Evenity (Romosozumab) East Asian Safety Profile Differences

What the Evidence Actually Shows

Romosozumab is a monoclonal antibody that inhibits sclerostin. It increases bone formation and decreases bone resorption. Because it is a therapeutic antibody rather than a small molecule cleared through a cytochrome P450 pathway, common CYP2C19 variants do not create an ethnicity-specific romosozumab dose. [1]

The global FRAME trial compared romosozumab with placebo for 12 months and then gave both groups denosumab. The ARCH trial compared romosozumab followed by alendronate with alendronate alone in women at high fracture risk. Those trials established efficacy and also generated the cardiovascular concern reflected in the current boxed warning. [2,3]

East Asian evidence includes:

• a randomized, double-blind, placebo-controlled phase 3 trial in 67 Korean postmenopausal women, in which the romosozumab group had a 9.5% mean lumbar-spine BMD increase at six months versus a 0.1% decrease with placebo; [4]
• a phase 2 trial in Japanese postmenopausal women showing dose-dependent BMD increases; [5] and
• a Japanese subgroup analysis from FRAME and its extension showing continued BMD gains when romosozumab was followed by denosumab. [6]

These data support efficacy in Japanese and Korean women. They do not establish that East Asian patients have a larger response than every other ethnic group, that body weight explains any difference, or that an ethnicity-specific biomarker such as serum sclerostin predicts response.

Cardiovascular Safety

The current U.S. label warns that romosozumab may increase the risk of myocardial infarction, stroke, and cardiovascular death. It should not be initiated in a patient who had myocardial infarction or stroke during the preceding year. For patients with other cardiovascular risk factors, the prescriber should weigh fracture benefit against cardiovascular risk. If myocardial infarction or stroke occurs during treatment, the drug should be discontinued. [1]

The placebo-controlled FRAME trial did not show the same imbalance seen in ARCH. In ARCH, positively adjudicated major adverse cardiovascular events occurred more often with romosozumab than with alendronate during the first year. The label reports 41 events (2.0%) with romosozumab and 22 (1.1%) with alendronate, hazard ratio 1.87 (95% CI 1.11 to 3.14). [1,3]

Small Japanese and Korean studies were not powered to detect modest differences in uncommon cardiovascular events. Absence of a signal in a small subgroup or short observational series is not evidence that the boxed warning is attenuated in East Asian patients.

Dosing and Monitoring in East Asian Patients

The U.S. regimen is two consecutive 105 mg injections, for a total of 210 mg, once monthly. Treatment is limited to 12 monthly doses because the anabolic effect wanes. If treatment is still needed afterward, an antiresorptive agent should be considered. [1]

The label does not recommend a lower dose for East Asian ancestry or lower body weight. It does require correction of pre-existing hypocalcemia and adequate calcium and vitamin D supplementation. Patients with severe renal impairment or receiving dialysis are at greater risk of hypocalcemia and require appropriate monitoring. [1]

Routine care should also include:

• review of myocardial infarction, stroke, and other cardiovascular risk factors;
• serum calcium assessment when clinically indicated, especially in severe renal impairment;
• oral examination before treatment and attention to osteonecrosis-of-the-jaw risk factors;
• counseling about symptoms of myocardial infarction, stroke, hypocalcemia, and hypersensitivity; and
• a plan for antiresorptive therapy after the 12-dose course.

What Should Not Be Claimed

Current evidence does not support claims that East Asian women universally gain a particular percentage more BMD than non-Asian women, that a CYP2C19 genotype changes romosozumab dosing, that an “Asian-specific” cardiovascular calculator is required by the FDA label, or that Japanese or Korean post-marketing data nullify the boxed warning.

Professional guidelines recommend romosozumab as an option for selected postmenopausal women at very high fracture risk and emphasize cardiovascular risk assessment and subsequent antiresorptive therapy. They do not create separate eligibility or dosing thresholds based solely on East Asian ethnicity. [7,8]