What is Paget disease of bone and McCune‑Albright syndrome?

Paget's Disease and McCune-Albright Syndrome: Two Distinct Bone Disorders

Paget's Disease of Bone

Paget's disease is a chronic, focal bone disorder characterized by excessive and disorganized bone remodeling, where abnormal osteoclast-mediated bone resorption is followed by compensatory but chaotic bone formation, resulting in structurally weak bone with a disorganized mosaic pattern of woven and lamellar bone. 1

Key Pathophysiology

• The disease involves abnormally large and hyperactive osteoclasts that resorb bone excessively, followed by compensatory osteoblastic activity that produces structurally inferior bone 1
• Genetic predisposition exists with mutations in the SQSTM1 gene (sequestosome 1), showing autosomal dominant inheritance with incomplete penetrance 1
• Environmental triggers, particularly chronic paramyxovirus infections (especially measles), likely interact with genetic factors 1, 2
• Family history is present in 10-20% of cases 1

Epidemiology

• Affects 2-3% of individuals over age 55 in the United States 1
• Most common in Western Europe, North America, Australia, and New Zealand 1
• Rarely manifests before age 40; frequency increases with advancing age 1
• Slight male predominance 1
• Recent evidence shows declining incidence and severity in many countries 2

Clinical Presentation

Many patients are asymptomatic, discovered incidentally through elevated alkaline phosphatase on routine labs or abnormal imaging for unrelated reasons 1, 3.

Most commonly affected bones:

• Pelvis
• Vertebrae
• Skull
• Femur
• Tibia 1

Symptomatic manifestations include:

Musculoskeletal:

• Deep, aching bone pain (worse at night)
• Bone deformity and enlargement
• Bowing of long bones (femur, tibia)
• Osteoarthritis in adjacent joints
• Pathological "chalk-stick" or "banana" fractures (transverse fractures through weakened bone)
• Increased warmth over affected bones due to increased blood flow 1

Neurological:

• Hearing loss and tinnitus (skull involvement)
• Spinal stenosis
• Nerve compression syndromes
• Rarely: paraplegia, cranial nerve deficits, basilar impression 1

Cardiovascular:

• High-output congestive heart failure (extensive disease)
• Increased cardiac output 1

Neoplastic (rare, <1%):

• Osteosarcoma (in patients with polyostotic disease)
• Giant cell tumors 1

Diagnosis

Plain radiographs of suspicious skeletal regions are the primary diagnostic tool 1. Radiological changes mirror pathological evolution:

• Early: osteolytic lesions (skull, long bones)
• Later: mixed osteolytic-sclerotic appearance
• Advanced: thickened, disorganized bone architecture 1

After radiological confirmation:

• Radionuclide bone scan to determine disease extent and identify asymptomatic sites 1
• Serum total alkaline phosphatase (ALP) for initial biochemical assessment 1
• In patients with liver/biliary disease or monostotic disease with normal total ALP: use specific bone turnover markers (P1NP, bone-specific ALP, CTx, or NTx) 1

Treatment

Bisphosphonates are the cornerstone of treatment for most patients with active Paget's disease at risk of future complications 1.

First-line therapy: A single 5-mg intravenous dose of zoledronate 1. This is superior to all other bisphosphonates based on:

• 89% normalization of ALP vs 58% with risedronate 1
• 96% therapeutic response vs 74% with risedronate 1
• More rapid onset of action 1
• Superior quality of life improvements including pain relief 1
• Sustained remission: 87% at 5-6 years vs 38% with risedronate 1
• Can normalize ALP for up to 6.5 years after a single infusion 4

Treatment goals:

• Reduce bone turnover below the midpoint of the reference range for the chosen marker to maximize remission duration 1
• Patients achieving P1NP <40 μg/L or total ALP <80 IU/L at 6 months post-zoledronate have >90% likelihood of sustained remission 1

Monitoring:

• Biochemical follow-up is more objective than symptoms for detecting relapse 1
• Repeat x-rays at 1 year for osteolytic lesions to assess response 1

Specific indications for bisphosphonate treatment:

