in active disease)
- Normal calcium distinguishes from malignancy and hyperparathyroidism
- Normal phosphate and PTH confirm isolated bone remodeling disorder
2. Radiological Hallmark: Bone Expansion with Cortical Thickening
- Increased bone diameter (expansion)
- Cortical thickening (widened cortex)
- Trabecular coarsening (thickened trabeculae)
- Mixed lytic-sclerotic pattern in active disease
3. Histological Hallmark: Mosaic Woven Bone
- Disorganized woven bone instead of lamellar bone
- Mosaic cement lines (multiple resorption-formation cycles)
- Giant osteoclasts (up to 100 nuclei)
- Mechanically weak despite increased bone mass
Clinical Principles
Key facts for orthopaedic surgeons:
- 70-80% asymptomatic (incidental finding on X-ray or bloods)
- Geographic variation (high in UK/Australia, rare in Asia/Africa)
- Zoledronic acid single dose: 90% ALP normalization, 2+ year remission
- Preoperative bisphosphonates reduce bleeding 40-50%
Orthopaedic impact:
- Pathological fractures need long implants bypassing pagetic bone
- Joint arthroplasty requires cemented long-stem components
- Hyperemic bone causes significant operative bleeding
- Deformity correction complicated by altered anatomy
Clinical Assessment
History
Most patients are asymptomatic (70-80% discovered incidentally). When symptomatic:
Skeletal Symptoms
- Bone pain: Deep, aching, worse at night
- Deformity: Bowing of long bones, skull enlargement
- Fracture: Minimal trauma or stress fracture
- Arthritis pain: Hip, knee adjacent to pagetic bone
Systemic Features (Rare)
- High-output cardiac failure: Extensive disease (greater than 35% skeleton)
- Nerve compression: Skull base (CN VIII deafness), spine (stenosis)
- Hypercalcemia: During immobilization
- Warmth over bone: Increased vascularity
Examination
Inspection:
- Bone enlargement (skull circumference increased, tibial bowing, femoral bowing)
- Skin warmth over affected bone (hypervascularity)
- Gait abnormality (leg length discrepancy, joint deformity)
Palpation:
- Bone tenderness over active lesions
- Increased temperature over pagetic bone
- Joint effusions if secondary arthritis
Neurological:
- Cranial nerve examination (skull base involvement)
- Spinal cord signs if vertebral disease with stenosis
Hat Size Increase - Classic Sign
Patients may report needing larger hat sizes due to progressive skull enlargement. This is a classic history finding in advanced skull Paget's. Similarly, tibial bowing may require shoe modifications.
Biochemical and Imaging Investigations
Biochemistry
Biochemical Profile in Paget's Disease
| Test | Finding | Interpretation | Differential |
|---|---|---|---|
| Alkaline Phosphatase (ALP) | Elevated (10-15x normal) | Reflects osteoblast activity and disease extent | Liver disease, bone metastases, hyperparathyroidism |
| Serum Calcium | Normal | Distinguishes from malignancy and hyperPTH | Elevated if immobilized or rare hypercalcemia |
| Serum Phosphate | Normal | Normal bone mineralization | Abnormal in renal osteodystrophy |
| PTH | Normal | Excludes primary hyperparathyroidism | Elevated in hyperPTH |
| Bone turnover markers | Elevated (urine N-telopeptide, serum CTX) | Reflects osteoclast activity, monitors treatment | Used to assess treatment response |
Normal Calcium Distinguishes Paget's
Elevated ALP with normal calcium and phosphate is diagnostic. If calcium is elevated, consider immobilization hypercalcemia, malignancy, or coexistent hyperparathyroidism. Check PTH and 25-OH vitamin D to differentiate.
Radiology
Plain radiographs are diagnostic in most cases:
Skull Paget's Radiological Features
Lytic phase:
- Osteoporosis circumscripta (geographic lytic area)
Mixed/sclerotic phase:
- Cotton-wool appearance (patchy sclerosis)
- Cortical thickening (skull base, calvarium)
- Basilar invagination (platybasia)
Complications:
- Cranial nerve foramina narrowing
- Inner table thickening
These findings help distinguish Paget's from other skull pathology.
