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Myelodysplastic neoplasms (MDS) are characterized by insufficient hematopoiesis and alterations of the bone marrow microenvironment. However, bone health in MDS has not been evaluated in a prospective, longitudinal setting. Within the Bone and Hematology in Elderly (BoHemE) study, bone mineral density (represented as T-score) and bone-specific serum markers were assessed in patients with MDS (n = 111; 36% female) and age-matched controls (n = 84; 55% female) at baseline and after 3 years. At baseline, patients with MDS had a lower T-score [-0.2; p < 0.05] compared to controls, which was mainly attributed to the lower T-score in women with MDS [-0.3; p < 0.05]. Furthermore, the DNMT3A mutation was associated with a lower T-score within the MDS cohort [-0.7; p < 0.05], but the occurrence in controls had no effect. Albumin-adjusted calcium and phosphate levels correlated with T-scores within the MDS cohort [p < 0.0001 and p < 0.01, respectively], independent of age, sex, MDS duration, IPSS-M score, or transfusion dependence. Quality of life was lower in patients with MDS [p < 0.01], and remained stable over 3 years, whereas T-scores declined [-0.3; p < 0.05]. The presence of osteoporosis was associated with poor overall survival in MDS [p < 0.01]. In conclusion, bone health should be evaluated as part of the diagnostic work-up and clinical management of MDS.