Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis

Study Overview
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Brief Summary
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Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents recruitment and differentiation of mature osteoclasts. Treatment markedly decrease bone resorption and fracture risk, and many patients will reach osteopenic bone mineral density (BMD) levels on treatment with denosumab. The treatment effect on bone turnover and BMD has, however, been demonstrated to be reversible. This study will show if the bone mass can be maintained by administrating zoledronic acid and if timing of the first dose of zoledronic acid after last dose of denosumab matters.

Detailed Description
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Background: Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents recruitment and differentiation of osteoclasts. Treatment decreases bone resorption and fracture risk. After discontinuation, however, bone resorption increases and the bone mass gained during 2 years of therapy is lost within 1 year. At present denosumab treatment is considered to be life-long. Aim: To investigate if infusion of zoledronic acid can prevent increases in bone turnover and bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronic acid at six or nine months after the last injection of denosumab or when bone turnover is increased. Methods: A randomized open label, interventional study in 60 patients investigating if treatment with zoledronic acid prevents bone loss after denosumab treatment when administrated six or nine months after last injection of deno-sumab or when bone turnover is increased. Forty patients will be allocated to the two intervention groups and 20 patients will be followed without treatment for up to 12 months after the last denosumab treatment. The patients in the observation group and the nine months group will be monitored monthly and if s-carboxy-terminal collagen cross-links (s-CTX) increases above 1.26ug/l (50% above the normal range for postmenopausal women and elderly men) infusion of zoledronic acid will be administered. Furthermore, a DXA scan (lumbar spine and hip sites) will be performed after three months in the observation group. If BMD has decreased more than 5% at any site, infusion of zoledronic acid will be administered. Finally, if a patient in the 9 months group or the in the observation group suffers an osteoporotic clinical vertebral or hip fracture, infusion of zoledronic acid will be administered. The patients will be monitored with DXA 6, 12 and 24 months after the infusion of zoledronic acid. Zoledronic acid will be re-administered if BMD has decreased more than 5% at the lumbar spine, total hip or femoral neck. If s-CTX in-creases above 1.26 ug/l during the 2nd year a second infusion of zoledronic acid will be administered. Perspectives: Many patients will reach osteopenic BMD levels on treatment with denosumab, however the treatment effect on bone turnover and BMD has been demonstrated to be reversible and it is therefore important to find out if denosumab treatment can be discontinued and bone mass maintained by other measures. This study will show if the bone mass can be maintained by administrating zoledronic acid and if timing of the first dose of zoledronic acid after last dose of denosumab matters. If bone loss can be prevented by zoledronic acid expenses on otherwise life-long denosumab treatment can be saved and long-term side effects of denosumab (atypical femur fractures and osteone-crosis of the jaw) can be prevented.

Official Title
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Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Zoledronic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women (postmenopausal for at least two years) Men above 50 years Treatment for at least two years with denosumab Last denosumab injection less than five months ago Exclusion Criteria: Low-energy vertebral fracture at any time Low-energy hip fracture within the last 12 months BMD T-score < -2,5 (lumbar spine, total hip or femoral neck) Alendronate treatment for more than three years prior to denosumab treatment Ongoing treatment with glucocorticoids Metabolic bone disease Hormone replacement therapy Cancer Estimated glomerular filtration rate (eGFR) < 35 mL/min Allergy to zoledronic acid Hypocalcaemia Contraindications for zoledronic acid according to the SPC

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 6-month group<br>Zoledronic acid will be administered at study day 0. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered. | Drug: Zoledronic Acid<br>* Intravenous infusion of 5 mg zoledronic acid<br>* Other names: Zoledronate;|
| Active Comparator: 9-months group<br>Zoledronic acid will be administered depending on increase in s-CTX (above 1.26 ug/l) or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 3. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered. | Drug: Zoledronic Acid<br>* Intravenous infusion of 5 mg zoledronic acid<br>* Other names: Zoledronate;|
| Active Comparator: Observation group<br>Zoledronic acid will be administered depending on increase in s-CTX (above 1.26 ug/l), decrease in BMD (more than 5% at any site), or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 6. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered. | Drug: Zoledronic Acid<br>* Intravenous infusion of 5 mg zoledronic acid<br>* Other names: Zoledronate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lumbar Spine BMD From Baseline to 6 Months After the Zoledronic Acid Infusion. | Change in lumbar spine BMD from baseline to 6 months after the zoledronic acid infusion. | baseline to 6 months after the zoledronic acid infusion | 
| Number of Participants Who Fail to Maintain BMD | Failure is defined as ≥ 3 % BMD loss at the lumbar spine | 2 years after the first ZOL treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in BMD From Baseline to One Year After the Zoledronic Acid Infusion. | Changes in lumbar spine BMD from baseline to one year after the zoledronic acid infusion. | from baseline to one year after the zoledronic acid infusion | 
| Changes in BMD From Baseline to Two Years After the Zoledronic Acid Infusion. | Changes in lumbar spine BMD from baseline to two years after the zoledronic acid infusion. | from baseline to two years after the zoledronic acid infusion. | 
| Changes in Cortical Porosity Measured by High-resolution Peripheral Quantitative Computed Tomography (HR-pQCT) Scan at the Radius and Tibia From Baseline to One Year After the Zoledronic Acid Infusion. | Changes in cortical porosity measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) scan at the radius and tibia from baseline to one year after the zoledronic acid infusion. | from baseline to one year after the zoledronic acid infusion. | 
| Changes in p-CTX From Baseline to Six Months After the Zoledronic Acid Infusion. | Changes in p-CTX from baseline to six months after the zoledronic acid infusion. | from baseline to six months after the zoledronic acid infusion. | 
| Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion. | Changes in p-CTX from baseline to 12 months after the zoledronic acid infusion. | from baseline to 12 months after the zoledronic acid infusion. | 
| Morphometric Vertebral Fractures Assessed by Vertebral Fracture Assessment (VFA) One and Two Years After the Zoledronic Acid Infusion. | Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) one and two years after the zoledronic acid infusion. | one and two years after the zoledronic acid infusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Denosumab, Bone turnover markers, Bone mineral density