Abstract
Abstract 1965
Bone mineral density (BMD) loss, osteoporosis, and avascular necrosis (AVN) of bone are relatively common in long term survivors of HCT with up to one half of recipients suffering post HCT bone loss. We performed a multi center phase II randomized open label trial of intravenous zolendronic acid (ZA) to prevent BMD loss in recipients of allogeneic HCT with pre-existing osteopenia prior to HCT.
Methods:
Eligible adult (>18 years) patients had baseline pre-transplant osteopenia defined as a T-score < −1 SD and > −2.5 SD (WHO definifition) at either the lumbar (L) spine and/or the proximal femur at a pre HCT screening evaluation with a dual energy X-Ray absorptiometry (DEXA) scan. Patients were eligible irrespective of donor source, stem cell type, or conditioning regimen intensity. Patients with myeloma, baseline renal dysfunction or concomitant active dental or endocrine issues precluding the use of ZA were excluded. Subjects were allocated by block randomization stratified by center and type of conditioning (myeloablative vs. non-myeloablative) to the treatment or control arms.
Both treatment and control groups received 1000 mg of calcium and 400 – 500 IU of vitamin D orally daily and were encouraged to remain active and refrain from tobacco smoking and alcohol. Additionally subjects randomized to the treatment arm received ZA 4 mg iv over 15 minutes within 28 days pre-HCT and at 3 and 6 months (mo) after HCT. Control subjects did not receive ZA or other additional therapy for bone strength. ZA dose was modified for post HCT renal dysfunction.
Primary outcome measure was change in BMD from baseline to 12 mo after HCT. Serum osteocalcin, serum bone specific alkaline phophatase (BSAP), and urinary N telopeptide (UNTX) were measured at baseline and at 6 and 12 mo.
Results:
Between 2006 and 2010, 61 patients were randomized – 32 to the ZA treatment cohort and 29 to the control arm. Cohorts were balanced for age, sex, performance score, donor type, diagnoses and conditioning regimen intensity. HCT co-morbidity index (HCTCI) was significantly worse in the ZA arm (50% with high risk scores > 3). Baseline BMD, T scores at the femoral neck and lumbar spine, urinary NTX, serum osteocalcin and BSAP were similar in both cohorts.
Differences between cohorts in bone density and bone specific laboratory parameters at 12 mo post HCT are summarized in Table 1. There was significant increase in BMD at the femoral neck and lumbar Spine; with concomitant decease in bone resorption markers for the treatment group (ZA cohort). Incidences of acute and chronic graft vs. host disease and relapse rates were similar between cohorts. There was significantly higher 1 year mortality in the ZA cohort (15 deaths vs. 6 in the control cohort). Thus overall survival was inferior in the ZA cohort 43% vs. 75% at 2 years post HCT. Grade 3–4 adverse events were similar.
Conclusions:
We randomized HCT recipients at high risk of post transplant bone loss to receive 3 doses ZA starting prior to HCT. ZA prevented further bone loss and resulted in improvement in BMD and T scores as well the bone resorption marker, urinary NTX. Lower survival was observed in the ZA cohort likely related to baseline imbalance in pretransplant HCTCI scores. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw, renal impairment or other serious adverse events. We conclude that intermittent ZA is effective in preserving long term bone health in HCT recipients at risk for osteoporosis.
Disclosures:
Hari: Novartis: Research Funding. Vesole:Novartis: Research Funding. Burns:Novartis: Research Funding.
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