Paget Disease of Bone

Definition, Etiology, PathogenesisTop

Paget disease of bone (PDB) is a chronic metabolic bone disease of unknown etiology. Research suggests that mutations in sequestosome 1 increase the susceptibility to the development of PDB, and the potential role of paramyxovirus infection in causing the disease has been studied. PDB is characterized by a disruption in normal osteoclastic bone resorption and osteoblastic bone formation, which leads to disorganized bone remodeling, with vascularized foci of osteopenia interwoven with focal osteosclerosis and secondary myelofibrosis. Lesions with predominant osteolysis exhibit lower resistance to stress and deformities, whereas lesions with predominant bone formation show overgrowth and thickening of the bone, which result in increased susceptibility to fractures. Osteolytic and osteosclerotic lesions usually coexist.

Clinical Features and Natural HistoryTop

Approximately 20% of patients have a solitary lesion. The lesions never involve an entire bone or the skeleton, but they may occur in any bone, most commonly in the pelvis, lumbar or thoracic spine (vertebral bodies), femur, skull, or tibia.

Signs and symptoms depend on the location and extent of the lesions and include pain, which may be caused by microfractures, secondary degeneration and expansion of bone, or mechanical stress of joints and the periarticular soft tissue (in 80% of symptomatic patients); warmth of the involved sites due to increased vascularity of the lesions; bone deformity (eg, the varus deformity or anterior bowing of the tibia, thickening of the bones of the skull); fractures of the long bones, usually of the femur, tibia, humerus, or forearm (these may be asymptomatic). There may be signs and symptoms related to compression of the cranial nerves or the medulla oblongata in patients with cranial involvement as well as the vascular steal syndrome (from the brain to a vascular lesion in the skull via the external carotid artery) compromising the cerebral perfusion and causing headaches, vision and hearing impairment, or ischemic stroke. One may encounter signs and symptoms of hyperkinetic circulation or even high-output heart failure, especially in patients with extensive (>35% of the skeleton) and highly vascular lesions.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests: Consider a diagnosis of Paget disease with increased levels of serum alkaline phosphatase (ALP), a marker of bone formation, in 95% of patients (up to 7 × upper limit of normal [ULN]; levels correlate with the extent of lesions on scintigraphy) and otherwise normal gamma-glutamyl transferase (GGT) levels. In those with underlying liver or hepatobiliary disease, other bone markers may be needed to monitor treatment response. Increased serum levels of N-terminal propeptide of type I collagen (PINP) and increased levels of markers of bone resorption (elevated levels of serum cross-linked C-terminal telopeptide of type I collagen [CTX] or cross-linked n-telopeptide of type I collagen [NTX]) correspond to the rate of bone turnover in PDB and may be used to determine the treatment response in those with an established history of liver disease. The use of these more specific markers should be weighed against their increased cost. Hypercalcemia and hypercalciuria (most commonly following a fracture and during periods of immobility) may be measured in those in whom abnormalities might be expected.

2. Imaging: Radiography reveals thickening and deformity of the outlines of long bones as well as coexisting osteolytic and osteosclerotic lesions. Radiologic changes evolve as osteolytic lesions progress with osteoblastic activity following, transforming the previously osteolytic bone into a mixed osteolytic-sclerotic bone, which finally is further transformed into a primarily sclerotic bone. In the spine the affected vertebral bodies manifest as a “picture frame” vertebra with an increased anteroposterior diameter and osteosclerotic vertebral body borders. An ivory vertebra is one that is predominantly sclerotic bone. Within the skull, thickening of the calvaria, loss of the periosteum, and thickening of the diploe and osteosclerotic lesions (the “cotton wool” appearance) are visible. Radiographs are recommended in suspected areas. Bone scintigraphy shows local uptake of radionuclide by the sites of intensive bone remodeling; compared with radiography, bone scintigraphy has higher sensitivity but lower specificity and will often identify asymptomatic lesions. Scintigraphy is recommended to determine the extent of the disease.

3. Bone biopsy and histology are indicated only in case of diagnostic uncertainty.

Diagnostic Criteria

Diagnosis is based on characteristic radiographic features and increased serum ALP levels; however, normal levels do not exclude PDB. In practice, PDB is suspected in patients with an increased serum ALP level or abnormal radiography results observed during a diagnostic workup performed for other reasons. Only 30% to 40% of patients have typical manifestations at diagnosis.

Differential Diagnosis

1. Focal lesions seen on radiography: Lymphoma, metastases (particularly prostate cancer), primary bone tumor (particularly osteolytic).

2. Focal uptake of radionuclide on scintigraphy: Osteomyelitis, arthritis, prior fracture, metastases, primary bone malignancy.

TreatmentTop

Indications for Treatment

1. Treatment is indicated in patients with active symptomatic PDB to prevent complications of the disease, which include hearing loss, osteoarthritis, paralysis, neoplasms, and congestive heart failure. Treatment of patients with asymptomatic disease may be influenced by a marked increase in ALP levels, imaging abnormalities indicative of complications from an untreated disease, localization of lesions, and risk of complications.

2. Hearing loss: Hearing loss was originally thought to be caused by the compression of nerve VIII. However, more recently it has been attributed to cochlear damage. There are no randomized controlled trials to demonstrate the benefits of anti-Paget therapy on hearing loss. In general, it is felt that treatment may prevent rapid hearing loss, but it does not reverse hearing loss.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to retrospective observational data. el Sammaa M, Linthicum FH Jr, House HP, House JW. Calcitonin as treatment for hearing loss in Paget's disease. Am J Otol. 1986 Jul;7(4):241-3. PMID: 3740234.

