<p>Systemic mastocytosis is a rare condition caused by the accumulation of abnormal mast cells (MC) in various organs, including the bone. The diagnosis of mastocytosis is sometimes challenging because of the incidence rate, the heterogeneity of clinical manifestations, and the varying sensitivity of diagnostic tools. While mastocytosis is an uncommon cause of osteoporosis, conversely, systemic mastocytosis (SM) is often associated with bone loss, resulting in low bone mineral density (osteopenia or osteoporosis) and fractures, particularly vertebral fractures. SM must be ruled out in young patients with fragility fractures, mainly vertebral fracture, or unexplained low bone mineral density accompanied by suspected SM symptoms or signs. Other bone manifestations of SM include bone pain, osteolytic lesions, and even osteosclerosis. The putative mechanisms of bone loss and damage in SM include the secretion of vasoactive mediators and inflammatory markers, bone mediators released from bone cells (osteoblast, osteoclast, and osteocyte) such as RANKL, OPG, sclerostin, and DKK1, and neoplastic infiltration of MCs. Usually, early diagnosis with appropriate therapeutic intervention can impact the outcome of this disease and its skeletal-related complications. Fracture prediction can be improved by considering risk factors and using bone mineral density, FRAX, and TBS values. High-resolution peripheral quantitative CT may not be feasible but provides more information. The first step is the detection of high-risk patients in SM by recognizing the risk factors for fragility fractures such as older age, male sex, lower hip BMD, increased mast cell mass, or KIT mutation in bone biopsies, and then estimating the risk of SM progression in order to determine the best type of medication for bone loss mastocytosis and for osteoporosis. The current medications for the treatment of mastocytosis itself include anti-inflammatory or mast cell stabilizers (ketotifen, cromolyn sodium, antihistamines, leukotriene antagonists, and anti-IgE monoclonal antibody). Anti-osteoporosis medications (bisphosphonates, denosumab, and teriparatide) and cytoreductive agents (interferon, chemotherapeutic agents, or tyrosine kinase inhibitors) are also used. Although controlling the underlying disease is usually most effective, the benefits and risks of each therapeutic approach should be balanced if needed.</p>