Paget Disease of Bone

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 Etiology references 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... read more , 2 Etiology references 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... read more ). 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 remains controversial, it is hypothesized that in genetically predisposed patients an as yet unidentified virus triggers abnormal osteoclast activity.

Any bone can be involved in Paget disease. 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.

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, signs may include skull enlargement bitemporally and frontally (frontal bossing), dilated scalp veins, and nerve deafness in one or both ears. Symptoms may include vertigo, headaches, and hearing impairment. Deformities may develop from bowing of the long bones or osteoarthritis. Pathologic fractures may be the presenting manifestation. New onset or severe pain at a site of pagetic bone should prompt consideration of osteosarcoma.

Paget disease should be suspected in patients with the following:

If Paget disease is suspected, plain x-rays and serum alkaline phosphatase, 25OH-vitamin D, creatinine, calcium, and phosphate levels should be obtained.

Characteristic laboratory findings include elevated serum alkaline phosphatase (increased anabolic activity of bone) but usually normal serum gamma-glutamyl-transpeptidase (GGT), 5'-nucleotidase, and serum phosphate levels. Serum calcium is usually normal, though in the setting of immobilization may be increased. If hypercalcemia is present, the patient should be evaluated for concurrent 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 alkaline phosphatase 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. A 25OH-vitamin D level and creatinine should be checked before treating symptomatic patients with bisphosphonates.

Confirmation on x-ray is required to establish the diagnosis. Characteristic x-ray findings include abnormal architecture with coarse trabeculae and cortical thickening and sclerosis. Involved bone may be enlarged, and pagetic lesions in the tibia or femur may result in bowing. Once a diagnosis of Paget's disease of bone is made on x-ray, a radionuclide bone scan using technetium-labeled phosphonates should be done to determine the extent of bone involvement. However, in cases of diagnostic uncertainty, a biopsy should be performed to exclude possible metastatic disease. A biopsy is also indicated for patients with known pagetic bone involvement who have worsening symptoms at the affected site to evaluate for osteosarcoma or other tumors (eg, giant cell tumor of bone).

Supportive treatment of Paget disease of bone includes analgesics or nonsteroidal anti-inflammatory drugs (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.