The Effect of Zoledronate on the Prevention of Pneumonia in Hip Fracture Patients (Zoo-P)

The Effect of Zoledronate on the Prevention of Pneumonia in Hip Fracture Patients (Zoo-P): An Open-label, Pragmatic, Randomised Controlled Trial

Nitrogen-containing bisphosphonates (N-BPs; such as alendronate and zoledronate) are commonly used in the treatment of osteoporosis and fracture prevention, in which zoledronate has a proven better efficacy than alendronate. In 2018, our real-world propensity score matched study showed that the use of N-BPs was significantly associated with reduced risk of myocardial infarction and stroke in hip fracture patients. In addition to cardiovascular diseases, both preclinical study and sensitivity analysis also suggest evidence for N-BPs in pneumonia prevention. Moreover, a pragmatic clinical trial is developed to evaluate effect of the tested intervention in real-life routine clinical practice since traditional explanatory radomised controlled trial (RCT) may have poor generalizability due to highly selected patients and controlled environments. This study aims to evaluate if zoledronate reduces risk of pneumonia in hip fracture patients using pragmatic clinical trial approach.

This is an open-label, multi-centre, pragmatic, randomised controlled trial. Patients will be recruited from 4 hospitals, namely Caritas Medical Centre, Prince of Wales Hospital, Queen Mary Hospital, and United Christian Hospital. Age, sex, body mass index, eGFR, history of fracture, chronic respiratory diseases, and other medical history, will be measured and recorded at recruitment.

Study Overview

• Status: Recruiting
• Conditions: Pneumonia; Hip Fractures
• Intervention / Treatment: Drug: Zoledronate

Detailed Description

N-BPs are widely used in the treatment of osteoporosis and fracture prevention. Although alendronate is the first-line antiosteoporosis medication in many countries, it is associated with esophageal and gastrointestinal irritation. In addition, the regimen for alendronate is one tablet per week and careful use of alendronate is required to avoid gastrointestinal irritation (e.g. take the tablet on an empty stomach, stay upright for at least 30 minutes after taking the medication), leading to relative low drug compliance. On the other hand, the regimen of zoledronate is 5mg infusion once a year. Since the route of administration is intravenous infusion, it avoids the gastrointestinal irritation problem. In terms of fracture prevention, zoledronate has a proven better efficacy than alendronate. Most importantly, previous HORIZON recurrent fracture trial showed that zoledronate use reduced risk of mortality in addition to fracture prevention. Thus, zoledronate is considered the most efficacious N-BP in clinical use.

N-BPs could exert extra-skeletal beneficial effects. In 2018, our real-world propensity score matched study (N=34,991) using the Clinical Data Analysis and Reporting System (CDARS), a clinical database managed by the Hong Kong Hospital Authority, showed that use of N-BPs was significantly associated with reduced risk of myocardial infarction and stroke in hip fracture patients. Later in the same year, a randomized controlled trial (RCT) in 2,000 osteopenic women showed that zoledronate may reduce risk of myocardial infarction with an odds ratio of 0.61 (95% CI: 0.36-1.02) after following up for 6 years. They subsequently performed a detailed post-hoc analysis and showed that zoledronate use was significantly associated with reduced risk of myocardial infarction, composite cardiovascular end-point, and fatal stroke. This example demonstrated not only the extra-skeletal effect of N-BPs, but also showed that high-quality real-world data with state-of-the-art statistical method could potentially be useful in causal inference.

In addition to cardiovascular diseases, N-BPs may be useful in preventing pneumonia. Preclinical study showed that N-BPs are anti-inflammatory and may modulate macrophages in response to pneumonia. In addition, pharmacokinetic studies showed that the highest concentration of N-BPs was detected in trachea other than bone after oral ingestion or intravenous infusion of N-BPs. Among various N-BPs, alendronate was detected in the trachea with a concentration of 607 ng/ml 72 hours after oral ingestion, which was almost half of the concentration (1370 ng/ml) detected in vertebrae. Thus, we conducted a real-world population-based propensity score matched study in a cohort of 54,047 hip fracture patients to investigate the association of N-BP use with risk of pneumonia. Among hip fracture patients, N-BP use was significantly associated with 24% risk reduction in pneumonia (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.70-0.83), with an absolute risk difference of 2%. Similar significant association was observed for pneumonia mortality. To further reduce the potential bias of confounding by indication, we performed a sensitivity analysis by including users of other anti-osteoporosis medications in the control group, instead of patients without using any anti-osteoporosis medications. A similar significant association was observed. In agreement with the preclinical studies, we provided evidence for N-BPs in pneumonia prevention. This finding attracted wide media coverage, including Reuters and the New York Times.

