Review of Romosozumab (EVENITY) for Severe Postmenopausal Osteoporosis

More than 10 million adults aged 50 years or older have osteoporosis, the most common bone disease in the United States.[1] Osteoporosis occurs when bone mass and bone mineral density decline.[2] The resulting decrease in bone strength can increase the risk of fractures, leading to pain, disability and an increased risk of death, for example after hip fractures. Although osteoporosis can develop at any age, postmenopausal women are at particular risk.

In 2019, the Food and Drug Administration (FDA) approved romosozumab (EVENITY), a subcutaneous (under the skin) injection for the treatment of osteoporosis in postmenopausal women who are at a high risk of fractures (such as those who have a history of osteoporotic fractures) and for whom other osteoporosis therapies have not worked.[3] Romosozumab is a monoclonal antibody and belongs to a novel class of osteoporosis drugs. This drug has a dual effect in preventing fractures: It prevents the resorption (dissolution) of bone and also stimulates the formation of new bone. Romosozumab is administered at a total dose of 210 milligrams subcutaneously once every month for 12 months in the abdomen, thigh or upper arm. Because the drug’s bone-forming effect decreases after one year, it should not be taken for more than 12 months. Patients should also maintain adequate calcium and vitamin D supplementation throughout their treatment.

Romosozumab is associated with several serious adverse events, the most concerning of which are an increased risk of myocardial infarction (heart attack), stroke and cardiovascular death.[4] For this reason, this drug has a boxed warning (the highest safety-related warning that can be required by the FDA), and patients with a heart attack or stroke in the past year should not use the drug. This added risk is particularly concerning because many of the patients most likely to consider taking romosozumab are already at increased risk for cardiovascular disease. If a patient has a heart attack or stroke during therapy, romosozumab should be discontinued.

Public Citizen’s Health Research Group strongly urged the FDA not to approve romosozumab.[5] We have classified romosozumab as a Do Not Use drug because its significant risks do not outweigh its benefits and because long-term data on its safety are not yet available.

Evidence on romosozumab’s effectiveness

The approval of romosozumab was based on two trials of postmenopausal women with osteoporosis who were between the ages of 55 and 90.[6] Less than 2% of the subjects in both trials were enrolled in the U.S. The first of these trials was placebo-controlled and included 7,180 subjects (with an average age of 71) who received a monthly injection of romosozumab or a placebo for the first 12 months of the trial. For the second 12 months, all subjects received the osteoporosis drug denosumab (PROLIA, XGEVA). At both 12 and 24 months, the subjects in the romosozumab group had significantly increased bone mineral density compared with those in the placebo group. At 12 months, they also had a significantly lower incidence of clinical fractures (referring to nonvertebral and symptomatic vertebral fractures) overall, while the absolute risk of any vertebral fractures was significantly reduced by 1.3% after 12 months and by 1.9% after 24 months for those in the drug group. It’s important to note that vertebral fractures are not broken bones as the word fracture is commonly used: Rather, they refer to collapsed vertebrae that can occur with little or no trauma as a result of osteoporosis. Many such fractures may not necessarily result in symptoms.[7] Of the clinical fractures that occurred in subjects taking romosozumab, 88% were nonvertebral fractures. For these fractures, the difference in fracture rates between the patient groups was not significant.

The second study was active-controlled and included 4,093 subjects who were randomized to either receive a monthly romosozumab injection or a weekly oral dose of the osteoporosis drug alendronate (BINOSTO, FOSAMAX) for the first 12 months of the study.[8] For the second 12 months of the study, all subjects received alendronate. Subjects were slightly older (average age of 74) and were also at a higher risk of fractures than those enrolled in the placebo-controlled trial. As in the other trial, subjects in the romosozumab group had significantly increased bone mineral density both after 12 and 24 months of follow-up. They also had a significantly lower incidence of clinical fractures (13%) compared with those taking alendronate (9.7%). Subjects in the alendronate-only group had a significantly higher incidence of any vertebral fractures (8.0%), compared to those who had received romosozumab for the first 12 months (4.1%). And, unlike the findings in the placebo-controlled trial, subjects who received romosozumab also had a lower risk for nonvertebral fractures (8.7%) as compared to the subjects in the alendronate group (10.6%).

Serious safety concerns for romosozumab

Across both trials, the most common adverse events associated with romosozumab were joint aches (arthralgia) and headaches.[9] However, other serious adverse events also occurred more frequently with use of romosozumab. These include hypersensitivity reactions, such as angioedema (swelling of the lips or other parts of the face or mouth that can make breathing difficult) and hypocalcemia (low blood calcium levels).[10] Osteonecrosis (death of bone) of the jaw is another less common adverse event that can occur in patients using osteoporosis drugs, including romosozumab. Across both trials, three subjects in the romosozumab groups and one subject in the alendronate group developed osteonecrosis of the jaw. Romosozumab may also increase the risk of femoral (thigh bone) fractures involving minimal to no trauma — called atypical fractures because they are associated with unusual pain.

