The Effect of Zoledronic Acid on Bone Density in Liver Transplant Patients
Condition: Osteoporosis; Liver Transplantation; Fractures
MeSH terms: Osteoporosis
Study type: Interventional
Phase: Phase 4

Summary: 
      Following liver transplantation, rapid bone loss occurs, particularly within the first 6
      months post-transplant. This may be associated with fractures, most notable vertebral. The
      ability to assess osteoporosis therapies in this system may provide useful information for
      osteoporosis management in general.

      Hypotheses:

        1. That treatment with the bisphosphonate, zoledronate, at the time of liver
           transplantation and at 1 month post-transplantation will prevent the early
           transplant-related bone loss (measured by bone densitometry and biochemical bone markers
           at 3 months) seen in patients who are not treated with a bisphosphonate

        2. That continuing treatment with zoledronate at 3 monthly intervals for a total duration
           of 12 months will result in further improvements in bone density beyond that seen at 3
           months

        3. That calcium and vitamin D (vit D) supplementation of liver transplant patients does not
           prevent marked bone loss following transplantation.
    

Detailed description: 
      This study is a prospective, randomised, double-blind, placebo-controlled clinical trial in
      liver transplant patients comparing therapy with the bisphosphonate, zoledronate, to patients
      who do not receive bisphosphonate therapy. All groups will receive calcium and vit D
      supplementation from the time patients are listed for transplantation and for 12 months
      post-transplantation. Recruited subjects will be 17 years or older (ie adult in terms of
      consent requirements).

      The study groups comprise:

      Group 1: Zoledronate plus calcium and vit D supplementation

      Zoledronate 4 mg will be administered by intravenous infusion (details below) at baseline
      (within 72 h of liver transplantation), followed by zoledronate 4 mg infused as outlined
      below at 1, 3, 6 and 9 months post-transplantation PLUS calcium 600mg daily (Caltrate, one
      tablet) and ergocalciferol 1000 IU daily (Ostelin, one capsule) for 12 months
      post-transplantation.

      Group 2: Placebo plus calcium and vit D supplementation

      Placebo will consist of 50 ml N/Saline infused over 15 minutes as for the zoledronate regime
      PLUS calcium 600mg daily (Caltrate, one tablet) and ergocalciferol 1000 IU daily (Ostelin,
      one capsule). Patients with low vitamin D levels (<60 nmol/L) and parathyroid hormone (Pth)
      levels above normal >6.5 should receive ergocalciferol 5000 U daily.

      Zoledronate/Placebo Infusion regime

      Zoledronate 4 mg will be infused in 100 ml N/Saline over 15 minutes in patients with a
      creatinine level <1.5 times the upper limit of the normal range (i.e <165 µmol/L). Patients
      with renal impairment as indicated by a serum creatinine level >1.5 x ULN will be discussed
      on an individual basis with the Medical Adviser of Novartis. If zoledronate is to be given,
      an extended infusion time may be used. Renal toxicity has been reported with rapid infusions
      (5 min) of 8 mg of zoledronate in patients with pre-existing renal failure. Further
      pharmacokinetic studies in patients with renal failure are being undertaken by Novartis to
      clarify this area. Zoledronate infusion should be freshly prepared and administered without
      delay.

      The Hospital Pharmacy will be responsible for providing the infusions (zoledronate
      reconstituted in N/Saline or N/Saline alone), appropriately masked, for both Groups 1 and 2.

      Primary Outcome Measures:

      1) Bone Density at 3 months post-transplantation

      Maximal loss of bone following transplantation is seen by 3 months. Earlier data on bone loss
      in liver transplant patients from the RPAH unit demonstrated an average of 24% bone loss by 3
      months post-transplantation. Prevention of this effect should provide a precise and early
      measurement of the effect of zoledronate on transplant-related bone loss. Bone density of the
      hip, spine, and total body will be measured by dual xray absorptiometry (DEXA) at baseline
      (not more than 6 months prior to liver transplantation), and 3, 6 and 12 months following
      liver transplantation.

      Secondary Outcome Measures:

        1. Bone Density at 6 and 12 months post-transplantation

           The BMD assessments at 6 and 12 months will assess further changes in bone density
           between the treated and control groups beyond those assessed at 3 months.

        2. Biochemical Markers of Bone Metabolism

           Biochemical markers of bone formation (osteocalcin and total and bone specific alkaline
           phosphatase) and bone resorption (urinary collagen cross-links, N-teleopeptide and
           deoxypyridinoline, as well as serum cross-links, C-teleopeptide) will be assayed in
           serum/urine collected at baseline, and 1, 3, 6, 9 and 12 months following liver
           transplantation.

        3. Fracture Events Fracture incidence in the RPAH patients has been previously reported as
           17% in the first 6 months post-transplantation. The fracture rate is now probably lower
           due to improvements in immunosuppressive therapy. It is not anticipated that this study
           will have sufficient power to detect a significant reduction in fractures however
           fracture events will be recorded, including reduction in height of vertebral bodies at
           baseline and 12 months post-transplantation.
    

Intervention name(s): zoledronic acid
Intervention type(s): Drug
Intervention MeSH terms: Zoledronic Acid
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double
Primary purpose: Prevention
Keywords: osteoporosis; liver transplantation