Paget disease of bone

Paget disease of bone (PDB, or osteitis deformans) is a slowly progressive skeletal disease; it can be monostotic or polyostotic. In PDB, increased bone turnover causes normal lamellar bone to be replaced by weak woven bone. PDB is common but underdiagnosed, and its etiology is not known. PDB predominantly affects individuals over 55 years of age. The condition is often identified incidentally based on a finding of isolated elevated serum alkaline phosphatase (ALP) on blood tests. Symptomatic patients present with localized pain and bony deformities (such as bowing of long bones). Skeletal x-rays, bone scans, and serum ALP are important tests for diagnosing and monitoring the progression of PDB. Treatment is mainly supportive and involves bisphosphonate use to inhibit osteoclastic function. Surgical therapy may be indicated in patients with bone deformities or pathological fractures.

PDB should not be confused with Paget disease of the breast or Paget disease of the vulva, which are named after the same physician.

• Prevalence: second most prevalent skeletal disease after osteoporosis in individuals > 50 years of age ^[1]
• Sex: ♂ > ♀ (1.2:1)
• Age of onset: : > 55 years ^[1]

Epidemiological data refers to the US, unless otherwise specified.

Overview

• Idiopathic disease
• Associated with a high rate of bone remodeling: ↑ RANKL-RANK activity → ↑ NF-κB signaling → ↑ osteoclast activity → ↑ osteoblast activity → formation of disorganized (woven) bone

Stages of Paget disease

Bone remodeling in Paget disease occurs in three phases, followed by a quiescent stage: ^[2]

• Lytic phase: ↑ number of osteoclasts appear in bone → ↑ osteoclastic activity → ↑ rate of bone resorption
• Mixed lytic and blastic phase: ↑ osteoclastic activity is accompanied by an ↑ number of osteoblasts, which infiltrate the lacunae: → ↑ rate of bone formation with haphazardly laid collagen fibers; → formation of abnormal hypervascular woven bone
• Sclerotic phase: Osteoblastic activity overtakes osteoclastic activity, which leads to formation of dense, sclerotic bone.
• Quiescent stage: Both osteoclastic and osteoblastic activity cease (“quiet phase” of the disease).

Disease localization

The pelvis, skull, vertebral column, and long bones of the lower extremities are the most commonly affected sites.

• Monostotic PDB: affects only one bone (∼ ⅓ of cases)
• Polyostotic PDB: affects two or more bones (∼ ⅔ of cases)

• Approximately 70–90% of cases are asymptomatic.
• Bone pain, which may be associated with erythema and elevated skin temperature over the affected bones
• Pathological fractures: chalk-stick fractures of long bones ^[2]
• Bony deformities, e.g., bowing of legs (saber shin)
• Skull involvement (in ∼ 40% of cases)
  • Skull enlargement (increasing hat size)
  • Cranial nerve deficits
  • Impaired hearing: due to ankylosis of the ossicles ; and narrowing of the internal auditory meatus
  • Headache
  • Leonine facies
• Cauda equina syndrome, nerve root compression, spinal stenosis

Approach

• Suspect PDB in adults with any of the following:
  • Idiopathic serum ALP elevation
  • Incidental radiographic findings of bone disease
  • Characteristic clinical features, e.g., bone pain
• Obtain x-rays to confirm the diagnosis. ^[3][4]
  • Symptomatic: targeted imaging of affected areas
  • Asymptomatic: imaging of abdomen, skull, facial bones, and tibias
• If PDB is confirmed:
  • Order bone scintigraphy.
  • Obtain laboratory studies.

PDB should be considered in asymptomatic patients with isolated total ALP elevation that cannot be explained by any other condition (e.g., cholestasis or bone metastases).

Imaging studies ^[3][4]

X-ray

In isolation, the following findings are nonspecific; in combination, they can confirm the diagnosis. ^[3][5]

• General findings ^[6]
  • Bone deformity with osteolytic and osteosclerotic lesions
  • Expansion or enlargement of a section of the bone
  • Thickened cortical bone
  • Coarsened trabeculae
  • Loss of distinction between the medulla and cortex
• Site-specific findings ^[6]
  • Skull x-ray: thickening of the diploe; osteoporosis circumscripta (cotton wool appearance)
  • Vertebral x-ray: thickening of the upper and lower plates of the vertebral body (picture frame appearance), diffuse enlargement of the vertebrae (ivory vertebra)
  • Pelvic x-ray: disruption and/or fusion of sacroiliac joints; thickened iliopectineal line (brim sign)

Bone scintigraphy

• Indications: all patients with confirmed PDB
• Use: to assess the extent of metabolically active disease ^[3]
• Findings: Increased uptake of Tc-99m resulting from increased vascularity in active pagetic foci

CT and/or MRI

• Not routinely required for diagnosis
• May be used to assess for complications of PDB, e.g., osteosarcoma

Laboratory studies ^[3][4][7]

Laboratory studies support the diagnosis and rule out alternative diagnoses, and they should be obtained after imaging studies.

Initial studies

• Serum total ALP: often significantly increased; first-line test to assess disease severity and monitor response to therapy
• Serum calcium, phosphate, and parathyroid hormone (PTH) levels: typically normal ^[6][8]
• Liver chemistries: to rule out ALP elevation due to liver dysfunction
• 25–hydroxyvitamin D: to assess for vitamin D deficiency
• Creatinine: to assess for renal dysfunction
• See also “Laboratory evaluation of bone disease.”

Immobilization of affected bones can cause non-PTH-mediated hypercalcemia (and hypercalciuria). Secondary hyperparathyroidism affects 12–18% of patients with PDB. ^[8]

Additional studies ^[3][7]

For patients with normal serum total ALP, consider the following in consultation with a specialist, e.g., endocrinology:

• Urinary markers of collagen degradation (e.g., deoxypyridinoline, N–telopeptide, and C–telopeptide) ^[3]
• Other markers of bone turnover (e.g., bone-specific ALP, procollagen type I N-terminal propeptide)

Bone biopsy

• Not routinely recommended or performed
• Typically shows a chaotic, mosaic-like pattern of irregularly juxtaposed lamellar and woven bone

• Bone metastases
• Primary hyperparathyroidism
• Osteopetrosis (marble bone disease)
• Fibrous dysplasia

The differential diagnoses listed here are not exhaustive.

Pharmacotherapy ^[3][4]

Bisphosphonates

• First-line therapy for patients with bone pain and those at risk of bone complications ^[9]
• Mechanism: induce apoptosis of osteoclasts
• Agents
  • Preferred: a single dose of IV zoledronate (off-label) ^[4]
  • Alternatives: IV pamidronate , oral bisphosphonates (e.g., tiludronate, alendronate, risedronate) ^[4]

Other agents ^[3][7]

• Calcitonin: less effective than bisphosphonates; may be considered if bisphosphonates are poorly tolerated
• Calcium and vitamin D supplementation: to prevent hypocalcemia and secondary hyperparathyroidism in patients undergoing bisphosphonate therapy
• Oral analgesics (e.g., NSAIDs): as needed for pain management

Surgical therapy ^[3][4]

• Indications: bone deformities, pathological fractures, osteoarthritis
• Techniques: osteotomy, fracture fixation, arthroplasty
• Important considerations: Active pagetic foci can be highly vascular and tend to bleed heavily during surgery.

• Osteoarthritis
• Malignant degeneration into osteosarcoma (very rare: < 1% of cases)
• High-output cardiac failure (due to the formation of arteriovenous shunts within the bone, which leads to an increased overall blood flow)
• Hyperuricemia

We list the most important complications. The selection is not exhaustive.