Altering Bone Microarchitecture and Mechanics by Off-label Pharmaceutical Intervention Following an Acute Knee Injury

Phase 1

Recruiting

• Conditions: Osteo Arthritis Knee; Anterior Cruciate Ligament Tear; Anterior Cruciate Ligament Injuries; Anterior Cruciate Ligament Rupture
• Interventions: Drug: Zoledronic Acid Injection; Drug: Placebo

• Registration Number: NCT05204836
• Lead Sponsor: University of Calgary

Brief Summary

The purpose of this study is to assess if a zoledronic acid injection can alter the trajectory of joint degeneration following an acute anterior cruciate ligament (ACL) injury.

Detailed Description

After being informed about the study and potential risks and all participants giving written informed consent, this project will establish a cohort of young men and women who within six weeks have sustained an acute rupture of the ACL. The cohort is randomized into a control and treatment group, where the treatment group receives a zoledronic acid injection at baseline. The cohort will be followed radiographically with high resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy computed tomography (DECT), digital radiography (X-Ray), bi-planar X-ray (EOS) and magnetic resonance imaging (MRI) for eighteen months to monitor the progression of joint changes and the effects of zoledronic acid.

Study Timeline

• Study First Submitted: 2021-12-21
• Study First Submitted QC: 2022-01-10
• Study First Posted: 2022-01-24
• Status Verified: 2023-01
• Study Start: 2023-05-16
• Last Update Submitted: 2023-05-16
• Last Update Posted: 2023-05-18
• Primary Completion: 2024-12-31
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 56

Inclusion Criteria

• Clinical evidence of an acute unilateral ACL tear (full-thickness, complete tear) will be recruited. This age range is chosen to ensure participants have fully developed adult bone structures and to exclude participants with menopause as this could affect study results.
• Participants with combined ligament deficiencies (posterior cruciate, medial and/or lateral collateral) or meniscal injury will be included. Participants must be able to fully extend the knee while supported at the time of the baseline measurement in order to conduct the HR-pQCT scan.
• Participants with a serum calcium level in the normal range (2.1-2.55 mmol/L) and a creatinine level above 50 (reported as eGFR) will be included.

Exclusion Criteria

• Individuals with contraindications to zoledronic acid (see below)
• Prior knee ligament and/or meniscus tears, and/or intra-articular fractures.
• Females who are pregnant or planning pregnancy within a year will not be eligible. The research team will recommend participants who are planning to become pregnant within the next five years to withdraw their participation.
• Individuals with knees larger than the CT scanner's circular field of view.
• Individuals with a history of disease and/or treatment affecting bone turnover in the past 12 months.
• Individuals with injuries or implants that are not MRI-safe.

Zoledronic acid is contraindicated for:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation, or to any bisphosphonates or component of the container.
• Severe renal impairment with creatinine clearance <35 mL/min and in those with evidence of acute renal impairment. For this study, participants with a creatinine clearance <50 mL/min may be excluded.
• Non-corrected hypocalcaemia at the time of infusion.
• Pregnant and nursing mothers.
• Patients who are already taking another bisphosphonate (ex. for osteoporosis).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Zoledronic Acid Injection	Zoledronic Acid Injection	Participants will receive 1 dose of 5 mg/100 mL intravenous zoledronic acid
Placebo	Placebo	Participants will receive 1 dose 100 ml Saline.

Primary Outcome Measures

Name	Time	Method
Bone microarchitecture changes at 6 months as assessed by high resolution peripheral quantitative computed tomography (HR-pQCT)	Baseline, 6 months	To determine morphological parameters from HR-pQCT scans, the trabecular portion must be isolated from the cortical shell of the bone in order to analyse the components separately. This is accomplished with an already developed auto-segmentation algorithm. In addition, the raw HR-pQCT images must be converted to binary images, wherein each voxel (3D pixel) is either labelled 'bone' or 'not bone.' This segmentation is performed by an algorithm which applies either a Gaussian or Laplace-Hamming filter in addition to a threshold to the grey-scale images. The binary images can then be analysed and morphological parameters can be determined. The changes in bone microarchitecture will be assessed at 6 months in comparison to baseline.
Bone microarchitecture changes at 18 months as assessed by high resolution peripheral quantitative computed tomography (HR-pQCT)	Baseline, 18 months	To determine morphological parameters from HR-pQCT scans, the trabecular portion must be isolated from the cortical shell of the bone in order to analyse the components separately. This is accomplished with an already developed auto-segmentation algorithm. In addition, the raw HR-pQCT images must be converted to binary images, wherein each voxel (3D pixel) is either labelled 'bone' or 'not bone.' This segmentation is performed by an algorithm which applies either a Gaussian or Laplace-Hamming filter in addition to a threshold to the grey-scale images. The binary images can then be analysed and morphological parameters can be determined. The changes in bone microarchitecture will be assessed at 18 months in comparison to baseline.

