Zoledronate Early to Hip Fracture Patients - Safe and Effective?

Study Overview
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Brief Summary
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To prevent hip fracture patients for having another fracture, secondary fracture preventing medication should be given as soon as possible. Zoledronate is the most efficient bisphosphonate and is given as an intravenous infusion once yearly. However, the appropriate time to initiate zoledronate treatment after a hip fracture has not yet been established. To clarify the optimal timing of zoledronate to hip fracture patients we have designed a double-blinded, placebo-controlled randomized non-inferiority trial to compare if zoledronate administered early (within 5 days) after hip fracture surgery is as good as zoledronate given late (3 months) after hip fracture surgery.

Detailed Description
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Hip fracture patients have the highest risk for recurrent hip or other osteoporotic fractures. We have efficient fracture preventing medication easily available, but few patients receive them. We therefore need to create simple systems to ensure that these frail patients with the highest risk for a new fracture are offered proper treatment early and any delay in treatment should be avoided. Zoledronate is the most efficient bisphosphonate and the drug of choice for hip fracture patients due to the results from the Horizon recurrent fracture trial. It is given as an intravenous infusion once yearly. However, the appropriate time to initiate zoledronate treatment after a hip fracture has not yet been established. The summary of product characteristics (SmPC) for Aclasta (zoledronate) in Norway says that Aclasta should not be administered within the first 2 weeks after the hip fracture, however there have been a practice over years in Norway to give zoledronate to the hip fracture patients during their stay in hospital for fracture treatment. There are logistical and practical advantages of giving zoledronate while the patient is still in hospital for her fracture. It has, however, been questioned whether the effect of zoledronate given within the first 2 weeks postoperatively really is fracture preventing. The results from the post hoc analysis from the Horizon recurrent fracture trial by Eriksen and co-workers in 2009, suggested that given zoledronate within 2-weeks after hip fracture surgery may be a little less fracture preventing. The results from this analysis can be due to the low number of study subjects as well as frailty in the study population causing the large variations. On the other hand, the lack of effect in the within 2-week group may be due to the affinity for zoledronate to bone mineral and the accumulation of zoledronate in the fracture callus during bone repair with less being incorporated in the rest of the skeleton. To clarify the optimal timing of zoledronate to hip fracture patients we wanted to compare if zoledronate administered early (within 5 days) after hip fracture surgery, while the patients is still in hospital, is as good as zoledronate given late (3 months) after hip fracture surgery. To test our hypothesis we designed a non-inferiority randomized trial using the bone turnover marker N-terminal propeptide of type I procollagen (P1NP) as the primary endpoint. PINP has in recent years been widely used as a marker to follow the effect of anti-resorptive therapy as it is more robust than the other well studied bone marker; cross-linked C-telopeptide of type I collagen (CTX). P1NP and CTX are recommended as reference markers for bone turnover by the International Osteoporosis Foundation (IOF). Anti-resorptive agents as bisphosphonates influence bone remodeling by decreasing bone resorption (amino-bisphosphonates kills osteoclasts) and thereby also reducing bone formation. This affects the bone turnover markers: Both P1NP and CTX drops in value in a consistent manner reflecting the level of bone suppression and has shown to correlate with the level of bone mineral density and the subsequent fracture risk. P1NP and CTX are therefore well suited to monitor the effect of anti-resorptive therapy as they reflect the bone turnover status in the entire skeleton. It is likely to believe that if zoledronate given early after fracture is accumulated in the fracture callus and too little is incorporated in the entire skeleton, the result will be just a local decrease in bone resorption (only in the fracture callus). This will not to the same extent as a decrease in bone resorption from the entire skeleton, be reflected by the bone turnover markers P1NP and CTX and the fall in these markers will be less than if we give zoledronate after the fracture has healed (after 6-12 weeks). Eligible patients that meets the study requirements and with an informed consent will be stratified on type of operation (arthroplasty versus internal fixation) and on hospital before randomization 1:1 to either zoledronate early (ZOLearly: zoledronate given within 5 days after hip fracture surgery) or zoledronate late (ZOLlate: zoledronate given 3 months after hip fracture surgery). The patients will be followed for 15 months with study visits at 3 months post fracture and at 6 and 12 months post treatment with zoledronate. The study is double-blinded the first 3 months to be able to test for the soft secondary endpoints; delirium and rehabilitation. Approximately 300 patients will be recruited. Estimated recruitment time is 2 years.

