Romosozumab
Indications
Romosozumab is the only sclerostin inhibitor approved for osteoporosis and the only available agent that simultaneously increases bone formation and decreases bone resorption. The FDA labelling confines its use to a single, well-defined population — postmenopausal women at high fracture risk — and explicitly limits the duration of therapy to 12 monthly doses because the anabolic effect wanes thereafter. The 2020 update to the Endocrine Society pharmacological management guideline positions romosozumab as a treatment option for postmenopausal women at very high risk of osteoporotic fracture, with cardiovascular risk informing patient selection.
| Indication | Status | Population / Notes |
|---|---|---|
| Treatment of osteoporosis in postmenopausal women at high risk for fracture | FDA Approved | “High risk” defined in the FDA labelling as: history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Limit duration to 12 monthly doses; follow with an anti-resorptive agent if osteoporosis therapy remains warranted. |
| Osteoporosis in men | Not FDA Approved (US) | The Phase 3 BRIDGE trial (Lewiecki 2018) demonstrated significant BMD gains in men with osteoporosis at 12 months. Romosozumab is approved for men in some non-US jurisdictions (e.g., Japan) but is not approved in men in the United States. Off-label use in the US is not endorsed in this monograph. |
| Glucocorticoid-induced osteoporosis | Not FDA Approved | Not studied in dedicated Phase 3 GIO trials. Use is not supported by the FDA labelling and is not recommended. |
| Premenopausal osteoporosis | Not FDA Approved | Romosozumab is not indicated in women of reproductive potential. Animal data show skeletal abnormalities at high exposures; embryo-fetal risk has not been characterized in humans. |
Romosozumab is positioned as a first-line option specifically for postmenopausal women at very high fracture risk (history of fracture, very low T-score, recent fracture) where rapid BMD gain matters. AACE/ACE 2020 and the Endocrine Society 2020 update both list romosozumab among very-high-risk first-line options alongside teriparatide, abaloparatide, and zoledronic acid, with the caveat that the boxed warning requires careful cardiovascular risk assessment. The 12-month course must be followed by an anti-resorptive (denosumab, alendronate, zoledronic acid) to consolidate BMD gains, mirroring the FRAME and ARCH study designs.
Dosing
Romosozumab is administered by a healthcare provider as a fixed monthly subcutaneous dose for 12 months. There is no oral form, no self-administration, and no titration. Hypocalcemia must be corrected and adequate calcium and vitamin D intake confirmed before each dose.
Standard Dosing — Postmenopausal Osteoporosis at High Fracture Risk
| Parameter | Specification | Notes |
|---|---|---|
| Total monthly dose | 210 mg subcutaneously | Delivered as two single-use 105 mg/1.17 mL prefilled syringes given one immediately after the other Both syringes are required for one full dose; do not omit either |
| Dosing frequency | Once monthly | Schedule successive doses one month apart from the previous administration date |
| Treatment duration | 12 monthly doses (maximum) | The anabolic effect wanes after 12 months per FDA labelling; do not exceed this duration. Do not retreat with romosozumab. |
| Injection sites | Abdomen, thigh, or upper arm | Use two separate sites — one for each syringe. Avoid the two-inch area around the navel; rotate sites; avoid tender, bruised, red, hard, or scarred areas |
| Calcium & vitamin D supplementation | Daily throughout therapy | Pivotal trials provided ≥500 mg calcium and ≥600 IU vitamin D daily; replete deficiency before initiation |
| Missed dose | Administer as soon as practicable | Reschedule subsequent doses monthly from the date of the rescheduled dose |
| Follow-on therapy | Anti-resorptive agent | If continued osteoporosis therapy is warranted, transition to an anti-resorptive (denosumab, oral or IV bisphosphonate) immediately to preserve BMD gains. BMD returns toward baseline within 12 months without follow-on therapy. |
Renal Dose Adjustment
| Renal Function | Recommendation | Notes |
|---|---|---|
| Normal to moderate impairment | No dose adjustment | Romosozumab is a monoclonal antibody not eliminated by renal mechanisms; PK is not clinically affected by renal function |
| Severe impairment (eGFR 15–29 mL/min/1.73 m²) or dialysis | No dose adjustment, but elevated hypocalcemia risk | Per FDA PI: monitor serum calcium more closely; ensure rigorous calcium and vitamin D supplementation; counsel on symptoms of hypocalcemia The effect of ESRD not requiring dialysis on PK has not been characterized |
Hepatic Impairment
No dose adjustment is required. As an IgG2 monoclonal antibody, romosozumab is degraded into peptides and amino acids by general catabolic pathways rather than hepatic CYP-mediated metabolism. No dedicated hepatic impairment study has been conducted, but clinically significant hepatic effects on PK are not expected.
