Paget’s Disease of Bone

Paget’s disease of bone (PDB), also known historically as osteitis deformans, is a focal disorder of bone metabolism that affects about 2%–9% of people. Commonly affected areas include the skull, spine, pelvis, and long bones of the lower extremity. The 2 main clinical manifestations of Paget’s disease are bone pain and the consequences of bone deformities, such as fractures, osteoarthritis, or nerve impingement. The management includes bisphosphonates, calcitonin, and surgery for the management of fractures, deformities, and complications. The prognosis for PDB is good, especially if treatment is started before major changes have occurred in the bones.

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Overview

Definition

Paget’s disease of bone (PDB, also known as osteitis deformans) is a disorder of bone metabolism affecting the aging skeleton.

Epidemiology

  • 2nd most common metabolic bone disorder, after osteoporosis
  • Most common after 55 years of age
  • 3:2 male predominance
  • Geographic variations in prevalence:
    • United States: 1% of population > 40 years old
    • Most common in Europe (except Scandinavia), Australia, and New Zealand, with an average of 3%–4%, and ranges from 2%–9%
    • Rare in Asia
  • Positive family history: in 12%–40% of patients 
  • Asymptomatic in 70% of cases
  • Overall, the incidence is declining.

Etiology

  • Uncertain: genetic and infectious etiologies implicated and likely additive
  • Genetic:
    • Autosomal dominant inheritance with variable penetrance
    • Mutations of genes SQSTM1, RANK, and regions of chromosomes 5 and 6 are all involved in bone metabolism.
    • Germline mutations in SQSTM1:
      • Approximately 40% of the PDB familial cases
      • Approximately 10% of sporadic cases
  • Viral infections:
    • Less well established than genetic etiologies
    • Substantial evidence for possible measles infection of osteoclasts
    • Measle vaccination may explain the declining incidence of PBD.

Pathophysiology

Pathogenesis

  • A disease of osteoclasts
  • Osteoclast activity accelerates the rate of bone remodeling, causing overgrowth and impaired structural integrity of affected bone.
  • This is followed by increased osteoblast activity.
  • Result is enlarged and thickened, but deformed and weakened, bone.
  • Only some areas of bone are affected, for unknown reasons.
  • 3 sequential phases of PDB:
    1. Initial osteolytic stage: predominant osteoclast activity
    2. Mixed osteoclastic-osteoblastic stage
    3. Burned-out quiescent osteosclerotic stage: Osteoblast activity predominates. 

PDB osteoclasts

  • Have unique characteristics:
    • Markedly increased number during the active osteolytic phase
    • Atypical/bizarre appearance, with numerous nuclei (up to 100 compared with 10–12 normally)
    • Intranuclear inclusions present in some
    • Hypersensitivity to vitamin D
  • 2 essential cytokines required for osteoclast differentiation: 
    • Macrophage colony-stimulating factor (M-CSF)
    • Receptor activator of nuclear factor-κB ligand (RANKL)
  • Differentiation is inhibited by osteoprotegerin (OPG; a soluble decoy receptor for RANKL) and modulated by other cytokines and hormones.
  • Abnormalities of these pathways form the basis for the genetic etiology of PDB.

Gross pathology

  • Most common sites: 
    • Skull
    • Thoracolumbar spine
    • Pelvis 
    • Long bones of the lower extremities
    • Axial skeleton or proximal femur is involved in 80% of cases.
  • Monostotic in 15% of cases; polyostotic in 85%
  • Focally enlarged and deformed bone 
  • Irregular thickening of both cortical and cancellous bone

Microscopic pathology

  • Osteolytic phase:
    • Numerous resorption pits
    • Osteoclasts increased in number and aberrant
  • Mixed phase: 
    • Many bone surfaces lined by plump osteoblasts
    • Loose connective tissue, osteoprogenitor cells, and numerous blood vessels adjacent to new bone
    • Woven bone becomes lamellar with a mosaic pattern.
    • Porous cortex
    • Thickened, but structurally unsound, trabecular structure
    • Evolves into an osteosclerotic phase, with some osteoblasts and few osteoclasts remaining in mosaic-patterned bone.
  • Sclerotic phase (pathognomonic of PDB):
    • Mosaic pattern of lamellar bone
    • Looks like a jigsaw puzzle
    • Prominent cement lines joining randomly oriented units of lamellar bone 

Clinical Presentation

Over 70% of cases are asymptomatic.

Pain

  • Transmitted by periosteal nerves and is due to:
    •  Bone overgrowth
    •  Hyperemia
    •  Microfractures
  • Dull, aching type of pain
  • Constant, day and night 
  • Worse in weight-bearing bones

Bone deformities and fractures

Sites involved rarely change over a patient’s lifetime.

  • Head:
    • Enlarged skull with frontal bossing
    • Dilated scalp veins
    • Basilar invagination (i.e., the tip of the odontoid process is above the foramen magnum) 
    • Jaw deformity, malocclusion, and periodontal disease 
    • Angioid streaks (cracks in Bruch’s membranes of the eyes, can cause choroidal neovascularization)
  • Spine and pelvis:
    • Compression fractures
    • Pelvis: 
      • Pain
      • Arthritis 
      • Protrusio acetabuli (femoral head projects medial to the ilioischial line)
  • Long bones: 
    • Bowing deformities, with arthritis of adjacent joints
    • Fractures:
      • Transverse fracture at the lesser trochanter of femur the most common
      • The most common complication in long bones
      • Blood loss increased due to increased vascularity
      • Casting or immobility can cause severe osteopenia. 
    • Skin overlying bones: warm due to increased vascularity in bone

