Intravenous Bisphosphonate Treatment for Osteoporosis

Bisphosphonates are potent anti-resorptive agents used in the treatment of osteoporosis. While oral bisphosphonates are documented to increase bone mineral density and reduce incidence of fractures, their major limitation to use has been their absorption and tolerability. The oral bisphosphonates are acid chemical structures with poor absorption (<1%). Their primary adverse side effect is esophageal irritation. For these reasons, the oral bisphosphonates are generally contraindicated in patients with dyspepsia and/or questionable gastrointestinal absorption. In these patients, the intravenous bisphosphonates pamidronic acid (Aredia) and zoledronic acid (Zometa) may be appropriate. While pamidronate is infused every three to four months, zoledronate is infused only once annually.

There have been no randomized controlled studies to date comparing the intravenous bisphosphonates to the oral bisphosphonates with fracture reduction as an outcome measure. Cohort studies have demonstrated that the intravenous bisphosphonates are superior to oral bisphosphonates in increasing bone mass.

Pamidronic acid (Aredia)

Pamidronic acid or pamidronate is a bisphosphonate containing basic aminoalkyl groups. It is FDA approved for the treatment of Paget's disease, hypercalcemia of malignancy, multiple myeloma, and bone metastases from solid tumors, and is used off-label for the treatment of osteoporosis. Parenteral pamidronate has also been successfully used in the treatment of postmenopausal women with osteoporosis who are intolerant to oral bisphosphonates. Peretz et al[1] followed 36 postmenopausal women with osteoporosis who received five courses of cyclical intravenous pamidronate. The authors found that pamidronate was effective in reducing bone turnover, as assessed by certain bone markers, which was followed by an increase of 2.9% in bone mineral density. Guttman et al[2] also showed that 13 patients who received 30 mg of pamidronate intravenously over three months had an increased bone mineral density of 6.2% in the lumbar spine and 4.7% in the hip. While there has been no fracture rate data reported for pamidronate in the treatment of osteoporosis to date, intravenous pamidronate has been shown to decrease fracture rate in children with severe osteogenesis imperfecta[3],[4].

There has been one case-control study performed at HSS[5], which compared fracture rate in patients given oral alendronate versus intravenous pamidronate. In each group, 50 elderly osteoporotic female patients were matched for age, presence of pre-treatment osteoporotic fracture, pre-treatment T-score, manufacturer of dual energy x-ray absorptiometry scanner, and body mass index. The authors found equivalent fracture rates in each group, with one fracture/year noted in both the alendronate and pamidronate group. In addition, there was an increase in lumbar spine bone mineral density per year of treatment of 1.37% versus 1.22% in the pamidronate group versus alendronate group, respectively. Furthermore, there was an increase of femoral neck bone mineral density per year of treatment of 0.91% versus 0.89%, in the pamidronate group versus alendronate group, respectively. This case-matched study therefore demonstrated comparable benefit for intravenous pamidronate and oral alendronate.

Zoledronic acid (Zometa)

Zoledronic acid or zoledronate is a new-generation bisphosphonate that is the most potent inhibitor of bone resorption to date. It is an imidazole ring structure containing two nitrogen atoms. While it is FDA approved for the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases from solid tumors, it has also been used off-label for the treatment of osteoporosis in patients unable to tolerate the oral bisphosphonates.

Preliminary data on the efficacy of zoledronate in the treatment of osteoporosis have been promising. Parenteral zoledronate administered at intervals of one year produced comparable effects on bone turnover and bone mineral density to those seen with oral dosing with bisphosphonates. Reid et al[6] performed a randomized, double-blind, placebo-controlled trial in 351 postmenopausal women with low bone mineral density over one year. Women received placebo or varying intravenous doses (0.25 mg, 0.5 mg or 1 mg) at three month intervals; 2 mg doses at six month intervals; and 4 mg as a single dose. Lumbar spine bone mineral density was used as the primary endpoint. The authors documented increases in bone mineral density in the spine for the treatment group that were 4.3 to 5.1 percent higher than those in the placebo group (p<0.001). In addition, bone mineral density values in the femoral neck were 3.1 to 3.5 percent higher than in the placebo group (p<0.001). In all groups, there were suppressed biochemical markers of bone resorption. Therefore, the authors concluded that a single infusion of zolendronate appears to be as effective in enhancing bone mass in postmenopausal osteoporosis as the oral bisphosphonates. No fracture prevention data for zolendronate is currently available.

Conclusion

The intravenous bisphosphonates pamidronate and zolendronate represent excellent alternative treatments to the oral bisphophonates in patients unable to tolerate the oral bisphosphonates or in patients with malabsorption difficulties. While there is limited data on these intravenous agents in the use of osteoporosis, preliminary studies demonstrate excelllent efficacy, with promising fracture data. Randomized controlled trials using these agents are needed to further support current evidence.