Special Populations
- Older adults (≥65 years): No dose adjustment. In the Phase 3 program, 80% of women were ≥65 years and 37% were ≥75 years; no overall efficacy or safety differences were observed, although greater sensitivity in some older individuals cannot be ruled out.
- Pediatrics: Safety and effectiveness have not been established. Romosozumab is not indicated in pediatric patients.
- Pregnancy and lactation: Not indicated for women of reproductive potential. In rats, weekly romosozumab at exposures ≥31× clinical produced skeletal malformations in 1 of 75 litters; lactation studies showed dose-dependent transfer to offspring.
- Body weight: Romosozumab exposure decreases with increasing body weight, but no dose adjustment is recommended; clinical efficacy in pivotal trials was preserved across baseline weight subgroups.
- Race, prior bisphosphonate exposure: No clinically significant PK differences observed.
Storage and Handling
- Store refrigerated at 2–8 °C (36–46 °F) in the original carton, protected from light. Do not freeze. Do not shake.
- Once removed from refrigeration, may be kept at room temperature up to 25 °C (77 °F) in the original carton for a maximum of 30 days; discard if not used within 30 days.
- Do not expose to temperatures above 25 °C (77 °F).
- Allow the syringes to sit at room temperature for at least 30 minutes before injection. Do not warm by any other method (e.g., microwave, hot water).
- Inspect visually before use — solution is clear to opalescent and colorless to light yellow. Discard if cloudy, discolored, or particulate.
The most common workflow error in clinical practice is administering only one of the two prefilled syringes. Each “dose” requires both 105 mg syringes given consecutively at two different sites; a single injection of 105 mg is a half-dose and not a recognized regimen. Plan the 12-month course at initiation, including the follow-on anti-resorptive scheduled for month 13, because BMD gains are lost rapidly without sequential therapy. The treatment is also irreversible in terms of duration — a missed dose extends the schedule but does not “reset” the 12-month limit; cumulative monthly doses across any timeframe should not exceed twelve.
Pharmacology
Mechanism of Action
Romosozumab is a humanized IgG2 monoclonal antibody that binds and inhibits sclerostin, a glycoprotein secreted predominantly by osteocytes that acts as a tonic brake on osteoblast-driven bone formation. Sclerostin antagonizes the canonical Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors on osteoblast lineage cells. By neutralizing sclerostin, romosozumab releases Wnt signaling, stimulating osteoblast differentiation, activity, and survival. The result is a rapid and sustained increase in bone formation, accompanied by a smaller decrease in bone resorption — a dual-action profile not seen with any other approved osteoporosis drug.
Histomorphometric analyses of transiliac bone biopsies during the FRAME trial confirmed normal bone architecture and quality at month 2, month 12, and month 24, with no evidence of woven bone, mineralization defects, or marrow fibrosis. At month 2, indices of bone formation at trabecular and endocortical surfaces were increased and indices of bone resorption decreased. By month 12, both formation and resorption indices were below baseline while bone volume and trabecular and cortical thickness had increased — reflecting the self-limiting nature of the anabolic effect that underpins the 12-month duration limit.
