A randomized trial of alendronate as prophylaxis against loss in bone mineral density following lymphoma treatment

Abstract

Lymphoma patients often receive high glucocorticoid doses as part of standard therapy. Observational studies have shown substantial risk of glucocorticoid-induced osteoporosis (GIO) with associated fractures. The aim of the SIESTA trial was to determine if oral alendronate (ALN) is a safe and effective prophylaxis against GIO in lymphoma. SIESTA was a single-center, randomized, double-blinded, phase 2 study of lymphoma patients planned for glucocorticoid-containing chemotherapy. After randomization, patients received weekly ALN 70mg or placebo for a total of 52 weeks. Bone mineral density (BMD) was assessed at baseline, after completion of chemotherapy (EOT, 4-6 month), and at end of study (EOS, 12 month). Vertebral fracture and biomarkers were assessed at baseline and EOS. Patients with baseline BMD assessment and at least one follow-up BMD assessment were analyzed for efficacy. Primary endpoint was change in lumbar spine T-score from baseline to EOS. Of the 59 patients enrolled, 23/30 in the ALN arm and 24/29 in the placebo arm were analyzed for efficacy. Mean change in T-score from baseline to 12 month at lumbar spine was +0.15 for ALN and -0.12 for placebo (P=0.023). The difference in ∆T_EOS between the ALN and placebo groups was larger among females (ALN 0.28; placebo -0.28) (P=0,01). Biomarker analyses confirmed reduced bone resorption in ALN treated patients. In conclusion, ALN is a safe and effective primary prophylaxis against loss in BMD following glucocorticoid-containing chemotherapy. Despite reduced BMD loss in the ALN arm, the treatment did not influence fracture risk in this small cohort of patients. This trial is registered at www.clinicaltrials.gov as 2015-005688-18.

Bone health and glucocorticoid‐containing lymphoma therapy — a review of risk factors and preventative measures

“…Collectively the biomarker results indicated reduced bone resorption in the ALN group and increased bone remodelling in placebotreated patients with more bone formation. 57 In summary, three relatively small sized randomized studies all provided consistent efficacy results for oral and intravenous BPs in reducing BMD loss during lymphoma treatment with the effect primarily observed at lumbar spine level. However, a reduction in the number of fractures was only reported in the trial by Kim et al where very high prednisolone doses were given.…”

“…[47][48][49][50] In several prospective trials, intravenous and oral bisphosphonates delivered synchronously with lymphoma therapy reduced BMD loss, although impact on fractures was not clearly documented likely due to the limited follow-up and limited sample size. 32,55,57 Importantly, biomarker analyses supported a favourable effect of BP on bone turnover. However, there remain some key uncertainties.…”

“…56 A randomized, phase 2 study of 59 patients with newly diagnosed or relapsed lymphoma from a single institution was recently published. 57 All enrolled patients were planned for GC-containing chemotherapy such as (R)-CHOP or (R)-CVP. Patients already receiving antiresorptive medication such as BPs were excluded.…”

“…Across all trials, 62 patients were exposed to intravenous BP and 30 patients to oral ALN. 32,55,57 No serious adverse events (SAEs) were reported in the studies of intravenous BP. 32,55 In the trial of oral BP, AEs were balanced between the two arms and no patients receiving oral ALN discontinued treatment because of AEs.…”

“…32,55 In the trial of oral BP, AEs were balanced between the two arms and no patients receiving oral ALN discontinued treatment because of AEs. 57 No osteonecrosis of the jaw (ONJ) or atrial fibrillation (AF) were reported, but these are known rare SAEs after BP. 59 For intravenous BP, the incidence of ONJ is approximately 1 in 10 000 to 100 000 patientyears and dental assessment is often recommended prior to therapy.…”