A Better Approach to Preventing Osteoporotic Fractures Save

Know-it-now

1. New FDA BMD-surrogate approval pathway may accelerate drug development but rests on data that excluded a contradictory RCT (fluoride) — treat new approvals under this pathway with appropriate scrutiny of durability/safety data.
2. AFF risk with long-term antiresorptives likely reflects cumulative microdamage from turnover suppression, not a fixed drug property — duration-limiting strategies remain warranted.
3. BMD gains ≠ fracture protection or safety — strontium and cathepsin K inhibitors are cautionary precedents.
4. Perimenopausal intervention (estrogen, or single-dose zoledronate as an alternative) may be the highest-yield prevention window; earlier screening (at menopause, not age 65) could support this.

A recent JAMA Viewpoints article by Dr. Susan Ott addresses our current problems with preventing osteoporosis (OP) related fractures.

Despite universal agreement that under-treatment is the core problem in osteoporosis — fewer than 15% of post-fracture patients get treated — Ott's Viewpoint argues the strategies being pursued to close that gap are themselves debatable, starting with a major regulatory shift.

The FDA has moved to allow bone mineral density (BMD) as a surrogate approval endpoint instead of clinical fracture, shrinking trials from thousands of patients/multi-year follow-up down to a few hundred patients over 24 months. This was driven by industry and ASBMR-affiliated researchers using pooled individual-patient data showing strong BMD-fracture correlation — but that analysis excluded the fluoride RCT, which raised spine BMD more than any agent tested yet increased fracture risk, undercutting BMD as a universally reliable surrogate.

Ott's larger concern is duration, not just endpoint choice. Trabecular bone remodels over ~5 years and cortical bone roughly twice that; antiresorptives suppress this turnover, and microdamage accumulation from prolonged suppression — not evident in 1-2 year trials — is the likely mechanism behind atypical femur fractures with long-term bisphosphonate/denosumab use. Anabolic-then-antiresorptive agents (teriparatide, denosumab, romosozumab) also lose their BMD gains on discontinuation. Off-target safety signals reinforce the point: strontium ranelate lost EU approval for cardiovascular harm despite raising DXA-measured BMD (artifactually, via atomic substitution), and cathepsin K inhibitors showed increased stroke risk after 2 years — both effects invisible in short trials.

Ott pivots to a perimenopause-focused prevention strategy as the more promising lever than new drug approvals (of which she notes none are currently in the pipeline). Bone loss is steepest in the year before/after final menses. A 4-year RCT in women 40-60 showed placebo lost 2.9% hip BMD vs. +1.4% with alendronate and +3.7% with estrogen; the Study of Osteoporotic Fractures showed durable fracture-risk reduction with estrogen use averaging 35 years, without atypical fracture or ONJ risk. WHI-era cardiovascular concerns were age-dependent (benefit near menopause, harm in older women), and transdermal estrogen now appears to lower clotting risk further. A single zoledronate dose in women 50-60 also cut fracture incidence (6.6% vs 11.1% placebo), with resorption markers rebounding over time — potentially avoiding long-duration ONJ/AFF risk, though confirmatory trials are needed.