Complications of bone overgrowth

  • Neurologic:
    • Hearing loss and dizziness (due to vestibulocochlear nerve and cochlear involvement)
    • Hydrocephalus
    • Instability of gait
    • Dementia from vascular steal due to bone vascularity 
    • Spinal stenosis
    • Spinal cord ischemia: due to vascular steal 
    • Radiculopathies (nerve compression)
  • Metabolic:
    • More common in untreated patients with polyostotic disease
    • High-output heart failure
    • Hypercalcemia during immobilization or fracture:
      • Hypercalciuria 
      • Increased risk of kidney stones  
  • Neoplastic:
    • Occur in < 1% of PDB
    • Risk is higher in polyostotic and long-standing disease.
    • Osteosarcoma the most common
    • Fibrosarcoma
    • Giant cell tumors: 
      • Mostly benign
      • Cause local destruction
      • Rarely metastasize

Diagnosis

History

  • Elderly patients 
  • Pathologic fractures
  • Hypercalcemia after bedrest

Laboratory findings

  • Serum alkaline phosphatase:
    • Often elevated, with normal gamma-glutamyl-transpeptidase (unlike liver disease)
    • Bone-specific alkaline phosphatase (bSAP) elevation
  • Other markers of bone turnover:
    • Urinary N-telopeptide crosslink (NTX) 
    • Serum C-telopeptide crosslink (CTX)
    • Amino-terminal propeptide of type I procollagen (PINP)
  • Serum calcium and phosphorus:
    • Normal in most patients
    • May be elevated in cases of fracture or immobility
    • If elevated in an ambulatory patient without fracture, may indicate other pathology (i.e., primary hyperparathyroidism)

Imaging

  • Most important diagnostic tool
  • Plain radiographs: 
    • Osteolytic lesions in early PDB: “osteoporosis circumscripta” in the skull
    • Thickened, denser, and enlarged bone as osteoblast activity increases
    • Mixed lytic/sclerotic lesions, with flame-shaped lytic lesion progressing ahead of thickened cortex and trabecular bone
    • Deformation of bone shape
    • Pseudofractures (Looser’s lines): small fissures on the convex surface of long bones
    • Protrusio acetabuli and iliopectineal line involvement
    • “Ivory spine”: thickened and enlarged vertebrae 
  • Bone scintigraphy:
    • Obtain a baseline scan in all cases.
    • Increased uptake at the sites of active lesions
    • May be the earliest imaging change
  • Other modalities:
    • Computed tomography (CT) or magnetic resonance imaging (MRI)
    • May be helpful if malignancy is suspected
    • Evaluate fractures in selected cases.

Bone biopsy

  • Rarely required 
  • To rule out malignancy 
  • Unusual clinical situation (young adult, Asian ethnicity)

Management

Indications for treatment

  • Symptomatic disease
  • Significant radiologic abnormalities
  • Significant biochemical abnormalities

Goals

  • Reduce pain.
  • Reduce the rate of bone remodeling.

Pharmacologic treatment

  • Bisphosphonates (first choice—zoledronic acid):
    • Inhibit osteoclast activity
    • Adverse effects: 
      • Gastrointestinal (GI) upset
      • Flu-like symptoms
      • Musculoskeletal pain
      • Osteonecrosis of the jaw (especially if invasive dental work done in the prior 6 months)
      • Hypocalcemia
  • Calcitonin (if bisphosphonates are not tolerated)

Surgical interventions

  • Fracture fixation 
  • Resection of bone tumors
  • Non-emergent correction of bone deformity
  • Joint arthroplasty
  • Spinal decompression: after treatment with bisphosphonates

Adjunctive measures

  • Walking aids
  • Analgesics
  • Physical therapy
  • Hearing aids (if associated with hearing loss)

Differential Diagnosis

  • Metastatic disease: The 5 most common malignancies that metastasize to the bone are thyroid, lung, breast, kidney, and prostate. Diagnosis is established by history, CT, MRI, and biopsy.
  • Osteomalacia: marked softening and weakening of bones due to impaired mineralization and most often caused by severe vitamin D deficiency; similar to PDB because of pain and elevated alkaline phosphatase, but typical PDB X-ray patterns are not seen. Pseudofractures (Looser’s lines) of osteomalacia occur on the concave, not convex, side of the bone. 
  • Osteosarcoma: a primary bone malignancy. Occasionally associated with PDB; pain and soft tissue swelling should prompt an MRI to help in diagnosis. Bone biopsy for confirmation. 
  • Giant cell tumor of bone: benign bone tumors that can be locally aggressive. Associated with increased pain and swelling. Can occur in association with PDB (usually in the skull or pelvis of patients with polyostotic disease); can also arise in non-osseous tissues. Diagnosis is confirmed with MRI and biopsy.

References

  1. Charles, J.F. (2020). Clinical manifestations and diagnosis of Paget disease of bone. Uptodate. Retrieved December 29, 2020, from   https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-paget-disease-of-bone#H22844044
  2. Paget Disease. (2020). In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). Robbins & Cotran Pathologic Basis of Disease. (10 ed. pp. 1182-1183).
  3. Charles, J.F. (2019). Paget’s Disease of Bone; Osteitis Deformans. MSD Manual Professional Edition. Retrieved December 29, 2020, from https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/paget-disease-of-bone/paget-disease-of-bone
  4. Alonso, N., Calero-Paniagua, I., & del Pino-Montes, J. (2017). Clinical and genetic advances in Paget’s disease of bone: A review. Clinical Reviews in Bone and Mineral Metabolism, 15(1), 37–48. https://doi.org/10.1007/s12018-016-9226-0
  5. Oiseth, S. J. (2017). Beethoven’s autopsy revisited: A pathologist sounds a final note. Journal of medical biography, 25(3), 139–147. https://doi.org/10.1177/096777201557588

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