Of greatest concern for romosozumab is the increased cardiovascular risk of the drug.[11] Although no difference between groups was noted in the placebo-controlled trial, in the alendronate-controlled trial, the risk of cardiovascular adverse events, including heart attack, stroke and cardiovascular death, was almost twice as high for subjects treated with romosozumab (2.0%) compared to those who had received alendronate (1.1%). Cardiovascular events occurred in patients with and without a history of heart attacks or stroke.[12]

Similar cardiovascular risks were also seen in a smaller placebo-controlled trial among men with osteoporosis.[13] Moreover, an analysis of adverse events reported to the FDA’s Adverse Event Reporting System in the year after the approval of romosozumab found more reports of cardiovascular adverse events than expected.[14] A similar analysis of voluntary adverse event reports through May 2021 in the Japanese adverse event report database showed comparable findings.[15]

What You Can Do

If you are a postmenopausal woman at high risk for fractures, Public Citizen’s Health Research Group recommends that you Do Not Use romosozumab because its limited benefits do not outweigh the serious cardiovascular risks associated with the drug.

Oral bisphosphonates, such as alendronate or risedronate (ACTONEL, ATELVIA), are approved by the FDA to reduce the risk of bone fractures in postmenopausal women.[16] However, due to the serious adverse events associated with these drugs, such as atypical femur fractures, we have designated bisphosphonates as Limited Use drugs and recommend that their use be limited to patients with high fracture risk. Additionally, we do not recommend the continuous use of bisphosphonates for more than five years to minimize the risk of adverse events.[17] If you have osteoporosis and are at high risk for fractures, discuss with your clinician the treatments which would work best for you.
 

References

[1] Centers for Disease Control and Prevention. Osteoporosis or low bone mass in older adults: United States, 2017–2018. March 31, 2021. https://www.cdc.gov/nchs/products/databriefs/db405.htm. Accessed September 26, 2023.

[2] National Institutes of Health. Overview of osteoporosis. Reviewed December 2022. https://www.niams.nih.gov/health-topics/osteoporosis. Accessed September 26, 2023.

[3] Amgen. Label: romosozumab (EVENITY). April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=471baba2-7154-4488-9891-0db2f46791e7&type=display. Accessed September 26, 2023.

[4] Amgen. Label: romosozumab (EVENITY). April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=471baba2-7154-4488-9891-0db2f46791e7&type=display. Accessed September 26, 2023.

[5] Public Citizen. Testimony before the FDA’s Bone, Reproductive and Urologic Drug Advisory Committee regarding romosozumab. January 16, 2019. https://www.citizen.org/article/testimony-before-the-fdas-bone-reproductive-and-urologic-drugs-advisory-committee-regarding-romosozumab/. Accessed September 26, 2023.

[6] Food and Drug Administration. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. April 9, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-osteoporosis-postmenopausal-women-high-risk-fracture. Accessed September 26, 2023.

[7] Harvard Health Publishing. Treating osteoporotic fractures of the spine. December 1, 2008. https://www.health.harvard.edu/newsletter_article/treating_osteoporotic_fractures_of_the_spine. Accessed September 28, 2023.

[8] Food and Drug Administration. FDA briefing document for BLA 761062, review of romosozumab for treatment of osteoporosis in postmenopausal women at risk of fracture; Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee. January 16, 2019. https://www.fda.gov/media/121257/download. Accessed September 26, 2023.

[9] Amgen. Label: romosozumab (EVENITY). April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=471baba2-7154-4488-9891-0db2f46791e7&type=display. Accessed September 26, 2023.

[10] Food and Drug Administration. FDA briefing document for BLA 761062, review of romosozumab for treatment of osteoporosis in postmenopausal women at risk of fracture; Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee. January 16, 2019. https://www.fda.gov/media/121257/download. Accessed September 26, 2023.

[11] Food and Drug Administration. FDA briefing document for BLA 761062, review of romosozumab for treatment of osteoporosis in postmenopausal women at risk of fracture; Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee. January 16, 2019. https://www.fda.gov/media/121257/download. Accessed September 26, 2023.

[12] Amgen. Label: romosozumab (EVENITY). April 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=471baba2-7154-4488-9891-0db2f46791e7&type=display. Accessed September 26, 2023.

[13] Food and Drug Administration. FDA briefing document for BLA 761062, review of romosozumab for treatment of osteoporosis in postmenopausal women at risk of fracture; Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee. January 16, 2019. https://www.fda.gov/media/121257/download. Accessed September 26, 2023.

[14] Vestergaard Kvist A, Faruque J, Vallejo-Yagüe E, et al. Cardiovascular safety profile of romosozumab: A pharmacovigilance analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS). J Clin Med. 2021;10(8):1660.]

[15] Kotake K, Mitsuboshi S, Omori Y, et al. Evaluation of risk of cardiac or cerebrovascular events in romosozumab users focusing on comorbidities: Analysis of the Japanese adverse drug event report database. J Pharm Technol. 2023;39(1):23-28.

[16] Romosozumab (EVENITY) and severe postmenopausal osteoporosis. Possible increase in mortality and cardiovascular events, with an efficacy barely superior to alendronic acid. Prescrire Int. 2021;30(224):61-64.

[17] Oral Bisphosphonates for osteoporosis: Important warnings. Worst Pills, Best Pills News. October 2021. https://www.worstpills.org/newsletters/view/1425. Accessed September 26, 2023.