Bone Density, Anemia Improve With Testosterone in Low-T Men

Becky McCall

February 23, 2017

Testosterone therapy increases bone-mineral density (BMD) and strength and corrects anemia of known and unknown cause in older men with low levels of the hormone, show the two latest publications from the Testosterone Trials (so-called T Trials), published in JAMA Internal Medicine February 21.

Also published in the same issue of JAMA Internal Medicine is a paper that reports a lower risk of cardiovascular outcomes in men with low testosterone treated with testosterone-replacement therapy after three and half years of follow-up, compared with those who never got testosterone treatment. This study is not part of the T-Trial series.

And in JAMA, results of two further T Trials studies are published. One study finds no effect of testosterone treatment on memory or other cognitive functions in men with memory impairment and low testosterone levels (JAMA. 2017;317:717-727) and the second shows that after giving men with hypogonadism a year of testosterone, there was a significant increase in noncalcified coronary artery plaque compared with placebo (JAMA. 2017;317:708-716). The author of this latter study warns that "Plaque progression is bad; there's no mechanism by which this could be helpful" and suggests caution in treating older men who have already had a cardiovascular event or have significant atherosclerosis. An accompanying editorial calls the findings "unprecedented" and "ominous."

Overall, experts say that these findings in their totality show some added benefits of testosterone therapy — in terms of bone density and anemia — in men with low testosterone levels. But they repeatedly stress that the hormone shouldn't be prescribed as an "elixir of youth" for those with normal or borderline-normal testosterone.

T Trials Designed to Address Risks and Benefits of Testosterone

The T Trials are a series of seven linked studies performed to address recommendations made by the US Institute of Medicine in 2003 to critically evaluate the usefulness — including potential benefits and harms — of testosterone supplementation for several clinical indications.

Susan Ellenberg, PhD, professor of biostatistics from Perelman School of Medicine, University of Pennsylvania, Philadelphia, is an author on all four newly published T Trials. "This therapy has been used by millions of men without much rigorous study," she told Medscape Medical News. "There have been many benefits claimed but also many risks that people have been worried about. The intent of these trials was to see whether there were any benefits that would warrant doing larger studies on risks."

Last year, Medscape Medical News reported on the publication of the first three T Trials in the New England Journal of Medicine. In brief,these studies found that testosterone treatment in older men may help improve sexual function, mood, depressive symptoms, and possibly walking distance, but not vitality.

Testosterone Ups Density and Strength of Trabecular Spinal Bone

The new bone-density T trial, published with lead author Peter J Snyder, MD, Perelman School of Medicine, University of Pennsylvania, randomly assigned men over 65 years with low testosterone levels (averaged less than 275 ng/dL) to receive testosterone or placebo gel for 1 year. Testosterone therapy aimed to raise levels of the hormone to the normal range for young men. Spine and hip volumetric bone-mineral density (vBMD) was determined after 1 year, with spine vBMD being the primary outcome.

Testosterone therapy was associated with significantly greater increases in mean spine trabecular vBMD from baseline than placebo, at 7.5% compared with 0.8% respectively, equating to a treatment effect of 6.8% (P < .001).

These BMD findings were reflected in the mean estimated strength of spine trabecular bone, which showed a change from baseline of 10.8% with testosterone treatment vs 2.4% with placebo, giving a treatment effect of 8.5% (P < .001). The estimated strength increases were greater in trabecular than in peripheral bone and greater in the spine than the hip.

"We were pleased to see a clear improvement in bone density and strength, as measured in this trial," remarked Dr Ellenberg, who is senior author on this paper.

However, the ultimate test of whether testosterone is beneficial in terms of increasing bone density and strength will be in whether the therapy reduces fractures in those older than 65, she noted.

"The fact that testosterone in this study increased bone density and strength may [mean that it] reduces fractures, but data on fractures were insufficient to draw any conclusions," Dr Ellenberg added.

Eric S Orwoll, MD, director of the Bone and Mineral Clinic and the Bone Density Lab at Oregon Health and Science University, Portland, penned an accompanying editorial to both T Trial papers in JAMA Internal Medicine.

