Objective: We aimed to describe the natural history of the rare clinical syndrome of transient osteoporosis (TO) and ascertain potential risk factors. Methods: Retrospective cohort study of adults with TO at Mayo Clinic, Rochester, Minnesota, over 15 years. Adults with acute-onset joint pain worsened by weight bearing and bone marrow edema on magnetic resonance imaging were included; exclusion criteria were trauma, tumors, rheumatic diseases, avascular necrosis, infection, and hyperesthesia. Results: Thirty-three patients with TO were identified: 20 males, median age at diagnosis 47 years, and median body mass index 28 kg/m2. Median time to diagnosis was 2 months, and time to symptom resolution was 4 months. All cases involved the lower extremity, with the majority affecting the hip. Most patients (79%) had at least one possible identified risk factor. The most frequent risk factor was low bone mineral density (BMD) in 13 patients (39% of cohort). Of the 16 patients with BMD measure, 8 had low BMD at a site other than TO. The next most frequent risk factors were sudden limb overuse and more than one episode of TO, observed in 30%, followed by a disorder of bone and mineral metabolism in 27%. Conclusion: TO affects middle-age men more than women, primarily involves weight-bearing joints, and usually resolves with conservative management. Its etiology remains unclear; however, the common presence of risk factors, abnormalities in bone and mineral laboratories, and decrease in BMD suggest that systemic factors may be important in its development. Abbreviations: AVN = avascular necrosis; BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; MRI = magnetic resonance imaging; TO = transient osteoporosis.