Musculoskeletal changes include osteoporosis, spinal ligament ossification, diffuse idiopathic skeletal hyperostosis (DISH), sacroiliitis, myalgia and cramping, increased muscle tone, axial muscle rigidity, myopathy, spontaneous fractures, and temporary pain in the rib cage. Observational and epidemiologic studies to determine a possible association between vitamin A and osteoporosis and/or fractures have produced controversial results. The DISH created by retinoids constitutes the main effect on the bones, and these effects usually occur over a 10-year period with prolonged and high doses of retinoid use. Development of DISH due to retinoids may be associated with mesenchymal stem cell proliferation that gives rise to osteoblastic differentiation in the entheses. Retinoids may be used in the treatment of neuroblastoma. Isotretinoin induces cytodifferentiation and apoptosis, and it also inhibits angiogenesis and oncogene expression. Arthritis occurs due to damage and the immunomodulatory effects of retinoids upon the lysosomal membranes of synovial cells. Many controversial studies and case reports about retinoids and their musculoskeletal side effects exist.