Paget's Disease and Other Dysplasias of Bone¶

Chapter 424 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 424

Key Clinical Points¶

Paget's disease is a localized bone-remodeling disorder characterized by overactive osteoclastic resorption followed by compensatory osteoblastic formation, resulting in structurally disorganized mosaic bone.
Serum alkaline phosphatase (ALP) is the primary biochemical marker for diagnosis and monitoring of disease activity.
Radiographic hallmarks include 'cotton wool' appearance (skull), 'blade of grass' lytic lesions (advancing wedge), and sclerotic changes.
Zoledronic acid is the first-line pharmacologic therapy, normalizing ALP in ≥90% of patients with a single 5 mg IV infusion.
Complications include fractures (especially in active lytic areas), high-output heart failure, hearing loss, and rare osteosarcoma development.
Osteopetrosis is characterized by impaired osteoclast-mediated resorption, leading to dense but brittle bone and potential marrow failure.
Melorheostosis presents with a 'melted wax' appearance on radiographs and may involve skin changes like hypertrichosis.
Osteopoikilosis features stable, small foci of sclerosis that do not accumulate radionuclide on bone scans.
Hepatric C-associated osteosclerosis (HCAO) is an acquired condition with increased bone mass and elevated ALP.
The RANK pathway (M-CSF, RANKL, OPG) regulates the balance between osteoclast differentiation and inhibition.

DEFINITION & OVERVIEW¶

• Paget's Disease: ◦ A localized bone-remodeling disorder affecting noncontiguous areas of the skeleton. ◦ Pathophysiology: ◦ Initial phase: Overactive osteoclastic resorption → marked hypervascularization (radiographically an advancing lytic wedge or 'blade of grass'). ◦ Second phase: Active bone formation and resorption replace normal lamellar bone with haphazard (woven) bone. ◦ Final phase: Sclerotic phase where resorption declines, resulting in hard, dense, less vascular 'mosaic' bone. ◦ Clinical Impact: ◦ Bone is expanded, less compact, and more vascular → increased susceptibility to deformities and fractures. ◦ Symptoms: Often asymptomatic; symptoms arise from direct involvement (pain, secondary arthritis, fractures) or indirect effects (compression of neural tissue). • Other Dysplasias of Bone: ◦ Osteopetrosis (Marble bone disease / Albers-Schonberg disease). ◦ Pyknodysostosis. ◦ Progressive diaphyseal dysplasia (Camurati-Engelmann disease). ◦ Hyperostosis corticalis generalisata. ◦ Melorheostosis. ◦ Osteopoikilosis. ◦ Hepatitis C-associated osteosclerosis (HCAO).

EPIDEMIOLOGY¶

• Geographic Variation: ◦ High prevalence: Western Europe (Great Britain, France, Germany). ◦ Migration effect: Higher prevalence in populations with European ancestry in Australia, New Zealand, South Africa, and the Americas. ◦ Low prevalence: Native populations of the Americas, Africa, Asia, and the Middle East. • Demographics: ◦ Prevalence increases with age; more common in males. ◦ Autopsy data: ~3% of individuals over age 40. ◦ Radiographic detection (age >55): 2.5% for men, 1.6% for women. • Other Conditions: ◦ Malignant osteopetrosis: 1 in 200,000 to 1 in 500,000 live births. ◦ Adult (benign) osteopetrosis: 1 in 100,000 to 1 in 500,000 adults. ◦ Melorheostosis: ~1 in 100,000 live births (common in Mennonites and Hutterites).

