Paget Disease Treatment & Management

Updated: Sep 12, 2022
  • Author: Mujahed M Alikhan, MD; Chief Editor: Herbert S Diamond, MD  more...
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Approach Considerations

The short-term objective of Paget disease treatment is to control disease activity. The long-term objectives of treatment are to minimize or prevent disease progression and to decrease complications from the disease, if possible.

Indications for drug treatment of Paget disease are as follows [33] :

  • Metabolic active disease - Bone pain, fatigue fracture, skull/spine fracture, radiculopathy, osteolytic lesions, bony deformities, weight-bearing bone involvement, compression of spinal cord and nerve roots, bone compression of the eighth cranial or optic nerve

  • Preparation for orthopedic surgery (joint replacement anticipated at involved sites within 6 months)

  • Hypercalcemia or hypercalciuria - Recurrent renal calculi due to hypercalciuria, or fractures; serum alkaline phosphatase or urine hydroxyproline levels greater than twice the upper limit of the reference range; immobilization

When Paget disease occurs around a joint, treatment is often administered in an attempt to prevent development of osteoarthritis. In addition, young patients with Paget disease and those with high levels of bone-specific alkaline phosphatase (BSAP) are often treated to avoid future complications. The concept that aggressive treatment is associated with prevention of progression and reduction in risk of future complications is not yet supported by clear findings from long-term placebo-controlled trials; however, indirect evidence suggests that this hypothesis is reasonable.

Drug therapy for Paget disease should include bisphosphonate treatment with serial monitoring of bone markers. Response to therapy is indicated by reduction of symptoms and decreases in levels of BSAP (a bone formation marker) and deoxypyridinoline, C-telopeptide, [5] or N-telopeptide (bone resorption markers).  A sustematic review of 20 studies found moderate-quality evidence that bisphosphonates improved pain in patients with Paget disease. [34]

Patients should receive 1000-1500 mg of calcium and at least 400 U of vitamin D daily. This recommendation is especially important in conjunction with bisphosphonate treatments.

Secondary osteoarthritic pain may be reduced by nonsteroidal anti-inflammatory drugs or other nonnarcotic analgesics. In contrast, bone pain in Paget disease typically responds poorly to these pain medications. 

Orthotic devices, including canes and walkers, may be useful for patients with gait abnormalities resulting from Paget disease that involves the lower limbs. See Rehabilitation for Paget Disease.

Because of the increased risk of malignancy, patients with Paget disease should be monitored indefinitely. Chemotherapy, radiation, or both may be used to treat neoplasms that arise from pagetic bone. Amputation may also be necessary in the presence of a malignant transformation.


Bisphosphonates and Calcitonin Analogues

The following prescription drugs have been approved and are available for treating Paget disease in the United States [35, 36] :

  • Etidronate
  • Pamidronate
  • Alendronate
  • Tiludronate
  • Risedronate
  • Zoledronic acid
  • Salmon calcitonin

Pamidronate and salmon calcitonin are administered parenterally. (Human calcitonin is no longer available.) Ibandronate (Boniva) and olpadronate are potent bisphosphonates but are not approved by the Food and Drug Administration (FDA) for the treatment of Paget disease. (Ibandronate is approved by the FDA for the treatment of osteoporosis.) They may play a role in the future, depending on the results of clinical trials.

Preliminary European studies have shown that a single 2-mg injection of ibandronate is capable of suppressing disease activity in patients with Paget disease over a 12-month period. [37] In patients in whom this was insufficient to suppress disease activity, application of a higher dose was sometimes more effective.

In a long-term follow-up study of 25 patients with active Paget disease who were treated with a single intravenous dose of  6 or 12 mg of ibandronate, Reid et al reported that although some patients showed gradual increases in alkaline phosphatase levels after 20-30 months, levels remained normal 3 years after treatment in 15 of the 25 patients, and after 6 years, six of the patients continued to maintain normal levels without further intervention. [38]

Olpadronate is chemically similar to pamidronate, with the nitrogen atom being converted to a tertiary amine by the addition of 2 methyl groups. Preliminary studies in Europe and South America have suggested that olpadronate may be useful in the treatment of Paget disease. [39]

All bisphosphonates have poor absorption from the gut. Furthermore, they also combine with any calcium in the stomach, further inhibiting absorption. Thus, an oral bisphosphonate should not be ingested with food or any drink containing calcium.