Pharmacodynamics
In postmenopausal women with osteoporosis, the bone formation marker procollagen type 1 N-telopeptide (P1NP) peaked at approximately 145% above placebo at week 2, returned to placebo levels by month 9, and was approximately 15% below placebo at month 12. The bone resorption marker C-telopeptide (CTX) decreased to approximately 55% below placebo at week 2 and remained roughly 25% below placebo at month 12. After discontinuation, P1NP returned to baseline within 12 months, while CTX rose above baseline within 3 months and returned to baseline by month 12. This biomarker pattern explains why BMD gains are not durable without follow-on anti-resorptive therapy.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Median Tmax 5 days (range 2–7 days) after subcutaneous administration; Cmax 22.2 (SD 5.8) mcg/mL and AUC 389 (SD 127) mcg·day/mL after a single 210 mg dose in healthy volunteers; nonlinear exposure with greater than dose-proportional increases in AUC across the 0.1–10 mg/kg range | Slow subcutaneous absorption matches the once-monthly dosing schedule; no oral form available |
| Distribution | Steady-state Vd ~3.92 L; trough serum concentrations at months 3, 6, 9, and 12 range 8–13 mcg/mL; steady state achieved by month 3 with monthly dosing | Distribution volume approximates plasma plus interstitial fluid, typical of an IgG monoclonal antibody; minimal tissue penetration outside the bone-targeting site of action |
| Metabolism | Not characterized in detail; expected to be degraded into small peptides and amino acids by general catabolic pathways, in the same manner as endogenous IgG | No CYP450 involvement; no clinically significant pharmacokinetic drug-drug interactions through hepatic metabolism |
| Elimination | Mean systemic clearance (CL/F) ~0.38 mL/hr/kg after 3 mg/kg subcutaneous; mean effective half-life ~12.8 days after three 3 mg/kg doses every 4 weeks; nonlinear elimination with clearance decreasing as dose increases (target-mediated drug disposition consistent with sclerostin saturation) | No renal or hepatic dose adjustment required; PK unaffected by age (20–89 years), sex, race, prior alendronate exposure, or renal impairment including dialysis |
| Immunogenicity | 18.1% of women treated with monthly 210 mg developed anti-romosozumab-aqqg antibodies; 4.7% of antibody-positive patients had neutralizing antibodies. Antibody formation reduced mean serum concentrations by up to 22% (any antibody) and up to 63% (neutralizing antibody) | Anti-drug antibodies were generally not associated with measurable changes in efficacy or safety in the Phase 3 program; routine ADA monitoring is not required |
Side Effects
Adverse-event rates below derive from the FDA prescribing information Table 1 (revised 1/2026), which combines the two pivotal Phase 3 trials: Study 1 (FRAME), a 12-month placebo-controlled trial in 7,180 randomized postmenopausal women with osteoporosis (safety population: 3,581 EVENITY and 3,576 placebo), and Study 2 (ARCH), a 12-month alendronate-controlled trial in 4,093 randomized postmenopausal women at higher fracture risk (safety population: 2,040 EVENITY and 2,014 alendronate). The two trials produced different cardiovascular signals — addressed in detail below — that drove the boxed warning. Per the FDA highlights, the only adverse reactions reported with EVENITY at ≥5% were arthralgia and headache.
| Adverse Event | Study 1 (vs placebo) | Study 2 (vs alendronate) | Clinical Note |
|---|---|---|---|
| Arthralgia | 13.1% vs 12.1% | 8.1% vs 9.6% | Most common adverse reaction; ~1 percentage point higher than placebo, but numerically lower than active comparator alendronate |
| Adverse Event | Study 1 (vs placebo) | Study 2 (vs alendronate) | Clinical Note |
|---|---|---|---|
| Headache | 6.6% vs 5.8% | 5.2% vs 5.5% | Second most common adverse reaction; reaches the FDA ≥5% reporting threshold |
| Muscle spasms | 4.6% vs 3.9% | 3.4% vs 4.0% | Modestly higher than placebo; similar to or below alendronate |
| Injection-site reactions (any) | 4.9% EVENITY vs 2.8% control (pooled) | Most common subtypes: injection-site pain (1.7% vs 1.3%) and erythema (1.4% vs 0.3%); led to discontinuation in 7 EVENITY (0.1%) vs 3 control (<0.1%) patients | |
| Edema, peripheral | 2.4% vs 1.9% | 1.7% vs 1.9% | Numerically similar between groups overall |
| Asthenia | 2.3% vs 2.2% | 2.5% vs 2.6% | Equivalent to control |
| Neck pain | 2.2% vs 1.5% | 1.7% vs 2.1% | Slightly higher than placebo in Study 1; similar to alendronate in Study 2 |
| Insomnia | 2.0% vs 1.9% | 1.7% vs 1.8% | Equivalent to control |
| Paresthesia | 2.0% vs 1.7% | 1.4% vs 1.7% | Numerically similar across groups |
| Hypersensitivity reactions (composite) | 6.5% EVENITY (364) vs 6.5% control (365) (pooled across both trials) | Includes rash 1.1% vs 0.9%, dermatitis 0.6% vs 0.8%, urticaria 0.4% vs 0.5%, angioedema <0.1% vs <0.1%, erythema multiforme <0.1% vs 0%. Although the overall composite rate was equal to control, individual cases of angioedema, dermatitis, and urticaria were judged related to EVENITY by investigators | |
Major Adverse Cardiac Events (MACE) — the central safety question
MACE was a positively adjudicated composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The two pivotal trials produced divergent results: no excess versus placebo in Study 1, but a significantly higher rate versus alendronate in Study 2. Both signals are reflected in the FDA boxed warning.
