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
About 10% of patients with Paget disease have mutations of the SQSTM1 (sequestosome-1) gene, resulting in increased nuclear factor kappa-B activity, which increases osteoclast activity (1). Several other mutations associated with Paget disease have been identified, many affecting the RANK (receptor activator of nuclear factor kappa-B) signaling pathway that is critical for osteoclast generation and activity. A viral etiology, such as measles, has been proposed because nuclear inclusions in diseased osteoclasts that are similar to those seen in paramyxovirus-infected cells have been seen on electron microscopy. 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
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1. Laurin N, Brown JP, Morissette J, Raymond V: Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 70:1582–1588, 2002. doi: 10.1086/340731.
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 usually 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
Paget disease should be suspected in patients with the following:
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Unexplained bone pain or deformity
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Suggestive findings on x-ray
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Unexplained elevation of serum alkaline phosphatase on laboratory tests done for other reasons, particularly if gamma-glutamyl-transpeptidase (GGT) is normal
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Hypercalcemia that develops during bed rest, particularly among elderly patients
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Bone sarcoma in elderly patients
If Paget disease is suspected, plain x-rays and serum alkaline phosphatase, calcium, and phosphate levels should be obtained. Confirmation on x-ray is required to establish the diagnosis. Characteristic x-ray findings include the following:
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 gamma-glutamyl-transpeptidase (GGT) and serum phosphate 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 (1). 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.
Diagnosis reference
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1. 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 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:
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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)
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To treat pain clearly related to the pagetic process and not to another source (eg, osteoarthritis)
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To prevent or minimize bleeding that can occur during orthopedic surgery
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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 zoledronate, more effectively suppress markers of disease activity and provide more prolonged response (1). 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 (2).
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
Treatment references
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1. 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.
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2. 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
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Paget disease of bone is a common and often asymptomatic abnormality, particularly among older adults.
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Complications can include osteoarthritis, fractures, neural compression, osteosarcoma, and rarely hypercalcemia.
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Complications of bisphosphonate treatment of Paget disease of bone include hyperparathyroidism and hypocalcemia.
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Confirmation is usually by x-rays showing findings such as bone sclerosis, coarse cortical trabeculation or cortical thickening, and bone bowing or enlargement.
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First-line treatment is zoledronate or another amino-bisphosphonate (alendronate, pamidronate, or risedronate).
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
zoledronic acid |
ZOMETA |
Tiludronate |
No US brand name |
Alendronate |
FOSAMAX |
Pamidronate |
AREDIA |
Risedronate |
ACTONEL |
Etidronate |
DIDRONEL |
calcitonin |
MIACALCIN |
denosumab |
PROLIA |
