About 1% of adults > 40 in the US 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.
General references
1. Ralston SH, Corral-Gudino L, Cooper C, et al: Diagnosis and management of Paget's disease of bone in adults: a clinical guideline. J Bone Miner Res 34(4):579-604, 2019. doi: 10.1002/jbmr.3657. Epub 2019 Feb 25. PMID: 30803025; PMCID: PMC6522384.
2. Reid IR: Recent advances in understanding and managing Paget's disease. F1000Res. 2019;8:F1000 Faculty Rev-1485. Published 2019 Aug 22. doi:10.12688/f1000research.19676.1
3. Singer FR, Bone HG 3rd, Hosking DJ, et al: Paget's disease of bone: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 99(12):4408-22, 2014. doi: 10.1210/jc.2014-2910. PMID: 25406796.
Etiology of 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 reference 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 reference 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 has not been established, it is hypothesized that in genetically predisposed patients an as yet unidentified virus triggers abnormal osteoclast activity.
Etiology reference
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
2. Rea SL, Walsh JP, Layfield R, et al: New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget's disease of bone. Endocr Rev 34(4):501-24, 2013. doi: 10.1210/er.2012-1034. Epub 2013 Apr 23. PMID: 23612225.
Pathophysiology of Paget Disease of Bone
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.
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 Lumbar Spinal Stenosis Lumbar spinal stenosis is narrowing of the lumbar spinal canal compresses the nerve rootlets and nerve roots in the cauda equina before their exit from the foramina. It causes positional back... read more 
or spinal cord compression Spinal Cord Compression Various lesions can compress the spinal cord, causing segmental sensory, motor, reflex, and sphincter deficits. Diagnosis is by MRI. Treatment is directed at relieving compression. (See also... read more 
may develop.
Rare complications include transformation to osteosarcoma Osteosarcoma (osteogenic sarcoma) Primary malignant bone tumors are much less common than metastatic bone tumors, particularly in adults. Primary malignant bone tumors include multiple myeloma, osteosarcoma, adamantinoma, chondrosarcoma... read more 
in < 1% of patients. Highly vascular bones may bleed excessively during orthopedic surgery. Very rarely, hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism, vitamin... read more develops in patients who are immobile; however, hypercalcemia in ambulatory patients suggests the coexistence of hyperparathyroidism Primary hyperparathyroidism Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism, vitamin... read more . High-output heart failure due to large or numerous lesions has been reported.
Symptoms and Signs of Paget Disease of Bone
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, and nerve deafness in one or both ears. Symptoms may include 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 of Paget Disease of Bone
Plain x-rays
Serum alkaline phosphatase, calcium, and phosphate
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 older patients
Bone sarcoma in older 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:
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. However, if x-ray findings are not definitive for Paget disease and there is diagnostic uncertainty, biopsy should be considered to exclude bony metastatic disease.
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.
Treatment of Paget Disease of Bone
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 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.
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 Drug Therapy for Paget Disease 
). The amino-bisphosphonates (bisphosphonates with an extra nitrogen atom), particularly zoledronic acid, more effectively suppress markers of disease activity and provide more prolonged response ( 1 Treatment 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 ). Zoledronic acid is recommended as first-line therapy for Paget disease of bone in professional guidelines, whereas other amino-bisphosphonates (such as alendronate, risedronate, and pamidronate) are 2nd-line and the simple bisphosphonates (bisphosphonates without an extra nitrogen atom, such as tiludronate and etidronate) are 3rd-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 Treatment 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 ).
Because bone turnover is increased, patients should ensure adequate intake of calcium and vitamin D, and supplements are often needed.
Treatment references
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
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
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 zoledronic acid.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
zoledronic acid |
ZOMETA |
alendronate |
FOSAMAX |
risedronate |
ACTONEL |
pamidronate |
AREDIA |
etidronate |
DIDRONEL |
calcitonin |
MIACALCIN |
denosumab |
PROLIA |
