The value of testosterone replacement therapy (TRT) older men is now being hotly debated. Our study offers comment on two points within that debate: 1) the musculoskeletal benefits of TRT and 2) the cardiovascular (CV) risks of TRT.

First, the Endocrine Society’s 2010 guidelines for TRT state that the musculoskeletal effects of testosterone are unproven (Bhasin et al., J Clin Endocrinol Metab 95(6):2536-59, see page 2552). However, the musculoskeletal effects of testosterone are dose-dependent and higher doses of T are typically administered by intra-muscular (i.m.) injection than with transdermal preparations (patch or gel). In a 2006 meta-analysis of 11 clinical trials, Ottenbacher et al. (J Am J Geriatr 54:1666-1673) found that i.m. injected TRT consistently produced moderate increases in one-repetition maximum (1-RM) strength, while the effects of transdermal and oral TRT were less. We surveyed 10 more recent publications addressing the effects of TRT on 1-RM muscle strength. Significant increases in muscle strength were observed in all 6 of the studies employing i.m. injected TRT and in none of the 4 employing transdermal TRT. Similarly, in a 2006 meta-analysis of 8 clinical trials, Tracz et al. (J Clin Endo Metab. 91:2011-2016) found that i.m. injected TRT produced a significant 8% increase in bone mineral density in the lumbar spine and a 4% increase in the hip. As such, it is apparent that the musculoskeletal benefits of i.m. injected TRT are proven and consistent, while the musculoskeletal effects of transdermal TRT are lesser and inconsistent.

Second, concern over potential CV adverse events resulting from TRT has resulted in warnings from the Endocrine Society, the Department of Veterans Affairs, and the FDA. Most recently, the FDA has mandated clinical trials for testosterone products addressing rates of CV disease, such as stroke, myocardial infarction, deep venous thrombosis, etc. These concerns arose because of a trial of TRT which was discontinued due a greater number of CV events in the treatment group and because of several observational studies indicating CV risk. Our meta-analysis is the largest and most recent evaluating the effect of TRT on CV events in randomized controlled trials (RCTs). Our analysis shows no significant CV risk when all TRT trials were considered; however, there is significant risk with oral TRT, a directional trend toward risk with transdermal TRT, and a directional trend toward benefit with i.m. injected TRT (Borst, Yarrow et al. BMC Medicine 12:211, 2014). Our findings are complemented by a meta-analysis by Corona et al. (Expert Opinion on Drug Safety 13:1327-1351, 2014) which included more studies (not all of which are RCTs) and found no CV risk when all forms of TRT were considered.

Although definite conclusions cannot be drawn until more subjects have been studied, available data suggests that i.m. injection may be both the most effective and safest form of TRT.

Written by:Borst SE, Yarrow JF.VA Medical Center Gainesville FL; Malcolm Randall VA Medical Center.

Abstract: Injection of Testosterone May be Safer and More effective than Transdermal Administration for combating Loss of Muscle and Bone in Older Men

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