Evenity (Romosozumab) Month-by-Month: What to Expect in the First 3 Months

What can actually be measured in the first three months

Romosozumab is a monoclonal antibody that inhibits sclerostin, which increases bone formation and, to a lesser extent, decreases bone resorption [1]. The bone-formation marker P1NP rose about 145% above placebo at 2 weeks, had returned to placebo level by month 9, and was about 15% below placebo by month 12 [1].

The label covers postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors, or patients who have failed or are intolerant to other osteoporosis therapy [1].

Month 1: two injections and a two-week marker signal

The first visit is two 105 mg/1.17 mL prefilled syringes given one after the other for a total of 210 mg, into the abdomen, thigh or upper arm [1]. The label says to let the syringes sit at room temperature for at least 30 minutes before injecting and not to warm them any other way [1].

Calcium is the main lab item the label tracks early. Hypocalcemia is a contraindication, and pre-existing hypocalcemia must be corrected before starting [1]. Across the two trials, albumin-adjusted calcium fell below 8.3 mg/dL in 0.2% of patients in both the Evenity and control groups, none dropped below 7.5 mg/dL, and the lowest point came by month 1 [1]. Patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or on dialysis are at greater risk and need serum calcium monitoring [1].

The adverse reaction rates the label reports come from the full 12-month treatment periods, so they describe the whole course rather than month 1 alone: arthralgia 13.1% versus 12.1% on placebo and headache 6.6% versus 5.8% in the placebo-controlled trial, and injection site reactions (pain, erythema) 4.9% versus 2.8% across the two trials [1].

Month 2: drug levels build and injection sites rotate

After a single 210 mg dose in healthy volunteers, the median time to peak concentration was 5 days. The label describes nonlinear pharmacokinetics and a mean effective half-life of about 12.8 days at 3 mg/kg every 4 weeks [1].

For the two injections at each visit, the label says to prepare and clean two injection sites, one for each injection, and to choose a different site each time; if the same site is reused, it should not be the same spot [1]. It says not to inject into skin that is tender, bruised, red or hard, to avoid scars and stretch marks, and to avoid the two-inch area around the navel [1].

On the safety side, the label lists muscle spasms in 4.6% of Evenity-treated women versus 3.9% on placebo, and hypersensitivity reactions in 6.5% of Evenity patients versus 6.5% of controls across both trials, including angioedema, erythema multiforme, dermatitis, rash and urticaria [1]. The label says to discontinue Evenity if a clinically significant allergic reaction occurs [1].

Month 3: steady state and the fracture data

With monthly dosing, Evenity reaches steady state by month 3 [1].

In FRAME, 7,180 postmenopausal women with a T-score of -2.5 to -3.5 received romosozumab 210 mg or placebo monthly for 12 months, then denosumab for 12 months [2]. At 12 months, new vertebral fractures had occurred in 0.5% of the romosozumab group versus 1.8% on placebo, a 73% lower risk (P<0.001); clinical fractures in 1.6% versus 2.5%, a 36% lower risk (P=0.008); and nonvertebral fractures in 1.6% versus 2.1%, which was not significant (P=0.10) [2].

If a dose is missed, the label says to give it as soon as it can be rescheduled and then schedule monthly doses from the date of that dose [1].

Side effects reported across the trials

The most common adverse reactions, at 5% or more, are arthralgia and headache [1]. In the alendronate-controlled ARCH trial the arthralgia rate was 8.1% on Evenity versus 9.6% on alendronate, and headache 5.2% versus 5.5% [1].

Two uncommon bone events carry label warnings. Osteonecrosis of the jaw has been reported; the label calls for a routine oral examination before starting, and risk rises with chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, corticosteroids, cancer, radiotherapy, poor oral hygiene and dental disease [1]. Across both trials the label reports one case of osteonecrosis of the jaw during Evenity treatment [1], and the FRAME report describes two cases in the romosozumab group [2]. Atypical femoral fractures have also been reported with causality not established; there was one case during treatment across both trials, and the label advises patients to report new or unusual thigh, hip or groin pain [1].

Boxed warning: heart attack, stroke and cardiovascular death

The boxed warning is titled Potential Risk of Myocardial Infarction, Stroke and Cardiovascular Death [1]. It says Evenity may increase these risks, should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year, and that benefits versus risks should be weighed in patients with other cardiovascular risk factors; Evenity should be discontinued if a myocardial infarction or stroke occurs during therapy [1]. A recent MI or stroke sits under this boxed warning rather than under Contraindications, which list hypocalcemia and systemic hypersensitivity [1].

The rates behind the warning come from ARCH: positively adjudicated major adverse cardiac events were 2.0% (41 of 2,040) on Evenity versus 1.1% (22 of 2,014) on alendronate, hazard ratio 1.87 (95% CI 1.11 to 3.14), with MI 0.8% versus 0.2%, stroke 0.6% versus 0.3% and cardiovascular death 0.8% versus 0.6% [1]. Serious cardiovascular adverse events in year 1 were 2.5% versus 1.9% [3]. In the placebo-controlled FRAME trial, adjudicated MACE was 0.8% in both groups (hazard ratio 1.03, 95% CI 0.62 to 1.72) [1]. The label instructs monitoring for signs and symptoms of myocardial infarction and stroke and prompt medical attention if they occur [1].

Calcium and vitamin D during treatment

The label says to adequately supplement calcium and vitamin D during treatment [1]. In the trials, women received at least 500 mg calcium and 600 international units of vitamin D daily, and 77% in the placebo-controlled study received a loading dose of 50,000 to 60,000 international units of vitamin D within a week of randomization if their 25-hydroxyvitamin D was 40 ng/mL or less [1].

After month 12: why the course is fixed

Use is limited to 12 monthly doses because the anabolic effect wanes after that, and if osteoporosis therapy is still warranted, continued therapy with an anti-resorptive agent should be considered [1]. After Evenity is stopped without follow-on anti-resorptive therapy, bone mineral density returns to about baseline within 12 months [1].