Bisphosphonate therapy and treating hair loss are the subjects of this expert update from The North American Menopause Society.
The following questions and answers summarize cases discussed in Menopause e-Consult, a newsletter of The North American Menopause Society (NAMS).
Bisphosphonates: How long is long enough?
How long should you continue bisphosphonate therapy for a postmenopausal woman with osteoporosis?1
Several recent developments have prompted reconsideration of how to use bisphosphonates in postmenopausal women:
IS A DRUG HOLIDAY FEASIBLE? It appears that the amount of bisphosphonate released back into the circulation after a bone "loading" period can maintain BMD and BTM for some time, maybe years.2,3 Bisphosphonates may have to be given for a certain amount of time-perhaps 5 years-to produce sustained benefit after discontinuation, and the duration of the benefit may vary among different bisphosphonates.4 Nevertheless, the data have prompted wider discussion of a "drug holiday" after 5 to 7 years of bisphosphonate administration, with annual assessment of BMD and BTM to evaluate whether lower bone turnover persists. Monitoring BMD and BTM is the only way to judge sustained biologic effect.5,6 Opinions vary concerning which patients should be offered a drug holiday, and no standard of care exists for this approach.7,8
THERAPY IN YOUNGER WOMEN. The use of bisphosphonates in younger postmenopausal women increased after many such women stopped taking estrogen in the wake of publication of the Women's Health Initiative. As bisphosphonates were prescribed for greater numbers of younger women who were osteopenic, the question arose, "Is this use for life?"
Consideration of a drug holiday was further stimulated by the data from the World Health Organization's 10-year fracture risk assessment model (FRAX), which revealed that younger, untreated postmenopausal women had a fairly low fracture risk,9 made even lower by treatment. Women with a high baseline risk (previous low-trauma fracture, aged 65 years or older with BMD criteria for osteoporosis) often aren't offered a drug holiday.
Whether bone strength at all skeletal sites is maintained during a drug holiday remains unclear. Observational data suggest that patients who have taken alendronate for fewer than 2 years may not necessarily have a lower risk of hip fracture when the drug is discontinued.4 It seems reasonable, therefore, to give alendronate to lower-risk, younger women for at least 5 years before considering a drug holiday.
WEIGHING THE RISK OF ONJ AND FRACTURES. A less scientifically sound reason for considering a drug holiday is the risk, based on anecdotal observational data, of ONJ or diaphyseal (femur) fractures in very small numbers of patients taking bisphosphonates. Although fewer than 100 adjudicated cases of ONJ have been validated in patients with osteoporosis-compared with the 1% to 10% risk in oncology patients who have received much higher, intravenous doses of pamidronate or zoledronic acid10 -the general dental and lay public perceive ONJ to be common. This perception has often led to unnecessary discontinuation of bisphosphonates, which could put high-risk patients at far greater risk of fracture than the calculated attributable risk of ONJ in the postmenopausal population (<0.7 cases/100,000 patients/year exposure). Although expert opinion suggests withholding or temporarily discontinuing bisphosphonates before dental extractions or implants, no data indicate that these strategies affect the risks for ONJ.
Several anecdotal reports describe spontaneous, often bilateral diaphyseal femoral shaft fractures associated with long-term (≥ years) use of alendronate.11 The mechanism is unknown, as is whether these unusual fractures occur in people not exposed to bisphosphonates. Careful study of large Medicare databases may reveal whether such fractures are confined to the bisphosphonate-exposed population.
All reported fractures have been associated with alendronate, the first FDA-approved bisphosphonate for osteoporosis management with the largest exposed population. Only time and careful reporting will tell whether the fractures might also occur with other bisphosphonates.
Most patients treated with bisphosphonates have experienced decreased fractures and costs as well as an exceptional safety record. In light of the strong science that has evolved in the pharmacokinetics of bisphosphonates, practitioners should consider drug holidays and maintain an open mind about safety issues that require clarification.
PAUL D. MILLER, MD, is Distinguished Clinical Professor of Medicine, University of Colorado Health Sciences Center, and Medical Director, Colorado Center for Bone Research Lakewood, CO.
DISCLOSURE: DR. MILLER REPORTS: AMGEN, NOVARTIS, PROCTER & GAMBLE, ELI LILLY (CONSULTANT, RESEARCH SUPPORT); JOURNAL OF CLINICAL DENSITOMETRY (EDITOR-IN CHIEF), CALCIFIED TISSUE INTERNATIONAL, AND OSTEOPOROSIS INTERNATIONAL (EDITORIAL ADVISORY BOARD).