Given the comparative double-blinded studies in which bisphosphonates were compared with one another (ie, tiludronate vs etidronate, alendronate vs etidronate, risedronate vs etidronate, pamidronate vs alendronate, zoledronic acid vs risedronate), the following conclusions can be made regarding these medications for the treatment of Paget disease [30, 35, 40, 41, 42, 43, 44, 45] :

  • Etidronate was less effective than the other bisphosphonates in suppressing biochemical markers of disease activity and should not be used as a first-line agent if the other bisphosphonates are available

  • No significant difference was noted between the bisphosphonates with regard to bone pain

  • Oral tiludronate (400 mg/day for 12 weeks), oral risedronate (30 mg/day for 2 months), and intravenous pamidronate (3 infusions of 60 mg at 2-week intervals, or 6 infusions of 30 mg at weekly intervals) have each been shown to be effective and superior to etidronate [43]

  • Bisphosphonates should be used as first-line agents over salmon calcitonin

  • Zoledronic acid infusions at 6 months shows significant normalization of alkaline phosphatase over oral risedronate [45]

Retreatment is indicated if a patient has not responded after 6 months following treatment or if clinical or biochemical relapse occurs. Some of these patients may respond better to a more potent bisphosphonate. Continued relapse or persistence can be evidenced by pain, but it should be confirmed by objective evidence of continuing disease activity. In the absence of continuing disease activity, other sources of pain should be investigated.

In situations in which treatment was based on the presence of asymptomatic disease in a critical site, retreatment must be based on biochemical criteria. No clinical-trial evidence supports this base criterion. However, the general consensus opinion is that an increase of alkaline phosphatase of 25% above nadir (even if the total is still within the normal range) indicates significant relapse.

The PRISM study, a randomized trial, concluded that intensive bisphosphonate therapy confers no clinical advantage over symptom-driven management in patients with established Paget disease. PRISM compared two treatment strategies with bisphosphonates: an aggressive approach in which patients were treated when they had alkaline phosphatase elevation, irrespective of symptoms, with a goal of primary biochemical normalization; and another, treating only symptomatic patients. On follow-up for a median of 3 years, no differences were found between groups in the number of prosthetic hip replacements, number of fractures, or hearing loss. Neither strategy provided significant pain relief or improvement in quality of life. [46]

A 3-year extension of the PRISM study using zoledronic acid (PRISM-EZ) reported that intensive bisphosphonate therapy may actually be harmful. In PRISM-EZ, patients in the intensive therapy arm were significantly more likely to experience a fracture or undergo orthopedic surgery than those in the symptomatic arm (hazard ratio 1.94, P=0.029). [47]

In patients who present with Paget disease at an older age, treatment may require only a single intravenous infusion of zoledronic acid. In a study of 107 patients who had been treated with intravenous zoledronate for the first time at a mean age of 76 years, Cundy et al found that by 9 years, only 14% had a biochemical relapse (defined as a procollagen-1 NT-peptide [P1NP] value >80 µg/L), although 64% of patients showed some loss of bisphosphonate effect (defined as a doubling of the P1NP level from the nadir value after treatment). The mortality rate was substantially greater than the relapse rate; by 10 years, more than half the cohort had died. [48]


In one study, 6 months of oral alendronate at the recommended 40-mg regimen produced normalization of alkaline phosphatase in 63% of patients with Paget disease, compared with 17% after treatment with 400 mg/day of etidronate. The mean initial alkaline phosphatase level was 5 times the upper limit of reference range.

In this study, after 18 months, 25 of 29 patients whose alkaline phosphatase levels had normalized and who were available for follow-up still had levels in the reference range. After 25-30 months, 15 patients still had alkaline phosphatase levels the in reference range. This study showed alendronate to be more potent at suppressing Paget disease activity than etidronate. Studies have also shown that alendronate treatment can lead to cessation of radiologic progression and healing of radiologic lesions.


Anderson et al induced biochemical remission with one or more complex courses of pamidronate in 90% of patients with elevated alkaline phosphatase levels. Average remission was 2 years, with a supposed permanent remission in 10-15%. The regimen consisted of a 30-mg infusion over 2 hours, followed by 3 infusions of 60 mg each over 4 hours for alkaline phosphatase levels less than 500 IU/L; levels greater than 500 IU/L required 6 infusions of 60 mg each at 2-week intervals.

Many single-dose regimens have been studied. Watts et al used a single infusion of 105 mg and achieved a remission rate of 71%, with a mean enzyme nadir at 6 months. Excellent symptomatic control was achieved at 1.5-2 years. Some patients required a second infusion, with a mean interval of 19 months after the first dose. Another single-dose regimen by Chakravarty et al, using 60 mg of IV pamidronate, provided efficacy similar to that of the Watts et al study.

Although a 30-mg IV infusion over 4 hours on 3 consecutive days is the approved therapeutic regimen, it is not used often. Infusions of 60 or 90 mg over 2-4 hours are more common. A single infusion is effective in mild disease, while 2-3 infusions may be needed in severe disease.

