Treatment with zoledronate subsequent to denosumab in osteoporosis 2

The primary objective of the study titled "Treatment with zoledronate subsequent to denosumab in osteoporosis 2" is to evaluate the efficacy of **zoledronate** in preventing rebound activation of bone turnover and subsequent bone loss in patients with **osteoporosis** who have previously been treated with denosumab. This is clinically relevant as it addresses the potential for bone loss following the discontinuation of denosumab, a common concern in osteoporosis management. The study aims to determine if multiple infusions of zoledronate at fixed time-points or at times of increased bone turnover can effectively mitigate this risk. Additionally, the study seeks to assess whether bone loss resumes after controlling the initial rebound activation within the first year post-denosumab discontinuation and if annual zoledronate infusions can prevent this. The investigation also includes an analysis of the underlying pathophysiological mechanisms by examining biochemical markers, osteoclast and osteoblast activation signals, and the pool of preosteoclasts/mature osteoclasts before and after zoledronate treatment. Furthermore, the study aims to explore the effects of denosumab discontinuation on muscle mass, muscle strength, and insulin sensitivity.

The clinical trial focuses on **osteoporosis** and involves a study population consisting exclusively of postmenopausal women who have been postmenopausal for at least two years. Participants are aged 40 years and older and have been treated with denosumab for a minimum of two years, with their last denosumab injection administered less than five months prior to the study. The trial does not include male subjects or vulnerable populations. Participants must have at least two lumbar vertebrae that can be evaluated by DXA. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the inclusion of individuals who have specific treatment histories and physiological characteristics relevant to the study's objectives.

The clinical trial is designed to evaluate the efficacy of **zoledronic acid** in preventing bone loss in postmenopausal women with **osteoporosis** who have previously been treated with denosumab. The study is structured in two parts: the first part is a randomized, open-label, interventional study involving 200 participants, while the second part is a 2-year randomized, double-blind, controlled study. The trial aims to assess whether yearly infusions of zoledronic acid can prevent the rebound activation of bone turnover and subsequent bone loss after discontinuation of denosumab. The trial is expected to last until January 2027, with recruitment starting in February 2023.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as being postmenopausal for at least two years, aged 40 years or older, and having received denosumab treatment for at least two years. The inclusion visit will also ensure that the last denosumab injection was administered less than five months prior and that at least two lumbar vertebrae can be evaluated by DXA. Follow-up visits will occur at regular intervals to monitor changes in bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck, as well as to assess secondary endpoints such as trabecular bone volume fraction, cortical porosity, and biochemical markers. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of all primary and secondary endpoints.

The expected length of participant involvement is up to 36 months, with conditions for early termination including significant adverse events or failure to adhere to the study protocol. The primary endpoints include changes in lumbar spine BMD after 12 and 36 months and the proportion of patients who fail to maintain BMD after 12 months. Secondary endpoints encompass a range of biochemical and physiological assessments, including changes in CTX and procollagen type I N-terminal propeptide, muscle mass and strength, and insulin sensitivity. The study will utilize a placebo control, with participants in groups 1 and 3 receiving zoledronic acid and those in groups 2 and 4 receiving a placebo, ensuring a robust evaluation of the treatment's efficacy.

The clinical trial involves the administration of **Zoledronic Acid**, marketed under the name Zoledronate EG 5mg/100ml Infusionslösung. This experimental medication is provided in the form of a **solution for infusion**. The active substance, **zoledronic acid**, is of chemical origin and is classified under the ATC code M05BA08. The medication is administered via **intravenous infusion**. The maximum daily and total dose is 5 mg, with a treatment period extending up to 36 months. The infusion is intended to be administered at specific intervals, either at fixed time points after the last injection of denosumab or when an increase in bone turnover is detected. The study aims to evaluate the efficacy of zoledronic acid in preventing rebound activation of bone turnover and subsequent bone loss in patients previously treated with denosumab.

In addition to the experimental treatment, the study utilizes a non-experimental treatment in the form of a **placebo**, which is 100 mL of isotonic saline. This placebo is used to maintain the study's integrity by providing a control for comparison against the active treatment. The isotonic saline does not contain any active pharmaceutical ingredients and serves as a standard comparator to assess the effects of the experimental medication. The administration route and frequency for the placebo are designed to match those of the zoledronic acid infusions to ensure consistency in the study protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change in lumbar spine bone mineral density (BMD) after 12 and 36 months, and the proportion of patients who fail to maintain BMD at the total hip, femoral neck, and spine after 12 months. Failure is defined as a loss of 3% or more in lumbar spine BMD or 5% or more in femoral neck or total hip BMD.

Secondary endpoints will evaluate additional parameters such as changes in total hip and femoral neck BMD after 12 and 36 months, and changes in trabecular bone volume fraction and cortical porosity using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius and tibia. Biochemical markers, including CTX and procollagen type I N-terminal propeptide (PINP), will be measured at multiple timepoints: 3, 6, 12, 24, and 36 months. Morphometric vertebral fractures will be assessed by vertebral fracture assessment (VFA) or spinal x-ray if clinically indicated.

Additional assessments include serum levels of RANKL/OPG, tartrate-resistant acid phosphatase type 5b (TRAcP-5b), sclerostin, and Dickkopf-1 (Dkk-1) at baseline and at 1, 3, 6, and 12 months. Molecular bone histology and single-nucleus transcriptomics will be conducted on jamshidi biopsies at baseline and at month 3 in a subset of participants. Osteoclast differentiation and function will be studied in cultures derived from peripheral blood at baseline. Epigenetic marker analysis will focus on genes involved in osteoclast activity. Muscle mass and strength will be evaluated using whole-body DXA and handgrip strength tests, while insulin sensitivity will be assessed through Hb1Ac, HOMA-IR, and OGTT, along with the evaluation of advanced glycation end products (AGEs).