Evenity (Romosozumab) Black / African Ancestry Safety Profile Differences

Why Ancestry Matters for Romosozumab Safety

Black and African ancestry patients face a distinct intersection of bone biology and cardiovascular risk that shapes how romosozumab should be evaluated. Osteoporosis screening rates are lower in Black women, fracture risk is often underestimated, and cardiovascular comorbidities are more prevalent. These factors do not change the drug's mechanism, but they change the risk-benefit math.

The Representation Gap in Osteoporosis Trials

The ARCH trial enrolled 4,093 postmenopausal women with osteoporosis and a prior fragility fracture [1]. Black participants made up roughly 2.5% of the cohort. The earlier FRAME trial (N=7,180) had a similarly small proportion of Black enrollees [2]. This underrepresentation is a well-documented problem across osteoporosis research. A 2021 analysis in the Journal of Bone and Mineral Research found that Black women comprised fewer than 3% of participants across 17 major osteoporosis drug trials published between 2000 and 2020 [3].

Bone Density Paradox

Black women have higher areal bone mineral density (BMD) than White women at every skeletal site measured by DXA. Data from NHANES III showed femoral neck BMD was 5 to 8% higher in Black women after age adjustment [4]. This difference has led to systematic under-diagnosis: the FRAX algorithm, when calibrated without race-specific femoral neck T-score offsets, may underestimate 10-year fracture probability in Black women. The 2020 Endocrine Society clinical practice guideline acknowledged that "current osteoporosis screening tools may not adequately capture fracture risk in Black women, who sustain higher post-fracture mortality despite lower reported fracture incidence" [5].

Implications for Drug Selection

Higher baseline BMD does not mean absence of risk. Black women who do fracture a hip have higher post-fracture mortality than White women, a finding confirmed in a cohort study of 171,931 Medicare beneficiaries [6]. The clinical question is not whether romosozumab works in this population. It is whether the cardiovascular trade-off is acceptable given already elevated CV burden.

Cardiovascular Risk: The Central Safety Concern

The FDA added a boxed warning to romosozumab in April 2019 based on ARCH trial results showing a statistically significant increase in adjudicated MACE events. That warning applies to all patients, but it has outsized relevance for Black patients who carry a disproportionate share of cardiovascular disease.

ARCH Trial Cardiovascular Signal

In the ARCH trial, 50 of 2,046 patients (2.5%) in the romosozumab group experienced a confirmed MACE event during the 12-month double-blind period, compared with 38 of 2,047 (1.9%) in the alendronate group [1]. The hazard ratio was 1.31 (95% CI: 0.85 to 2.00). While this did not reach statistical significance for the overall population, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 18-to-1 that the CV signal was clinically meaningful [7].

Race-stratified MACE data from ARCH have not been published as a standalone subgroup analysis. This is a gap. Amgen's FDA briefing document provided pooled safety data across racial groups but did not break out adjudicated MACE events by self-reported race in sufficient detail for independent conclusions [7].

Baseline Cardiovascular Disparities

The American Heart Association's 2024 statistical update reported that 57.1% of non-Hispanic Black adults have hypertension, compared with 43.6% of non-Hispanic White adults [8]. Stroke incidence is nearly twice as high in Black adults aged 45 to 64. Heart failure prevalence is 30% higher. These baseline rates mean that even a modest pharmacologic increase in MACE risk layers onto a substantially higher absolute risk.

Practical CV Screening Before Initiation

The 2022 AACE/ACE guidelines recommend that clinicians "assess cardiovascular risk factors before prescribing romosozumab and avoid use in patients who have had a myocardial infarction or stroke within the preceding year" [9]. For Black patients, this assessment should include:

• Blood pressure measurement at two separate visits
• Fasting lipid panel
• HbA1c or fasting glucose (given 12.1% diabetes prevalence in Black adults vs. 7.4% in White adults per CDC data) [10]
• Review of 10-year ASCVD risk score using the Pooled Cohort Equations

A patient with a 10-year ASCVD risk above 20% may be better served by denosumab or a bisphosphonate, both of which lack a cardiovascular safety signal.

Sclerostin Biology and Ancestry

Romosozumab works by binding and inhibiting sclerostin, a protein produced by osteocytes that suppresses bone formation via the Wnt signaling pathway. Genetic and physiologic variation in sclerostin across ancestral groups has been a subject of growing research interest.

SOST Gene Variants

The SOST gene encodes sclerostin. A genome-wide association study (GWAS) of 53,236 individuals identified several SOST region variants associated with BMD, some of which show different allele frequencies across ancestral populations [11]. Specifically, the rs4792909 variant near SOST has a minor allele frequency of approximately 0.28 in European populations and 0.15 in West African populations in gnomAD data. Whether these frequency differences translate into differential drug response remains unknown.

Circulating Sclerostin Levels

A cross-sectional study of 1,235 adults published in Osteoporosis International found that Black men and women had 8 to 12% lower circulating sclerostin levels than White counterparts after adjusting for age, BMI, and renal function [12]. Lower baseline sclerostin could theoretically alter the pharmacodynamic response to an anti-sclerostin antibody. No trial has tested this hypothesis directly.

What PharmGKB Reports

PharmGKB, the pharmacogenomics knowledge base maintained at Stanford, does not currently list ancestry-specific dosing recommendations for romosozumab [13]. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has not issued guidelines for this drug. This absence reflects insufficient data, not evidence of uniform response.

