Treatment with zoledronate subsequent to denosumab in osteoporosis 2
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1
- 试验地点
- 2
- 主要终点
- Change in lumbar spine BMD after 12 and 36 months.
研究概览
简要总结
The aims of ZOLARMAB2 are fourfold. First, we want to investigate if multiple infusions of zoledronate can prevent the rebound activation of bone turnover and the subsequent bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronate at fixed time-points after the last injection of denosumab or when bone turnover is increased. Second, we want to investigate if bone loss will resume after controlling the rebound activation of bone turnover during the first year after denosumab discontinuation and if this can be prevented by yearly infusions of zoledronate. Third, we want to investigate the underlying pathophysiological mechanisms by investigating biochemical markers, oste-oclast and osteoblast activation signals in the bone and bone marrow, and the pool of preosteoclasts/mature osteoclasts before and after treatment with zoledronate. Fourth, we want to investigate the effect of denosumab discontinuation on muscle mass and muscle strength and on insulin sensitivity.
研究设计
- 分配方式
- Randomized
- 主要目的
- The second part
- 盲法
- Double (Monitor, Subject, Investigator)
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Postmenopausal women (postmenopausal for at least two years)
- •Age ≥ 40 years
- •Treatment for at least two years with denosumab
- •Last denosumab injection less than five months ago
- •At least 2 lumbar vertebrae that can be evaluated by DXA
排除标准
- •Low-energy vertebral fracture within the last ten years
- •Treatment with other bisphosphonates (risedronate, ibandronate) for more than three years prior to denosumab treatment within the last five years
- •Diabetes Mellitus
- •Ongoing treatment with systemic glucocorticoids
- •Estimated glomerular filtration rate (eGFR) ≤ 35 mL/min
- •Contraindications for zoledronate according to the SPC
- •Unable to read and understand Danish
- •Metabolic bone disease (for example osteogenesis imperfecta, Paget's disease of bone)
- •Hormone replacement therapy
- •Active cancer within the last 5 years with the exception of basal cell skin cancer
- •Multiple low-energy vertebral fractures (>= 3) at any time
- •Low-energy hip fracture within the last 12 months
- •BMD T-score < -2.0 (lumbar spine, total hip or femoral neck)
- •Zoledronate treatment for more than three years prior to denosumab treatment within the last ten years
- •Alendronate treatment for more than three years prior to denosumab treatment within the last five years or for more than five years within the last the years
结局指标
主要结局
Change in lumbar spine BMD after 12 and 36 months.
Change in lumbar spine BMD after 12 and 36 months.
The proportion of patients who fails to maintain BMD (total hip, femoral neck and spine) after 12 months. Failure is defined as ≥ 3 % BMD loss at the lumbar spine or ≥ 5 % BMD loss at the femoral neck or total hip.
The proportion of patients who fails to maintain BMD (total hip, femoral neck and spine) after 12 months. Failure is defined as ≥ 3 % BMD loss at the lumbar spine or ≥ 5 % BMD loss at the femoral neck or total hip.
次要结局
- Changes in total hip and femoral neck BMD after 12 and 36 months.
- Changes in trabecular bone volume fraction (bone volume/tissue volume, BV/TV) and cortical porosity measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius and tibia after 12 and 36 months.
- Changes in CTX and procollagen type I N-terminal propeptide (PINP) after 3, 6, 12, 24 and 36 months.
- Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) after 12 and 36 months or by spinal x-ray if clinical suspicion of vertebral fracture.
- Serum RANKL/OPG, tartrate-resistant acid phosphatase type 5b (TRAcP-5b), sclerostin and Dickkopf-1 (Dkk-1) at 0, 1, 3, 6 and 12 months
- Molecular bone histology of accumulating osteoclast activation sites and pre-osteoclasts as well as single-nucleus transcriptomics on jamshidi biopsies at baseline in a total of 100 patients from groups 1 and 2 and in up to 15 participants in groups 1 and 2 at month 3 with a strong rebound response (p-CTX > 0.6 ug/l).
- Osteoclasts differentiation, fusion, function, and response to ZOL in cultures derived from peripheral blood at baseline from groups 1 and 2. 30 patients will be recruited from each group, hence 60 patients.
- Epigenetic marker analysis with special focus on genes involved in osteoclast activation, differentiation, fusion, function and response to ZOL. Samples collected at baseline from all participants.
- Muscle mass assessed by whole-body DXA and muscle strength assessed by handgrip strength and muscle strength over the knee and elbow joints. A total of 100 patients from groups 1 and 2 will be investigated at base-line month 3 and 12.
- Insulin sensitivity assessed by Hb1Ac, HOMA-IR and OGTT. Accumulation of advanced glycation end products (AGEs) will also be evaluated.
研究者
Anne Sophie Sølling
Scientific
Aarhus University Hospital