Bile acids help facilitate intestinal lipid absorption and have endocrine activity in glucose, lipid and bone metabolism. Obesity and exercise influence bile acid metabolism and have opposite effects in bone. This study investigates if regular exercise helps mitigate the adverse effects of obesity on bone, potentially by reversing alterations in bile acid metabolism. Four-month-old female Sprague Dawley rats either received a high-fat diet (HFD) or a chow-based standard diet (lean controls). During the 10-month study period, half of the animals performed 30 min of running at moderate speed on five consecutive days followed by two days of rest. The other half was kept inactive (inactive controls). At the study’s end, bone quality was assessed by microcomputed tomography and biomechanical testing. Bile acids were measured in serum and stool. HFD feeding was related to reduced trabecular (−33%, p = 1.14 × 10⁻⁷) and cortical (−21%, p = 2.9 × 10⁻⁸) bone mass and lowered femoral stiffness (12–41%, p = 0.005). Furthermore, the HFD decreased total bile acids in serum (−37%, p = 1.0 × 10⁻⁶) but increased bile acids in stool (+2-fold, p = 7.3 × 10⁻⁹). These quantitative effects were accompanied by changes in the relative abundance of individual bile acids. The concentration of serum bile acids correlated positively with all cortical bone parameters (r = 0.593–0.708), whilst stool levels showed inverse correlations at the cortical (r = −0.651–−0.805) and trabecular level (r = −0.656–−0.750). Exercise improved some trabecular and cortical bone quality parameters (+11–31%, p = 0.043 to 0.001) in lean controls but failed to revert the bone loss related to the HFD. Similarly, changes in bile acid metabolism were not mitigated by exercise. Prolonged HFD consumption induced quantitative and qualitative alterations in bile acid metabolism, accompanied by bone loss. Tight correlations between bile acids and structural indices of bone quality support further functional analyses on the potential role of bile acids in bone metabolism. Regular moderate exercise improved trabecular and cortical bone quality in lean controls but failed in mitigating the effects related to the HFD in bone and bile acid metabolism.

Aims: To investigate the role of CXCR4 in response to teriparatide (TPTD) treatment in osteoblasts and osteoclasts.Methods: Primary murine and human osteoblasts and osteoclasts, MC3T3 cell lines, and hMSC-TERT4 cell lines were treated with TPTD and/or AMD3100, a pharmacological inhibitor of CXCR4. Changes in gene expression, osteoblast viability, mobility, mineralization capacity, and alkaline phosphatase activity were investigated. Osteoclastogenesis and cell fusion were also assessed in response to both treatments.Results: TPTD increased messenger RNA levels of CXCR4 in all stages of both murine and human osteoblast differentiation. Mineralization analysis showed that CXCR4 was involved in bone matrix formation in response to TPTD. Alkaline phosphatase activity was also impaired by CXCR4 inhibition at early stages of osteoblast differentiation, while it was promoted at late stages, suggesting that CXCR4 could produce a delay in osteoblast maturation. Moreover, we also found a direct activation of osteoclastogenesis after TPTD treatment in murine and human osteoclasts. This process seems to involve CXCR4 activity, since AMD3100-induced CXCR4 inhibition led to a reduction in both murine and human osteoclastogenesis. This process, however, could not be prevented by TPTD treatment.Conclusion: Our results suggest that CXCR4 is a responsive gene to TPTD treatment, involved in the regulation of osteoblast and osteoclast generation and function. Further in vivo studies are required to confirm this role, and to determine whether pharmacological strategies targeting CXCR4 could potentially improve the treatment outcome for osteoporotic patients.Cite this article: Bone Joint Res 2025;14(5):463–476.

Background: Bile acids help facilitate the intestinal lipids absorption, and have endocrine activity in glucose, lipid and bone metabolism. Obesity and exercise influence bile acid metabolism and have opposite effects in bone. This given study investigates if regular exercise helps mitigate the adverse effects of obesity on bone, potentially by reversing alterations in bile acid metabolism. Methods: Four-month-old female Sprague Dawley rats either received high fat diet (HFD) or chow-based standard diet (lean controls). During the 10-month study period, half of the animals performed 30 min of running at moderate speed on five consecutive days followed by two days of rest. The other half was kept inactive (inactive controls). At study end, bone quality was assessed by micro computed tomography and biomechanical testing. Bile acids were measured in serum and stool. Results: HFD feeding was related to reduced trabecular (−33%, p=1.14×10 ^-7 ) and cortical (−21%, p=2.9×10 ^-8 ) bone mass, and lowered femoral stiffness (12-41%, p=0.005). Furthermore, HFD decreased total bile acids in serum (−37%, p=1.0×10 ^-6 ), but increased bile acids in stool (+2-fold, p=7.3×10 ^-9 ). These quantitative effects were accompanied by changes in the relative abundance of individual bile acids. The concentration of serum bile acids correlated positively with all cortical bone parameters (r=0.593 - 0.708), whilst stool levels showed inverse correlations at cortical (r=-0.651 - −0.805) and trabecular level (r=-0.656 - −0.750). Exercise improved some trabecular and cortical bone quality parameters (+11-31%, p=0.043 to 0.001) in lean controls, but failed to revert the bone loss related to HFD. Similarly, changes in bile acid metabolism were not mitigated by exercise. Conclusion: Prolonged HFD consumption induced quantitative and qualitative alterations in bile acid metabolism, accompanied by bone loss. Tight correlations between bile acids and structural indices of bone quality support further functional analyses on the potential role of bile acids in bone metabolism. Regular moderate exercise improved trabecular and cortical bone quality in lean controls but failed mitigating the effects related to HFD in bone and bile acid metabolism.