A Clinical Trial to Evaluate Efficacy of Once or Twice ZOledronic Acid After Different Duration of denOsumMab Administration in Postmenopausal Women With Osteoporosis (ZOOM Study)

Study Overview
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Brief Summary
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Denosumab(Dmab) is a monoclonal antibody that inhibits the receptor-activator of nuclear factor kappa-B ligand. It improves bone density and reduces fractures by inhibiting osteoclast recruitment and differentiation. Although the FREEDOM trial showed Dmab increase bone mineral density for ten years, the effect was reversible. When Dmab is discontinued, the rebound phenomenon, the bone mineral density returns to the pre-treatment value, and multiple vertebral fractures may occur. Recently, a guideline to administer bisphosphonates sequentially when Dmab is discontinued has been published. In several studies, Zoledronic acid prevented bone loss after denosumab discontinuation with a single administration in Dmab short-term(less than 2.5years) users, but in Dmab long-term(more than 2.5years) users, zoledronic acid did not fully prevent loss of BMD. Our study tried to evaluate that ZOL administration twice for six months apart in long-term Dmab users is not inferior to a single administration of ZOL in Dmab short-term users.

Detailed Description
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Background Dmab is an osteoporosis treatment that improves bone density and lowers the risk of fractures. However, in a recent study, it is known that cases in which bone density decreases and multiple vertebral fractures occur when Dmab is discontinued. Therefore, the guideline recommends using zoledronic acid sequentially when discontinuing Dmab. However, the effect of preserving bone mineral density in patients who discontinue Dmab after using a long period is still not known. Aim To investigate the difference in lumbar bone mineral density between the two groups when zoledronic acid was administered differently according to the administration period after discontinuation of denosumab in postmenopausal osteoporosis patients. Methods A prospective, single-center, open-label, parallel, intervention study in 114 patients investigating the difference in bone mineral density between the short-term denosumab group and long-term denosumab group when zoledronic acid was administered differently. Each group is classified into a short-term group when used for less than 2.5 years and a long-term group when used for more than 2.5 years according to the maintenance period of the denosumab. The short-term group administrates zoledronic acid once six months after the last denosumab injection, and the long-term group administrates zoledronic acid six months and 12 months after the last denosumab injection, respectively. In the long-term group, if the side effect is severe after the first zoledronic acid administration and additional administration is difficult, it can be replaced with risedronic acid and maintained for another six months. The patients will be monitored with DXA at baseline and 12 months. Bone turnover marker (b-crosslap(CTx), P1NP) will be monitored at 6 and 12 months after the infusion of the first zoledronic acid. Whole spine x-rays are taken at baseline and 12 months after the zoledronic acid injection to check for vertebral fractures. Perspectives Osteoporosis is a disease that requires continuous management in old age. In order to prevent fractures, the order and maintenance of drug administration should be decided from a long-term perspective. Denosumab is a potent inhibitor of bone resorption which can be used in patients with high risk and very high fracture risk. But since it is reversible, additional treatment must be continued to maintain bone mass when the drug is discontinued. This study will show if two injections of zoledronic acid six months apart in long-term denosumab patients can effectively prevent bone loss compared to a single administration of zoledronic acid in the short-term denosumab group.

Official Title
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A Single Center, Open-label, Parallel, Phase IV Clinical Trial to Evaluate Efficacy of Once or Twice ZOledronic Acid After Different Duration of denOsumMab Administration in Postmenopausal Women With Osteoporosis

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Zoledronic acid, once
* Drug: Zoledronic acid, twice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women (defined as no menstruation for more than 48 weeks prior to screening and no other pathological or physiological causes. If in doubt, a serum follicle-stimulating hormone (FSH) test may be performed at screening) Patients diagnosed with osteoporosis, osteoporotic fractures, received at least two doses of denosumab, and who have osteopenia in follow-up DXA Exclusion Criteria: Secondary osteoporosis (Systemic glucocorticoid use, aromatase inhibitor, thyrotoxicosis, hypeparathyroidism, etc) Active cancer treatment Inflammatory bowel disease History of medication related osteonecrosis of jaw(MRONJ) low-energy fracture within the last 12months Estimated glomerular filtration rate (eGFR) < 35 mL/min Hepatic dysfunction (aspartate transaminase (AST)/alanine transferase (ALT) > 3 x upper normal limit) Contraindication for zoledronic acid according to the SPC Allergic to zoledronic acid

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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Female

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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Denosumab short-term user<br>Denosumab injection less than 5 times | Drug: Zoledronic acid, once<br>* Intravenous infusion of 5mg zoledronic acid, once<br>* Other names: Zoledronate;|
| Active Comparator: Denosumab long-term user<br>Denosumab injection more than 5 times | Drug: Zoledronic acid, twice<br>* Intravenous infusion of 5mg zoledronic acid for 6month interval, twice<br>* Other names: Zoledronate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMD lumbar spine | Change in lumbar spine BMD from baseline to one year after the zoledronic acid infusion | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMD Femoral neck and total hip | Changes in femoral neck and total hip BMD from baseline to one year after the zoledronic acid infusion | One year | 
| Bone turnover marker | Changes in p-CTX and P1NP From Baseline to Six and twelve months After the Zoledronic Acid Infusion. | One year | 
| Vertebral fracture | Morphometric Vertebral Fractures Assessed by whole spine x-ray | One year |