B. Osipov, L. Robison, J. Hanel, SV. Orr, YY. Lin, A. Buxton, M. Rahmati, MC. Tseng, MR. Renato, R. Shenoy, AS. Bhat, A. Saiz, VL. Ferguson, GG. Loots, et al. (2026). Ketogenic diet causes bone loss in growing and adult mice and reduces the skeletal response to exercise. Bone, 207, 117854. https://doi.org/10.1016/j.bone.2026.117854

PubMed 41812964

[Abstract]
The ketogenic diet (KD) is an established treatment for intractable epilepsy in children. KD has also become increasingly popular for weight loss, and it has shown therapeutic potential for treating neurodegenerative diseases. However, KD causes bone loss in epileptic children, and its effects on the adult skeleton are unknown. In the current study, we investigated the effect of KD on bone at different ages using growing (4-week-old) and adult (14-week-old) male C57BL/6 J mice. We also examined if KD-induced bone loss could be recovered via exercise. We hypothesized that KD would cause bone loss at all ages, the rate of bone loss would depend on age, and that KD alters osteoblast, osteoclast, and osteocyte activity. We also predicted KD would reduce the anabolic effects of exercise. We quantified bone density in-vivo and conducted ex-vivo analysis of bone microstructure and strength, osteoblast and osteoclast activity, and osteocyte lacunar size. KD induced bone loss was evident after 4 weeks in growing animals and after 8 weeks in adult mice. Analysis of serum showed that KD caused declines in bone formation markers, and measurement of osteocyte lacunar dimensions via x-ray microscopy showed increases in lacunar volume, but osteoclasts were unaffected. KD also reduced the magnitude of exercise induced changes in cortical bone mechanical properties. These findings suggest that KD-initiated bone loss is not a clinical problem limited to children, and it may be a significant risk factor for osteoporotic fracture in adults.