Nuclear Medicine
Bone scan (Tc-99m MDP): Highly sensitive for active lesions. Shows increased uptake at pagetic sites. Useful for determining disease extent before treatment. Cannot distinguish from metastases (need X-ray correlation). Helpful for planning surgery, detecting polyostotic disease, and monitoring response.
Management Algorithm
Bisphosphonates - First-Line Treatment
Mechanism: Inhibit osteoclast activity, reduce bone turnover, normalize ALP
Bisphosphonate Options for Paget's Disease
| Agent | Dosing | Efficacy | Indications |
|---|---|---|---|
| Zoledronic acid (IV) | 5mg single infusion | 90% ALP normalization at 6 months, durable response years | First-line, convenient, high efficacy |
| Alendronate (oral) | 40mg daily × 6 months | 70-80% ALP normalization | Alternative if IV not tolerated |
| Risedronate (oral) | 30mg daily × 2-3 months | 75-85% ALP normalization | Oral option, shorter course |
| Pamidronate (IV) | 60-90mg infusions | Effective but multiple doses required | Second-line if zoledronic acid unavailable |
Indications for Treatment
Symptomatic disease:
- Bone pain attributable to Paget's
- Neurological complications (nerve compression)
- High-output cardiac failure (rare)
High-risk lesions (even if asymptomatic):
- Weight-bearing long bones (risk of fracture/deformity)
- Skull base involvement (risk of cranial nerve compression)
- Spine with stenosis risk
- Juxta-articular disease (risk of secondary arthritis)
Preoperative optimization:
- Planned surgery on pagetic bone (reduce vascularity and bleeding)
- Give bisphosphonate 3-6 months before elective surgery
Bisphosphonate Side Effects
Acute phase reaction (fever, myalgia) occurs in 30% after IV bisphosphonate, managed with paracetamol. Rare complications: osteonecrosis of jaw (dental hygiene critical), atypical femoral fractures (long-term use). Ensure adequate calcium and vitamin D before treatment.
Calcium and Vitamin D Supplementation
Always coadminister:
- Calcium 1000-1200mg daily
- Vitamin D 800-1000 IU daily
- Prevents hypocalcemia after bisphosphonate treatment
- Optimizes bone health
Monitoring
ALP at 3, 6, 12 months (goal: normalize or 75% reduction). Rising ALP = reactivation. Bone turnover markers (NTX, CTX) more sensitive.
Surgical Management and Orthopaedic Complications
Indications for Surgery
Fracture Management
- Pathological fractures: Fixation often required
- Stress fractures: Prophylactic fixation if high-risk (femoral neck)
- Nonunion: May require bone graft and revision fixation
Reconstructive Surgery
- Joint arthroplasty: Secondary arthritis (hip most common)
- Corrective osteotomy: Severe deformity affecting function
- Decompression: Spinal stenosis, nerve root compression
Preoperative Optimization
Bisphosphonate treatment 3-6 months before surgery:
- Reduces bone vascularity
- Decreases operative blood loss (up to 50% reduction)
- Normalizes bone turnover
- Improves fixation quality
Cross-match blood:
- Pagetic bone highly vascular
- Risk of significant intraoperative bleeding
- Have blood products available
Operative Considerations
Surgical Challenges in Pagetic Bone
| Challenge | Mechanism | Management Strategy |
|---|---|---|
| Increased bleeding | Hypervascularity of pagetic bone | Preop bisphosphonate, tourniquet, cell saver, controlled hypotension |
| Altered anatomy | Bone expansion, deformity | Preop CT for templating, custom implants if needed |
| Poor fixation | Soft woven bone | Cement augmentation, long-stem components, prophylactic cerclage |
| Fracture propagation | Weak bone during manipulation | Gentle handling, prophylactic fixation extensions |
Total Hip Arthroplasty in Paget's
Special considerations:
- Altered femoral anatomy (bowing, coxa vara)
- Acetabular protrusion common
- Use cemented long-stem femoral component (better fixation in soft bone)
- Consider cementless acetabular component with screw fixation
- Higher rate of heterotopic ossification (consider prophylaxis with indomethacin or radiation)
Cement Fixation Preferred in Pagetic Bone
Cemented femoral stems provide better fixation in the soft woven bone of Paget's disease compared to press-fit cementless stems. Long-stem components bypass deformity and stress risers. Acetabular components can be cementless if bone quality adequate.
