Does the Use of Methylphenidate Affect Bone Health? A Systematic Review and Meta-analysis of Preclinical Studies

Methylphenidate (MP) is widely prescribed for attention-deficit/hyperactivity disorder in children and adults. Concerns have emerged regarding its potential effects on bone health, including changes in bone mineral density, fracture risk, and size. However, its effects on skeleton remains controversial. This systematic review and meta-analysis aimed to clarify whether MP administration affects bone health in animal models. Our review was registered with PROSPERO (CRD 42023468466) following PRISMA guidelines. A comprehensive search of MEDLINE, Embase, Scopus, and CINAHL was conducted through May 2025, with no restrictions on year or language. Eight studies from 508 identified articles met the inclusion criteria after full-text screening. These studies compared the effects of different doses of MP on bone morphology, biomechanical properties, microarchitecture, and histomorphometric endpoints in rats' axial and appendicular skeletons. The studies also compared the effects of age at initiation of MP treatment and different durations of MP treatment. Overall, a trend emerged indicating that MP may exert detrimental effects on various bone parameters, particularly in long bones, with age at MP treatment initiation and dose- and duration- dependent responses. Additionally, MP treatment may influence bone tissue directly, through actions on bone cells, and indirectly, through changes in body weight. Meta-analyses revealed significant adverse effects on bone morphology and mechanical properties, especially with higher doses and prolonged exposure. However, the overall risk of bias ranged from unclear to high across included studies, requiring caution in interpretation. The findings emphasize the need for further research into the mechanisms behind MP's impact on bone, including age at MP treatment initiation and treatment duration, dose-response relationships, and sex differences. Better understanding of the metabolic pathways which influence MP's effects on the above endpoints could clarify broader implications of MP use on skeletal health and inform clinical practices.