Official Title
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Zoledronate Early to Hip Fracture Patients - Safe and Effective? A Double-blinded Randomized Controlled Treatment Strategy Trial on Zoledronate in Hip Fracture Patients

Conditions
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Hip Fractures, Osteoporosis

Intervention / Treatment
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* Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj
* Drug: sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Low energy hip fracture Surgery within 72 hours >50 years old norwegian Women age 50-60 must be postmenopausal or not pregnant Acceptable kidney function (estimated GFR >=35) and calcium levels Fit to complete the follow-up judged by the recruiting physician Signed informed consent by the patient or the next of kin Exclusion Criteria: Metal in the opposite hip Anti-osteoporosis treatment with bisphosphonates, denosumab, teriparatide, abaloparatide or romosozumab within the last 10 years Glucocorticoid therapy Too sick to receive treatment with zoledronate judged by the recruiting or treating physician Any other contraindication listed on the SmPC of the IMP(s) including pregnancy Participating in another trial that might affect the current study

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
Interventional Model Description: Double-blinded randomized controlled non-inferiority trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZOLearly<br>Within 3 days after hip fracture surgery: A single dose of 100 ml containing 5mg zoledronate (Aclasta) will be administered intravenously. The ZOLearly group will have no further infusions during the study period. | Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj<br>* 100ml Zoledronic acid (5mg/100ml) administered intravenously<br>* Other names: Aclasta;|
| Placebo Comparator: ZOLlate<br>Within 3 days after hip fracture surgery: A single dose of 100 ml containing 100ml NaCl 9mg/ml (placebo) will be administered intravenously. 3 months after hip fracture surgery (at the out-patient clinic): A single dose of 100 ml containing 5mg zoledronate (Aclasta) will administered intravenously. | Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj<br>* 100ml Zoledronic acid (5mg/100ml) administered intravenously<br>* Other names: Aclasta;Drug: sodium chloride<br>* 100ml NaCl 9mg/ml administered intravenously<br>* Other names: NaCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference between the two groups (ZOLearly vs ZOLlate) in proportion of patients having P1NP>35µg/L 12 months after treatment with zoledronate | Measured by the bone turnover marker N-terminal propeptide of type 1 procollagen (P1NP) (µg/ml) in blood samples | 12 months after treatment with zoledronate | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade of early mobilization | Measured by Cumulated Ambulation Score (CAS) in hospital and at discharge from hospital. The score range from 0 to 6, where 6 is the best. The patient is scored daily during the stay in hospital. | 1-30 days | 
| Delirium assessment | Number of patients with delirium assessed by 4 A test (4AT) in hospital | 1-30 days | 
| Difference between the two groups in proportion of patients having CTX>0.28µg/L 12 months after treatment with zoledronate | Measured by the bone turnover marker C-telopeptide of type 1 collagen (CTX) (µg/ml) in blood samples | 12 months after treatment with zoledronate | 
| Change in bone mineral density (BMD) | Measured by dual-energy x-ray absorbtiometry (DXA) in g/cm2 right after hip fracture surgery and after 12 months with zoledronate treatment | 12 months after treatment with zoledronate | 
| Grade of mobilization and rehabilitation | Measured by Time-up-and-go (TUG) test | 3 months after fracture surgery | 
| Fever (T> 38'C) during hospital stay for fracture surgery | Temperature measured in 'C in each patient | 1-30 days | 
| Use of antibiotics during hospital stay for fracture surgery | Measure duration of antibiotic treatment in each patient | 1-30 days | 
| Hospital stay after hip fracture surgery | Measure time from admission to discharge from hospital and time from hip fracture surgery to discharge from hospital | 1-30 days | 
| Time to readmission to hospital (any department) after first discharge | Measure time to first readmission for each patient | 15 months | 
| Number of readmissions to hospital (any department) after first discharge | Measure number of readmissions for each patient | 15 months | 
| Time to new fracture | Measure time to first new fracture after the index fracture for each patient | 15 months | 
| Total number of new fractures | Measure total number of new fractures | 15 months | 
| Deaths | Measure total number of deaths | 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hip fractures, zoledronic acid, bone turnover markers, delirium, early rehabilitation, bone mineral density