Exercise training is increasingly recognized as a complementary therapy to support skeletal health in postmenopausal women. However, its epigenetic influence on circulating bone-related microRNAs and its hormonal impact on bone turnover remain insufficiently characterized. This study examined whether a 12-week supervised exercise program could modulate bone-related miRNAs, regulate key endocrine markers of bone remodeling, and enhance functional capacity.

Eighty-six participants aged 55–65 years without osteoporosis were assigned to either an exercise or control group. The intervention involved supervised sessions three times weekly for 12 weeks. Circulating levels of bone-related microRNAs (miR-21, miR-29b, miR-133a, miR-148a), biochemical markers of bone metabolism (osteocalcin, CTX, P1NP, bone-specific ALP), and functional performance (6-min walk and 30-s chair-stand tests) were assessed.

The exercise group demonstrated pronounced epigenetic changes, with substantial upregulation of miR-21 and miR-29b (p < 0.001) and a modest increase in miR-133a (p = 0.02), while miR-148a remained unchanged. Hormonal markers indicated a shift toward bone anabolism, including higher osteocalcin (+29.4%), increased P1NP (+14.8%), and reduced CTX (−12.0%) (all p < 0.01), whereas bone-specific ALP showed no significant change. Functional performance improved significantly (+32.07 m in 6MWT; +27.8% in chair-stand). ANCOVA confirmed significant group differences for all outcomes except miR-148a and bone-specific ALP. No meaningful changes were observed in controls.

Supervised combined aerobic and weight-bearing exercise produced coordinated epigenetic and endocrine adaptations that favor bone formation and improve physical function. These findings support its role as an effective complementary, non-pharmacological strategy to mitigate skeletal decline in postmenopausal women.