Study Links Osteoporosis Injections and Increased MACE in Dialysis Patients

In patients on dialysis, the use of an injectable monoclonal antibody for prevention of osteoporosis-related fractures may increase the risk of MACE compared with oral bisphosphonates, observational data from Japan suggest.

While patients taking the injectable denosumab (Prolia; Amgen) had 45% fewer fractures than those on bisphosphonates, their 3-year risk weighted risk ratio (RR) for MACE was 1.36 (95% CI 0.99-1.87), with the difference being driven by acute MI and hospitalization for heart failure (HF), say Soichiro Masuda, MD, PhD (Kyoto City Hospital, Japan), and colleagues in a paper published January 6, 2025, in Annals of Internal Medicine.

“Given the high risk for cardiovascular events associated with denosumab in dialysis-dependent patients, comparative effectiveness and safety of these medications should be confirmed in future studies,” Masuda and colleagues write.

While the data have a number of limitations that the authors acknowledge, including unmeasured confounders such as family history and the preciseness of kidney disease severity, the subgroup analyses suggested that those with longer histories of osteoporosis and dialysis might have a greater susceptibility to the differences between denosumab and oral bisphosphonates.

Commenting for TCTMD, Geoff Barnes, MD (University of Michigan, Ann Arbor), said the data are hypothesis-generating and an opportunity for cardiologists to take a closer look at how risk factors are being managed for their patients with osteoporosis and fracture risk.

“Hopefully the folks who are more expert in these therapies can continue to dig into this more and get us the information we need to know whether this is truly a concerning therapy or whether it’s a signal due to confounding,” he said. “We would really need prospective, very well-controlled studies to know for sure if there is a risk associated here.”

Outcome Differences

For the study, Masuda and colleagues analyzed data from a commercial administrative claims database covering the period from April 2014 to October 2022. Patients were dialysis-dependent and were new users of denosumab (n = 658) or oral bisphosphonates (n = 374) for osteoporosis. The mean age was 74.5 years and 62.9% were women. Compared with bisphosphonate users, those on denosumab had a longer mean time since initial diagnosis of osteoporosis and starting therapy, were more likely to have a history of diabetes, and had a greater likelihood of having undergone bone mineral density testing.

Over 3-year follow-up, MACE occurred in 34.6% of denosumab users and 21% of bisphosphonate users. Acute MI occurred in 5.9% and 1.5%, respectively (weighted RR 3.50; 95% CI 1.44-21.40), while hospitalization for HF occurred in 11.8% and 8.2%, respectively (weighted RR 1.31; 95% CI 0.74-2.18).

Hopefully the folks who are more expert in these therapies can continue to dig into this more and get us the information we need to know. Geoff Barnes

Cardiovascular death was high in both groups at 23.8% for the denosumab patients and 18.1% for those on bisphosphonates (weighted RR 1.04; 95% CI 0.70-1.53). Total mortality also was high at 28.4% and 22.6%, respectively (weighted RR 1.06; 95% CI 0.72-1.48).

Composite fracture (including vertebral, hip, pelvis, femur, leg, ankle, shoulder, arm, forearm, and wrist) occurred in 5.7% of denosumab users and 11.7% of bisphosphate users.

In subgroup analyses, denosumab users with a duration since first eligibility for fracture therapy exceeding 18 months had a MACE rate at 3 years of 14.9%, compared with 4.1% for those with a shorter time since first eligibility. Longer duration since first eligibility was associated with a -2.4% risk of composite fracture, compared with -9.9% for those with shorter durations.

Masuda and colleagues note that safety data in dialysis-dependent patients on denosumab is scarce, but that their findings are consistent with a recent meta-analysis of postmenopausal women taking denosumab for osteoporosis, which found a 46% increase in CV events compared with bisphosphonates.

While bisphosphonates have been hypothesized to reduce coronary calcification and have anti-inflammatory effects on vascular cells, the authors say denosumab carries a higher risk for severe hypocalcemia in dialysis-dependent patients, which may increase the risk for some CV events.

“Although we found increased rates of hypocalcemia with denosumab based on claims data, these mostly occurred within a few weeks after administration of treatments and may not fully explain the differences in MACE, which were greater after 6 months,” Masuda and colleagues write. “We did not have actual clinical or laboratory data, and future studies are needed to confirm this potential mechanism.”

High MACE Rate Overall

Another area of uncertainty is whether denosumab is more likely to be prescribed in patients with more severe kidney disease or risk factors, “which would have biased the findings toward overestimation of cardiovascular event risk with denosumab use,” they add.

According to Barnes, the high rate of CV events in both treatment groups is a key takeaway.

“One in five developed MACE over 3 years with the bisphosphonates, and one in three with denosumab. That’s really staggering. It highlights the fact that when our patients have end-stage renal disease, they are at very high risk of adverse cardiovascular events,” he said.

Yet another consideration in this patient population is that bisphosphonates can be associated with worsening of kidney disease, potentially making denosumab the better option for fracture prevention depending on what the primary concerns are for an individual patient and their risk factors for CV disease, Barnes said.

“If you have somebody who’s maybe a CKD stage 3 or CKD stage 4 where we are very concerned about progression, you might think about selecting your therapies differently [than in] someone with a lower stage of disease [where] you’re thinking primarily about the impact on their cardiovascular health,” he added.