Potential cardiovascular (CV) risks of testosterone replacement therapy (TRT) are currently a topic of intense interest. However, no studies have addressed CV risk as a function of the route of administration of TRT. Two meta-analyses were conducted, one of CV adverse events (AEs) in 35 randomized controlled trials (RCTs) of TRT lasting 12 weeks or more, and one of 32 studies reporting the effect of TRT on serum testosterone and dihydrotestosterone (DHT). CV risks of TRT: Of 2,313 studies identified, 35 were eligible and included 3,703 mostly older men who experienced 218 CV-related AEs. No significant risk for CV AEs was present when all TRT administration routes were grouped (relative risk (RR) = 1.28, 95% confidence interval (CI): 0.76 to 2.13, P = 0.34). When analyzed separately, oral TRT produced significant CV risk (RR = 2.20, 95% CI: 1.45 to 3.55, P = 0.015), while neither intramuscular (RR = 0.66, 95% CI: 0.28 to 1.56, P = 0.32) nor transdermal (gel or patch) TRT (RR = 1.27, 95% CI: 0.62 to 2.62, P = 0.48) significantly altered CV risk. Serum testosterone/DHT following TRT: Of 419 studies identified, 32 were eligible which included 1,152 men receiving TRT. No significant difference in the elevation of serum testosterone was present between intramuscular or transdermal TRT. However, transdermal TRT elevated serum DHT (5.46-fold, 95% CI: 4.51 to 6.60) to a greater magnitude than intramuscular TRT (2.20-fold, 95% CI: 1.74 to 2.77). Oral TRT produces significant CV risk. While no significant effects on CV risk were observed with either injected or transdermal TRT, the point estimates suggest that further research is needed to establish whether administration by these routes is protective or detrimental, respectively. Differences in the degree to which serum DHT is elevated may underlie the varying CV risk by TRT administration route, as elevated serum dihydrotestosterone has been shown to be associated with CV risk in observational studies.

Background: Inconsistent fat‐free mass (FFM) and muscle strength responses have been reported in randomized clinical trials (RCTs) administering testosterone replacement therapy (TRT) to middle‐aged and older men. Our objective was to conduct a meta‐analysis to determine whether TRT improves FFM and muscle strength in middle‐aged and older men and whether the muscular responses vary by TRT administration route.Methods: Systematic literature searches of MEDLINE/PubMed and the Cochrane Library were conducted from inception through 31 March 2017 to identify double‐blind RCTs that compared intramuscular or transdermal TRT vs. placebo and that reported assessments of FFM or upper‐extremity or lower‐extremity strength. Studies were identified, and data were extracted and validated by three investigators, with disagreement resolved by consensus. Using a random effects model, individual effect sizes (ESs) were determined from 31 RCTs reporting FFM (sample size: n = 1213 TRT, n = 1168 placebo) and 17 reporting upper‐extremity or lower‐extremity strength (n = 2572 TRT, n = 2523 placebo). Heterogeneity was examined, and sensitivity analyses were performed.Results: When administration routes were collectively assessed, TRT was associated with increases in FFM [ES = 1.20 ± 0.15 (95% CI: 0.91, 1.49)], total body strength [ES = 0.90 ± 0.12 (0.67, 1.14)], lower‐extremity strength [ES = 0.77 ± 0.16 (0.45, 1.08)], and upper‐extremity strength [ES = 1.13 ± 0.18 (0.78, 1.47)] (P < 0.001 for all). When administration routes were evaluated separately, the ES magnitudes were larger and the per cent changes were 3–5 times greater for intramuscular TRT than for transdermal formulations vs. respective placebos, for all outcomes evaluated. Specifically, intramuscular TRT was associated with a 5.7% increase in FFM [ES = 1.49 ± 0.18 (1.13, 1.84)] and 10–13% increases in total body strength [ES = 1.39 ± 0.12 (1.15, 1.63)], lower‐extremity strength [ES = 1.39 ± 0.17 (1.07, 1.72)], and upper‐extremity strength [ES = 1.37 ± 0.17 (1.03, 1.70)] (P < 0.001 for all). In comparison, transdermal TRT was associated with only a 1.7% increase in FFM [ES = 0.98 ± 0.21 (0.58, 1.39)] and only 2–5% increases in total body [ES = 0.55 ± 0.17 (0.22, 0.88)] and upper‐extremity strength [ES = 0.97 ± 0.24 (0.50, 1.45)] (P < 0.001). Interestingly, transdermal TRT produced no change in lower‐extremity strength vs. placebo [ES = 0.26 ± 0.23 (−0.19, 0.70), P = 0.26]. Subanalyses of RCTs limiting enrolment to men ≥60 years of age produced similar results.Conclusions: Intramuscular TRT is more effective than transdermal formulations at increasing LBM and improving muscle strength in middle‐aged and older men, particularly in the lower extremities.

Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n = 11–19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via μCT and histomorphometry) and distal femur (via μCT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population. © 2014 American Society for Bone and Mineral Research.

Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77-85% reduction in hindlimb cancellous bone volume at the distal femur (measured via μCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13-27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI.