Endocrine Society Advises on Use of Romosozumab for Osteoporosis

Pam Harrison

February 21, 2020

Latest guidelines on the treatment of osteoporosis have been released that include new recommendations for the use of romosozumab (Evenity, Amgen) in postmenopausal women with severe osteoporosis, but they contain caveats as to which women should — and should not — receive the drug.

The updated clinical practice guideline from the Endocrine Society is in response to the approval of romosozumab by the US Food and Drug Administration (FDA) in April 2019, and more recently, by the European Medicines Agency.

It was published online February 18 in the Journal of Clinical Endocrinology & Metabolism.

In the new guidelines, committee members recommend the use of romosozumab for postmenopausal women with osteoporosis at very high risk of fracture. Candidates would include women with severe osteoporosis (T-score < –2.5 and a prior fracture) or women with a history of multiple vertebral fractures.

Women should be treated with romosozumab for up to 1 year followed by an antiresorptive agent to maintain bone mineral density gains and further reduce fracture risk.

"The recommended dosage is 210 mg monthly by subcutaneous injection for 12 months," the authors state.

However, and very importantly, romosozumab should not be considered for women at high risk of cardiovascular disease (CVD) or cerebrovascular disease. A high risk of CVD includes women who have had a prior myocardial infarction (MI) or stroke.

Experts questioned by Medscape Medical News stressed romosozumab should not be a first-line, or even generally a second-line, option for osteoporosis but can be a considered for select patients with severe osteoporosis, taking into account CV risk.

Romosozumab Has Boxed Warning For CV Events

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH), there were more major adverse cardiovascular events (MACE) in the first year of the trial with romosozumab, and patients had a 31% higher risk of MACE in the romosozumab versus alendronate group.

As a result, the drug was first rejected by a number of regulatory agencies.

In the United States and Canada, it was eventually approved with a boxed warning, which cautions against the use of the drug in patients at risk for MI, stroke, and CVD death.

"Romosozumab offers promising results for postmenopausal women with severe osteoporosis or who have a history of fractures," Clifford Rosen, MD, Maine Medical Center Research Institute in Scarborough and chair of the writing committee, said in an Endocrine Society statement.

"It does, however, come with a risk of heart disease, so clinicians need to be careful when selecting patients for this therapy," he added.

Exact Risk of CV Events, if Real, Remains Unknown

Asked by Medscape Medical News to comment, Kenneth Saag, MD, professor of medicine, University of Alabama at Birmingham and principle investigator of the ARCH study, feels physicians need more data from real-world studies to resolve the issue as to whether romosozumab heightens the risk of CV events in women with osteoporosis or whether this particular finding from ARCH was an artifact. 

"Women who have had a recent cardiovascular event should not receive the drug," he said, agreeing with the new guidelines.

But whether women at slightly higher risk of having a CV event by virtue of their age alone, for example, are also at risk remains unclear, he noted.

In the meantime, results from the ARCH study clearly showed that not only was romosozumab more effective than alendronate, "but it is more effective than other bone-building drugs as well," Saag observed — leading to a significantly greater reduction in vertebral, nonvertebral, and hip fractures than the bisphosphonate alendronate, the current standard of care in osteoporosis.

"In patients who have very severe osteoporosis and who have had a recent fracture or who are at risk for imminent future fracture, physicians need to balance the benefit versus the risk in favor of using romosozumab," Saag suggested.

"And while I would say most women prefer not to inject themselves, the women I have put on this medicine have all had recent fractures and they are very aware of the pain and the disability of having a broken bone so it is something they are willing to do," he added.

Romosozumab Not for All Women, but an Option in Severe Osteoporosis

Giving his opinion, Bart Clarke, MD, of the Mayo Clinic in Rochester, Minnesota, underscored the fact that the Fracture Study in Postmenopausal Women With Osteoporosis (FRAME), again conducted in postmenopausal women, showed no increase in CV events in patients treated with romosozumab compared with placebo.

"So there are questions about what this means because if these events really were a drug effect, then that effect would be even more evident compared with placebo and they did not see any signal of CV events [in FRAME]," said Clarke, past president of the American Society of Bone and Mineral Research.

Like everything else in medicine, "there is always some risk," Clarke observed.

However, what physicians should do is talk to women, ensure they have not had either an MI or stroke in the last year, and if patients have severe osteoporosis and a high risk of fracture, "then we can say, here's another option," he suggested.

"Then if a woman develops chest pain or shortness of breath while they are on the drug, they need to let us know and then we'll stop the drug and reassess the situation," he added.

Clarke also pointed out that if the FDA had received further reports of CV events linked to romosozumab, physicians would know about it by now, but to his knowledge, there has been no change to the drug's current warning label.

Furthermore, neither he nor any of his colleagues who treat metabolic bone disease at the Mayo Clinic has seen a single CV event in patients prescribed the agent.

"This is not a drug we would use as first-line for most patients, and we don't even use it as second-line for most patients, but in people who have not responded to other drugs or who have had terrible things happen to them already, hip fracture especially, then we are saying, you can consider this," he concluded.

The guidelines were supported by the Endocrine Society. Rosen has reported no relevant financial relationships. Disclosures for the other committee members are listed in the publication. Saag has reported receiving grants and personal fees from Amgen, personal fees from Radius, and is a consultant for Amgen, Radius, Roche, and Daiichi Sankyo. Clarke has reported no relevant financial relationships.

J Clin Endocrinol Metab. Published online February 18, 2020. Full text

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