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Paget Disease of Bone

(Paget's Disease of Bone; Osteitis Deformans)

By Julia F. Charles, MD, PhD, Instructor in Medicine;Department of Medicine, Division of Rheumatology, Immunology and Allergy, Harvard Medical School;Brigham and Women's Hospital

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Paget disease of bone is a chronic disorder of the adult skeleton in which bone turnover is accelerated in localized areas. Normal matrix is replaced with softened and enlarged bone. The disease may be asymptomatic or cause gradual onset of bone pain or deformity. Diagnosis is by x-ray. Treatment includes symptomatic measures and often drugs, usually bisphosphonates.

About 1% of adults in the US > 40 have Paget disease, with a 3:2 male predominance. Prevalence increases with age. However, overall prevalence seems to be decreasing. The disease is most common in Europe (except Scandinavia), Australia, and New Zealand.

Etiology

Several genetic abnormalities, many affecting receptor activator of nuclear factor kappa-B (RANK-NFk B) signaling for osteoclast generation and activity, have been identified. Mutations of the SQSTM1 (sequestosome-1) gene resulting in increased nuclear factor kappa-B activity, which leads to increased osteoclast activity, are present in about 10% of patients with Paget disease (1). Appearance of involved bone on electron microscopy suggests a viral infection. Although a viral cause has not been established, it is hypothesized that in genetically predisposed patients an as yet unidentified virus triggers abnormal osteoclast activity.

Etiology reference

Pathophysiology

Any bone can be involved. The bones most commonly affected are the pelvis, femur, and skull. Other less commonly involved bones are the tibia, vertebrae, clavicle, and humerus.

Bone turnover is accelerated at involved sites. Pagetic lesions are metabolically active and highly vascular. Excessively active osteoclasts are often large and contain many nuclei. Osteoblastic repair is also hyperactive, causing coarsely woven, thickened lamellae and trabeculae. This abnormal structure weakens the bone, despite bone enlargement and areas of bone sclerosis.

Complications

The most common complication of Paget disease of bone is

Osteoarthritis occurs in up to 50% of patients and develops in joints adjacent to involved bone. Pathologic fracture is also common due to focal areas of weakened bone.

Overgrown bone may compress nerves and other structures passing through small foramina. Spinal stenosis or spinal cord compression may develop.

Rare complications include transformation to osteosarcoma in up to 1% of patients. Highly vascular bones may bleed excessively during orthopedic surgery. Very rarely, hypercalcemia develops in patients who are immobile; however, hypercalcemia in ambulatory patients suggests the coexistence of hyperparathyroidism. High-output heart failure due to large or numerous lesions has been reported.

Symptoms and Signs

Paget disease of the bone is commonly asymptomatic. If symptoms occur, they develop insidiously, with pain, stiffness, fatigue, and bone deformity. Bone pain is aching, deep, and occasionally severe, sometimes worse at night. Pain also may arise from compression neuropathy or osteoarthritis. If the skull is involved, there may be headaches and hearing impairment.

Signs may include skull enlargement bitemporally and frontally (frontal bossing), dilated scalp veins, nerve deafness in one or both ears or vertigo, and headaches. Deformities may develop from bowing of the long bones or osteoarthritis. Pathologic fractures may be the presenting manifestation. Osteosarcoma is often suggested by increasingly severe pain.

Diagnosis

  • Plain x-rays

  • Serum alkaline phosphatase, calcium, and phosphate (PO4)

  • Bone scan to establish the extent and location of disease

Paget disease should be suspected in patients with the following:

  • Unexplained bone pain or deformity

  • Suggestive findings on x-ray

  • Unexplained elevation of serum alkaline phosphatase on laboratory tests done for other reasons, particularly if gamma-glutamyl-transpeptidase (GGT) is normal

  • Hypercalcemia that develops during bed rest, particularly among elderly patients

  • Bone sarcoma in elderly patients

If Paget disease is suspected, plain x-rays and serum alkaline phosphatase, calcium, and PO4 levels should be obtained. Confirmation on x-ray is required to establish the diagnosis. Characteristic x-ray findings include the following:

  • Increased bone sclerosis

  • Abnormal architecture with coarse cortical trabeculation or cortical thickening

  • Bowing

  • Bone enlargement

There may be lateral stress microfractures of the tibia or femur.

Radionuclide bone scan using technetium-labeled phosphonates should be done at baseline to determine the extent of bone involvement.

Characteristic laboratory findings include elevated serum alkaline phosphatase (increased anabolic activity of bone) but usually normal GGT and serum PO4 levels. Serum calcium is usually normal but can increase because of immobilization or hyperparathyroidism. If alkaline phosphatase is not elevated or it is unclear whether the increased serum alkaline phosphatase is of bony origin (ie, if GGT is increased in proportion to alkaline phosphatase), a bone-specific fraction can be measured. Serum markers of bone turnover, such as procollagen type I intact N-terminal propeptide (PINP) and C-telopeptide cross-links (CTX), may be elevated (2). Occasionally, increased catabolic activity of bone, as demonstrated by elevated urine markers of bone collagen turnover (eg, pyridinoline cross-links), helps confirm increased bone turnover.

