Inadequate response to treatment reveals persistent osteoclast bone resorption in osteoporotic patients

Several drugs are able to reduce fracture risk in osteoporotic patients. Incident fractures occur despite good adherence to treatment. Inadequate response has been found related to high serum bone biomarkers of bone turnover. We here aimed to analyze bone microarchitecture and cellular profiles of inadequate responders. We retrospectively analyzed bone biopsies from patients with major fractures despite long-term treatment (inadequate responder [IR] n = 31) in comparison to patients with untreated osteoporosis (U-OP, n = 31) and controls without osteoporosis (Ctrl, n = 16). Bone samples were analyzed by histomorphometry and micro-computed tomography. Clinical and bone turnover markers and bone mineral density were assessed. As compared with U-OP patients, IRs were older (mean age 69.7 ± 8.8 vs 63.3 ± 9.3 years, p = 0.007) and had lower mean hip bone mineral density (0.685 ± 0.116 vs 0.786 ± 0.093 g/cm²), p = 0.019 and T-score (-2.3 ± 0.769 vs -1.6 ± 0.900, p = 0.032). BV/TV was lower for IRs than U-OP patients and Ctrls (13.9 ± 3.8% vs 15.2 ± 5.1 and 17.6 ± 5.2%, p = 0.044) as was trabecular thickness (145.6 ± 23.1 vs 160.5 ± 22.7 and 153.7 ± 21.4 μm, p = 0.033). Mean structure model index was lower for IRs than U-OP patients (1.9 ± 0.806 vs 2.4 ± 0.687, p = 0.042) and osteoclast number was higher for IRs than U-OP patients and Ctrls (0.721 ± 0.611 vs 0.394 ± 0.393 and 0.199 ± 0.071 mm^-2, p < 0.001). The mean Obl.S/BS was lower for IRs than U-OP patients and Ctrls (1.2 ± 1.3 vs 1.9 ± 1.4 and 3.0 ± 0.638 mm^-2, p < 0.0001), and the mean number of labelled surfaces was lower for IRs than U-OP patients (51.6% vs 87%, p = 0.002). Cortical parameters did not significantly differ. We show an imbalance of bone remodeling in favor of bone resorption in IRs. The persistence of high bone resorption suggests insufficient inhibition of bone resorption that could explain the incident fractures with anti-osteoporotic drug use. Adaptation to treatment should be considered to inhibit bone resorption and prevent further fractures.