Optimal Drug Sequencing for Postmenopausal Osteoporosis Treatment

In a recent study published in eClinicalMedicine, researchers assessed the efficacy and safety of various sequential therapies for the long-term management of postmenopausal osteoporosis (PMO) in women.

Background

Osteoporosis (OP) affects postmenopausal women, leading to increased bone fragility and fracture risk due to low bone mineral density (BMD). By 2030, PMO could impact around 13.2 million American women over 50.

Most people with OP survive for a long time; nevertheless, they are regularly treated. As a result, guidelines urge that OP patients receive therapies sequentially.

However, the best sequential order in which anti-resorptive medicines (AR) and anabolic agents (AB), which are currently employed for OP treatment, should be administered is unknown.

As a result, there is a need for strong evidence to guide and support the therapeutic choice of various sequential treatments for OP.

About the study

In the current investigation, researchers did a thorough search on ClinicalTrials.gov, EMBASE, PubMed, Web of Science, and the Cochrane Library from the beginning to September 19, 2023, to discover randomized clinical trials (RCTs) including consecutive OP treatments and reporting PMO outcomes.

Next, they did a network meta-analysis (NMA) utilizing the multivariate random effects technique to analyze five successive interventions of PMO: i) ABtAR; ii) ARtAAR; iii) ARtAB; iv) ABtC; and v) ARtC and used the surface under the cumulative ranking curve (SUCRA) to evaluate outcomes.

The first intervention group changed from an AB to an AR, the second from one AR to another AR regimen, the third from an AR to an AB treatment, and the fourth and fifth from an AB to an AB and AR combined regimen and from an AR to a combined regimen, respectively.

The study’s endpoints included vertebral fracture risk, % change in BMD in various body areas (e.g., hips), and all safety measures after switching treatments.

Finally, the team used the Confidence in Network Meta-Analysis (CINeMA) framework to determine the certainty of the evidence.

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) standards.

Results
This investigation comprised 19 RCTs published between 2003 and 2021, totaling 18,416 participants with an average age of 71.2 years.

ARtC significantly reduced the risk of vertebral fractures compared to other therapies, with a risk ratio (RR) of 0.11 and 95% confidence intervals (CIs). ARtC was also the most effective medication at preventing vertebral fractures in stage two (SUCRA 81.5%).

Interventions ABtAR and ARtAB in the second stage also significantly reduced the incidence of vertebral fractures, with ABtAR best suited to reducing total fractures (SUCRA: 94.3%).

The ABtC and ABtAR groups also demonstrated greater improvement in lumbar spine BMD. ARtAAR induced the greatest substantial change in lumbar spine BMD, with an SUCRA of 69.4%.

Furthermore, ARtAAR was found to be more effective than other therapies in improving femoral neck BMD (77.3% likelihood) and total hip BMD (96.1% probability).

The ABtAR group had the lowest incidence of stage two adverse events (AEs) (SUCRA 83.2%) as compared to the ARtAAR and monotherapy groups. The scientists found no difference in safety outcomes in other comparisons. Furthermore, ABtC (SUCRA 86.2%) had the fewest discontinuations, indicating a high tolerability.

Conclusions
This study is a comprehensive data synthesis of sequential therapies for women with PMO, with strong evidence supporting their sensible clinical usage.

Following therapy switching, ABtAR and ARtAAR were linked with significant fracture reduction and BMD improvements as compared to monotherapies.

Combination treatment following AB, known as ABtC, only protected the lumbar spine since it improved the percentage change in BMD and reduced the incidence of vertebral fractures.

ARtAB reduced non-vertebral fractures and increased lumbar spine BMD relative to non-sequential regimens.

Furthermore, ARtC rated best in terms of minimizing the incidence of vertebral fractures in the second stage, according to the NMA. However, more research on ARtC and ARtAB is required to completely understand their efficacy.

Overall, the study findings may be useful for patients, caregivers, physicians, and legislators as they inform future clinical practice, guidelines, and legislation regarding the sequential treatment of osteoporosis.

For more information: Safety and efficacy of sequential treatments for postmenopausal osteoporosis: a network meta-analysis of randomised controlled trials, eClinicalMedicine, https://doi.org/10.1016/j.eclinm.2024.102425