Zoledronic acid does not affect insulin resistance in men receiving androgen deprivation therapy: a prespecified secondary analysis of a randomised controlled trial

Background: Animal studies suggest that undercarboxylated osteocalcin may improve insulin sensitivity via its effect on testicular testosterone production. Human studies have been conflicting. Men undergoing androgen deprivation therapy (ADT) for prostate cancer experience profound hypogonadism resulting in increased insulin resistance. In a randomised controlled trial (RCT) of zoledronic acid versus placebo in men commencing extended-duration ADT, we aimed to examine the effects on fat mass and glucose metabolism. We hypothesised that zoledronic acid, which reduces osteocalcin concentrations, would worsen ADT-induced insulin resistance. Methods: This was a prespecified secondary analysis of an RCT designed to evaluate the effects of zoledronic acid on bone microarchitecture in 76 men with non-metastatic prostate cancer undergoing curative radiotherapy combined with adjuvant ADT (n=39 randomised to a single dose of zoledronic acid 5mg, n=37 randomised to matching placebo). Oral glucose tolerance tests to determine Matsuda Index were performed at 0, 3, 12 and 24months. Using a mixed model, mean adjusted differences [MAD (95% confidence interval)] between the groups over time are reported. Results: Over 24months of ADT, fat mass increased and lean mass decreased for both groups, with no significant between group difference [MAD 401g (-1307; 2103), p=0.23 and -184g (-1325; 955), p=0.36 respectively]. Bone remodelling markers C-telopeptide [MAD -176ng/l (-275; -76), p<0.001 and P1NP -18mg/l (-32; -5), p<0.001] as a surrogate for osteocalcin, remained significantly lower in the zoledronic acid group, compared with placebo. There was no mean adjusted between-group difference for homeostatic model assessment 2 insulin resistance (HOMA2-IR) [-0.2 (-0.6; 0.2), p=0.45], HbA1c [-0.1% (-0.3; 0.1), p=0.64] or Matsuda Index [0.8 (-1.1; 2.7), p=0.38]. The Matsuda Index decreased in both groups consistent with worsening insulin resistance with ADT. Conclusion: A single dose of zoledronic acid does not appear to influence glucose metabolism in men newly commencing ADT. Further study to evaluate the endocrine relationship between bisphosphonates, bone and glucose metabolism is required. Trial Registration Number: [ClinicalTrials.gov identifier: NCT01006395].

Automated summary

The study aimed to investigate the effects of zoledronic acid on fat mass and glucose metabolism in men undergoing ADT, with results showing no exacerbation of ADT-induced insulin resistance by zoledronic acid. Both groups experienced an increase in fat mass and a decrease in lean mass, but there was no significant difference between the two groups.