Complications
Major Complications of Paget's Disease
| Complication | Incidence | Presentation | Management |
|---|---|---|---|
| Pathological fracture | 10-30% lifetime risk | Minimal trauma fracture, stress fracture (femur, tibia) | Fixation (often requires long plates/nails), bisphosphonates |
| Secondary arthritis | Common in hip/knee | Progressive joint pain, stiffness, juxta-articular disease | Arthroplasty (THA most common), preop bisphosphonate |
| Sarcomatous transformation | 1% lifetime risk | Sudden pain increase, soft tissue mass, rapid lytic expansion | Biopsy, staging, wide resection or amputation + chemo |
| Deformity | Common (tibia, femur) | Progressive bowing, leg length discrepancy, gait abnormality | Corrective osteotomy if severe functional impairment |
| Neurological compression | Skull base, spine | Deafness (CN VIII), spinal stenosis, radiculopathy | Bisphosphonates, surgical decompression if progressive |
| Hypercalcemia | Rare (immobilization) | Polyuria, confusion, immobilization triggers | Hydration, bisphosphonates, mobilize patient |
Sarcomatous Transformation - Suspect When Pain Changes
Osteosarcoma (most common), fibrosarcoma, or malignant fibrous histiocytoma can arise in pagetic bone (1% lifetime risk). Suspect when sudden increase in pain, soft tissue mass, rapid radiological change. Prognosis is poor (5-year survival under 10%). Requires biopsy, staging MRI/CT, wide resection or amputation with chemotherapy.
Evidence Base and Key Studies
Zoledronic Acid vs Risedronate in Paget's Disease
- Randomized trial: 357 patients with Paget's disease
- Zoledronic acid 5mg single IV dose vs risedronate 30mg daily × 2 months
- Zoledronic acid achieved 96% therapeutic response (ALP normalization) vs 74% risedronate at 6 months
- Remission duration significantly longer with zoledronic acid (median greater than 2 years)
Bisphosphonate Use Before Elective Surgery Reduces Bleeding
- Retrospective cohort: 50 patients undergoing elective surgery on pagetic bone
- Preoperative bisphosphonate treatment (3-6 months) reduced intraoperative blood loss by 40-50%
- Normalized bone turnover markers associated with reduced bleeding complications
- No difference in surgical outcomes or complications between treated vs untreated
Total Hip Arthroplasty Outcomes in Paget's Disease
- Case series: 43 THAs in patients with Paget's disease
- Higher complication rate compared to osteoarthritis THAs (15% vs 5%)
- Increased blood loss (mean 1200mL vs 600mL)
- Cemented long-stem components had better survivorship than short stems
- Heterotopic ossification rate higher (20% vs 5%)
Exam Viva Scenarios
Practice these scenarios to excel in your viva examination
Scenario 1: Incidental Diagnosis and Treatment Decision
"A 68-year-old man has routine blood tests showing alkaline phosphatase of 850 U/L (normal 30-120 U/L). Calcium, phosphate, and PTH are normal. He has no bone pain or symptoms. Pelvic X-ray shows cortical thickening and trabecular coarsening of the left hemipelvis. How do you assess and manage this patient?"
Scenario 2: Pathological Fracture Management
"A 72-year-old woman with known Paget's disease affecting her right femur presents with sudden onset thigh pain after a minor fall. X-ray shows a complete transverse fracture through pagetic bone in the mid-femoral shaft. Discuss your management approach."
MCQ Practice Points
Biochemical Diagnosis
Q: What is the characteristic biochemical profile of Paget's disease of bone?
