Paget disease of bone

Paget disease of bone (PDB, or osteitis deformans) is a slowly progressive monostotic or polyostotic skeletal disease. It is characterized by increased bone turnover, which causes normal lamellar bone to be replaced by weak woven bone. The cause of this common yet underdiagnosed skeletal disease is not known. It predominantly affects individuals over the age of 55 and is characterized by localized pain and bony deformities (such as bowing of long bones). Skeletal x-ray, bone scans, and serum alkaline phosphatase are important tests for diagnosing and monitoring the progression of PDB. Treatment is mainly supportive and involves the use of bisphosphonates to inhibit osteoclastic function.

Paget disease of the bone should not be confused with Paget disease of the nipple 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

Laboratory tests

• Blood work
  • Normal calcium, phosphate, and parathyroid hormone (PTH) levels
  • ↑↑ Serum alkaline phosphatase (ALP)
  • Hyperuricemia
• Urinalysis: ↑ markers of collagen degradation ^[3]
  • Deoxypyridinoline
  • N-telopeptide, C-telopeptide
  • Hydroxyproline
• See “Laboratory evaluation of bone disease.”

Paget disease should be considered in an asymptomatic patient who presents with isolated ALP elevation that cannot be explained by any other means (e.g., cholestasis or bone metastases).

Imaging ^[4][5]

• X-ray
  • Deformed bones with both sclerotic and osteolytic lesions
    • Sclerotic lesion: focus/foci of ↑ density (usually the result of increased mineralization and/or thickening).
    • Osteolytic lesion: focus/foci of ↓ density (usually the result of decreased demineralization).
  • Thickened cortical bone
    • Coarsened trabeculae; expansion or enlargement of a region of the bone.
    • 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 gives rise to a “picture frame” appearance; diffuse enlargement of the vertebrae (ivory vertebra)
    • Pelvic x-ray: disruption/fusion of sacroiliac joints; thickened iliopectineal line (brim sign)
• Bone scans (skeletal scintigraphy): to test for additional bony lesions

Pathology

• Bone biopsy: 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.

Medical therapy ^[6]

• First-line: bisphosphonates
  • Bisphosphonates induce apoptosis of osteoclasts
    • Oral bisphosphonates: tiludronate, alendronate, risedronate
    • IV bisphosphonates: zoledronate, pamidronate
• Second-line: calcitonin therapy ^[7]
  • Less effective than bisphosphonate therapy
  • May be used when bisphosphonates are poorly tolerated by patients
  • Administered as a subcutaneous injection
  • Side effects include facial flushing, nausea, and tachyphylaxis.
• Supportive therapy
  • Vitamin D₃ (cholecalciferol) and calcium
  • NSAIDs may be used in addition to bisphosphonates to treat pain.

Medical therapy should be initiated among all patients with active disease (elevated ALP levels or active disease foci on skeletal scintigraphy).

Surgical therapy ^[6]

• Indications
  • Bone deformities
  • Pathological fractures

• 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)

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