Depending on initial response, pamidronate may be readministered at irregular intervals. In general, more severe disease produces more severe biochemical and radiographic abnormalities that require higher dosages to achieve remission.

In a 2-year, open-label study comparing intravenous administration of pamidronate 60 mg every 3 months with daily oral administration of alendronate 40 mg in 3-month blocks, there were no significant differences in the proportion of patients whose alkaline phosphatase levels normalized (86% and 91%, respectively) or the proportion of patients who had an improvement in symptoms. [44]


In a comparative study, normalization of alkaline phosphatase was achieved in 77% of patients treated with risedronate, compared with 10% using a 400-mg etidronate regimen. After 12 and 18 months, respectively, 60% and 53% of patients treated with risedronate still had alkaline phosphatase levels in the reference range. A randomized, double-blinded comparison study of risedronate with etidronate showed that alkaline phosphatase levels were normalized in 75% of patients taking risedronate but in only 1 in 7 patients taking etidronate.


When given for 12 weeks, a daily regimen of 400 mg of tiludronate reduced alkaline phosphatase activity by 58% at 24 weeks. Pretreatment alkaline phosphatase levels were twice those of the reference range. Double-blinded controlled studies demonstrate that bone turnover markers are better suppressed by tiludronate than by placebo. These studies suggest tiludronate treatment is associated with 40-72% reduction in alkaline phosphatase activity. Pagetic bone pain also improved.

Zoledronic acid

In a randomized, double-blind trial comparing a single intravenous infusion of 5 mg of zoledronic acid with oral administration of 30 mg of risedronate daily for 2 months, normalization of alkaline phosphatase levels was achieved at 6 months in 89% and 58% of patients, respectively. Those receiving zoledronic acid had greater improvement in some domains of health-related quality of life, but the changes observed were small—1 to 2 points—which is below the threshold of 5 points for a change that is considered to be clinically significant. [45]

Given the development of several intravenous infusions for treatment of Paget bone disease, a 15-month, randomized study compared different intravenous bisphosphonates in patients with active disease. The medications used were pamidronate or zoledronate. After 6 months, the nonresponders to pamidronate were crossed over to zoledronate or neridronate. It was concluded that zoledronic acid was more effective and associated with an earlier response and longer remission. [49]

A follow-up study of the subset of patients whose alkaline phosphatase levels had been normalized during the trial compared the use of a single infusion of zoledronic acid, [45, 50] with a 2-month course of oral risedronate. Better quality-of-life scores and more prolonged suppression of alkaline phosphatase levels were reported for the patients receiving zoledronic acid. [51]

A study by Devogelaer and colleagues examining Paget disease remission after treatment with a 5 mg intravenous infusion of zoledronic acid in routine clinical practice found effectiveness and safety data similar to those observed in the original trial populations. Response rates were 93.3% at 1 year, 89.5 % at 2 years, and 91.6 % at 3 years. [52]

These studies have shown that a single infusion of 5 mg of zoledronic acid is associated with a greater percentage of normalization of serum alkaline phosphatase in treated patients and a prolonged biochemical remission with lower relapse rate, [51] making it the most effective therapy available to date.

A randomized placebo-controlled trial is currently examining whether genetic testing coupled with targeted intervention with zoledronic acid can modify the development and progression of bone lesions secondary to Paget disease. [53]



Amputation usually is the most appropriate treatment for neoplasms because of the aggressive behavior of this type of sarcoma, which is the typical late presentation in elderly patients. Amputation has been the most effective palliative or curative surgical management, especially with a spontaneous pathologic fracture. A localized long-bone lesion without metastases may be treated with preoperative chemotherapy, followed by wide tumor resection and limb-salvage procedure.

Management of metastatic sarcomas with pathologic fractures may involve internal fixation and local irradiation as a palliative approach. Pagetic sarcomas have a less favorable prognosis than primary nonpagetic osteosarcomas. Chemotherapy regimens effective for nonpagetic sarcomas are ineffective against pagetic sarcomas.


Joint Disease

Though few patients with Paget disease ever need surgical treatment, successful surgical management of severe orthopedic complications of this disease has improved the quality of life for these patients. [54] Indications for surgery include unstable fractures and severe arthritis refractory to medical and physical therapy. Malalignment of major weight-bearing bones may be treated with functional bracing and antipagetic medications. Realignment of severe lower limb deformities may help reduce mechanical joint pain and restore function. Joint replacement surgery may be indicated for end-stage joint disease if nonsurgical treatment fails to relieve pain adequately.

