Efficacy and safety of long-term bisphosphonates in postmenopausal osteoporosis.

Bisphosphonates have been in clinical use since the first approval of etidronate for myositis ossficans progressiva. They have now been used since the early 1990s for osteoporosis. As patients are continued on bisphosphonates and with consideration for bisphosphonate application in younger postmenopausal women, questions of 'how long to treat' are emerging in the clinical community. What is the evidence for continual efficacy and safety? The longest efficacy data where a placebo group was maintained is the 5-year risedronate vertebral fracture data, which demonstrated additional fracture reduction benefit with this bisphosphonate during years 4-5 of use. As bone mineral density (BMD) or biochemical markers of bone resorption (BCM) change very little for at least 1-2 years (and possibly longer) after discontinuing long-term (3-5 years) bisphosphonate use, it seems reasonable to suggest discontinuation for some indefinite period of time after 5 years of use in younger lower-risk postmenopausal women. Monitoring of both BMD and BCM may indicate when to consider reinitiation of bisphosphonate therapy. In higher-risk elderly postmenopausal women who are doing well on long-term bisphosphonate therapy as defined by a stable BMD, height and no incident fractures, the same discussion of a 'honeymoon' period of no treatment could be entertained. However, because there are no data on fracture events post-treatment even without changing BMD or BCM, this author is reluctant to stop bisphosphonates in elderly high-risk patients. My opinion on the continuation of the use in high-risk patients is also predicated on the observations that there does not appear to be any clinically important safety issues with long-term (10-year) use. Concerns about 'oversuppression' of bone turnover and accumulation of microdamage are theoretical and, so far, have no clinical basis for discontinuation in high-risk patients. It will be important, however, for the continual surveillance of bone safety issues by capturing postmarketing fracture data in patients on long-term therapy as well as long-term bone histomorphometry and measurements of bone quality to reassure clinicans about long-term bisphosphonate continuation.