Evaluation of Zoledronic Acid Monohydrate Efficacy Following Denosumab Discontinuation in Postmenopausal Osteoporosis: A Biomarker-Driven Versus Standardized Approach

The primary objective of this study is to compare the 1-year lumbar clinical and **densitometric** efficacy of biomarkers-driven zoledronic acid (ZOL) treatment versus standardized ZOL treatment following denosumab withdrawal in postmenopausal osteoporosis. This is clinically relevant as it aims to determine the most effective strategy for maintaining bone density and reducing fracture risk in patients transitioning off denosumab, a common treatment for osteoporosis.

Secondary objectives include:

• Comparing the 1-year hip densitometric efficacy of biomarkers-driven ZOL treatment versus standardized ZOL treatment.
• Assessing the 2-year densitometric efficacy of these treatment strategies.
• Evaluating the 1-year and 2-year biological efficacy of the treatments.
• Comparing the 1-year and 2-year anti-fracture efficacy.
• Assessing the 1-year and 2-year tolerance of the treatments.
• Comparing the use of a second ZOL infusion in biomarkers-driven versus standardized treatment approaches.

The clinical trial focuses on **postmenopausal osteoporosis** and involves a study population exclusively comprising women aged 18 years and older. The participants are specifically those who have been treated with denosumab for a minimum of two years and have reached a decision for denosumab withdrawal due to achieving therapeutic targets, such as no fractures during treatment, no new risk factors, and no significant bone mineral density decrease. The trial does not include male subjects or vulnerable populations. Participants are required to have a history of severe fracture or a femoral or lumbar T-score of ≤ -2.5 prior to denosumab initiation. All participants must provide free, informed, and written consent and be affiliated with or beneficiaries of the French social security scheme. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **zoledronic acid** treatment strategies following the discontinuation of denosumab in patients with postmenopausal osteoporosis. This study is a randomized, double-blind, controlled trial, aiming to compare biomarker-driven zoledronic acid treatment with standardized treatment over a one-year period. The trial is expected to commence recruitment on October 1, 2024, and conclude by April 1, 2029. Participants will be involved for a duration of up to two years, with the primary endpoint being the maintenance of lumbar bone mineral density (BMD) as assessed by dual-energy x-ray absorptiometry (DXA) after one year of treatment.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, previous treatment with denosumab, and specific BMD thresholds. Following successful screening, participants will be randomized into one of the treatment groups. Regular follow-up visits will be scheduled to monitor BMD, bone turnover markers, and the occurrence of any fractures or adverse events. The end-of-study visit will occur at the two-year mark, where final assessments will be conducted to evaluate the long-term effects of the treatment strategies.

Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial will also assess secondary endpoints, including changes in hip BMD, bone turnover markers, and the incidence of vertebral and peripheral fractures over the study period. The study is categorized as a low-intervention phase IV trial, focusing on optimizing treatment strategies for postmenopausal osteoporosis management.

The clinical trial involves the administration of **zoledronic acid monohydrate** as the experimental medication. The product used is "ACIDE ZOLEDRONIQUE SANDOZ 5 mg/100 ml, solution for perfusion," which is a **solution for infusion**. The active substance, **zoledronic acid monohydrate**, is of chemical origin. The pharmaceutical form is a solution specifically designed for infusion, and it is administered via the infusion route. The maximum daily dose is 50 mg/l, with a total maximum dose of 50 mg/l. The treatment period is limited to a maximum of one year. The product is not a pediatric formulation and is classified under the ATC code M05BA08, indicating its use in bone diseases. The administration of the drug is monitored to ensure compliance with the dosing schedule.

In this study, the experimental treatment is compared against a standardized treatment regimen following the withdrawal of denosumab in postmenopausal osteoporosis. The trial aims to evaluate the efficacy of a biomarker-driven zoledronic acid treatment strategy versus a standardized approach. No placebo or additional comparator treatments are specified in the trial data. The study focuses on the clinical and densitometric outcomes over a one-year period, with particular attention to lumbar spine efficacy. Compliance with the treatment protocol is monitored throughout the study to ensure accurate assessment of the treatment's efficacy.

Efficacy in the clinical trial titled "Strategies for zoledronic acid post-denosumab discontinuation in postmenopausal osteoporosis" will be assessed through both primary and secondary endpoints. The primary endpoint focuses on the proportion of patients who fail to maintain lumbar bone mineral density (BMD), as assessed by dual-energy x-ray absorptiometry (DXA) after one year of treatment with **zoledronic acid**. A failure is defined as a change in BMD that is less than the least significant change of 0.03 g/cm² or the occurrence of an additional vertebral fracture during the first year.

Secondary endpoints include the proportion of patients who fail to maintain hip BMD after one year, with the same least significant change threshold of 0.03 g/cm². Additionally, changes in hip and lumbar BMD from baseline to one year, and from year one to year two, will be evaluated. The trial will also assess changes in bone turnover markers, such as crosslaps, bone alkaline phosphatase, osteocalcin, amino-terminal propeptide of type 1 procollagen, TRAP5b, dickkopf 1, and sclerostin, at year one and year two. The number of morphometric vertebral fractures, clinical vertebral fractures, and clinical peripheral fractures will be recorded at both year one and year two. Furthermore, the trial will monitor the number of adverse events and serious adverse events, as well as the proportion of patients requiring a second infusion of zoledronic acid across the treatment groups.