The mechanism for the disparity remains incompletely characterized. Possible contributors include the older, higher-risk Study 2 population (mean age 74 versus 71 in Study 1), the cardiovascular protective effects of alendronate biasing the comparator group, or a true, modest increase in cardiovascular events with romosozumab that was masked by a low-event placebo group in Study 1. Regulators in the US, Europe, and Canada considered the Study 2 finding sufficient to justify the boxed warning and the contraindication against initiation within 12 months of MI or stroke.
Other Serious Adverse Reactions
| Adverse Event | Incidence | Clinical Note |
|---|---|---|
| All-cause mortality | 0.8% vs 0.7% placebo (Study 1); 1.5% vs 1.1% alendronate (Study 2) | Numerical excess in Study 2 paralleled the MACE imbalance; no significant difference in Study 1 |
| Nonfatal serious adverse events (overall) | 9.1% vs 8.3% placebo (Study 1); 11.9% vs 13.3% alendronate (Study 2) | Slightly higher than placebo; lower than alendronate; reflects the older, sicker Study 2 population |
| Hypocalcemia (clinical events) | 2 EVENITY vs 1 control (across both trials) | Albumin-adjusted serum calcium <8.3 mg/dL: 14 (0.2%) EVENITY vs 10 (0.2%) control; no patient developed serum calcium <7.5 mg/dL. Nadir occurs by month 1 in patients with normal renal function. Risk markedly elevated in severe renal impairment / dialysis |
| Anaphylaxis or severe hypersensitivity | Rare; angioedema in 3 (<0.1%) EVENITY vs 3 (<0.1%) control; erythema multiforme in 1 EVENITY vs 0 control | Discontinue permanently if anaphylaxis or other clinically significant allergic reaction occurs; prior systemic hypersensitivity is a contraindication |
| Osteonecrosis of the jaw (ONJ) | 1 patient across both trials (~5,600 EVENITY-treated women) | Rare class effect of antiresorptives and antibody bone agents; risk increases with concomitant chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, or corticosteroids; pre-existing dental disease or invasive dental procedures are additional risks |
| Atypical femoral fracture | 1 patient across both trials | Causality not established; may be a class effect of agents that suppress bone turnover. Counsel patients to report new or unusual thigh, hip, or groin pain; evaluate radiographically and assess the contralateral femur |
| Trial | Discontinuation Rate | Most Common Reasons |
|---|---|---|
| Study 1 (FRAME, vs placebo, 12 months) | 1.1% vs 1.1% placebo | Equivalent withdrawal rates; arthralgia was the most common reason for discontinuation (5 EVENITY [0.1%] vs 6 placebo [0.2%]) |
| Study 2 (ARCH, vs alendronate, 12 months) | 1.2% vs 1.2% alendronate | Equivalent withdrawal rates between groups |
| Injection-site reactions (pooled) | 0.1% vs <0.1% | 7 EVENITY vs 3 control patients discontinued specifically for injection-site reactions |
Romosozumab is contraindicated as initiation therapy in any patient with MI or stroke within the preceding 12 months and should generally be avoided in patients with established or high-risk cardiovascular disease. Document a baseline cardiovascular history including coronary artery disease, prior MI or stroke, peripheral arterial disease, heart failure, atrial fibrillation, hypertension, diabetes, dyslipidemia, smoking, and family history of premature CAD. For patients with intermediate risk, the boxed warning instructs consideration of whether benefits outweigh risks. Monitor for new symptoms of MI or stroke at every clinic encounter during the 12-month course; permanently discontinue romosozumab if either event occurs and transition to an alternative anti-osteoporosis therapy.
