Does Romosozumab Deserve Its Black Box Warning?

Medscape

16-07-2025

Osteoporosis drug romosozumab showed no increased risk for the development of cardiovascular (CV) events compared with anabolic osteoporosis drugs, contrary to its black box warning, new research found.
'These findings suggest there is no heightened risk for major adverse cardiovascular events in patients with osteoporosis treated with romosozumab compared to the anabolic agents teriparatide or abaloparatide,' the authors reported at ENDO 2025: The Endocrine Society Annual Meeting.
'Further observational data is required to concur with such findings, which may lead to a discontinuation of the black box warning,' they said.
Romosozumab, a monoclonal antibody targeting sclerostin, has a unique dual action of anabolic properties (increasing bone formation while reducing resorption and improving bone mineral density while reducing vertebral fracture risk).
The drug is injected monthly for 12 months, after which time its anabolic effects decline and patients must transition to other antiresorptive therapies, such as bisphosphonates or denosumab, to maintain gains in bone density.
Although the FDA approved romosozumab for osteoporosis management, it has given a black box warning after clinical trials (including the ARCH study) comparing romosozumab with alendronate suggested an increased risk for serious CV events, including myocardial infarction, stroke, and CV death.
The drug is therefore contraindicated in patients with hypocalcemia and those who have had a myocardial infarction or stroke within the previous year.
However, data on those risks has been highly inconsistent, first author Maxim John Levy Barnett, MD, of Jefferson-Einstein Hospital, Philadelphia, told Medscape Medical News .
'Most previous studies on this issue show a nonsignificant trend toward a higher risk but do not reach statistical significance,' he said.
Even the ARCH trial 'showed a trend of higher incidence of adverse outcomes, but it was not statistically significant,' he noted.
New Findings
To further investigate the risks, Barnett and colleagues evaluated data on patients with osteoporosis in the TriNetX database, including 14,760 patients treated with romosozumab and 45,302 treated with either teriparatide or abaloparatide anabolic agents.
For the propensity score analysis, patients in the two groups were matched for age, sex, race, glycated hemoglobin, hypertension, chronic kidney disease, ischemic heart disease, cerebrovascular disease, diabetes, and other factors. After matching, the romosozumab group had 14,288 patients compared with 14,362 in the anabolic agent group.
Patients had a mean age at baseline of 70.5 years, 94% were women — as the drug is approved in the US for women only — and 71% were White.
With a mean follow-up of 5 years (including the 1-year treatment with romosozumab), there was a nonsignificant trend toward a reduced risk for CV incidents among those treated with romosozumab (relative risk [RR], 0.601; P = .0692).
The romosozumab group also had significantly lower ischemic heart disease rates than the anabolic agent group (RR, 0.848; P = .0017).
In addition, those receiving romosozumab had a lower risk of acute myocardial infarction (RR, 0.654; P < .0001).
Likewise, acute heart failure, either systolic or diastolic, was also significantly lower in the romosozumab group (RR, 0.664; P = .0029).
'After propensity-score matching, there was still a significant reduction [with romosozumab], which was a surprise,' Barnett said. 'Three out of the 4 outcomes actually showed a significant decrease in risk with romosozumab.'
'To the best of my knowledge, similar trends have not been noted in other studies,' he said, adding that there have been no significant changes to romosozumab's treatment regimen or other factors that might explain differences in risk since the issuance of the black box warning.
'It is important to note that this was not the primary objective of the noninferiority study, and it was not powered for this endpoint,' Barnett said.
The findings nevertheless add to evidence from others showing results that call into question the concerns behind the black box warning.
'There is no substantial evidence for cardiovascular risk and this medication; nonetheless, the black box warning is present,' Barnett said.
Commenting on the study, Tiffany Kim, MD, of the University of California, San Francisco, who co-moderated the session, agreed that 'these are definitely interesting findings that add to growing data that romosozumab may not be associated with increased cardiovascular risk.'
She noted that, as intended, 'any black box warning has a big effect on how clinicians consider and talk to a patient about the risks of a medication.'
'From a medico-legal perspective, I always inform my patient so they aren't surprised if they read this later, and so that I can document that they accept the benefits outweigh the risk for their individual situation.'
'This study adds to the reassuring literature that romosozumab may not be associated with increased risk of cardiovascular disease,' Kim said.
'In my clinical practice, I only consider anabolic therapy for my patients with severe osteoporosis at high fracture risk who really need treatment, so having more data about the CV risk helps with my clinical decision-making and with discussions with my patients about the risks and benefits of this drug.'
In terms of caveats, Kim noted that 'the study did a good job of matching for medical comorbidities, but there may be other factors that cause a clinician to prescribe the drugs that are associated with cardiovascular disease.'
'This study is a helpful addition to the literature, but it's hard to be definitive in an observational study,' she added.