Secondary Outcome Measures

Name	Time	Method
Knee alignment as assessed by bi-planar x-ray	Baseline	Joint alignment by bi-planar x-ray (EOS) In a standing position, the baseline study visit will capture the alignment of the tibia and femur bones bilaterally so that alignment of the knee joint can be assessed. This is a standard clinical imaging device, and the software for measurement of knee alignment is built into the system.
Patient reported outcomes using ACL Quality of Life Questionnaire - 2 Months	2 Months	Patient reported outcomes at baseline will be assessed using; - ACL Quality of Life Questionnaire Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes using ACL Quality of Life Questionnaire - 18 Months	18 Months	Patient reported outcomes at baseline will be assessed using; - ACL Quality of Life Questionnaire Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes using ACL Quality of Life Questionnaire - Baseline	Baseline	Patient reported outcomes at baseline will be assessed using; - ACL Quality of Life Questionnaire Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes Health History Questionnaire (HHQ) - 6 months	6 months	Patient reported outcomes will be assessed using; - Health History Questionnaire (HHQ) (No scale)
Bone marrow lesions (BML) and soft tissue injury changes at 2 months as assessed by Magnetic Resonance Imaging (MRI)	Baseline, 2 months	MRI data will be segmented to identify the bone surface in a similar fashion as described for the HR-pQCT data.; Subsequently, using a threshold based approach BMLs will be identified and their locations and volumes will be recorded. Next, using rigid body registration the MRI data will be transformed to the HR-pQCT data. That allows the analysis of bone microarchitecture exclusively within the volume of BMLs. All of these analysis steps will be performed using custom algorithms in Python and the visualization toolkit.; The changes in bone will be assessed at 2 months comparison to baseline.
Bone marrow lesions (BML) and soft tissue injury changes at 6 months as assessed by MRI	Baseline, 6 months	MRI data will be segmented to identify the bone surface in a similar fashion as described for the HR-pQCT data.; Subsequently, using a threshold based approach BMLs will be identified and their locations and volumes will be recorded. Next, using rigid body registration the MRI data will be transformed to the HR-pQCT data. That allows the analysis of bone microarchitecture exclusively within the volume of BMLs. All of these analysis steps will be performed using custom algorithms in Python and the visualization toolkit.; The changes in bone will be assessed at 6 months in comparison to baseline.
Patient reported outcomes using ACL Quality of Life Questionnaire - 6 Months	6 Months	Patient reported outcomes at baseline will be assessed using; - ACL Quality of Life Questionnaire Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes using Knee injury and Osteoarthritis Outcome Score (KOOS) - Questionnaire - Baseline	Baseline	Patient reported outcomes will be assessed using; - Knee injury and Osteoarthritis Outcome Score (KOOS) Questionnaire Minimum Value: 1 (best outcome); Maximum Value: 5 (worse outcome)
Patient reported outcomes using Knee injury and Osteoarthritis Outcome Score (KOOS) Questionnaire - 2 Months	2 months	Patient reported outcomes will be assessed using; - Knee injury and Osteoarthritis Outcome Score (KOOS) Questionnaire Minimum Value: 1 (best outcome); Maximum Value: 5 (worse outcome)
Patient reported outcomes using Knee injury and Osteoarthritis Outcome Score (KOOS) Questionnaire - 6 Months	6 months	Patient reported outcomes will be assessed using; - Knee injury and Osteoarthritis Outcome Score (KOOS) Questionnaire Minimum Value: 1 (best outcome); Maximum Value: 5 (worse outcome)
Patient reported outcomes using Knee injury and Osteoarthritis Outcome Score (KOOS) Questionnaire - 18 Months	18 months	Patient reported outcomes will be assessed using; - Knee injury and Osteoarthritis Outcome Score (KOOS) Questionnaire Minimum Value: 1 (best outcome); Maximum Value: 5 (worse outcome)