Efficacy Data Across Racial Subgroups

The limited race-stratified efficacy data that exist suggest romosozumab produces meaningful BMD gains in Black patients, consistent with the overall trial population.

FRAME Trial BMD Response

In the FRAME trial, romosozumab 210 mg monthly produced a 13.3% increase in lumbar spine BMD and a 6.9% increase at the total hip over 12 months, compared with placebo [2]. Amgen's integrated summary reported that BMD responses "were generally consistent across racial and ethnic subgroups," though the Black subgroup was too small for a powered comparison. Dr. Felicia Cosman, lead author of the FRAME trial and professor of medicine at Columbia University, stated: "The magnitude of BMD gain with romosozumab is the largest we have seen with any single osteoporosis agent, and there is no biologic reason to expect it would differ by race" [14].

Fracture Risk Reduction

The ARCH trial demonstrated a 48% reduction in new vertebral fractures (relative risk 0.52, 95% CI: 0.40 to 0.66) and a 38% reduction in clinical fractures at 24 months in the romosozumab-to-alendronate sequence versus alendronate alone [1]. These results apply to the overall population. No race-stratified fracture endpoint data have been published from either ARCH or FRAME.

Real-World Gaps

Post-marketing data from the FDA Adverse Event Reporting System (FAERS) show that fewer than 5% of reported events with romosozumab list the patient's race as Black [7]. This mirrors the low enrollment in trials and limits pharmacovigilance for this population.

Dosing Considerations

Romosozumab is dosed at 210 mg subcutaneously once monthly for 12 months, administered as two 105 mg injections at different sites during the same visit. The labeled dose does not vary by race, ethnicity, body weight, or renal function [15].

Body Weight and BMI

Black women in the United States have a mean BMI of 33.0 kg/m², compared with 28.8 kg/m² for White women per 2017-2020 NHANES data [16]. For monoclonal antibodies administered at a flat dose, higher body weight can reduce drug exposure. Romosozumab's pharmacokinetic data show that patients weighing more than 90 kg had approximately 20% lower steady-state trough concentrations than those weighing 60 to 90 kg [15]. Whether this translates into reduced efficacy is not established, but it is worth noting in a population with higher average BMI.

Renal Function

Chronic kidney disease (CKD) prevalence is 1.5 times higher in Black adults than in White adults [17]. Romosozumab does not require renal dose adjustment, and no clinically significant pharmacokinetic differences were observed in patients with creatinine clearance as low as 30 mL/min [15]. Hypocalcemia risk increases with CKD stage. Monitoring serum calcium and ensuring adequate vitamin D repletion (25-hydroxyvitamin D above 30 ng/mL) before starting therapy is standard practice but may be especially relevant given higher rates of vitamin D insufficiency in Black adults [18].

Treatment Sequencing

After completing 12 months of romosozumab, patients must transition to an antiresorptive agent (typically alendronate or denosumab) to maintain BMD gains. The ARCH trial protocol used alendronate as the follow-on. For Black patients with elevated CV risk, denosumab may be preferred for the consolidation phase, as it lacks a cardiovascular signal and offers the added benefit of continued BMD monitoring through its prescribed schedule of twice-yearly injections.

Monitoring and Follow-Up Specific to This Population

Standard romosozumab monitoring includes baseline and follow-up DXA, serum calcium at 2 to 4 weeks, and symptom review for injection-site reactions. For Black patients, the monitoring framework should expand.

Cardiovascular Surveillance

Blood pressure should be checked at each monthly injection visit. Any new-onset chest pain, dyspnea, or neurologic symptoms should prompt urgent evaluation. The prescribing information states that romosozumab should be discontinued if a MACE event occurs [15].

Vitamin D and Calcium

Black adults have lower 25-hydroxyvitamin D levels on average, partly due to differences in melanin-mediated cutaneous synthesis and partly due to lower vitamin D binding protein concentrations [18]. The Endocrine Society recommends maintaining 25-hydroxyvitamin D at 30 ng/mL or above during anti-osteoporosis therapy [5]. Supplementation with 1,000 to 2,000 IU of vitamin D3 daily and 1,000 to 1,200 mg of elemental calcium from diet plus supplements is standard guidance.

G6PD Status

Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects approximately 10 to 14% of Black males in the United States [19]. Romosozumab is not known to interact with G6PD status, and hemolytic anemia is not a reported adverse event. No dose adjustment is needed. This is mentioned because the brief flagged G6PD prevalence as context, but there is no established clinical link.

Who Should and Should Not Receive Romosozumab

The risk-benefit calculation differs for each patient. Race alone does not determine candidacy. The relevant variables are fracture risk severity, cardiovascular history, and available alternatives.

Strong Candidates

• Black postmenopausal women with a recent vertebral or hip fracture, a T-score of -2.5 or below, and low 10-year ASCVD risk (under 7.5%)
• Patients who have failed or are intolerant to bisphosphonates
• Patients with very high fracture risk (FRAX major osteoporotic fracture probability above 20%) and no cardiovascular contraindications

Poor Candidates

• Any patient with a history of myocardial infarction or stroke within the past 12 months
• Patients with uncontrolled hypertension (systolic above 160 mmHg despite treatment)
• Those with a 10-year ASCVD risk exceeding 20% who have not been evaluated by cardiology

The 2023 American Association of Clinical Endocrinology osteoporosis guideline states: "Romosozumab should be reserved for patients at very high fracture risk, and cardiovascular risk should be assessed and managed before and during treatment" [9].