Pearls & Pitfalls

  • Consider Paget disease of bone in older adults with elevated alkaline phosphatase but normal GGT levels.

Diagnosis reference

  • 2. Shankar S, Hosking DJ: Biochemical assessment of Paget's disease of bone. J Bone Miner Res 21 Suppl 2:P22–P27, 2006. doi: 10.1359/jbmr.06s204.

Treatment

  • Supportive care for symptoms and complications

  • Bisphosphonates if disease is symptomatic or active in bones at risk of complications

Supportive treatment of Paget disease of bone includes analgesics or NSAIDs for pain. Orthotics help correct abnormal gait caused by bowed lower extremities. Some patients require orthopedic surgery (eg, hip or knee replacement, decompression of the spinal cord). Weight bearing should be encouraged, and bed rest should be avoided.

Localized, asymptomatic disease may not require treatment.

Drug therapy

Drug therapy suppresses osteoclast activity. It is indicated for the following:

  • To prevent or retard progression of complications (eg, hearing loss, deformity, osteoarthritis, paraparesis or paraplegia related to vertebral Paget disease, or other neurologic deficits, particularly in a poor surgical candidate)

  • To treat pain clearly related to the pagetic process and not to another source (eg, osteoarthritis)

  • To prevent or minimize bleeding that can occur during orthopedic surgery

  • To suppress excessive osteoclast activity when serum alkaline phosphatase (of bony origin) is > 2 times the normal level, even in the absence of symptoms

Although disease progression can be retarded, existing deficits (eg, deformity, osteoarthritis, hearing loss, neural impingement) are not reversed.

Several bisphosphonates are available and are the drugs of choice (see Table: Drug Therapy for Paget Disease). The amino- bisphosphonates (bisphosphonates with an extra nitrogen atom), particularly zolendronate, more effectively suppress markers of disease activity and provide more prolonged response (3). Amino-bisphosphonates are first-line therapy for Paget disease of bone, whereas the simple bisphosphonates (bisphosphonates without an extra nitrogen atom) are 2nd-line therapy.

Synthetic salmon calcitonin is an alternative to bisphosphonates for patients intolerant of or resistant to them. For patients with contraindications to bisphosphonates, case reports suggest that denosumab may also be an alternative to bisphosphonates (4).

Because bone turnover is increased, patients should ensure adequate intake of calcium and vitamin D, and supplements are often needed.

Drug Therapy for Paget Disease

Drug

Dosage

Comments

Alendronate*

40 mg po once/day for 6 mo

Taken as a single dose after rising in the morning, at least 30 min before eating

First-line therapy

Etidronate

5–10 mg/kg po once/day for 6 mo; higher doses (11–20 mg/kg po once/day for 3 mo) possibly needed in markedly active disease

Taken as a single dose on an empty stomach at least 2 h before or after eating; can be repeated after a 3- to 6-mo interim if needed

Second-line therapy due to impaired mineralization

Pamidronate*

30 mg IV once/day given as a 4-h infusion for 3 consecutive days or 90 mg IV given once

For patients intolerant of oral bisphosphonates; possibly more frequent doses in patients with resistant disease

May repeat if clinically indicated

First-line therapy

Risedronate*

30 mg po once/day for 2 mo

Taken the same way as alendronate

First-line therapy

Tiludronate

400 mg po once/day for 3 mo

Taken the same way as alendronate

Second-line therapy

Zoledronate*

5 mg IV given as a single 15-min infusion

For patients intolerant of oral bisphosphonates

First-line therapy

Synthetic salmon calcitonin

50–100 IU (0.25–0.5 mL) sc or IM once/day

Dose sometimes tapered to 50 IU every other day and perhaps to twice or once weekly after a favorable initial response (often after 1 mo)

Indicated for patients who cannot tolerate bisphosphonates

*Indicates an amino-bisphosphonate (a bisphosphonate with an extra nitrogen atom).

This drug is not available in the US.

Treatment references

  • 3. Reid IR, Lyles K, Su G, et al: A single infusion of zoledronic acid produces sustained remissions in Paget disease: Data to 6.5 years. J Bone Miner Res 26(9):2261–2270, 2011. doi: 10.1002/jbmr.438.

  • 4. Reid IR, Sharma S, Kalluru R, Eagleton C: Treatment of Paget's disease of bone with denosumab: Case report and literature review. Calcif Tissue Int 99(3):322–325, 2016. doi: 10.1007/s00223-016-0150-6.

Key Points

  • Paget disease of bone is a common and often asymptomatic abnormality, particularly among older adults.

  • Complications can include osteoarthritis, fractures, neural compression, osteosarcoma, and rarely hypercalcemia.

  • Complications of bisphosphonate treatment of Paget disease of bone include hyperparathyroidism and hypocalcemia.

  • Confirmation is usually by x-rays showing findings such as bone sclerosis, coarse cortical trabeculation or cortical thickening, and bone bowing or enlargement.

  • First-line treatment is zolendronate or another amino-bisphosphonate (alendronate, pamidronate, or risedronate).

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • FOSAMAX
  • AREDIA
  • ACTONEL
  • PROLIA
  • MIACALCIN
  • DIDRONEL