ETIOLOGY & PATHOPHYSIOLOGY¶

• Genetic Factors: ◦ Family history: Found in 15–25% of patients; increases risk for first-degree relatives by 7- to 10-fold. ◦ Key Genes: ◦ SQSTM1 (sequestasome-1/p62): Mutations in C-terminal ubiquitin-binding domain. ◦ CSF1: Encodes M-CSF (required for osteoclast differentiation). ◦ RIN3, OPTN, TNFRSF11A, TM7SF4. ◦ Pro-oncogene c-fos: Increased in pagetic bone; increases osteoclastic activity. ◦ Antiapoptotic oncogene Bcl-2: Overexpressed in pagetic bone. • Viral Hypothesis: ◦ Evidence: Inclusion bodies (measles, RSV, canine distemper) and viral mRNA in osteoclasts. ◦ Correlation: Decline in Paget's incidence correlates with widespread measles vaccination. • Osteoclast Abnormalities: ◦ Quantity: 10- to 100-fold increase in number. ◦ Morphology: Larger size, more nuclei (up to 100 vs. normal 3–5). ◦ Activity: ~7-fold increase in resorptive surfaces; erosion rate of 9 μg/d (normal is 1 μg/d). ◦ Mechanisms for activation: ◦ Hypersensitivity to 1,25(OH)D. ◦ Hyperresponsiveness to RANK ligand (RANKL). ◦ Increased IL-6 in blood and overexpressed in osteoclasts. • Other Dysplasias Pathophysiology: ◦ Osteopetrosis: Loss of osteoclastic resorption; caused by mutations in CA II, TCIRG1, or CLCN7. ◦ Pyknodysostosis: Mutation in cathepsin K. ◦ Hyperostosis corticalis generalisata: Mutations in SOST gene (also linked to sclerosteosis and van Buchem's disease). ◦ Melorheostosis: Somatic mutations in MAP2K1 and SMAD3. ◦ Osteopoikilosis: Mutation in LEMD3 (BMP signaling). ◦ HCAO: Increased formation, decreased resorption; one patient showed increased TRAP and brain isoenzyme of creatine kinase.

RANK PATHWAY MECHANISM¶

• M-CSF Pathway: Mesenchymal cells → M-CSF → c-fms receptor (on osteoclast precursors) → Promotion of osteoclast differentiation/function. • RANKL/OPG Balance Path: Mesenchymal cells produce RANKL and OPG. Mechanism: OPG acts as a "decoy" receptor → binds to RANKL → inhibits interaction with the RANK receptor. Outcome: High RANKL/Low OPG ratio → Increased osteoclast activity. • Growth Factor & Cytokine Path: Mesenchymal cells produce IGF-1 and IGF-2 → act on Osteoblasts. Osteoblasts produce IL-1 and IL-6 → promote osteoclast function. Osteoblasts produce Collagen and Osteocalcin → bone formation.

CLINICAL FEATURES¶

• General Presentation: ◦ Often asymptomatic; detected via elevated ALP or incidental radiograph. ◦ Common sites: Pelvis, vertebral bodies, skull, femur, and tibia. • Pain & Deformity: ◦ Pain sources: Increased vascularity, expanding lytic lesions, fractures, bowing, or secondary arthritis. ◦ Bowing: Femur/tibia → gait abnormalities, altered mechanical stress → secondary osteoarthritis of hip/knee. ◦ Back pain: Enlarged vertebrae, compression fractures, spinal stenosis, kyphosis. • Skull & Facial Involvement: ◦ Skull: Headaches, frontal bossing (enlargement of parietal/frontal bones). ◦ Cranial expansion → narrowed foramens → hearing loss, cranial nerve palsies, platybasia. ◦ Face: Facial deformity, dental issues, rare airway compression. • Complications: ◦ Fractures: Common in long bones at active/advancing lytic sites (femur shaft, subtrochanteric). ◦ Neoplasms: Rare; mostly osteosarcomas (present as new pain in old lesions). ◦ Benign Giant Cell Tumors: May occur near pagetic bone; respond to glucocorticoids. ◦ Cardiovascular: High-output heart failure, calcific aortic stenosis, diffuse vascular calcifications. • Other Dysplasias Features: ◦ Osteopetrosis: Cranial nerve palsies, marrow failure → pancytopenia, hypocalcemia in children. ◦ Pyknodysostosis: Short stature, high arched palate, proptosis, blue sclerae. ◦ Melorheostosis: Pain/stiffness in childhood; scleroderma-like skin changes; hypertrichosis. ◦ Osteopoikilosis: Stable lesions (no radionuclide uptake); may have associated dermatofibrosis lenticularis disseminata. ◦ HCAO: Appendicular pain, increased bone mass, elevated ALP.

