To study the effectiveness and safety of semi-annual zoledronic acid treatment for reducing articular cartilage and pain loss in knee osteoarthritis.
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in total mean cartilage thickness in the tibial and load-bearing femoral
regions of the most affected compartment of the tibiofemoral joint of the index
knee on MRI, 24 months vs. baseline.
Secondary outcome
- Pain on a numeric rating scale at 6, 12, 18, and 24 months vs. baseline.
- KOOS (Knee injury and Osteoarthritis Outcome Score) at 6, 12, 18, and 24
months vs. baseline (pain, symptoms, daily activity, sport, quality of life).
- Pain medication use at 6, 12, 18, and 24 months vs. baseline.
- Bone marrow lesion size at 24 months vs. baseline.
- Change in joint space width on standardized knee radiographs at 24 months vs.
baseline.
- Change in total mean cartilage thickness in the tibial and load-bearing
femoral regions of the tibiofemoral compartment contralateral to the most
affected compartmen of the index knee at 24 months vs. baseline.
- Change in total mean cartilage thickness in the tibial and load-bearing
femoral regions of the index knee at 24 months vs. baseline.
- Safety.
Background summary
There is a great and growing need for disease-modifying treatment for primary
knee osteoarthritis.
Study objective
To study the effectiveness and safety of semi-annual zoledronic acid treatment
for reducing articular cartilage and pain loss in knee osteoarthritis.
Study design
A placebo-controlled, double-blinded, randomized clinical trial, with a
two-year follow-up.
Intervention
Zoledronic acid, intravenously, 4 mg in 100 cc 0.9% NaCl, semi-anually, four
times.
Placebo: 100 cc 0.9% NaCl.
Study burden and risks
The burden and risks of participating in this study are estimated to be
moderate.
Zoledronic acid is a registered drug for the prevention of fractures in
patients with osteoporosis and Paget disease of bone. Mild side effects such as
a flu-like reaction within the first 3 days after infusion are common. Patients
will be advised to use paracetamol for alleviating symptoms. The frequency and
severity of this adverse effect decrease with sequential infusions.
Potential side effects of concern are kidney dysfunction or hypocalcaemia
(symptomatic or asymptomatic). To minimize the occurrence of these side
effects, only patients without risk factors for these adverse effects will be
included in this study. Daily calcium and vitamin D supplementation will be
prescribed. This supplementation has no expected, significant adverse effects
in this poulation. Kidney function and serum calcium levels will be checked
before each infusion. Because medication is given intravenously there is a
small risk for phlebitis or subcutaneous infusion.
All patients receive usual care for osteoarthritis, including lifestyle
advices, physical therapy, pain medication. Only intra-articular treatments are
not allowed.
The six required hospital visits will each take maximum 3 hours. To assess the
effect of the treatment two radiographs and MRI's of the index knee will be
made at the start and end of the study and questionnaires will be obtained at
every hospital visit. Each MRI will take approx. 30 minutes. The two additional
7T-MRI's of the index knee in a subset of 20 participants will take 45 minutes
each. Radiation exposure of the radiographs is considered negligible (0.04 mSv
vs. yearly background radiation of 3.0 mSv).
Patients treated with zoledronic acid may benefit if cartilage degradation is
slowed down and/or pain is reduced. Patients receiving placebo have no other
risks than those related to intravenous saline treatment.
If zoledronic acid appears to be effective for reducing cartilage loss and/or
pain, extended observation of study participants will be pursued. Patients from
the placebo group will very likely not yet get access to treatment with
zoledronic acid at that stage.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
- Age between 40 and 70 years.
- Primary tibiofemoral (TF) knee OA according to clinical and radiographic ACR
criteria. When two knees are eligible, the most painful knee is chosen as index
knee. When knees are equally painful the index knee will be selected randomly.
The most affected compartment (MAC) of the index is defined as the TF
compartment with the most radiographic joint space loss.
- Pain in the index knee on at least 50% of the days of the previous month (NRS
between 4/10 and 8/10).
- At least one bone marrow lesion (BML) in the MAC of the index knee on MRI, as
judged by a trained researcher. A BML is defined on T2-weighted MRI sequences
as a zone of altered signal intensity in the bone and marrow, located
immediately beneath the articular cartilage and visible on at least two
consecutive slices.
Exclusion criteria
- Severe structural OA of the MAC of the index knee on plain radiograph: grade
3 radiographic joint space narrowing of the index knee, according to the
Osteoarthritis Research Society International atlas.
- Planned or expected surgery of index knee in the next 2 years (physician
judgment).
- Intra-articular injection into the index knee: glucocorticoids, hyaluronic
acid, or platelet-rich plasma within the last 6 months.
- Knee pain from other causes than knee OA (e.g. fibromyalgia)
- Secondary OA, such as secondary to inflammatory joint disease, significant
trauma, metabolic disease, and/or extreme varus or valgus position of the knee
(i.e. more than 10ยบ).
- Other self-reported diseases with potential effects on current bone
metabolism (e.g. thyroid or parathyroid disease, malignancy, bone fracture
within past 6 months).
- Self-reported disease that limits intestinal absorptive capacity (e.g. celiac
disease or short bowel syndrome).
- Previous allergic reaction to zoledronic acid, another bisphosphonate, or
other substances in the solute.
- Previous and/or current use of bisphosphonates, denosumab, teriparatide,
strontium ranelate, calcitonin and/or raloxifene.
- Current use of loop diuretics, glucocorticoids, aminoglycoside antibiotics.
- Uncontrolled or actively treated dental disease and/or otitis.
- Current or previous atrial fibrillation.
- Abnormal blood tests: serum ionized calcium higher than 1.32 mmol/l or lower
than 1.15 mmol/l, serum (25OH) vitamin D lower than 50 nmol/l, or estimated
creatinine clearance lower than 60 ml/min.
- Contraindications to MRI (e.g. claustrophobia, MRI-incompatible
devices/implants/foreign objects).
- Insufficient ability to communicate in Dutch.
- Pregnancy or lactation.
- Other factors that prevent subjects from adhering to the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001157-14-NL |
| CCMO | NL61307.041.17 |
| OMON | NL-OMON24160 |