Total hip replacement is the most common orthopedic surgery performed on patients with Paget disease. The indication for total hip replacement is severe mechanical joint pain unrelieved by antipagetic medication. Thus, it is important to differentiate mechanical joint pain from pagetic bone pain.

Flexible intramedullary fixation devices are preferred over plate and screw fixation, which is associated with increased risks of perioperative complications, such as acetabular protrusion, aseptic loosening, and varus deformity of the femoral components. Heterotopic ossification is a common complication.

Mechanical failure requiring revision of the operation occurred in 10-15% of patients in several studies; however, total hip arthroplasties have been quite successful in relieving pain and improving mobility, with good to excellent results in 75-85% of patients on the basis of well-accepted scales of pain relief and function.

Preoperative treatment with bisphosphonates or calcitonin reduces intraoperative bleeding by decreasing disease activity. [30] Antipagetic medication should be started at least 6 weeks prior to elective surgery.

Tibial and fibular osteotomies have been effective in correcting tibial varus deformities and in relieving knee and ankle pain associated with these deformities. The indication for a tibial osteotomy is severe joint pain unresponsive to medical treatment.

Patient education about delayed bone healing and a long rehabilitation process is important. Reinforcement about the importance of careful, prolonged, protected weight bearing should be provided because the pagetic bone is abnormal and weak. Complete immobilization should be avoided because of its association with osteopenia and increased risk for hyperkalemia and hypercalciuria.


Spinal Disease

The most common cause of neurologic dysfunction from pagetic spinal stenosis is osseous compression from an enlarged vertebral body. Symptomatic pagetic spinal stenosis can be treated successfully with bisphosphonates and calcitonin. [30]

Surgical decompression rarely is needed. Decompressive laminectomies may be helpful for pagetic spinal stenosis and persistent mechanical pain unresponsive to nonsurgical treatment. [55]


Diet and Activity

No specific dietary modifications are necessary in patients with Paget disease. However, in patients with Paget disease who are receiving bisphosphonate therapy, ensure adequate intake of calcium and vitamin D.

No specific adjustments in physical activity levels are necessary in patients with Paget disease. If secondary osteoarthritis occurs in the knee, quadriceps-strengthening exercises may be helpful. If bone pain occurs with weightbearing or if gait abnormalities are present, individualized adjustment in physical activity regimens may be made.



Patients with Paget disease usually are medically stable. Complications (eg, neurologic compromise from spinal cord compression or hydrocephalus; brainstem compression from platybasia, basilar invagination, vertebral fracture, spinal stenosis) require transfer to the neurosurgical service.

Neoplastic complications, such as pagetic sarcomas, may require surgical debridement, radiation, or chemotherapy, with subsequent transfer to an oncologic service.



No preventive programs exist for Paget disease, because the etiology remains unknown, and no long-term prospective studies have been conducted to support the preventive effects of chronic suppressive therapy on the risk of pagetic complications.

A patient who has a family history of Paget disease and is older than 40 years may wish to have an alkaline phosphatase blood test every 2-3 years. If the alkaline phosphatase level is within the reference range, radiography or bone scanning also may be performed.



Consultations sometimes are indicated for patients with Paget disease. Because each patient has a unique combination of symptoms, the appropriate consultations may include any or all of the following:

  • Orthopedic surgeon for fractures, dislocations, and bony deformities
  • Neurosurgeon or orthopedic surgeon for spinal complications
  • Ear, nose, and throat (ENT) specialist or neurologist for impaired hearing or cranial nerve palsies
  • Rheumatologist or endocrinologist for management of Paget and joint disease
  • Ophthalmologist for optic atrophy or angioid retinal streak
  • Oncologist for neoplastic complications

Cardiology consultation is indicated for evaluation of cardiac status, including the following:

  • Left ventricular hypertrophy (LVH)
  • High cardiac output
  • Calcific aortic stenosis

Radiologist consultation is indicated for any of the following tests:

  • Radiologic films
  • Bone scanning
  • Computed tomography scanning
  • Magnetic resonance imaging

A physical medicine and rehabilitation specialist is indicated for any of the following:

  • Physical therapy
  • Occupational therapy
  • Speech therapy
  • Electrodiagnostic examination (electromyelogram [EMG]/nerve conduction study [NCS])
  • Evaluation for rehabilitation

Long-Term Monitoring

Careful follow-up of patients with Paget disease is indicated for life. Untreated patients with mild disease should be scheduled for annual serum alkaline phosphatase levels and annual radiographs of osteolytic lesions.

Treated patients should have serum alkaline phosphatase levels every 3-4 months and should undergo annual radiographs of osteolytic lesions, if present. Alternatively, urinary hydroxyproline or collagen cross-links can be used.