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Testosterone use in men and its effects on bone health: a systematic review and meta-analysis of randomized placebo-controlled trials |
Tracz M J, Sideras K, Bolona E R, Haddad R M, Kennedy C C, Uraga M V, Caples S M, Erwin P J, Montori V M |
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CRD summary This review assessed the effects of testosterone on bone mineral density in men. The authors concluded that intramuscular testosterone moderately increased lumbar bone spine density, but the effects on femoral neck density were uncertain. Overall, this was a well-conducted review and the authors' conclusions are likely to be reliable.
Authors' objectives To evaluate the effects of testosterone on measures of bone health in men.
Searching MEDLINE, EMBASE and the Cochrane CENTRAL Register were searched from inception to March 2005; the search terms were not reported. The reference lists of primary studies and reviews identified from a search of MEDLINE were screened. In addition, experts who were members of the Endocrine Society Task Force were contacted. [A: No language restrictions were applied.]
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) were eligible for inclusion. The duration of the included studies ranged from 3 to 36 months; only two studies lasted more than 12 months.
Specific interventions included in the reviewStudies that compared any available preparation of testosterone with placebo were eligible for inclusion. In the included studies, testosterone was given intramuscularly or transdermally. Intramuscular interventions were testosterone enanthate 200 mg every week, 2 weeks or month, or testosterone mixed esters 200 mg every 2 weeks or 250 mg monthly. Transdermal interventions were a 2.5-mg patch, 5-mg Androderm patch, or 6-mg scrotal patch per day.
Participants included in the reviewStudies of men with any level of androgen deficiency were eligible for inclusion. The mean age of the participants in the included studies ranged from 36 to 75 years, and the mean baseline total testosterone levels ranged from 291 to 646 nanog/dL. Where reported, the included studies were in men with different characteristics, including chronic glucocorticoid use, wasting due to acquired immune deficiency syndrome, and Leydig cell dysfunction. One study included men with known osteoporotic fractures.
Outcomes assessed in the reviewStudies that assessed bone fractures, or lumbar or femoral neck bone mineral density (BMD), were eligible for inclusion. Studies that only assessed changes in biomarkers of bone turnover were excluded.
How were decisions on the relevance of primary studies made?Teams of two reviewers independently selected the studies. Any disagreements on inclusions were resolved through recourse to a third reviewer.
Assessment of study quality Two reviewers independently assessed the validity of each study. The studies were assessed for adequacy of randomisation, concealment of allocation, blinding of the patients, health care providers and collectors of data, and losses to follow-up. [A: The authors assumed that studies described as double-blind were blinded.]
Data extraction Two reviewers independently extracted the data onto a standardised form. For each study, data on the BMD (either end point or change from baseline) were extracted for the longest follow-up period with sufficiently complete data whilst patients were still taking testosterone or placebo. This was then used to calculate the effect size (ES) and 95% confidence interval (CI) of the difference in BMD between treatments. Authors of the primary studies were contacted for missing outcomes data. The studies were classified according to the mean testosterone level at baseline; a low testosterone level was defined as a total testosterone level of 300 nanog/dL or lower. Men in studies that did not report previous osteoporotic fractures were assumed to have not experienced previous fractures.
Methods of synthesis How were the studies combined?Pooled standardised mean differences with 95% CIs were calculated using a random-effects model for BMD at lumbar spine and femoral neck separately. Pooled percentage changes in BMD were also reported with 95% CIs.
How were differences between studies investigated?Statistical heterogeneity was assessed using the I-squared statistic. Pre-planned subgroup analyses were used to evaluate the effects of study quality, patient characteristics (age >60 years, primary or secondary prevention, level of androgen deficiency and previous glucocorticoid use), interventions (route of administration) and duration of follow-up.
Results of the review Eight RCTs (n=365) were included: seven parallel-group RCTs and one crossover RCT.