With regard to the bone effects, he noted, "These results provide very strong evidence that testosterone therapy in older men with low testosterone levels yields a positive skeletal effect. Nevertheless, important issues remain."

Average BMD in the trial participants was not low, and "whether testosterone replacement would be as effective in men with osteoporosis was not directly addressed," he observes.

Nevertheless, if a man needs testosterone therapy due to hypogonadism and looks like he may also require osteoporosis agents, then testosterone would be a good start, he noted. He also points out that testosterone treatment for more than 1 year would likely show accumulated positive effects on bone but that has yet to be demonstrated.

One of the bone study's coauthors, Jane Cauley, DrPH, from the University of Pittsburgh, Pennsylvania, said the findings were exciting: "Men who are taking testosterone therapy for low testosterone have an added benefit that their bone density will increase."

However, she also pointed out the lack of fracture data with testosterone treatment. Given that approved medications for osteoporosis have all demonstrated efficacy in preventing/reducing fractures, she noted, "It would be prudent for men with osteoporosis to be treated with a medicine proven to reduce fractures, even if they have low testosterone."

However, the magnitude of effect of testosterone on BMD was similar to other drugs for osteoporosis, suggesting a true beneficial effect. "But we need a clinical trial large enough to show an effect on fractures," she emphasized.

And Bradley Anawalt, MD, an endocrinologist from the University of Washington, Seattle, who was not involved in the T Trials, said that testosterone therapy could be a good initial therapy to increase bone mass and strength.

"The gain was comparable to commonly used drugs that have been approved for treatment of osteoporosis," he commented.

Testosterone for Anemia of Known and Unknown Cause

In the second T trial published in JAMA Internal Medicine, with Cindy N Roy, PhD, from Johns Hopkins University, Baltimore, Maryland, as lead author, testosterone treatment significantly increased the hemoglobin levels in older men with low levels of testosterone, whether they had unexplained anemia or anemia from known causes.

A greater percentage of men (54%) with unexplained anemia had 1-year hemoglobin levels that increased by 1.0 g/dL or more over baseline compared with men (15%) who received placebo (adjusted odds ratio [OR], 31.5; P = .002).

In men with anemia of known cause and treated with testosterone, a greater number (52%) had 1-year hemoglobin levels that had increased by 1.0 g/dL or more over baseline, compared with men (19%) on placebo (adjusted OR, 8.2; P = .003).

The authors note that few studies have specifically addressed the effect of testosterone in anemic men, and none, until now, have examined the effect of testosterone on men with unexplained anemia.

They point out that the findings do not translate into improved walking distance or reduction in fatigue, however, but the rise in hemoglobin level was significantly associated with participants' global impression of change in overall health and energy, suggesting that the increase in hemoglobin levels was clinically significant.

In his editorial, Dr Orwoll points out that, given the response seen in older men with anemia, "an assessment of gonadal status would be warranted. If hypogonadism is present, testosterone replacement should be considered."

But he also emphasized that, given the potential for adverse effects with excessive levels of hemoglobin, "these results serve to highlight the need to monitor hemoglobin levels in [testosterone]-treated men."

Harvey Jay Cohen, MD, from Duke University Medical Center, Durham, North Carolina, who was a coauthor on the anemia paper, said, "Since there are no other known treatments of unexplained anemia in the elderly, assessment of testosterone levels followed by a trial of testosterone treatment in those with low testosterone might be considered."

Commenting on the modest findings related to physical performance in the anemia study, Dr Cohen nevertheless suggested, "They might be meaningful to an older man with precariously balanced functional status. Often small changes in function can make a big difference in quality of life for those whose decline in functional level interferes with their daily activities."

Reassuring Cardiovascular Data, but Questions Remain

In the entire T Trial population of 790, no significant differences were found in major adverse cardiovascular events, serious adverse events, or prostate cancer between those receiving testosterone or placebo.

