Update on the Bisphosphonates

Introduction

The bisphosphonates are a class of medications that slow bone resorption. Many studies have shown that this class of medication can improve bone density and reduce the risk of fracture in patients with a reduced bone density.

The orally available agents include alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva). All seem to be associated with a small degree of gastrointestinal irritation, but are generally well-tolerated. Ibandronate (Boniva) is also available as an intravenous injection given quarterly. When given intravenously, there is no associated gastrointestinal distress, but patients can have flu-like symptoms for 1-5 days. This is usually just after the first infusion.

Results of a Recent Study

Recently, the results of a large, double-blind, placebo-controlled study on the use of zoledronic acid for use in osteoporosis was published (1). 3889 patients were randomly assigned to receive a 15-minute infusion of zoledronic acid (5mg) yearly for three years, and 3876 patients were assigned to a placebo infusion. Patients who received zoledronic acid had a 70% decrease in the risk of vertebral fractures and a 41% decrease in the risk of hip fractures. There was a statistically significant increase in bone density and a reduction in bone resorption markers.
 
There were no reported cases of avascular necrosis of the jaw in the study patients. There was one case in a patient who received a placebo. This complication, primarily involving the intravenous bisphosphonates, has been recognized over the past few years. It is felt to be uncommon. It probably is associated with a low bone turnover state. This is most common in the patients who received intravenous bisphosphonates monthly for the treatment of cancer metastatic to bone.

Change in renal function was similar in both groups. There has been concern about renal insufficiency and the intravenous bisphosphonates. This was not demonstrated in this study. In addition, another recent study (2) evaluated the use of oral bisphosphonates in patients with mild renal insufficiency and did not demonstrate significant side effects.

This therapy offers greater ease of dosing, as it is given yearly. In addition, patients who cannot tolerate oral bisphosphonates due to gastrointestinal distress often can tolerate the intravenous bisphosphonates. Many studies show poor compliance with weekly and monthly oral bisphosphonates, and a yearly infusion may well help with compliance.

This study did demonstrate a statistically significant increase in atrial fibrillation in patients who received the drug (50 patients in the study group and 20 patients in the placebo group). In a recent editorial (3), the authors from the FIT trial, which was a randomized trial of alendronate involving 6459 postmenopausal women, did note a nonstatistically significant increase in atrial fibrillation in the women who received alendronate. This is not an adverse event that has generally been noted by clinicians, and all agree further study is warranted. For now, patients should be advised of this risk.
 
It should be noted that zoledronic acid is not yet FDA-approved for use in osteoporosis. It is FDA-approved under the name Zometa for treatment of Paget’s disease, hypercalcemia of malignancy, multiple myeloma, and for several malignancies metastatic to bone. Novartis is seeking FDA-approval for zolendronic acid for the treatment of osteoporosis under the name Reclast.