Is drug-induced bone loss acceptable in premenopausal women? A practical fracture risk modeling exercise

Premenopausal bone loss increases fracture risk later in life. Depending on peak values, varying degrees of bone mass and microarchitectural loss can be tolerated. We suggest that risk-benefit assessments of drugs that cause premenopausal bone loss be individualized considering baseline status and subsequent BMD and TBS loss.

It is logical that drug-induced loss of bone mass and microarchitecture in young adults increase fracture risk later in life. However, no existing data quantify how drug-induced bone loss in younger adults impacts fracture risk later in life. As such, no guidance exists to address the question "How much, if any, drug-induced bone loss in premenopausal women is acceptable?" Thus, we performed a systematic fracture risk modeling exercise examining various degrees of bone loss, and estimated the impact on 10-year major osteoporosis-related fracture risk later in life.

The FRAX® tool was used in conjunction with BMD and trabecular bone score (TBS) adjustment to estimate major osteoporotic fracture probability later in life resulting from varying degrees of hypothetical premenopausal drug-induced BMD and TBS loss. The resulting 10-year fracture probabilities were assessed against the US and the UK treatment guidance to determine the amount of premenopausal BMD and TBS loss that would result in a recommendation to initiate medical treatment to reduce fracture risk later in life that would not otherwise have been recommended in the absence of premenopausal bone loss.

For women whose peak bone mass is between the 5th and 50th percentiles, varying degrees of BMD and TBS loss could be tolerated without reaching treatment thresholds. The degree of tolerable bone loss was primarily dependent on baseline bone status. Those whose peak BMD and TBS are in the 50th percentile or above could tolerate a 10% reduction in BMD and TBS without reaching treatment thresholds by age 75, whereas those in the 5th percentile would reach treatment thresholds by age 75 with no drug-induced reduction in BMD or TBS. Women in the 25th percentile could tolerate a 4% BMD loss and 2% TBS decline without reaching treatment thresholds by age 75.

For clinicians and regulatory bodies to assess the consequence of drug-induced premenopausal bone loss, we propose an individualized approach considering both loss of BMD and TBS in concert with baseline bone status and the resultant effect on fracture risk in later life using the assumption that such losses are irreversible.