Although intravenous pamidronate has been available and efficacious, the requirement for a prolonged intravenous infusion over 4 hours for 3 consecutive days inhibits its use.

Zoledronic acid, a nitrogen-containing bisphosphonate, is a potent inhibitor of farnesyl pyrophosphate synthetase and induces osteoclast apoptosis. Zoledronic acid is given by intravenous infusion as a single 5-mg dose over a 15-minute period. Data indicate that a single 5-mg infusion of zoledronic acid results in remission in most patients with Paget disease for at least 24 months and possibly up to 61/2 years without further treatment. A transient acute phase reaction that is manifest as myalgias and fever may occur with any intravenous bisphosphonate infusion, although the symptoms rarely last more than 2 or 3 days and can be treated with acetaminophen or a nonsteroidal anti-inflammatory medication.

Therapeutic efficacy of bisphosphonate therapy in Paget disease can be defined as normalization of the serum alkaline phosphatase levels or a 75% reduction from baseline levels of alkaline phosphatase. Six months after the zoledronic acid infusion, 96% patient had reached the primary end point as compared with 74.3% of patients who were treated with oral risedronate. The pain score on the SF-36 improved in patients with zoledronic acid and risedronate treatment but was significantly greater with zoledronic acid compared with risedronate. The biochemical markers of bone turnover showed greater reductions with zoledronic acid then with risedronate in these comparative studies. In the first 3 days after infusion, 53.7% of patients receiving zoledronic acid reported adverse events compared with 25% of those receiving risedronate. The symptoms included flulike illness, myalgias, fever, fatigue, headaches, nausea, or bone pain, but after 3 days the rate of adverse events was comparable. Hypocalcemia can occur in patients after intravenous bisphosphonate treatment for Paget disease but seldom requires treatment. Patients should receive adequate calcium and vitamin D supplementation during the 2 weeks after zoledronic acid infusion. Zoledronic acid did not adversely affect renal function in patients with Paget disease if given over 15 to 20 minutes, but it should not be administered in patients with renal insufficiency with a glomerular filtration rate less than 35 mL/min. Studies are underway to assess the potential efficacy in Paget disease of denosumab, a monoclonal antibody that inhibits osteoclastogenesis by binding to RANKL. Denosumab is administered subcutaneously every 6 months.