DIFFERENTIAL DIAGNOSIS¶

• Common Mimics: ◦ Osteoporosis: Normal bone mass (unlike Paget's). ◦ Metastatic disease: Lytic lesions but different imaging characteristics. ◦ Multiple myeloma: Different laboratory profile. • Distinguishing Features of Other Dysplasias: ◦ Osteopetrosis: Dense bone, marrow failure, cranial nerve palsies. ◦ Pyknodysostosis: Short-limb dwarfism, normal life span, frequent fractures. ◦ Melorheostosis: Asymmetric linear hyperostosis; "melted wax" appearance. ◦ Osteopoikilosis: Stable over time; no radionuclide accumulation on bone scan (distinguishes from metastasis). ◦ HCAO: Distinct from other dysplasias by its association with prior hepatitis C infection.

DIAGNOSTIC APPROACH¶

Clinical Examination:
Identify skull enlargement, frontal bossing, bowing of extremities, or short stature with simian posturing.
Assess for warmth/tenderness in areas of suspected pagetic lesions.
Radiographic Imaging (Primary Diagnostic Tool):
General: Look for expansion of bone, cortical thickening, and coarsening of trabecular markings.
Skull: Identify "cotton wool" appearance, thickened diploic areas, or enlargement/sclerosis of skull bones.
Spine: Identify "picture frame" vertebrae (thickened end plates) or "ivory vertebra" (dense, radiodense expansion).
Pelvis: Look for "brim sign" (thickened iliopectineal line), sacroiliac joint fusion, and porotic lesions of the ilium.
Long Bones: Identify "blade of grass" (advancing lytic wedge) and cortical thickening/expansion.
Nuclear Medicine:
99mTc bone scan: More sensitive than standard radiographs for identifying sites of active skeletal lesions.
Advanced Imaging & Biopsy:
CT: Useful for assessing potential fractures.
MRI: Necessary to evaluate for sarcoma, giant cell tumor, or metastatic disease.\
Bone biopsy: Required for definitive diagnosis of malignancy.
Biochemical Markers:
Serum ALP: Primary marker for diagnosis and monitoring; reflects bone turnover (coupling of formation and resorption).

MANAGEMENT & TREATMENT¶

Pharmacologic Therapy (First-line):
Zoledronic acid: 5 mg IV over 15 min.
Outcome: Normalizes ALP in ≥90% of patients at 6 months.
Alternative Oral Bisphosphonates:
Risedronate: 30 mg/d PO for 2 mo OR 40 mg/d PO for 6 mo (73% success rate).
Tiludronate: 800 mg/d PO for 3 mo OR 200–400 mg/d PO imes 6 mo (35% success rate).
Calcitonin (Miacalcin):
Dose: 100 U SC daily for 6–18 mo (may reduce to 50 U 3 imes per week).
Outcome: Reduction of ALP by up to 50%.
Surgical Management:
Indicated for management of deformities, fractures, or potential malignancy.

PROGNOSIS & COMPLICATIONS¶

• Fracture Risk: - High risk in areas of active or advancing lytic lesions. - Common sites: Femoral shaft and subtrochanteric regions. • Neoplasms: - Rare (less than 0.5%). - Most common type: Osteosarcoma (presents as new pain in long-standing lesion). - Benign Giant Cell Tumors: May occur near pagetic bone; respond to glucocorticoids. • Cardiovascular: - High-output heart failure. - Calcific aortic stenosis and diffuse vascular calcifications.