The third testosterone-related study in this week's JAMA Internal Medicine was a retrospective cohort study looking at the cardiovascular risks of testosterone-replacement therapy in 8808 men with androgen deficiency who were categorized as "ever-dispensed' testosterone therapy (mean age, 58.4 years). By comparison, data from 35,527 men also with androgen deficiency categorized as "never-dispensed" testosterone therapy (mean age, 59.8 years) were analyzed.

In the study, led by Craig Cheetham, PharmD, from Southern California Permanente Medical Group, Pasadena, testosterone therapy was not associated with an increased risk of cardiovascular outcomes.

In fact, write the authors, testosterone was associated with a lower risk of cardiovascular outcomes over a median follow-up of 3.4 years, with a rate of 23.9 vs 16.9 events per 1000 person-years in the never–testosterone-therapy and ever–testosterone-therapy groups, respectively.

The adjusted hazard ratio (HR) for the composite cardiovascular end point in the ever–testosterone-therapy group was 0.67 (P < .001). The same pattern was reflected when the outcome was restricted to combined stroke events (HR, 0.72; P < .001) and combined cardiac events (acute myocardial infarction, sudden cardiac death, unstable angina, revascularization procedures) (HR, 0.66; P < .001).

There has long been debate about whether giving testosterone therapy to older men is associated with any alteration in the risk of cardiovascular events, and in 2015, the US Food and Drug Administration required the manufacturers of prescription testosterone products to add information about the possible increased risk for heart attack and stroke with use of these products, warning that they should be used only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism. The European Medicines Agency, however, concluded there was little consistent evidence of any increased risk of cardiovascular events associated with use of testosterone products.

Now in his editorial, Dr Orwoll points out that most of the men included in this current study were relatively young and healthy, and it is likely older men who are at higher risk of cardiovascular events with testosterone therapy: "While the study certainly provides reassuring data concerning the effects of testosterone on cardiovascular health, convincing answers about this question…remain elusive and will require large, prospective randomized trials.

"At this point, clinicians and their patients should remain aware that the cardiovascular risks and benefits of testosterone replacement in older hypogonadal men have not been adequately resolved," he writes.

Overall Clinical Implications: Still Reserve T Therapy for Hypogonadism

Summarizing these latest findings, Dr Anawalt discussed the potential clinical use of testosterone in men with low levels of the hormone with Medscape Medical News.

"Because results of the T Trials have shown improved sexual function in many men with a low blood testosterone concentration, testosterone therapy would be a particularly good choice for such men who have low bone-mineral density and decreased sexual function," he observed.

And testosterone therapy "would be a reasonable treatment for men with mild anemia that is not due to bleeding, iron or vitamin deficiency, or a disease of the bone marrow," he added.

Finally, he agreed that there remains uncertainty about whether testosterone therapy affects the risk of heart attack or stroke in men, and therefore "testosterone therapy should be reserved for men who have unequivocally low blood testosterone concentrations and symptoms or signs of testosterone deficiency."

Importantly, he highlighted that testosterone should not be used as an "elixir of youth" for the large number of older men worldwide who have normal or borderline low blood concentrations without clear evidence of specific effects of testosterone deficiency, such as low bone-mineral density, low sex drive, or unexplained loss of muscle mass and strength.

Drs Ellenberg declares grants from the National Institutes of Health (NIH) and AbbVie during the conduct of the study and grants from AbbVie outside the submitted work. Dr Snyder reports grants from the National Institute on Aging (NIA) and the NIH and grants and nonfinancial support from AbbVie during the conduct of the study; and personal fees from Watson Laboratories outside the submitted work. Dr Roy reports grants from the NIH during the conduct of the study and grants from Celgene Corporation and the NIH outside the submitted work. Disclosures for the coauthors are listed in the papers. Dr Cheetham and coauthors report no relevant financial relationships, as do Drs Anawalt, Cohen, Cauley, and Orwoll.

JAMA Intern Med. Published online February 21, 2017. Snyder article, Roy article, Cheetham article, Editorial

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