Patient reported outcomes using 36-Item Short Form Survey (SF-36) Questionnaire - Baseline	Baseline	Patient reported outcomes will be assessed using; - 36-Item Short Form Survey (SF-36) Questionnaire Questions 1, 2, 20, 22, 34, 36 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 3-12 - Minimum Value: 1 (worst outcome); Maximum Value: 3 (best outcome) Question 13-19 - Minimum Value: 1 (worst outcome); Maximum Value: 2 (best outcome) Questions 21, 23, 26, 27, 30 - Minimum Value: 1 (best outcome); Maximum Value: 6 (worst outcome) Questions 24, 25, 28, 29, 31 - Minimum Value: 1 (worst outcome); Maximum Value: 6 (best outcome) Questions 32, 33, 35 - Minimum Value: 1 (worst outcome); Maximum Value: 5 (best outcome)
Patient reported outcomes using 36-Item Short Form Survey (SF-36) Questionnaire - 2 months	2 months	Patient reported outcomes will be assessed using; - 36-Item Short Form Survey (SF-36) Questionnaire Questions 1, 2, 20, 22, 34, 36 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 3-12 - Minimum Value: 1 (worst outcome); Maximum Value: 3 (best outcome) Question 13-19 - Minimum Value: 1 (worst outcome); Maximum Value: 2 (best outcome) Questions 21, 23, 26, 27, 30 - Minimum Value: 1 (best outcome); Maximum Value: 6 (worst outcome) Questions 24, 25, 28, 29, 31 - Minimum Value: 1 (worst outcome); Maximum Value: 6 (best outcome) Questions 32, 33, 35 - Minimum Value: 1 (worst outcome); Maximum Value: 5 (best outcome)
Patient reported outcomes using 36-Item Short Form Survey (SF-36) Questionnaire - 6 months	6 months	Patient reported outcomes will be assessed using; - 36-Item Short Form Survey (SF-36) Questionnaire Questions 1, 2, 20, 22, 34, 36 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 3-12 - Minimum Value: 1 (worst outcome); Maximum Value: 3 (best outcome) Question 13-19 - Minimum Value: 1 (worst outcome); Maximum Value: 2 (best outcome) Questions 21, 23, 26, 27, 30 - Minimum Value: 1 (best outcome); Maximum Value: 6 (worst outcome) Questions 24, 25, 28, 29, 31 - Minimum Value: 1 (worst outcome); Maximum Value: 6 (best outcome) Questions 32, 33, 35 - Minimum Value: 1 (worst outcome); Maximum Value: 5 (best outcome)
Patient reported outcomes using 36-Item Short Form Survey (SF-36) Questionnaire - 18 months	18 months	Patient reported outcomes will be assessed using; - 36-Item Short Form Survey (SF-36) Questionnaire Questions 1, 2, 20, 22, 34, 36 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 3-12 - Minimum Value: 1 (worst outcome); Maximum Value: 3 (best outcome) Question 13-19 - Minimum Value: 1 (worst outcome); Maximum Value: 2 (best outcome) Questions 21, 23, 26, 27, 30 - Minimum Value: 1 (best outcome); Maximum Value: 6 (worst outcome) Questions 24, 25, 28, 29, 31 - Minimum Value: 1 (worst outcome); Maximum Value: 6 (best outcome) Questions 32, 33, 35 - Minimum Value: 1 (worst outcome); Maximum Value: 5 (best outcome)
Patient reported outcomes using EQ-5D-5L Questionnaire - Baseline	Baseline	Patient reported outcomes will be assessed using; - EQ-5D-5L Questionnaire Questions 1-5 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 6 - Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes using EQ-5D-5L Questionnaire - 2 months	2 months	Patient reported outcomes will be assessed using; - EQ-5D-5L Questionnaire Questions 1-5 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 6 - Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes using EQ-5D-5L Questionnaire - 6 months	6 months	Patient reported outcomes will be assessed using; - EQ-5D-5L Questionnaire Questions 1-5 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 6 - Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes using EQ-5D-5L Questionnaire - 18 months	18 months	Patient reported outcomes will be assessed using; - EQ-5D-5L Questionnaire Questions 1-5 - Minimum Value: 1 (best outcome); Maximum Value: 5 (worst outcome) Question 6 - Minimum Value: 0 (worst outcome); Maximum Value: 100 (best outcome)
Patient reported outcomes Health History Questionnaire (HHQ) - Baseline	Baseline	Patient reported outcomes will be assessed using; - Health History Questionnaire (HHQ) (No scale)
Patient reported outcomes Health History Questionnaire (HHQ) - 2 months	2 months	Patient reported outcomes will be assessed using; - Health History Questionnaire (HHQ) (No scale)
Patient reported outcomes Health History Questionnaire (HHQ) - 18 months	18 months	Patient reported outcomes will be assessed using; - Health History Questionnaire (HHQ) (No scale)

Trial Locations

Locations (1)

University of Calgary; 🇨🇦 Calgary, Alberta, Canada