Recently, the Pharmacovigilance Unit, HSA has received 25 reports of fractures and one of delayed bone healing with long-term use of alendronate in our local patients.

We are currently following up with these reports to determine the causality and the date of occurrence of these events as many of them lacked details such as onset of the adverse event, dose and duration of alendronate given, use of concomitant medicines and whether bone mineral density (BMD) was measured.

Based on an interim analysis of the available data, the adverse events were observed in female patients who were on alendronate for 1–10 years (duration reported in 22 patients), with median age of 66.5 years (range: 37–82 years). Only 12 reports included patients' BMD T-scores for hip which ranged from 1.29 to –2.8.

Seven patients were reported to have pain in the fractured limb up to four months prior to sustaining the fracture. Six out of the 26 patients did not encounter any trauma prior to experiencing the fracture. Ten patients had minimal trauma, mainly spontaneous falls, and one patient had delayed bone healing. In nine patients, the events leading to sustaining of the fractures were not stated.

The types of fractures experienced by these patients were mainly sub-trochanteric in nature. Most of these fractures were either simple transverse fractures or short oblique fractures and reporting physicians described them as distinctly different from typical osteoporotic fractures.

Alendronate (Fosamax®, Merck Sharp & Dohme) has been registered by HSA since 1996 for the treatment and prevention of osteoporosis in post-menopausal women. The recommended dosage for treatment of osteoporosis in post-menopausal women is one 70mg tablet once weekly or one 10mg tablet once daily. For the prevention of osteoporosis in post-menopausal women, the recommended dosage is one 5mg tablet once daily (the 5mg tablet is not marketed locally).

Other similar drugs that are registered include risedronate (Actonel®, Sanofi-aventis) in 2001 and ibandronate (Bonviva®, Roche) in 2005. These drugs belong to the bisphosphonate class of drugs which acts as specific inhibitors of osteoclast-mediated bone resorption.

Bisphosphonates have demonstrated to have fracture reduction benefits for post-menopausal women with prior vertebral fracture or T-scores of –2.5 or lower. There are however anecdotal reports in recent years that suggest bisphosphonates may be associated with the risk of fractures in certain susceptible individuals.

A review of the published medical literature indicates that there are about ten cases of spontaneous nonspinal fractures in patients on alendronate therapy. For the nine patients who were reported to continue taking alendronate after the fractures, six displayed either delayed or absent fracture healing for 3 months to 2 years.^1,2 The description of these cases appears similar to some of our local cases in that these were mainly post-menopausal female patients who developed atraumatic nonspinal fractures after 3–8 years of alendronate treatment.

The MOH Clinical Practice Guidelines for Osteoporosis³ recommends that for treatment with bisphosphonates, alendronate or risedronate therapy is recommended when patient's T-score is less than or equal to –2.5, whether or not patient has a fracture. For such cases, it is recommended to consider monitoring BMD after one year.

For patients with T-score between –1 to –2.5 (with respect to bisphosphonate use in prevention of osteoporosis), it recommends that it might be a reasonable option to defer intervention in those at low risk for fracture prevention as bisphosphonates have not demonstrated to reduce fractures when used in prevention, despite reducing bone loss.

HSA will be following up with the case reports to investigate whether there is a causal link between the reported adverse events and the drug, and whether there could be other factors that may have predisposed to the fracture. Although the reports received were for alendronate, it may be premature to form the direct causal link between alendronate and these fractures. At the same time, the possible association of such adverse events with other bisphosphonates cannot be excluded.

Healthcare professionals are encouraged to report all serious adverse effects especially fractures suspected to be associated with bisphosphonates to the Pharmacovigilance Unit of HSA.