Glucocorticoid chronotherapy and bone metabolism: a scoping review and future research agenda

Glucocorticoids are widely used in inflammatory, respiratory, renal, gastrointestinal, and transplant-related disorders, but prolonged or moderate-to-high dose exposure increases the risk of glucocorticoid-induced osteoporosis. Previous reviews have mainly emphasized cumulative dose, treatment duration, fracture risk assessment, and pharmacological prevention. Because bone turnover and endogenous cortisol secretion both follow circadian rhythms, dosing time and rhythmicity of glucocorticoid exposure may represent an underexplored dimension of skeletal safety. This scoping review mapped mechanistic, preclinical, and clinical evidence on glucocorticoid dosing time, circadian glucocorticoid exposure, and bone-related outcomes. PubMed, Embase, and the Cochrane Library were searched from database inception to 17 December 2025; searches were conducted between 12 and 17 December 2025. Supplementary targeted PubMed searches were performed for rheumatoid arthritis chronotherapy, circadian-patterned hydrocortisone replacement, and bone turnover in relation to cortisol or glucocorticoid rhythm. Evidence was synthesized narratively using the Arksey-O’Malley framework, with reporting informed by PRISMA-ScR. Bone resorption markers such as CTX and NTX peak overnight and in the early morning, whereas bone formation markers such as osteocalcin and P1NP also show diurnal fluctuation. Animal studies indicate that identical glucocorticoid exposure administered at different circadian phases can produce different degrees of bone loss. Clinical evidence, including rheumatoid arthritis chronotherapy trials, studies of physiological replacement in adrenal insufficiency, and data from circadian disruption settings, supports the biological plausibility of avoiding unnecessary nocturnal exposure, prioritizing morning dosing when clinically feasible, and better mimicking physiological cortisol profiles. However, these inferences are based largely on surrogate markers, endocrine physiology, and indirect clinical evidence. Direct evidence for effects on bone mineral density and fracture outcomes remains limited. Glucocorticoid dosing time should be considered a potentially modifiable determinant of skeletal safety, but definitive practice recommendations require long-term trials with bone endpoints, disease-specific stratification, and circadian phenotyping.