In terms of study quality, one study reported allocation concealment, while the reporting and use of blinding varied between studies. Losses to follow-up ranged from 6 to 34% (median 14).
None of the included studies assessed bone fractures.
The meta-analysis showed a small significant increase in lumbar spine BMD in men taking testosterone compared with placebo; the ES was 0.31 (95% CI: 0.02, 0.61), corresponding to a 4% (95% CI: 0.3, 8) gain in lumbar BMD. Moderate heterogeneity was found (I-squared 46%).
There was a small but non significant increase in femoral BMD with testosterone compared with placebo; the ES was 0.17 (95% CI: -0.11, 0.45). Moderate heterogeneity was found (I squared 26%).
The subgroup analysis showed that intramuscular testosterone significantly increased lumbar spine BMD in men taking testosterone compared with placebo; the ES was 0.62 (95% CI: 0.32, 0.92), corresponding to an 8% (95% CI: 4, 13) gain in lumbar BMD. This effect was significantly greater than the effect of transdermal testosterone on lumbar BMD (p=0.009). No significant heterogeneity was found in this subgroup analysis (I squared 0%). The review authors stated that this explained the heterogeneity among studies evaluating lumbar spine BMD (no data were presented). There was no difference between i.m. testosterone and transdermal testosterone for femoral neck BMD.
Subgroup analyses showed no significant interaction between treatment and use of glucocorticoids, testosterone level at baseline, age, duration of follow-up and losses to follow-up.
Authors' conclusions Intramuscular testosterone moderately increased lumbar bone spine density in men, but the effects on femoral neck density were uncertain.
CRD commentary The review addressed a clear question that was defined in terms of the participants, intervention, outcomes and study design. Several relevant sources were searched and attempts were made to minimise language bias. However, the search terms were not reported and only published studies were eligible; this raised the possibility of publication bias, as the authors acknowledged. Two reviewers independently selected studies, assessed validity and extracted the data, thereby reducing the potential for reviewer bias and errors. Validity was assessed using defined criteria, but the results were only partially reported. The review authors appear to have presumed that blinding was used in several studies but the justification for this was not clear.
The data were combined in a meta-analysis, statistical heterogeneity was assessed, and pre-planned subgroup analyses were used to examine potential sources of heterogeneity. Where the authors were unable to identify factors responsible for the heterogeneity this was stated. However, high drop-out rates might indicate that there were problems with the treatments and reasons for drop-outs were not reported. Overall, this was a well-conducted review and the authors' conclusions are likely to be reliable.
Implications of the review for practice and research Practice: The authors stated that patients and clinicians need to take the potential benefits and side-effects (see Other Publications of Related Interest) of testosterone into account when making treatment choices, and that clinicians who are uncertain about whether or not to recommend testosterone to their patients should instead enrol patients in future RCTs.
Research: The authors stated that large RCTs are required to assess the long-term (3 years or more) effects of testosterone plus adequate calcium and vitamin D on bone fractures in men with and without previous osteoporotic fractures. There is also a need to compare testosterone with other therapies such as bisphosphonates.
Funding Department of Medicine, Mayo Clinic College of Medicine.
Bibliographic details Tracz M J, Sideras K, Bolona E R, Haddad R M, Kennedy C C, Uraga M V, Caples S M, Erwin P J, Montori V M. Testosterone use in men and its effects on bone health: a systematic review and meta-analysis of randomized placebo-controlled trials. Journal of Clinical Endocrinology and Metabolism 2006; 91(6): 2011-2016 Other publications of related interest Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005;60:1451-7.
Indexing Status Subject indexing assigned by NLM MeSH Bone Density /drug effects; Glucocorticoids /adverse effects; Humans; Male; Osteoporosis /prevention & Randomized Controlled Trials as Topic; Testosterone /administration & control; dosage /blood /therapeutic use AccessionNumber 12006003552 Date bibliographic record published 31/07/2007 Date abstract record published 31/07/2007 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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