Intravenous Zoledronic Acid in Postmenopausal Women With Low Bone Mineral Density

Abstract

Although effective, oral bisphosphonate treatment for osteoporosis is limited by problems in compliance, gastrointestinal effects, and variable absorption. Intravenous bisphosphonates, given intermittently, might eliminate some problems of oral dosing, and they have increased bone mineral density (BMD) in small-scale, short-term studies of osteoporotic patients. The present phase 2 study evaluated zoledronic acid, the most potent bisphosphonate so far subjected to clinical trial, in 351 women seen at 24 centers in 10 countries who were at least 5 years postmenopausal and had a lumbar spine BMD at least 2 standard deviations below the mean for young adults. None had more than a single vertebral fracture at the outset. The women received 1 g of calcium daily and were randomly assigned in a double-blind design to receive an intravenous infusion of zoledronic acid every 3 months (0.25, 0.5, or 1 mg), a single 4-mg infusion, two 2-mg doses at a 6-month interval, or a saline placebo. All actively treated groups had a progressive rise in lumbar spine BMD over the 12-month study period; differences from placebo were significant. BMD in the femoral neck also rose progressively, and at the distal radius it did respond, though to a lesser degree. Markers of bone resorption reached their low point after a month of treatment, when they did not differ significantly from levels in placebo recipients. Bone biopsies demonstrated a lower proportion of mineralizing surface and a lower rate of bone formation in women given any dose of zoledronic acid. Cortical bone thickness and porosity, trabecular thickness, and cancellous bone volume were unchanged. No vertebral fractures were diagnosed during the study. Serum calcium fell significantly in women given zoledronic acid, but there were no significant group differences in levels of intact parathyroid hormone after 12 months. Adverse effects were significantly more common with zoledronic acid treatment than in placebo recipients. Most common were musculoskeletal pain, nausea, and fever. Five women withdrew because of a reaction to the first infusion. Intermittent intravenous zoledronic acid affected BMD to about the same degree as daily oral bisphosphonate therapy in these postmenopausal women. Conceivably an annual infusion might effectively control postmenopausal osteoporosis.