Bone of contention: osteoporosis in advanced kidney disease

People with advanced chronic kidney disease (CKD) have a four-fold increased risk of developing osteoporotic fractures compared to the general population, which can lead to increased morbidity and mortality. However, osteoporosis management is a major challenge in people on dialysis due to the complex pathophysiology of bone disease and the lack of evidence for the efficacy and safety of osteoporotic medications.

Small studies have suggested that both denosumab and bisphosphonates have some effectiveness in improving bone density in dialysis patients and the drugs appear to be safe.^1,2 In contrast, a systematic review suggested uncertain benefits on fracture risk with bisphosphonates and denosumab in people with advanced CKD and on dialysis, with a potential increased risk of safety outcomes with denosumab.³ 

This month, Masuda et al have used target trial emulation to try to shed light on this area of uncertainty, looking at the effectiveness of denosumab or oral bisphosphonates in fracture prevention and major adverse cardiovascular events (MACE) for people receiving dialysis.⁴ Studies that use advanced statistical techniques to emulate clinical trials are becoming more common, particularly in areas of uncertainty, or where conducting a trial is particularly challenging. By setting out a specified protocol for the study, and then emulating the protocol using observational data, causal inference can be determined, although there are limitations to these studies and often confirmatory trials are still warranted.⁵ Nevertheless, Masuda et al found that compared with oral bisphosphonates, denosumab lowered fracture risk by 45% but increased the risk for MACE by 36%.⁴ 

The authors postulate that the increased MACE with denosumab could be related to development of severe hypocalcaemia. Severe hypocalcaemia following denosumab administration in people with advanced kidney disease and dialysis has been identified by the US Food and Drug Administration as cause of severe harm, including hospitalisation, life-threatening events and death. 

This month, a report on the major themes resulting from the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on chronic kidney disease–mineral and bone disorder (CKD-MBD) was published. It recommends that in future, rather than using the term CKD-MBD, two clinical syndromes should be considered, the first being CKD-associated osteoporosis encompassing increased fracture risk in patients with CKD.⁶ 

The KDIGO group details the complexity of treating CKD-associated osteoporosis, with the requirement of a personalised approach taking into account severity of bone mineral density abnormalities, disordered mineral metabolism, bone turnover and estimated treatment duration.⁶They also highlight the lack of evidence to base management on and raise concerns about adverse effects from the treatments. Both bisphosphonates and denosumab have a risk of osteonecrosis of the jaw and atypical femoral fractures, with bisphosphonates causing nephrotoxicity and denosumab hypocalcaemia and rebound bone resorption.⁶

Unfortunately, Masuda et al did not have access to data on severity of BMD, which is a limitation of their study. However, what the study highlights is that denosumab and oral bisphosphonates may have benefits in reducing fracture risk but, for denosumab treatment, adequate calcium and vitamin D supplementation is required to prevent severe hypocalcaemia. These data are useful, but far from confirmatory one way or the other and further study is certainly warranted given the seriousness of the consequences of bone disease in end-stage kidney disease. More, modelling with larger and better phenotyped cohorts may help, but traditional trial data would be ideal.

A digest of the study can be read here.

References

1. Iseri K, Watanabe M, Yoshikawa H et al (2019) Effects of denosumab and alendronate on bone health and vascular function in hemodialysis patients: A randomized, controlled trial. J Bone Miner Res 34: 1014–24
2. Park C, Kim C, Park RW, Jeon JY (2024) Comparative effectiveness and safety outcomes between denosumab and bisphosphonate in South Korea. J Bone Miner Res 39: 835–43
3. Wilson LM, Rebholz CM, Jirru E et al (2017) Benefits and harms of osteoporosis medications in patients with chronic kidney disease: A systematic review and meta-analysis. Ann Intern Med 166: 649–58
4. Masuda S, Fukasawa T, Matsuda S, Kawakami K (2025) Cardiovascular safety and fracture prevention effectiveness of denosumab versus oral bisphosphonates in patients receiving dialysis: A target trial emulation. Ann Intern Med 178: 167–76
5. Hernán MA, Wang W, Leaf DE (2022) Target trial emulation: A framework for causal inference from observational data. JAMA328: 2446–7
6. Ketteler M, Evenepoel P, Holden RM et al; Conference Participants (2025) Chronic kidney disease–mineral and bone disorder: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 107: 405–23