When to Treat With Bisphosphonates

First, it should be appreciated that patients with Paget disease seen in specialty clinics do not neces sarily reflect the full and accurate spectrum of the disease. In a large populationbased study in rotterdam that used radiographic and alkaline phosphatase screening, the overall prevalence of Paget disease was 3.6%.^[60] Only 14% of the individuals with radiologic evidence of the disease had elevated serum alkaline phosphatase activity and, as would be expected, most had monostotic disease. Musculoskeletal symptoms were not assessed in these patients, but it seems possible that only a small pe rcentage would have symptoms that require treatment.

Symptomatic Patients

Bone, Arthritic and Neurogenic Pain. Guidelines for treatment proposed by experienced physicians from a variety of countries^[61-66] are in general agreement that a patient with bone pain who has metabolically active disease should be considered for bisphosphonate therapy (Box 1). Preliminary data from the PrisM (Paget’s disease randomized trial of intensive versus symptomatic Management) study^[67] in the uK suggests analgesics are as effective as a bisphosphonates for reducing pain in this context. The difficulty in assessing the exact cause of pain in an individual patient (that is, bone pain, joint pain, neurogenic pain or a combination of these) makes the assessment of the PrisM results difficult. Analgesic therapy should reduce the severity of all types of pain, whereas bisphosphonate therapy only treats bone pain. It is possible that chronic bisphosphonate therapy could prevent worsening of joint or neurogenic pain over time by stabilizing the bone structure, but there is little evidence to support this at present. If relief of presumed bone pain does not occur within 2-4 weeks of starting bisphosphonate therapy, it can be assumed that the patient did not have severe bone pain. Arthritic or neurogenic pain could respond to simple analgesics, or, if necessary, to narcotic therapy, but inadequate pain relief or drug toxicity might mean surgical intervention should be considered.

Preparation for Orthopedic Surgery. As mentioned, patients with metabolically active disease who are candidates for elective orthopedic surgery involv ing a pagetic bone should receive drug therapy for 2-3 months before surgery to reduce the vascularity of the bone in order to prevent excessive hemorrhage (Box 1). Although there are no randomized clinical trials to prove the benefit of this, adjacent soft tissue and skeletal blood flow is increased, and the reduction of metabolic activity induced by drug therapy reduces vascularity. Another theo retical reason for treatment is to prevent the rapid postoperative osteolytic stimulation that might occur after an orthopedic procedure in a patient with Paget disease.^[14]

Other Indications for Treatment. Hypercalcemia associated with immobilization is a rare indication for treatment of Paget disease.^[22] Drug suppression of the osteoclast hyperactivity, which is stimulated by absence of gravitational forces on the skeleton, is an effective means of restoring the normocalcemic state.^[68] Treatment should also be considered in patients with hearing loss; although there is little evidence that hearing can be restored by drug therapy, this approach could prevent further deterioration of auditory acuity.^[29] Finally, treatment might prevent progression of skeletal deformities that would otherwise occur in untreated patients. The value of chronic treatment to prevent affected regions becoming increasingly abnormal with time is unproven, but might be considered in patients who have a relatively long life expectancy.

Asymptomatic Patients

A much more controversial proposal is the use of drug therapy to prevent complications of Paget disease in the asymptomatic patient (Box 1). Paget disease evolves over many years from an initial osteolytic lesion to osteosclerotic dominance, often resulting in enlarged but structurally weaker bone that is prone to bow and fracture in the lower extremities. It seems reasonable to consider early treatment if the generally asympto matic osteolytic phase of the disease is discovered in an indivi dual. This would be most likely to be detected in the children of patients with familial Paget disease. Even in the presence of normal serum alkaline phosphatase activity, a bone scan might detect an early lesion that could be assessed radiographically to define the osteolytic process. As drug therapy retards or reverses osteolytic lesions and allows formation of normal lamellar bone,^[69] it is likely that chronic treatment, particularly with the most potent bisphos phonates, could reduce future complications of Paget disease, such as skeletal deformity, arthritis in joints adjacent to pagetic bone and neurologic complications arising from spinal or cranial disease. The ongoing PrisM study might provide data to address the efficacy of a preven tive approach in the manage ment of Paget disease, if the followup of patients in this trial is sufficiently long.

Follow-up and Re-treatment

Before treatment, a bone scan should be performed to determine the extent of disease together with radiographs of affected bones and measurement of serum alkaline phosphatase activity (adequate if other liver enzymes are normal). Followup tests should include serum alkaline phosphatase activity every 3 months during the first year and radiography of osteolytic lesions after 1 year. Further followup would depend on the drug being administered and whether symptoms recurred: if zoledronate was used, annual measurements of serum alkaline phosphatase activity would be appropriate for the first 3 years and then more frequently; if lesspotent therapy was used, biochemical assessment could be performed every 3-6 months.

Retreatment would be appropriate if bone pain recurred and if serum alkaline phosphatase activity rose at least 25% above the nadir. Progression of an osteolytic lesion would suggest that a more potent drug should be considered, if available.