Efficacy of Zoledronic Acid in Enhancement of Early Stability of Cementless Primary Hip Prosthesis

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind and placebo-controlled study to evaluate the efficacy of zoledronic acid on the biologic incorporation of cementless hip prosthesis in postmenopausal female patients.The study population consists of postmenopausal female patients scheduled for total hip replacement because of degenerative hip osteoarthritis. The patients will receive either a single dose of 5 mg zoledronic acid or placebo intravenously after surgery before hospital discharge. The patients will be followed-up for 1 year. Zoledronic acid therapy has been shown to promote bone ingrowth into porous implants in pre-clinical models. The investigators hypothesis is that zoledronic acid, given as a single intravenous infusion after hip replacement surgery, enhances bone ingrowth into porous surface of cementless hip prostheses. As a primary outcome, the therapy is expected to reduce periprosthetic bone loss measured by DXA. Enhancement of bone ingrowth is expected to increase primary stability of the hip prosthesis and this effect can be detected with high-precision three-dimensional RSA imaging modality and in a faster functional recovery of the patients.

Detailed Description
-----------------
All the patients enrolled in the study will receive the standard of care with respect to surgical prosthetic replacement of the diseased hip. The patients will receive a custom-modified (RSA marked) hydroxyapatite-coated prosthesis with ceramic-on-ceramic bearing surfaces (SYMAX-TRIDENT, Stryker). The prosthesis modification provided by the manufacturer has a CE mark. The patients in the active-treatment group will receive a single 5 mg dose of zoledronic acid intravenously just prior to release from the hospital (about 5th day post-surgery) as an adjunct therapy. The control group will receive a placebo (saline) infusion. The active and placebo infusion vials will be provided by Norvartis Pharmaceutical. After surgery, before the administration of zoledronic acid or placebo, each patient will be re-screened for the level of serum calcium. In the case of postoperative hypocalcemia, the infusion will be postponed for a minimum of 3-4 weeks and the infusion will be given after the repeated measurements of serum calcium. All patients will receive calcium and D-vitamin supplementation throughout the study period. Efficacy will be assessed on the basis of clinical, radiographic (RSA, DXA, Spiral CT, conventional radiography) and laboratory criteria. The clinical benefit of zoledronic acid therapy is defined in terms of faster functional recovery, which will be analyzed in two ways: (1) the functional outcome (muscle strength, gait analysis and pedometry) will be repeatedly evaluated before and after surgery, and (2) the subjective outcome of the procedure as well as the general health assessment will be determined at each follow-up visits using standardized outcome measures. The primary objective of this study is to test whether a single infusion of zoledronic acid reduces periprosthetic bone loss measured by DXA at 12 months. Statistical significance of differences in periprosthetic bone mineral density between active-treatment and placebo groups will be analyzed using repeated analysis of variance.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy of Zoledronic Acid in Enhancement of Early Stability of Cementless Primary Hip Prosthesis

Conditions
-----------------
Hip Osteoarthritis

Intervention / Treatment
-----------------
* Drug: zoledronic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Degenerative hip osteoarthritis as the indication for hip replacement Postmenopausal female patient Age of at least 20 years Signed Informed Consent Exclusion Criteria: Evidence of secondary osteoporosis Clinical or laboratory evidence of hepatic or renal disease Disorders of parathyroid function, or D-vitamin metabolism History of malignancy, radiotherapy, or chemotherapy for malignancy (except for basal cell carcinoma of the skin) within the past 5 years No metastatic cancer or cancer diagnosed less than 2 years ago where treatment is still ongoing Administration for more than 7 days of drugs, which may interfere with bone metabolism: cumulative dose of 500 mg of prednisone or equivalent within the last 6 months calcitonin within the last 6 months bisphosphonates for 30 days or more within the last 12 months bone therapeutic doses of fluoride for 30 days or more within the last 24 months Rheumatoid arthritis or any other inflammatory arthritis History of osteogenesis imperfecta, multiple myeloma, or Paget's disease Active primary hyperparathyroidism History of uveitis, iritis, or chronic conjunctivitis History of retinopathy or nephropathy, especially in the presence of uncontrollable IDDM (Hb1AC > 10%) AST or ALT > 2X the upper limit of normal ALP > 1.5X the upper limit of normal Serum creatine > 2 mg/dl Creatine clearance < 40 ml/min Serum calcium > 11.0 mg/dL and < 8mg/dL Serum 25(OH)D < 15 ng/ml In subjects with HIV must have a plasma HIV-1 RNA level of < 5000, a CD4+ count of > 100 cells/mm3m and be receiving stable ART for a minimum of 12 weeks prior study entry, with no plan at study entry to significantly alter ART Allergy to zoledronic acid Severe dental problems or current dental infections or with recent or impending dental surgery within three months of dosing

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: zoledronic acid|The patients in the active-treatment group will receive a single 5 mg dose of zoledronic acid intravenously just prior to release from the hospital (about 5th day post-surgery) as an adjunct therapy. The control group will receive a placebo (saline) infusion. All infusions will be given 100 ml in volume and infused over a period of 15 minutes with a pre- and post-infusion flush with normal saline.|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective of this study is to test whether a single infusion of zoledronic acid reduces periprosthetic bone loss measured by DXA. |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RSA outcome, functional recovery and metabolic treatment response | to demonstrate that the treatment can enhance biologic incorporation of cementless hip prostheses as shown by reduced prosthetic migration measured by RSA (radiostereometry) to demonstrate that enhanced incorporation of the hip prostheses following the therapy lead to faster functional recovery and better subjective outcome of the procedure. to demonstrate that the treatment suppresses biochemical markers of bone resorption. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hip osteoarthritis, Bisphophonate therapy, Zoledronic acid, Radiostereometric analysis, Osteoporosis