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While it is clear that long-term bisphosphonate therapies reduce fracture risk in women with osteoporosis, it is unclear how to counter-balance these benefits against rare serious harms and how to optimize therapeutic benefits with appropriate drug holidays.
A systematic analysis of 48 studies compared long-term osteoporosis drug treatment (ODT) (>3 years) versus control versus ODT continuation versus durg discontinuation, to examine incident fractures or harms.
In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate strength of evidence - SOE).
Long-term bisphosphonates showed an increased risk for atypical femoral fractures and osteonecrosis of the jaw (both low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms.
After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE).
Trials and data in men with clinical fracture data were sparse.
No trials compared sequential treatments or different durations of drug holidays.
It appears that long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may also reduce the risk for fractures.
Until there are well designed trials informing us on the magnitude of benefit vs. risk with drug holidays of varying duration, the decision to continue or discontinue ODT must be based on the individuals risk for future fracture.