• Before elective surgery on pagetic bone to reduce intraoperative hemorrhage 1
• To prevent worsening hearing deficit 1
• Before total joint replacement in severe adjacent osteoarthritis 1
• Immediate IV bisphosphonate for paraplegia from spinal Paget's disease (with neurosurgical consultation) 1
• In patients with congestive heart failure 1

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McCune-Albright Syndrome (MAS)

McCune-Albright syndrome is a rare, sporadic mosaic disorder caused by postzygotic somatic activating mutations in the GNAS gene, classically presenting with the triad of polyostotic fibrous dysplasia of bone, café-au-lait skin macules, and endocrine hyperfunction. 5

Key Pathophysiology

• Caused by somatic gain-of-function mutations in the GNAS gene encoding the Gsα subunit of stimulatory G protein 5, 6
• Pathogenic variants concentrated at codons R201 (R201H, R201C) and Q227 5
• Results in constitutive Gsα signaling independent of normal regulatory mechanisms 6
• Mosaic distribution explains variable phenotypic expression depending on timing and distribution of mutation during embryogenesis 5

Epidemiology

• Estimated prevalence: 1 in 100,000 to 1 in 1,000 5
• No clear ethnic predilection 5
• Sporadic occurrence (not inherited) 5

Clinical Presentation

Classic Triad:

1. Polyostotic Fibrous Dysplasia (FD):

   • Replacement of normal bone with disorganized fibro-osseous tissue 5, 6
   • Leads to bone pain, deformities, and increased fracture risk 5
   • Commonly affects craniofacial bones, including maxilla and mandible 7
   • Can affect any skeletal site 6

2. Café-au-lait Macules:

   • Hyperpigmented skin lesions with irregular "coast of Maine" borders 5
   • Typically respect the midline 5

3. Endocrine Hyperfunction:

   • Gonadotropin-independent precocious puberty (most common endocrinopathy) 5, 6
   • Hyperthyroidism 5, 6
   • Growth hormone excess/acromegaly 5, 6
   • Hypercortisolism (Cushing syndrome)
   • Hypophosphatemic rickets/osteomalacia 5

Diagnosis

Diagnosis is clinical, supported by biochemical and imaging findings 5, 7:

• Clinical recognition of the classic triad
• Imaging studies (CT, MRI) to characterize fibrous dysplasia extent and distribution 7
• Scintigraphy is fundamental for identifying and evaluating disease progression/stability 7
• Biochemical assessment of endocrine function
• Genetic testing can confirm GNAS mutations but is not always necessary with classic presentation 5

Management

MAS requires multidisciplinary management addressing skeletal, endocrine, and other systemic manifestations 5:

Skeletal management:

• Bisphosphonates (particularly IV pamidronate) for symptomatic fibrous dysplasia
• Orthopedic intervention for fractures, deformities, or functional impairment
• Dental management crucial for craniofacial involvement 7

Endocrine management:

• Aromatase inhibitors or selective estrogen receptor modulators for precocious puberty
• Antithyroid medications or radioiodine for hyperthyroidism
• Somatostatin analogs or surgery for growth hormone excess
• Targeted therapy for specific endocrinopathies 5

Long-term monitoring:

• Serial imaging to assess fibrous dysplasia progression 7
• Ongoing endocrine surveillance
• Assessment for complications including malignant transformation (rare) 5

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Key Distinctions Between Paget's Disease and McCune-Albright Syndrome

Feature	Paget's Disease	McCune-Albright Syndrome
Genetics	SQSTM1 mutations; familial in 10-20% [1]	GNAS somatic mutations; sporadic [5]
Age of onset	Rarely before age 40 [1]	Childhood (endocrine manifestations often first) [5]
Bone pathology	Excessive, disorganized remodeling with mosaic pattern [1]	Fibro-osseous replacement [6]
Distribution	Focal; commonly pelvis, spine, skull, long bones [1]	Polyostotic; often craniofacial [7]
Skin findings	None	Café-au-lait macules [5]
Endocrine	None	Multiple endocrinopathies [5]
Treatment	Bisphosphonates (zoledronate preferred) [1]	Multidisciplinary; bisphosphonates for FD [5]