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Paget Disease of Bone

(Osteitis Deformans)

by Roy D. Altman, MD

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 Sequestrum 1 gene related to ubiquitin binding from chromosome 6 are present in about 10% of patients with Paget disease. 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.

Pathophysiology

Any bone can be involved. The bones most commonly affected are, in decreasing order, the pelvis, femur, skull, 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 heavy calcification.

Complications

Overgrown bone may compress nerves and other structures passing through small foramina. Spinal stenosis or spinal cord compression may develop. Osteoarthritis may develop in joints adjacent to involved bone.

In about 10 to 15% of patients, increased bone formation and Ca requirement leads to secondary hyperparathyroidism; if this need is not matched by an increase in Ca intake, hypocalcemia may occur. Hypercalcemia (see Hypercalcemia) occasionally develops in patients who are immobile. It also occurs in patients with Paget disease who develop secondary hyperparathyroidism.

Large or numerous lesions may lead to high-output heart failure. Highly vascular bones may bleed excessively during orthopedic surgery.

Symptoms and Signs

There are usually no symptoms for a prolonged period. 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; headaches; angioid streaks in the fundus of the eye; a short kyphotic trunk with simian appearance; hobbling gait; and anterolateral angulation (bowing) of the thigh, leg, or humerus, often with warmth and tenderness. Deformities may develop from bowing of the long bones or osteoarthritis. Pathologic fractures may be the presenting manifestation. Osteosarcoma develops in < 1% and is often suggested by increasingly severe pain.

Diagnosis

  • Plain x-rays

  • Serum alkaline phosphatase, Ca, and phosphate (PO 4 )

  • Bone scan after the diagnosis is established

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 γ-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, Ca, and PO 4 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.

Characteristic laboratory findings include elevated serum alkaline phosphatase (increased anabolic activity of bone) but usually normal GGT and serum PO 4 levels. Serum Ca is usually normal but can increase because of immobilization or hyperparathyroidism or decrease (often transiently) because of increased bone synthesis. 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.

Pearls & Pitfalls

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

Occasionally, increased catabolic activity of bone, as demonstrated by elevated urine markers of bone collagen turnover (eg, pyridinoline crosslinks), supplements the findings.

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

Treatment

  • Supportive care for symptoms and complications

  • Bisphosphonates

Localized, asymptomatic disease requires no treatment. Symptomatic treatment 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. Rarely, rapid correction of severe hypercalcemia is necessary, using IV fluids and furosemide (see Hypercalcemia : 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 Drug Therapy for Paget Disease). Synthetic salmon calcitonin is an alternative to bisphosphonates for patients intolerant of or resistant to them. The newer bisphosphonates (amino-containing bisphosphonates, eg, zolendronate) more effectively suppress markers of disease activity and provide more prolonged response.

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

Etidronate

5–10 mg/kg po once/day for 6 mo; higher doses (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

Pamidronate

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

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

Risedronate

30 mg po once/day for 2 mo

Taken the same way as alendronate

Tiludronate

400 mg po once/day for 3 mo

Taken the same way as alendronate

Zoledronate

5 mg IV given as a single 15-min infusion

For patients intolerant of oral bisphosphonates

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)

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

Key Points

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

  • Complications can include neural compression, osteoarthritis, fractures, secondary hyperparathyroidism, and hypocalcemia or hypercalcemia.

  • 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 newer bisphosphonate.

Resources In This Article

Drugs Mentioned In This Article

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

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