3. Osteoarthritis: Treatment with analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) is suggested in Paget disease and considered adjunctive treatment, as the agents do not deal with the underlying disease process. Treatment in those with joint pain, particularly of the hip and knee, and pagetic involvement of the adjacent bone often results in significant improvement in pain, and treatment prior to joint arthroplasty may be important in preventing bleeding at the site of surgery and for preventing loosening of the joint.

4. Paralysis: Paralysis may occur with vertebral body involvement. Treatment with an IV bisphosphonate or calcitonin is suggested to correct the vascular steal that may be occurring.

5. Neoplasm: The incidence of osteosarcomas complicating PDB is estimated at <1%. These cancers occur mostly in persons with long-standing polyostotic disease and affect patients in their seventh decade. Epidemiologic studies suggest that this late peak of osteosarcomas is absent in regions where PDB is infrequently reported. Whereas PDB has a predilection for the axial skeleton, skull, femurs, and tibias, pagetic osteosarcomas tend to spare the spine and are reported more commonly in the pelvis, femur, humerus, and skull.

Pharmacotherapy

1. Antiresorptive drugs relieve bone pain caused by the increased metabolic activity of the lesions and heal the lesions. Nevertheless, the long-term effect of the drugs on the disease progression is not known. Antiresorptive drugs have not been demonstrated to prevent complications of PDB.

1) Aminobisphosphonates are the drugs of choice. They are indicated mainly for bone pain due to the increased metabolic activity of the lesions, manifesting as elevated serum ALP levels. The first-line agent is zoledronic acid; it is recommended for symptomatic patients in a single IV dose of 5 mg. Second-line agents are alendronate sodium (INN alendronic acid) 40 mg/d for 6 months or risedronate sodium 30 mg/d for 2 months; they are recommended for patients intolerant of IV zoledronic acid or those who prefer an oral medication.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Corral-Gudino L, Tan AJ, Del Pino-Montes J, Ralston SH. Bisphosphonates for Paget's disease of bone in adults. Cochrane Database Syst Rev. 2017 Dec 1;12:CD004956. doi: 10.1002/14651858.CD004956.pub3. PMID: 29192423. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med. 2005 Sep 1;353(9):898-908. PMID: 16135834. Reid IR, Nicholson GC, Weinstein RS, et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med. 1996 Oct;101(4):341-8. Erratum in: Am J Med 1997 Mar;102(3):322. PMID: 8873503. Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group. Am J Med. 1999 May;106(5):513-20. PMID: 10335722. Caution with zoledronic acid should be given to those with renal insufficiency. Additionally, before initiating bisphosphonate therapy, calcium, vitamin D, and phosphate testing should be performed and supplementation started to prevent secondary hyperparathyroidism. In patients who are hypercalcemic, serum parathyroid hormone (PTH) levels should be measured. PTH levels can be low in patients with hypercalcemia associated with immobilization and elevated in those with coexisting primary hyperparathyroidism, which can be present in Paget disease. In patients in whom serum ALP levels do not normalize despite good pain control, continue the antiresorptive therapy for several consecutive months (except for zoledronic acid, which may decrease the levels of bone markers for 5 years and may be administered again if there is an increase in ALP and worsening of symptoms during that period) and monitor the patient for complications. Although rare, in patients who relapse after initial zoledronic acid therapy, retreatment with another course may be able to reachieve a chemical and clinical response.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of the study and very small number of patients.Reid IR, Brown JP, Levitt N, et al. Re-treatment of relapsed Paget's disease of bone with zoledronic acid: results from an open-label study. Bonekey Rep. 2013 Nov 6;2:442. doi: 10.1038/bonekey.2013.176. eCollection 2013. PMID: 24422139; PMCID: PMC3844974.

2) Calcitonin is used exclusively in patients in whom bisphosphonates are not tolerated, ineffective, or contraindicated, as the evidence for its use is derived only from observational studies.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of the study. DeRose J, Singer FR, Avramides A, et al. Response of Paget's disease to porcine and salmon calcitonins: effects of long-term treatment. Am J Med. 1974 Jun;56(6):858-66. PMID: 4857531. The dose is 100 IU/d subcutaneously or IM; later it may be reduced to 50 to 100 IU every other day. Due to the increased risk of malignancy, treatment should be limited to 3 months (6 months in exceptional cases). After a careful analysis of risks and benefits, a repeated short-term treatment may be considered.

2. Analgesics: Opioids (dosage: see Pain Management: Basic Principles) and NSAIDs (dosage: see Osteoarthritis) relieve bone pain related to the increased metabolic activity but are used mainly in patients with pain related to complications, such as bone deformity and osteoarthritis, that cannot be controlled with antiresorptive therapy.

3. Surgery may be necessary for bone-related and joint-related complications.

Follow-UpTop

Follow-up includes clinical assessment of pain and deformities and determination of ALP and one of PINP, CTX, or NTX levels for more specific measures when there is underlying hepatobiliary disease.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Al Nofal AA, Altayar O, BenKhadra K, et al. Bone turnover markers in Paget's disease of the bone: A Systematic review and meta-analysis. Osteoporos Int. 2015 Jul;26(7):1875-91. doi: 10.1007/s00198-015-3095-0. Epub 2015 Jun 3. Review. PMID: 26037791. Radiographic monitoring of the involved bones every 12 months may be used to evaluate treatment effectiveness or disease progression in patients not receiving treatment. Adequate pain control and normalization of ALP levels during treatment indicate remission, which may last for many years. After the administration of zoledronic acid, evaluate disease progression and treatment effects every 1 to 2 years after the normalization of bone markers, or every 6 to 12 months in the case of less potent bisphosphonates. An increase in the levels of markers of bone resorption by 20% to 30% above the ULN is an indication for retreatment.