Romosozumab (Evenity): mechanism, boxed warning, trials

Romosozumab, sold as Evenity, is a monoclonal antibody that blocks sclerostin, a protein that regulates bone metabolism. Its US label says it increases bone formation and, to a lesser extent, decreases bone resorption. It is FDA-approved for postmenopausal women with osteoporosis at high risk for fracture, and it carries a boxed warning for heart attack, stroke and cardiovascular death that comes from a trial comparing it with alendronate.

Evidence grade A: what kinds of studies support the claims on this page, with limits. It is not a verdict on any product. How we grade

How Evenity works: mechanism of action

The FDA-approved label describes romosozumab-aqqg as "a humanized monoclonal antibody (IgG2)" made in a Chinese Hamster Ovary cell line by recombinant DNA technology, which "binds to and inhibits sclerostin."¹ Its mechanism-of-action section says: "EVENITY inhibits the action of sclerostin, a regulatory factor in bone metabolism. EVENITY increases bone formation and, to a lesser extent, decreases bone resorption."¹ The label adds that in animal studies romosozumab-aqqg stimulated new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic (bone-building) activity.¹

For how the other bone drugs on this site work, see teriparatide, abaloparatide, calcitonin and denosumab.

What is in it, and is there a steroid?

The Medication Guide in the label lists one active ingredient, romosozumab-aqqg, and these inactive ingredients: acetate, calcium, polysorbate 20, sodium hydroxide, sucrose and water for injection.¹ No steroid appears in that list. The active ingredient is an antibody, which is a protein.¹

Who it is approved for

The label says Evenity is "indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy."¹ Under limitations of use it says to "limit duration of use to 12 monthly doses," and that if osteoporosis therapy is still warranted, "continued therapy with an anti-resorptive agent should be considered."¹ The label says it should be given by a healthcare provider.¹

The boxed warning, contraindications and other warnings

Boxed warning. The label's boxed warning is titled "Potential risk of myocardial infarction, stroke and cardiovascular death." It says Evenity "may increase the risk of myocardial infarction, stroke, and cardiovascular death," that it "should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year," and that prescribers should consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors.¹ The warnings section adds that if a patient has a heart attack or stroke during therapy, Evenity should be discontinued.¹

Contraindications. The label lists two: hypocalcemia, which must be corrected before starting, and a history of systemic hypersensitivity to romosozumab-aqqg or to any component of the product formulation.¹ The one-year heart attack or stroke rule appears in the boxed warning, not in the contraindications section.¹

Other warnings and side effects. The label's other warnings cover hypersensitivity reactions, hypocalcemia, osteonecrosis of the jaw and atypical femoral fracture. It lists arthralgia (joint pain) and headache as the most common adverse reactions (5% or more) in clinical trials.¹

The MACE data behind the boxed warning

The label defines major adverse cardiac events (MACE) as a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. It reports a higher MACE rate with Evenity than with alendronate in a randomized controlled trial.¹ Its adverse-reactions section gives these figures for the 12-month double-blind period:¹

The label says the heart attacks and strokes in Study 2 "occurred in patients with and without a history of myocardial infarction or stroke."¹ The published ARCH paper reports a different measure: positively adjudicated serious cardiovascular adverse events during year 1, in 2.5% of the romosozumab group (50 of 2,040) and 1.9% of the alendronate group (38 of 2,014).³ The two sets of numbers count different things, so they should not be mixed.

The FRAME and ARCH trials

FRAME enrolled 7,180 postmenopausal women with a T score of -2.5 to -3.5 at the total hip or femoral neck. They were randomly assigned to romosozumab or placebo for 12 months, and then both groups moved to denosumab.² At 12 months, new vertebral fractures occurred in 0.5% of the romosozumab group and 1.8% of the placebo group, a 73% lower risk. At 24 months, after both groups had moved to denosumab, the figures were 0.6% and 2.5%, a 75% lower risk.² Nonvertebral fractures were not significantly different at 12 months (1.6% versus 2.1%; P=0.10).²

ARCH enrolled 4,093 postmenopausal women with osteoporosis and a fragility fracture. They were randomly assigned to romosozumab or alendronate for 12 months, followed by open-label alendronate in both groups.³ Over 24 months the romosozumab-to-alendronate group had a 48% lower risk of new vertebral fractures (6.2% versus 11.9%) and a 27% lower risk of clinical fractures (9.7% versus 13.0%).³

US approval history

The FDA's approval letter refers to Amgen's Biologics License Application dated and received July 19, 2016, and to a resubmission dated July 9, 2018, "which constituted a complete response to our July 13, 2017, action letter."⁵ Drugs@FDA lists the original approval of BLA 761062 on 04/09/2019 and lists Evenity as a prescription product.⁴ The current label on DailyMed is marked "Revised: 1/2026."¹

Questions people ask

What is Evenity's mechanism of action?

It inhibits sclerostin. The label says it "increases bone formation and, to a lesser extent, decreases bone resorption."¹

Are there steroids in Evenity?

The label's ingredient list does not include a steroid. It lists romosozumab-aqqg, an antibody, plus acetate, calcium, polysorbate 20, sodium hydroxide, sucrose and water for injection.¹

Who should not use Evenity (contraindications)?

The label lists hypocalcemia and a history of systemic hypersensitivity to romosozumab-aqqg or any component of the product. Separately, its boxed warning says it should not be started in someone who has had a heart attack or stroke within the preceding year.¹

What MACE data are behind the boxed warning?

In the alendronate-controlled study, positively adjudicated MACE occurred in 2.0% of women on Evenity and 1.1% on alendronate (hazard ratio 1.87). In the placebo-controlled study, the rate was 0.8% in both groups.¹