Highlights
The LIDA trial yielded several critical insights for the management of postmenopausal osteoporosis:
- A 3-month abbreviated course of romosozumab followed by 9 months of denosumab was non-inferior to the standard 12-month romosozumab regimen regarding changes in total hip bone mineral density (BMD).
- The mean 12-month change in total hip BMD was 5.7% in the 3-month group compared to 6.0% in the 12-month group, comfortably meeting the non-inferiority threshold.
- Safety outcomes and adverse events were balanced between the two treatment arms, with no new safety signals identified.
- These findings suggest that the therapeutic benefit of romosozumab is largely front-loaded, supporting the potential for shorter, more cost-effective treatment durations.
Background: The Challenge of Postmenopausal Osteoporosis
Postmenopausal osteoporosis remains a formidable challenge in clinical medicine, characterized by decreased bone mass and microarchitectural deterioration, leading to an increased risk of fragility fractures. These fractures are associated with significant morbidity, loss of independence, and increased mortality. While bisphosphonates and other anti-resorptive agents have long been the cornerstone of therapy, patients at very high risk for fracture often require more potent intervention.
Romosozumab, a humanized monoclonal antibody that binds to and inhibits sclerostin, represents a paradigm shift in osteoporosis pharmacology. By inhibiting sclerostin, romosozumab exerts a dual effect: it increases bone formation (an anabolic effect) and, to a lesser extent, decreases bone resorption (an anti-resorptive effect). However, the anabolic effect of romosozumab is known to be transient, typically waning after the first few months of administration. Furthermore, the standard 12-month course is associated with high financial costs, the requirement for monthly clinical visits, and ongoing concerns regarding a potential cardiovascular risk profile.
Study Design: The LIDA Trial
The LIDA trial was a 12-month, prospective, open-label, randomized, controlled, non-inferiority trial designed to evaluate whether a shorter course of romosozumab could achieve similar results to the standard duration. The study was conducted at a single academic medical center in the United States and enrolled 50 postmenopausal women at high risk of fracture.
Intervention and Comparators
Participants were randomly assigned into two groups:
- 3-month ROMO Group: Received 210 mg of romosozumab subcutaneously every month for 3 months, followed by 60 mg of denosumab subcutaneously every 6 months for the remaining 9 months.
- 12-month ROMO Group: Received 210 mg of romosozumab subcutaneously every month for the full 12-month duration.
Endpoints and Analysis
The primary endpoint was the percentage change in total hip bone mineral density (BMD) from baseline to 12 months. The researchers established a non-inferiority threshold of 2%. Analysis was performed on a modified intention-to-treat basis, including all participants who completed at least one post-baseline visit.
Key Findings and Results
Between March 2022 and May 2023, 188 participants were screened, with 50 undergoing randomization. The study population had a mean age of 69.6 years (SD 4.5), reflecting a cohort at significant risk for osteoporotic complications.
Primary Outcomes: Bone Mineral Density
The results confirmed the non-inferiority of the abbreviated regimen. At the 12-month mark, the mean increase in total hip BMD was 5.7% (SD 3.3) in the 3-month ROMO group and 6.0% (SD 3.2) in the 12-month ROMO group. The difference between the groups was well within the pre-specified 2% non-inferiority margin. This suggests that the majority of the BMD gains attributable to romosozumab occur early in the treatment course, and that transitioning to a potent anti-resorptive like denosumab can effectively maintain or continue those gains.
Secondary Outcomes and Safety
The safety profile of both regimens was consistent with previous clinical trials. Adverse events reported included back pain, cough, fatigue, headache, joint pain, muscle cramps, palpitations, and injection site reactions. These events were balanced across both groups, and no significant differences in the frequency or severity of side effects were observed between the 3-month and 12-month cohorts.
Expert Commentary and Mechanistic Insights
The LIDA trial provides compelling evidence for the “anabolic window” theory in sclerostin inhibition. Sclerostin is a natural inhibitor of the Wnt signaling pathway in osteoblasts. When romosozumab blocks sclerostin, it triggers a surge in bone formation. However, compensatory mechanisms in the bone microenvironment eventually dampen this anabolic response, leading to a plateau in formation markers while the anti-resorptive effect persists. By utilizing romosozumab for only three months, clinicians may be capturing the peak anabolic phase before the drug’s incremental benefit begins to diminish.
Clinical Implications
From a health policy and patient-centered perspective, these results are significant. Romosozumab is expensive, and reducing the course by nine months could lead to substantial cost savings for healthcare systems and patients. Additionally, reducing the number of injections from twelve to three (plus denosumab) significantly lowers the burden of treatment and may improve long-term adherence.
Limitations
While the results are promising, the LIDA trial was a small, single-center study (n=50). Larger, multi-center trials are necessary to confirm these findings across more diverse populations and to assess long-term fracture reduction outcomes, which remains the gold standard for osteoporosis therapy. Furthermore, the open-label nature of the trial introduces the potential for bias, although BMD measurements provide an objective endpoint.
Conclusion
In postmenopausal women at high risk of fracture, a 3-month course of romosozumab followed by denosumab is non-inferior to the standard 12-month romosozumab regimen in increasing total hip BMD. This abbreviated approach offers a potential pathway to increase the accessibility and affordability of one of the most effective osteoporosis therapies available today. Clinicians should monitor subsequent larger-scale trials to see if this strategy becomes the new standard of care for high-risk patients.
Funding and Trial Registration
This study was funded by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases and the US National Center for Advancing Translational Science. The trial is registered at ClinicalTrials.gov, NCT05010590.
References
Leder BZ, Ramchand SK, Jordan M, Ryan S, Patnaik A, Lee H, Tsai JN. 3 months vs 12 months of romosozumab for postmenopausal osteoporosis (LIDA): an open-label, non-inferiority, randomised controlled trial. Lancet Diabetes Endocrinol. 2026 Mar;14(3):216-222. doi: 10.1016/S2213-8587(25)00319-5. Epub 2026 Jan 29. PMID: 41621431.
