Bisphosphonates are used in the treatment of osteoporosis, Paget's disease of bone, and may be used to lower high calcium levels in people with cancer. When used to treat osteoporosis, the optimal duration of treatment is not yet known; however, the majority of benefits appear to happen within the first five years of treatment and long-term use has been associated with atypical femur fractures, osteonecrosis of the jaw and esophageal cancer. Experts recommend the need for bisphosphonate treatment should be reviewed every three to five years.
The beneficial effects of a three-year course of zoledronic acid (5 mg yearly) appear to be maintained in the subsequent three years, as illustrated by the finding of an extension of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial described below [ 25 ], in which a subset of women (n = 1233 of 3889) who had received zoledronic acid (5 mg yearly) for three years in the core study were randomly assigned to three additional years of zoledronic acid or placebo [ 17 ]. The mean change in femoral neck BMD (the primary endpoint) from year 3 to 6 was + and - percent, respectively. The mean change in LS (a secondary endpoint) was + and +, respectively. There were fewer morphometric vertebral fractures (a secondary endpoint) in the group that received zoledronic acid for six years (3 versus percent; odds ratio [OR] , 95% CI -). However, the overall fracture event rate was low, reducing the precision of the analysis. There was no difference in the incidence of nonvertebral, clinical vertebral, or all clinical fractures. Markers of bone turnover remained below pretreatment values in both groups. A greater proportion of patients in the active treatment group had transient increases in serum creatinine (> mg/dL) . There were no cases of atypical fractures, and there was one case of ONJ in the group receiving zoledronic acid for six years. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw' .)
In summary, FDA is continuing its ongoing safety review of bisphosphonate use and the occurrence of atypical femur fractures. As of this notice, the FDA is notifying patients and healthcare professionals of new Warnings and Precautions information that is being added regarding this risk to the labels of all bisphosphonate products approved for the prevention or treatment of osteoporosis. A new Limitations of Use statement will describe the uncertainty of the optimal duration of use of bisphosphonates for the treatment and/or prevention of osteoporosis. In addition, the FDA will require that a Medication Guide be included with all bisphosphonate medications approved for osteoporosis indications to better inform patients of the risk for atypical femur fracture.