A: Elevated alkaline phosphatase (ALP) with NORMAL serum calcium and phosphate. This distinguishes Paget's from hyperparathyroidism (elevated calcium with elevated PTH) and malignancy (elevated calcium with suppressed PTH). ALP can be elevated 10-15x normal, reflecting high bone turnover.
Radiological Phases
Q: What are the three radiological phases of Paget's disease and their characteristic appearances?
A: Lytic phase: Osteoporosis circumscripta (skull), advancing V-shaped or flame-shaped lytic lesion (long bones). Mixed phase: Active remodeling with "blade of grass" appearance. Sclerotic phase: Dense cortical thickening, trabecular coarsening, "cotton wool" skull appearance. Most lesions show mixed pattern.
Most Common Site
Q: What is the most commonly affected site in Paget's disease?
A: Pelvis (70% of polyostotic cases). Order of frequency: pelvis, spine (lumbar more than thoracic), femur, skull, tibia. Paget's typically affects the axial skeleton but spares hands and feet. Monostotic disease occurs in 15-30% of cases.
Sarcomatous Transformation
Q: What clinical features suggest sarcomatous transformation in a patient with known Paget's disease?
A: Sudden increase in pain with new soft tissue mass and rapid lytic expansion on imaging. Risk is approximately 1% lifetime but prognosis is devastating (median survival 6-12 months). Most are osteosarcoma (65%), followed by fibrosarcoma and chondrosarcoma. Requires wide resection/amputation with chemotherapy.
Australian Context
Epidemiology in Australia: Paget's disease is relatively common in Australia, particularly in those of Anglo-Celtic descent. Prevalence increases with age, affecting approximately 3-4% of those over 55 years.
PBS-Listed Bisphosphonates: Zoledronic acid (5mg IV single dose) and risedronate are PBS-subsidised for Paget's disease treatment. Zoledronic acid is preferred for its efficacy and single-dose convenience.
Therapeutic Guidelines: Australian Therapeutic Guidelines recommend bisphosphonate treatment for symptomatic disease, elevated ALP greater than twice normal, or prior to surgery on pagetic bone.
AOANJRR Considerations: Joint replacement in Paget's disease is documented in the Australian Orthopaedic Association National Joint Replacement Registry, with outcomes generally favourable when perioperative bisphosphonates are used.
PAGET'S DISEASE OF BONE
High-Yield Exam Summary
Key Pathophysiology
- •Abnormal osteoclast activity (up to 100 nuclei) leads to excessive bone resorption
- •Osteoblasts lay down disorganized woven bone (not lamellar)
- •Mosaic pattern on histology, mechanically weak despite increased mass
- •Three phases: Lytic, Mixed (active), Sclerotic (burnt-out)
Biochemistry
- •ALP elevated 10-15x normal (reflects osteoblast activity)
- •Calcium NORMAL (key distinguishing feature)
- •Phosphate NORMAL
- •PTH NORMAL (excludes hyperparathyroidism)
Radiology Triad
- •Bone expansion (increased diameter)
- •Cortical thickening (widened cortex)
- •Trabecular coarsening (thickened trabeculae)
- •Flame/V-shaped lytic front (advancing edge), Cotton-wool sclerosis (skull)
Treatment Algorithm
- •First-line: Zoledronic acid 5mg single IV dose
- •Indications: Symptoms, high-risk sites (pelvis/long bones/skull/spine), preoperative
- •Coadminister calcium 1000-1200mg + vitamin D 800-1000 IU daily
- •Monitor ALP at 3, 6, 12 months (goal normalize or 75% reduction)
Surgical Pearls
- •Preop bisphosphonate 3-6 months before elective surgery (reduces bleeding 40-50%)
- •Cross-match blood (pagetic bone highly vascular)
- •Long-stem cemented implants for arthroplasty (better fixation in soft bone)
- •Gentle handling (risk of fracture propagation)
Complications
- •Pathological fracture 10-30% (transverse stress fractures common)
- •Secondary arthritis (hip/knee juxta-articular disease)
- •Sarcomatous transformation 1% (sudden pain increase, soft tissue mass)
- •Deformity (tibial/femoral bowing, skull enlargement)