OTHER DYSPLASIAS & CALCIFICATION¶

• Osteopetrosis: - Malignant: Severe, infantile, autosomal recessive (1 in 200k to 500k). - Benign: Adult, autosomal dominant (Type I and II; 1 in 100k to 500k). - Features: Cranial nerve palsies, marrow failure → pancytopenia, hypocalcemia in children. • Pyknodysostosis: - Autosomal recessive; mutation in cathepsin K. - Features: Short stature, high arched palate, proptosis, blue sclerae. • Melorheostosis: - Mutation in MAP2K1 or SMAD3. - Features: "Melted wax" appearance, skin changes (hypertrichosis). • Osteopoikilosis: - Mutation in LEMD3; stable lesions; no radionuclide accumulation. • Hepatitis C-associated Osteosclerosis (HCAO): - Acquired; high bone mass, elevated ALP, increased formation/decreased resorption. • Ectopic Calcification & Ossification: - Metastatic calcification: - Hypercalcemic states: Primary hyperparathyroidism, Sarcoidosis, Vitamin D intoxication, Milk-alkali syndrome, Renal failure, Hyperphosphatemia. - Secondary hyperparathyroidism: Renal failure, Hemodialysis, Cell lysis following chemotherapy, Therapy with vitamin D and phosphate. - Dystrophic calcification: - Inflammatory disorders: Scleroderma, Dermatomyositis, Systemic lupus erythematosus. - Trauma-induced: Myositis ossificans, Postsurgery, Burns, Neurologic injury, Other trauma. - Fibrodysplasia ossificans progressiva.

KEY PEARLS & CLINICAL TRAPS¶

• Diagnostic Clues: - "Cotton wool" (skull), "Iv100% ivory vertebra" (spine - note: not in source, use 'sclerotic changes'), and "blade of grass" (long bones) are classic radiographic descriptors. - ALP is the primary marker for monitoring; a rise in both formation and resorption markers confirms coupled turnover.\ • Treatment Efficacy: - Zoledronic acid is highly effective (≥90% success) compared to other bisphosphonates (Risedronate 73%, Tiludronate 35%). • Clinical Traps: - Osteopoikilosis must be distinguished from metastasis by its stability and lack of radionuclide uptake.\ - High-output heart failure is associated with high disease activity.\ - Neoplasms are rare but require vigilance in patients with new pain.

Reference Tables¶

TABLE 424-1 Pharmacologic Agents Approved for Treatment of Paget’s Disease¶

Harrison's 22e, p.3314

NAME	DOSE AND MODE OF DELIVERY	NORMALIZATION OF ALKALINE PHOSPHATASE (ALP)
Zoledronic acid	5 mg IV over 15 min	90% of patients at 6 mo
	30 mg/d IV over 4 h on 3 days
Risedronate	30 mg/d PO for 2 mo	73% of patients
	40 mg/d PO for 6 mo
Tiludronate	800 mg/d PO for 3 mo	35% of patients
	200–400 mg/d PO × 6 mo
Calcitonin (Miacalcin)	100 U SC daily for 6–18 mo (may reduce to 50 U 3× per week)	(Reduction of ALP by up to 50%)

TABLE 424-2 Diseases and Conditions Associated with Ectopic Calcification and Ossification Metastatic calcification¶

Harrison's 22e, p.3318

Metastatic calcification Hypercalcemic states Primary hyperparathyroidism Sarcoidosis Vitamin D intoxication Milk-alkali syndrome Renal failure Hyperphosphatemia Tumoral calcinosis Secondary hyperparathyroidism Pseudohypoparathyroidism Renal failure Hemodialysis Cell lysis following chemotherapy Therapy with vitamin D and phosphate	Dystrophic calcification Inflammatory disorders Scleroderma Dermatomyositis Systemic lupus erythematosus Trauma-induced Ectopic ossification Myositis ossificans Postsurgery Burns Neurologic injury Other trauma Fibrodysplasia ossificans progressiva