Drug Interactions
As a humanized monoclonal antibody, romosozumab is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes or drug transporters. The FDA labelling lists no formal drug-drug interactions, and no dedicated drug-interaction studies have been performed. The relevant interaction profile is therefore limited to overlapping pharmacological effects on calcium homeostasis and bone, and to drugs that share class-level adverse-event risks (e.g., agents associated with osteonecrosis of the jaw).
Tertiary drug interaction resources may flag romosozumab against many cardiovascular drugs (statins, antihypertensives, anticoagulants) on the basis of the boxed warning rather than any pharmacokinetic interaction. These listings reflect background cardiovascular risk in the patient, not drug interactions in the conventional sense. There is no PK interaction with warfarin, direct oral anticoagulants, statins, beta-blockers, ACE inhibitors, ARBs, or calcium channel blockers; co-prescription is appropriate when clinically indicated.
Monitoring
Monitoring focuses on cardiovascular risk surveillance during the 12-month course, confirming biochemical safety before each dose, and confirming therapeutic response. Recommendations below combine FDA labelling guidance with current AACE/ACE 2020 and Endocrine Society 2020 (Shoback update) consensus.
-
Cardiovascular history & symptoms
Baseline; reassess at every monthly visit
Routine Document prior MI, stroke, CAD, peripheral arterial disease, heart failure, atrial fibrillation, hypertension, diabetes, dyslipidemia, smoking, and family history at initiation. At each monthly dose, screen for new chest pain, dyspnea, focal neurologic symptoms, or other signs of MI or stroke. Permanently discontinue romosozumab and switch to an alternative agent if MI or stroke occurs. -
Serum calcium (corrected)
Baseline; reassess at month 1; recheck monthly in patients with severe RI / dialysis
Routine Hypocalcemia is a contraindication and must be corrected before initiation. The serum calcium nadir occurs by month 1 in patients with normal renal function. Decreases below 8.3 mg/dL occurred in 0.2% of EVENITY-treated women in trials; no patient developed serum calcium below 7.5 mg/dL. Greater monitoring intensity is warranted in eGFR 15–29 mL/min/1.73 m² or dialysis. -
25-OH vitamin D
Baseline; periodic reassessment per individual risk
Routine Pivotal trials provided ≥600 IU vitamin D daily, with a one-time 50,000–60,000 IU loading dose for women with serum 25-OH vitamin D ≤40 ng/mL. Replete deficiency before initiation and continue daily supplementation throughout the 12-month course. -
Serum creatinine / eGFR
Baseline; reassess with intercurrent illness or new nephrotoxic exposure
Routine No dose adjustment based on renal function. eGFR 15–29 mL/min/1.73 m² or dialysis identifies patients at higher hypocalcemia risk who require closer biochemical monitoring and rigorous calcium / vitamin D supplementation. -
Bone mineral density (DEXA)
Baseline; at end of 12-month romosozumab course; then per follow-on therapy schedule
Routine Lumbar spine and total hip / femoral neck T-scores. BMD response to romosozumab is rapid — gains over placebo at 12 months were ~12.7% at the lumbar spine, 5.8% at the total hip, and 5.2% at the femoral neck in FRAME. After the 12-month course, BMD is maintained or further increased only with sequential anti-resorptive therapy. -
Bone turnover markers (P1NP, CTX)
Optional, baseline and as adherence/response check
Trigger-based P1NP rises sharply (peak ~145% above placebo at 2 weeks) then declines toward baseline by month 9; CTX falls (max ~55% below placebo at 2 weeks) and remains modestly suppressed at month 12. Markers are not required for routine care but can support clinical decisions about adherence or sequential therapy. -
Oral / dental examination
Baseline; before any invasive dental procedure
Routine Per FDA PI, a routine oral examination should be performed by the prescriber prior to initiation. Address active dental disease and consider deferring elective invasive dental procedures during the 12-month course where feasible. ONJ is rare (1 case across both pivotal trials) but the risk is real and is augmented by prior or concomitant antiresorptive exposure. -
Atypical femoral fracture surveillance
Throughout therapy; symptom-driven
Trigger-based Counsel patients to report new or unusual thigh, hip, or groin pain. Image both femurs (X-ray ± MRI) if atypical fracture is suspected; assess the contralateral femur if a fracture is confirmed. Interrupt therapy based on benefit-risk assessment. -
Injection-site assessment
At each monthly visit
Routine Inspect prior injection sites and rotate sites. Injection-site reactions occurred in 4.9% of EVENITY-treated patients (vs 2.8% control) and led to discontinuation in 0.1% — most commonly pain (1.7%) or erythema (1.4%).
