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) ^[6]

• Definition: Osteopetrosis is an inherited, diffuse bone disease that results in increased sclerotic appearance of the skeleton on radiological examination.
• Etiology
  • Type I osteopetrosis (malignant osteopetrosis): autosomal recessive disease
    • Incidence: 2–5 per 1,000,000 live births
    • Age of onset: infancy
    • Clinical course: severe
  • Type II osteopetrosis (benign osteopetrosis, Albers-Schonberg disease): autosomal dominant disease
    • Incidence: 2–10 per 1,000,000 live births
    • Age of onset: early adulthood
    • Clinical course: mild
  • Carbonic anhydrase II deficiency
    • Autosomal recessive disease that leads to renal tubular acidosis, osteopetrosis of intermediate severity, and cerebral calcification that causes intellectual disabilities.
    • Rare cause of osteopetrosis: Osteoclasts are unable to generate an acidic environment for bone resorption.
• Pathophysiology: mutations → inability of osteoclasts to generate acidic environment in the bone matrix → impaired bone resorption with preserved osteoblastic function → overgrowth of bone with pathological bone composition
• Clinical features
  • Recurring pathological fractures: The osteopetrotic bone tissue is very dense but brittle.
  • Cranial nerve disorders (e.g., palsies): due to hyperostosis and stenosis of the cranial nerve foramina
  • Pancytopenia: due to reduced marrow space
  • Hepatosplenomegaly: due to extramedullary hematopoiesis
• Diagnostics
  • X-ray: symmetrical, homogenous, sclerotic thickening of both cortical and trabecular bone (“stone bone”)
  • Laboratory findings: See “Laboratory evaluation of bone disease.”
    • Calcium levels may be normal or low (especially in severe form, e.g., type I osteopetrosis).
    • ↑ CK-BB
    • ↑ Tartrate-resistant acid phosphatase (TRAP)
• Therapy
  • Bone marrow transplant (potentially curative treatment): Functional osteoclasts may develop from unimpaired monocytes deriving from transplanted stem cells.
  • Surgical decompression is required in the case of optic and/or auditory nerve compression.

Fibrous dysplasia ^[7]

• Description: Fibrous dysplasia is a benign, developmental disorder of bone that causes normal skeletal tissue to be replaced by fibrous tissue.
• Epidemiology
  • Fibrous dysplasia accounts for approx. 5% of benign bone lesions
  • Age of onset: most commonly presents during adolescence
    • Monostotic fibrous dysplasia: 20–30 years
    • Polyostotic fibrous dysplasia: < 10 years
  • Sex: ♂ = ♀
• Etiology: post-zygotically acquired, somatic, gain-of-function mutation in GNAS1 gene on chromosome 20q
• Pathophysiology
  • GNAS1 codes for the α subunit of the G_s protein (G_sα).
  • Mutation → constitutive activation of certain Gs-cAMP coupled pathways → inhibition of mesenchymal differentiation into osteoblasts → lack of osteocytes → skeletal lesions composed largely of mesenchymal cells → weak, imperfect bone with fibrous tissue
• Clinical features
  • Common to all disease phenotypes
    • Bone pain, bone deformities, and/or pathological fractures
    • Entrapment neuropathies may occur as a result of expanding bone lesions
• Subtypes and variants (disease phenotype)
  • Monostotic fibrous dysplasia (∼ 70% of cases)
  • Polyostotic fibrous dysplasia (∼ 25% of cases)
  • Mazabraud syndrome
    • Polyostotic fibrous dysplasia
    • Intramuscular myxomas
  • Jaffe-Lichtenstein syndrome
    • Polyostotic fibrous dysplasia
    • Café au lait spots
  • McCune-Albright syndrome
• Diagnostics
  • Laboratory tests
    • ↑ Alkaline phosphatase (occasionally)
    • Normal calcium, PTH, and 1,25-dihydroxyvitamin D levels
  • Imaging: x-ray
    • Long bones: well-defined, lobulated lesions with a thin cortex and a radiolucent, ground-glass appearance
    • Facial bones: radiodense lesions with a leonine appearance
  • Pathology: bone biopsy
• Therapy
  • Bisphosphonates
  • Management of precocious puberty: See “Peripheral precocious puberty.”
• Prognosis
  • The lesions do not heal spontaneously.
  • Osteosarcomas occur in < 1% of cases.

McCune-Albright syndrome

• Pathophysiology: postzygotic GNAS gene mutation → impaired G_s-protein signaling → constitutively activated adenylate cyclase → excess production of cAMP ^[8]
• Clinical features
  • Polyostotic fibrous dysplasia
  • Café au lait spots with unilateral, ragged edges
    • Usually occur on the same side as bony lesions.
    • In contrast to the café au lait spots in neurofibromatosis that have smooth borders (“coast of California” appearance), those associated with fibrous dysplasia have rough, serpiginous borders (“coast of Maine” appearance).
  • Hormonal abnormalities (at least one)
    • Most commonly peripheral precocious puberty
    • Hyperthyroidism
    • Cushing syndrome
    • Acromegaly
• Prognosis: The condition is lethal when the mutation affects all cells (i.e., occurs before fertilization), but survivable in patients affected by mosaicism.

The 3 P's of McCune-Albright syndrome: Polyostotic fibrous dysplasia, Pigmentation (cafe au lait spots), Precocious puberty

The differential diagnoses listed here are not exhaustive.

Medical therapy ^[9]

• First-line: bisphosphonates
  • Bisphosphonates induce apoptosis of osteoclasts
    • Oral bisphosphonates: tiludronate, alendronate, risedronate
    • IV bisphosphonates: zoledronate, pamidronate
• Second-line: calcitonin therapy ^[10]
  • 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 ^[9]

• 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.

1. Lalam RK, Cassar-pullicino VN, Winn N. Paget Disease of Bone. Semin Musculoskelet Radiol. 2016; 20 (3): p.287-299. doi: 10.1055/s-0036-1592368 . | Open in Read by QxMD
2. Le T, Bhushan V,‎ Sochat M, Chavda Y, Abrams J, Kalani M, Kallianos K, Vaidyanathan V. First Aid for the USMLE Step 1 2019. McGraw-Hill Medical
3. Alexandersen P, Peris P, Guañabens N, et al. Non-isomerized C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy in Paget's disease of bone. J Bone Miner Res. 2004; 20 (4): p.588-595. doi: 10.1359/JBMR.041212 . | Open in Read by QxMD
4. Whyte MP. Clinical practice. Paget's disease of bone. N Engl J Med. 2006; 355 (6): p.593-600. doi: 10.1056/NEJMcp060278 . | Open in Read by QxMD
5. Sclerotic bone tumors and tumor-like lesions. http://www.radiologyassistant.nl/en/p4bc9a97980036/sclerotic-bone-tumors-and-tumor-like-lesions.html. Updated: November 1, 2013. Accessed: January 15, 2017.
6. Gupta RK. Long bone fractures in osteopetrosis: awareness of primary pathology and appropriate pre-operative planning necessary to avoid pitfalls in fixation. Injury Extra. 2005; 36 (9): p.411. doi: 10.1016/j.injury.2004.05.032 . | Open in Read by QxMD
7. ller L, Wood NH, Khammissa RA, Lemmer J, Raubenheimer EJ. The nature of fibrous dysplasia. Head Face Med. 2009; 5 : p.22. doi: 10.1186/1746-160X-5-22 . | Open in Read by QxMD
8. Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis. 2008; 3 (1). doi: 10.1186/1750-1172-3-12 . | Open in Read by QxMD
9. Ralston SH, Langston AL, Reid IR. Pathogenesis and management of Paget's disease of bone. Lancet. 2008; 372 (9633): p.155-163. doi: 10.1016/S0140-6736(08)61035-1 . | Open in Read by QxMD
10. Singer FR, Fredericks RS, Minkin C. Salmon calcitonin therapy for Paget's disease of bone: The problem of acquired clinical resistance. Arthritis Rheum. 1980; 23 (10): p.1148-1154.