Background: Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are hematological stem cell diseases mainly of the elderly. Studies indicate a close relationship between bone metabolism and hematopoietic stem cells within the osteo-hematopoietic niche. However, it remains unclear how the disturbed interaction within the osteo-hematopoietic niche affects bone homeostasis in MDS and AML patients. Methods: We utilized data of a large German statutory health insurance of approximately 2 million persons living in the German federal state of Saxony. Applying case definitions based on diagnosis, procedures and prescriptions we identified prevalent and incident cases with MDS, AML and osteoporosis (OSP) in persons aged ≥60 years. We applied time-to-event analyses to determine the relationship of MDS and AML with OSP with a specific focus on temporality. Results: Among all individuals aged ≥60 years (n = 891,095), 2.62% (n = 23,326), 0.14% (n = 1219) and 0.10% (n = 893) were identified with incident OSP, MDS and AML, respectively. The risk of incident OSP was significantly increased in patients with prevalent MDS (sex and age-adjusted model: HR = 1.87, 95%CI: 1.51–2.23). Conversely, patients with prevalent OSP had an increased risk to be diagnosed with incident MDS in the adjusted model (HR = 1.42, 1.19–1.65). For AML no significant associations were observed (adjusted models: inc. OSP with pre. AML; HR = 1.06, 0.65–1.47; inc. AML with pre. OSP; HR = 0.82, 0.41–1.23). Discussion: Our results could indicate a clinically relevant relationship between MDS and OSP in elderly patients, most likely resulting from a disturbed microenvironment within the osteo-hematopoietic niche. An alternative, non-causal explanation that MDS is caused by the medication prescribed for OSP can be partially ruled out, as the association between the two diseases remains if incident OSP cases are considered in patients with pre-existing MDS. These results need to be confirmed within other prospective studies and may allow then for comprehensive strategies for the prevention, early detection and clinical care of patients with MDS and OSP.