Although utilisation of real-world data is an emerging approach in evaluating drug effectiveness, RCT is still considered the gold standard in evaluating drug efficacy. However, traditional explanatory RCT may have poor generalizability due to highly selected patients and controlled environments. Thus, pragmatic clinical trial is developed to evaluate if the tested intervention is effective in real-life routine clinical practice, by reducing bias using randomization and improving generalizability using real-world setting. We aim to evaluate if zoledronate reduces risk of pneumonia in hip fracture patients using pragmatic clinical trial approach.

• Study Type: Interventional
• Enrollment (Estimated): 2692
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ching-Lung Cheung, PhD; Phone Number: +852 2831-5080; Email: lung1212@hku.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Queen Mary Hospital
    • Contact: Ching-Lung Cheung, PhD; Phone Number: +852 2831-5080; Email: lung1212@hku.hk
  • Kwun Tong, Hong Kong
    • Recruiting
    • United Christian Hospital
    • Contact: Ching-Lung Cheung, PhD; Phone Number: +852 2831-5080; Email: lung1212@hku.hk
  • Sha Tin, Hong Kong
    • Not yet recruiting
    • Prince of Wales Hospital
    • Contact: Ching-Lung Cheung, PhD; Phone Number: +852 2831-5080; Email: lung1212@hku.hk
  • Sham Shui Po, Hong Kong
    • Recruiting
    • Caritas Medical Centre
    • Contact: Ching-Lung Cheung, PhD; Phone Number: +852 2831-5080; Email: lung1212@hku.hk
  • Tai Po, Hong Kong
    • Recruiting
    • Tai Po Hospital
    • Contact: Ching-Lung Cheung, PhD; Phone Number: +852 2831-5080; Email: lung1212@hku.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female ≥ 60 years
• With recent fragility hip fracture at proximal femur
• Have the ability to understand the requirements of the study, provide written informed consent, including consent for the use and discloser of research-related health information, and comply with the study data collection procedures. Provide signed and dated informed consent form

Exclusion Criteria:

• Known to be hypersensitive to any N-BPs
• Estimated glomerular filtration rate (eGFR) < 30 ml per minute per 1.73 m2 of body surface area
• Regular user of anti-osteoporosis medications (including bisphosphonates, denosumab, teriparatides, and raloxifene) or oral or intravenous systemic glucocorticoids in the previous year.
• Subject currently involved in a clinical trial or in an exclusion period following participation in another clinical trial

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zoledronate; Zoledronate intravenous infusion (5mg) once and usual care will be provided to the patient and mark the start of 12-month follow-up period	Drug: Zoledronate; Aclasta Solution for Infusion 5mg/100ml (zoledronic acid); Other Names: Zoledronic acid; Aclasta
No Intervention: Control; Only usual care will be provided to the patient with 12-month follow-up period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pneumonia hospitalizations	Diagnosis records of pneumonia from electronic medical records	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular events	Diagnosis records of cardiovascular events from electronic medical records	12 months
Refracture events	Diagnosis records of refracture from electronic medical records	12 months
Problems associated with fracture healing, including revision surgery	Diagnosis and operation records from electronic medical records	12 months
All-cause mortality	Date of death and cause of death information from electronic medical records	12 months

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Prince of Wales Hospital, Shatin, Hong Kong; Queen Mary Hospital, Hong Kong; United Christian Hospital; Caritas Medical Centre, Hong Kong
• Investigators: Principal Investigator: Kathryn Tan, MD, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2022
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: February 14, 2023
• First Submitted That Met QC Criteria: February 14, 2023
• First Posted (Actual): February 24, 2023

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Pneumonia; Hip Fractures; Zoledronic Acid
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Wounds and Injuries; Leg Injuries; Femoral Fractures; Hip Injuries; Pneumonia; Fractures, Bone; Hip Fractures; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: Zoo-P_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will be shared upon special request to the principal investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No