Intravenous Bisphosphonate in Stress Fracture Treatment -A Randomised Controlled Double Blinded Multicenter Trial

Intravenous Bisphosphonate in Stress Fracture Treatment

The effect of an intravenous bisphosphonate (zoledronic acid) on healing and symptoms of stress fractures that do not respond to conservative/conventional treatment within 6 months, will be investigated.

Study Overview

• Status: Terminated
• Conditions: Stress Fracture Foot; Stress Fracture Ankle
• Intervention / Treatment: Drug: Placebo; Drug: Zoledronic Acid Injectable Product

Detailed Description

Randomised controlled multicenter trial. Prospective study. The trial will be performed in accordance with the CONSORT-statement. The inclusion period will be two years. The patients will be randomised to standard treatment (casting, partial weight-bearing, orthotic insoles) in addition to either zoledronic acid or placebo (saline) infusions. The randomization process will be carried out through a web based randomization service (Norwegian University of Science and Technology, Unit for applied clinical research). Patient data will be kept and organized by a study coordinator (nurse) and will not be revealed for the clincal investigators, except in medical emergency situations. In such cases, the patient will be excluded from the study. A number of bottles containing zoledronic acid or placebo will be available in each of the participating hospitals. The bottles containing zoledronic acid and placebo are visually identical, numbered from 1 through 80 (two bottles with similar number, the second bottle will be kept for the second infusion). The patients will be randomised in blocks, creating evenly sized groups given zoledronic acid or placebo. When a patient is included and thereafter randomised, the study coordinator decides which bottle number to be given and provides this information to the physician. The study coordinator is the only person in the study group which is not blinded.

On the first visit, the included patients will undergo clinical examination and baseline parameters will be registered. If MRI is not previously obtained, this will be performed as quickly as possible. The clinical controls will be scheduled 4 and 12 and 26 weeks thereafter, the latter including MRI. If healing has still not occured, the patients will be given the second infusion and meet for clinical examination every 4 weeks until healing. Clinical healing is defined as painless or near painless (VAS pain 0-2) weight bearing. If healing has not occured 12 months after inclusion, surgery will be considered.

MRI will be obtained at (or before) baseline, 6 months and one year. MRIs will be examined by a blinded radiologist. Bone marrow lesions (BMLs) will be measured (area and volume) and fracture lines registered.

All patients (both groups) will be prescribed calcium and vitamin D (Calcigran Forte 500mg/400IE) taken orally once daily in the whole study period. This is recommended as an adjunct to bisphosphonate treatment on a general basis/standard treatment and is not to be investigated separately.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0450
    • Oslo University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-70 years
• Stress fractures in the foot. A stress fracture is defined as a fracture occured after repetitive trauma, with characteristic MRI findings (ref) and distinctive pain over the fracture site at weight bearing.
• at least 6 months of pain history
• compliant patient
• non-aided ambulatory patient prior to the injury

Exclusion Criteria:

• Ongoing use of bisphosphonates, PTH/PTH-analogues or use within 12 months prior to the injury
• Use of bisphophonates for more than 6 months within the last 5 years
• Intolerance to zoledronic acid
• Renal failure (GFR<30)
• S-25(OH)vitD > 25
• pregnancy
• breast feeding
• hypocalcemia
• MRI contraindications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Zoledronic Acid Injectable Product; Patients randomized to treatment with Zoledronic Acid 5mg infusion, repeated after 3 months	Drug: Zoledronic Acid Injectable Product; One Group are randomiced to Zoledronic Acid Injectable Product and one Group to Placebo; Other Names: Aclasta
Placebo Comparator: Placebo; Patients randomized to Placebo infusion (saline), repeated after 3 months	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The American Orthopedic Foot and Ankle Score (AOFAS) mid foot scale	a scale evaluating pain, function and alignment of the foot. 0-100, With 100 as maximum score	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual analoge scale (VAS) for pain	Patient Reported Outcome Measure (PROM) for evaluating local pain	3, 6, 8, 10 and 12 months
Change in bone marrow lesions evaluated by magnetic resonance imaging (MRI)	the intensity and the amount of bone marrow oedema is evaluated	1 year
The American Orthopedic Foot and Ankle Score (AOFAS) mid foot scale	a scale evaluating pain, function and alignment of the foot	3, 6, 8, 10, 12 months

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Sykehuset Ostfold; Betanien Hospital
• Investigators: Study Chair: Elisabeth E Husebye, PhD, Oslo University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2017
• Primary Completion (Actual): June 26, 2019
• Study Completion (Actual): June 26, 2019

Study Registration Dates

• First Submitted: June 22, 2018
• First Submitted That Met QC Criteria: July 2, 2018
• First Posted (Actual): July 3, 2018

Study Record Updates

• Last Update Posted (Actual): September 13, 2019
• Last Update Submitted That Met QC Criteria: September 11, 2019
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Wounds and Injuries; Fractures, Bone; Fractures, Stress; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: REK 2014/1986

Drug and device information, study documents

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