A major new study published in the New England Journal of Medicine has found that testosterone treatment in hypogonadal men does not reduce the risk of fracture. The findings challenge previous assumptions about the bone-protective effects of testosterone therapy.
Background
Testosterone levels naturally decline with age in men, and over 2 million men in the United States have been diagnosed with hypogonadism, meaning they produce abnormally low levels of testosterone. Common symptoms include low sex drive, erectile dysfunction, depressed mood, fatigue, and loss of muscle mass.
In addition to these symptoms, there have been long-standing concerns that low testosterone levels could have negative impacts on bone health. Multiple observational studies have found positive associations between higher endogenous testosterone levels, as well as testosterone treatment, and higher bone mineral density.
Based on this evidence, testosterone therapy has often been assumed to protect against osteoporosis and fracture risk. However, data directly linking testosterone treatment to fracture outcomes have been lacking.
Details of the New Study
Researchers conducted an industry-funded, double-blind, placebo-controlled trial involving 790 men over age 65 with hypogonadism and low bone mineral density. The men were randomized to receive testosterone treatment or placebo for 2 years.
The primary outcome was the incidence of fractures, which were assessed every 3 months through patient reporting and medical record review. Bone mineral density was also measured periodically by dual-energy x-ray absorptiometry (DXA).
Key Findings
The study found no significant difference in fracture incidence between the testosterone and placebo groups:
| Group | Fracture Incidence |
|---|---|
| Testosterone | 5.2% |
| Placebo | 6.2% |
There was also no difference in rates of vertebral fracture, nonvertebral fracture, traumatic fracture, or hip fracture analyzed separately.
Meanwhile, testosterone treatment was associated with significantly increased bone mineral density at the lumbar spine, total hip, and femoral neck compared to placebo over 2 years. This indicates that testosterone has anabolic effects on bone, but that these effects do not appear to translate into reduced fracture risk on the timeframe studied.
Interpretation
These findings challenge the concept that testosterone treatment protects against fractures in older hypogonadal men. Although testosterone increased bone mineral density relative to placebo, it did not lead to a lower fracture incidence.
One potential explanation is that testosterone treatment may improve bone quantity, as reflected in DXA scans, but not bone quality. There are other architectural and turnover-related factors beyond bone mineral density that contribute to bone strength.
It’s also possible that a study longer than 2 years is needed to detect an antifracture effect. But for now, the use of testosterone therapy solely for fracture prevention does not appear evidence-based.
Responses from Experts
Experts in osteoporosis and bone health have weighed in on the study’s implications:
“This well-conducted industry-sponsored trial provides high-quality evidence that testosterone therapy for 2 years does not reduce fracture risk in older men with age-related hypogonadism,” said Dr. Ethel Siris, an endocrinologist and osteoporosis specialist at Columbia University. “While testosterone increased BMD relative to placebo, it did not lead to lower fracture incidence over 2 years of treatment. Longer and larger trials are needed to definitively determine whether testosterone therapy reduces fracture risk over a longer duration.”
Dr. Sundeep Khosla, an expert in osteoporosis in men at the Mayo Clinic, said: “These findings should change clinical practice. Many providers have assumed testosterone therapy would have bone-protective effects in hypogonadal men akin to estrogen in postmenopausal women. But this study found no fracture risk reduction despite improvements in BMD. Testosterone should not be prescribed solely for preventing fractures without further evidence.”
What This Means for Patients
For hypogonadal men considering testosterone replacement, these results indicate that any beneficial bone effects do not translate to reduced fractures within the first couple years of treatment. Patients should not expect testosterone therapy to provide rapid fracture prevention.
However, this study does not mean testosterone has no bone-protective effects in men. It may still help preserve bone health over longer durations. Patients should discuss the pros and cons of testosterone therapy with their doctor, including effects on symptoms, bone health, and potential side effects.
Decisions around starting testosterone should be based primarily on symptoms rather than attempting to prevent osteoporosis. Additionally, patients with high fracture risk could benefit from consulting with an endocrinologist or osteoporosis specialist.
What Happens Next?
Further research is warranted to clarify if testosterone therapy reduces fractures with longer duration treatment extending beyond 2 years. It will also be important to study effects of testosterone withdrawal on bone health.
In the meantime, expert guidelines may be updated to reflect the current evidence that testosterone therapy has not yet been shown to reduce clinical fractures in hypogonadal men, despite increases in BMD.
Providers should avoid routinely prescribing testosterone solely for fracture prevention unless further evidence emerges. Shared decision-making around testosterone therapy should focus primarily on effects on hypogonadal symptoms.
This study raises doubts about assumed bone-protective effects of testosterone in men. But longer-term data on fracture outcomes are still needed to definitively determine if testosterone treatment can help prevent fractures in aging hypogonadal males over an extended duration. Patients with high fracture risk should speak to their doctor about additional preventative strategies.
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