Contraindications & Warnings
Romosozumab may increase the risk of myocardial infarction, stroke, and cardiovascular death. Romosozumab should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors. If a patient experiences a myocardial infarction or stroke during therapy, romosozumab should be discontinued.
The basis for this warning is the alendronate-controlled ARCH trial, in which positively adjudicated MACE occurred in 41 (2.0%) EVENITY-treated women versus 22 (1.1%) alendronate-treated women through 12 months (HR 1.87, 95% CI 1.11–3.14). The placebo-controlled FRAME trial did not show an excess (0.8% vs 0.8%, HR 1.03), but FDA, EMA, and Health Canada considered the ARCH signal sufficient to warrant the boxed warning.
Absolute Contraindications
- Hypocalcemia (uncorrected). Pre-existing hypocalcemia must be corrected before initiation. Romosozumab will further depress serum calcium during the first 1–2 months after initiation; the nadir typically occurs by month 1 in patients with normal renal function.
- Known systemic hypersensitivity to romosozumab or any product component. Reported reactions have included angioedema, erythema multiforme, and urticaria. Permanent discontinuation is required.
Use Not Recommended (Strong Caution)
- MI or stroke within the preceding 12 months. Per the FDA boxed warning, do not initiate.
- Pregnancy or women of reproductive potential. Romosozumab is not indicated in this population. Animal data show skeletal malformations at exposures ≥31× clinical and dose-dependent transfer to offspring during lactation.
- Pediatric patients. Safety and effectiveness have not been established.
Use With Caution
- Established cardiovascular disease or multiple cardiovascular risk factors outside the absolute 12-month exclusion window. The FDA labelling instructs prescribers to consider whether benefits outweigh risks; document a shared decision-making conversation. Alternative anti-osteoporosis options (denosumab, zoledronic acid, oral bisphosphonates) should be considered first in this group.
- Severe renal impairment (eGFR 15–29 mL/min/1.73 m²) or dialysis. Greater risk of hypocalcemia; monitor calcium more closely and supplement aggressively.
- Pre-existing dental disease, planned invasive dental procedures, or prior antiresorptive exposure. Higher risk of ONJ; perform routine oral examination before initiation; consider addressing dental disease before starting therapy.
- Active or planned major surgery during the 12-month course. Although no formal contraindication, the perioperative cardiovascular risk profile should be reviewed alongside the boxed warning.
Patient Counselling
Romosozumab is a healthcare-provider-administered injection given monthly for one year. Counselling priorities are very different from oral bisphosphonates: there are no fasting or upright requirements, but cardiovascular awareness, calcium and vitamin D supplementation, and the planned transition to a different drug after 12 months are essential.
Sources
- U.S. Food and Drug Administration / Amgen Inc. EVENITY (romosozumab-aqqg) injection — full prescribing information. Revised January 2026. Available via DailyMed: dailymed.nlm.nih.gov Primary source for the boxed warning, FDA-approved indications and limitations of use, dosing, contraindications, adverse-reaction Table 1, MACE adjudication results, and clinical study summaries cited throughout this monograph.
- U.S. Food and Drug Administration. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. FDA News Release, April 9, 2019. fda.gov Initial U.S. approval announcement under BLA 761062, summarizing the regulatory rationale and the boxed warning’s basis.
- Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532–1543. doi.org/10.1056/NEJMoa1607948 FRAME trial (NCT01575834) — pivotal placebo-controlled RCT in 7,180 postmenopausal women showing 73% reduction in new vertebral fractures at 12 months and 75% reduction at 24 months following transition to denosumab. Source for Study 1 efficacy and safety data.
- Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017;377(15):1417–1427. doi.org/10.1056/NEJMoa1708322 ARCH trial (NCT01631214) — pivotal alendronate-controlled RCT in 4,093 postmenopausal women at higher fracture risk showing 50% reduction in new vertebral fractures and 27% reduction in clinical fractures versus alendronate alone. Source for Study 2 efficacy and the MACE imbalance that drives the boxed warning.
- Lewiecki EM, Blicharski T, Goemaere S, et al. A phase III randomized placebo-controlled trial to evaluate efficacy and safety of romosozumab in men with osteoporosis. J Clin Endocrinol Metab. 2018;103(9):3183–3193. doi.org/10.1210/jc.2017-02163 BRIDGE trial — Phase 3 placebo-controlled trial in 245 men with osteoporosis (12 months). Demonstrated significant BMD increases at the lumbar spine and total hip and a numerical cardiovascular SAE imbalance (4.9% vs 2.5%). Romosozumab is not FDA-approved for men in the United States, although it is approved for men in some non-US jurisdictions.
- Lewiecki EM, Dinavahi RV, Lazaretti-Castro M, et al. One year of romosozumab followed by two years of denosumab maintains fracture risk reductions: results of the FRAME extension study. J Bone Miner Res. 2019;34(3):419–428. doi.org/10.1002/jbmr.3622 FRAME extension showing maintained fracture-risk reduction with 24 months of denosumab follow-on after a 12-month romosozumab course.
- Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists / American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis — 2020 update. Endocr Pract. 2020;26(Suppl 1):1–46. Executive summary: doi.org/10.4158/GL-2020-0524 Risk-stratified treatment selection for postmenopausal osteoporosis; positions romosozumab among first-line options for women at very high fracture risk.
- Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105(3):587–594. doi.org/10.1210/clinem/dgaa048 2020 update of the Endocrine Society guideline incorporating romosozumab; recommends romosozumab as a treatment option for postmenopausal women at very high osteoporotic fracture risk, with cardiovascular risk informing patient selection.
- Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595–1622. doi.org/10.1210/jc.2019-00221 Original 2019 Endocrine Society pharmacological management guideline (subsequently updated in 2020 to add romosozumab).
- Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(1):16–35. doi.org/10.1002/jbmr.2708 ASBMR consensus relevant to the population most likely to be candidates for sequential anabolic-then-antiresorptive therapy following long-term bisphosphonate exposure.
- Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26(1):19–26. doi.org/10.1002/jbmr.173 First-in-human Phase 1 study of romosozumab (then AMG 785) demonstrating proof-of-mechanism: dose-dependent increases in bone formation markers and decreases in resorption markers.
- McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370(5):412–420. doi.org/10.1056/NEJMoa1305224 Phase 2 dose-finding RCT establishing the 210 mg monthly subcutaneous regimen used in the Phase 3 program.
- Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3–23. doi.org/10.1002/jbmr.2405 International consensus on ONJ definition, risk factors, and dental management — relevant to the rare ONJ class effect of bone-targeted antibody and bisphosphonate therapies.
- Cosman F, Crittenden DB, Ferrari S, et al. Romosozumab FRAME study: a post hoc analysis of the role of regional background fracture risk on nonvertebral fracture outcome. J Bone Miner Res. 2018;33(8):1407–1416. doi.org/10.1002/jbmr.3439 Post hoc analysis exploring the failure to demonstrate a statistically significant nonvertebral fracture reduction in FRAME, attributing it largely to a low background nonvertebral fracture rate in Latin American sites.
- Bovijn J, Krebs K, Chen CY, et al. Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics. Sci Transl Med. 2020;12(549):eaay6570. doi.org/10.1126/scitranslmed.aay6570 Mendelian randomization and clinical-trial meta-analysis suggesting that sclerostin inhibition may causally increase cardiovascular event risk; provides mechanistic context for the FDA boxed warning.
- Cummings SR, McCulloch C. Explanations for the difference in rates of cardiovascular events in a trial of alendronate and romosozumab. Osteoporos Int. 2020;31(6):1019–1021. doi.org/10.1007/s00198-020-05379-z Editorial discussion of the divergent FRAME and ARCH cardiovascular signals, considering active-comparator effects and population differences as potential explanations for the boxed warning.