Abstract Summary Bisphosphonates are contraindicated in moderate-to-severe chronic kidney disease patients. However, they are used to prevent fragility fractures in patients with impaired kidney function, despite a lack of evidence on their effects on bone density in these patients. We demonstrated that Alendronate had a positive effect on bone in these patients. Purpose This study aimed to assess the association between alendronate use and bone mineral density (BMD) change in subjects with moderate-severe chronic kidney disease (CKD). Methods We created a cohort of CKD stage 3B–5 patients by linking all DXA-based measurements in the Funen area, Denmark, to biochemistry, national health registries and filled prescriptions. Exposure was dispensation of alendronate and the outcome was annualized percentage change in BMD at the femoral neck, total hip and lumbar spine. Individuals were followed from first BMD to the latest of subsequent DXA measurements. Alendronate non-users were identified using incidence density sampling and matched groups were created using propensity scores. Linear regression was used to estimate average differences in the annualized BMD. Results Use of alendronate was rare in this group of patients: propensity score matching (PSM) resulted in 71 alendronate users and 142 non-users with stage 3B–5 CKD (as in the 1 year before DXA). Whilst alendronate users gained an average 1.07% femoral neck BMD per year, non-users lost an average of 1.59% per annum. The PSM mean differences in annualized BMD were + 2.65% (1.32%, 3.99%), + 3.01% (1.74%, 4.28%) and + 2.12% (0.98%, 3.25%) at the femoral neck, total hip and spine BMD, respectively, all in favour of alendronate users. Conclusion In a real-world cohort of women with stage 3B–5 CKD, use of alendronate appears associated with a significant improvement of 2–3% per year in the femoral neck, total hip and spine BMD. More data are needed on the anti-fracture effectiveness and safety of bisphosphonate therapy in moderate-severe CKD.