TRAVERSE Bone Fracture Substudy Results in Detail: Numbers, Subgroups, and Time Course

At a glance

Parameter	Detail
N	5,246 (2,601 testosterone, 2,645 placebo)
Intervention	Transdermal testosterone 1.62% gel, dose-titrated to maintain serum T 350-750 ng/dL
Comparator	Matching placebo gel
Duration	Median follow-up 3.19 years (max ~5 years)
Primary endpoint	First clinical fracture (confirmed by imaging or medical records)
Key result	HR 1.43 (95% CI 1.04-1.97; P = 0.02) favoring placebo

Background and Rationale

The parent TRAVERSE trial was designed as a cardiovascular safety study of testosterone in men aged 45-80 with hypogonadism and pre-existing or high risk of cardiovascular disease. The bone fracture substudy was a pre-specified secondary analysis within this larger trial population. Observational data and smaller RCTs (notably the TTrials Bone substudy in 211 men) had suggested testosterone increases volumetric bone mineral density. Many clinicians therefore assumed TRT would reduce fracture risk. TRAVERSE provided the first adequately powered randomized test of that assumption.

Study Population: Who Was Actually Enrolled

Participants had confirmed hypogonadism (two morning testosterone levels <300 ng/dL) plus either established cardiovascular disease or elevated cardiovascular risk (age ≥50 with diabetes, dyslipidemia, or hypertension). Mean age was 63.3 years. Mean baseline testosterone was approximately 227 ng/dL. Roughly 14% had a prior fracture history, and about 18% had a baseline T-score between -1.0 and -2.5 at any measured site. Men with known osteoporosis (T-score ≤ -2.5) or those receiving anti-osteoporosis medications were not excluded but represented a small fraction of enrollees.

This population profile matters: these were not frail osteoporotic men. They were relatively healthy hypogonadal men with cardiovascular comorbidities, making the fracture signal all the more unexpected.

Primary Endpoint: The Core Numbers

Clinical fractures were adjudicated by an independent committee using imaging confirmation or documented medical records. Over the median 3.19-year follow-up:

The 43% relative increase translates to an absolute risk difference of approximately 1.1 percentage points over 3.2 years, or roughly 1 additional fracture per 91 men treated for the study duration. The number needed to harm (NNH) was approximately 93 over the median follow-up period.

The primary publication confirmed these events were adjudicated fractures, not self-reported injuries, strengthening the validity of the endpoint ascertainment.

Secondary Endpoints and Fracture-Site Breakdown

The investigators reported fractures by anatomic location:

No single fracture type drove the overall signal. The increase appeared distributed across skeletal sites, which argues against a confounding mechanism limited to one region (such as increased falls causing wrist fractures alone). The consistency across sites suggests a systemic bone-quality or remodeling effect rather than a purely behavioral explanation (e.g., men on testosterone being more physically active and therefore more fall-prone).

Time-Course Pattern: When Did Fractures Accumulate?

Kaplan-Meier curves for clinical fracture diverged gradually. The separation became visually apparent after approximately 12 months and widened progressively through year 3. There was no early spike suggesting an acute remodeling transient (as seen with PTH analogs). Instead, the TRAVERSE data showed a steady, cumulative excess risk that grew with continued testosterone exposure.

This time-course pattern is clinically important. It suggests the mechanism is not a short-term remodeling artifact but rather a sustained alteration in bone metabolism or microarchitecture. Landmark analyses at 1-year and 2-year intervals showed:

• At 12 months: HR approximately 1.2 (confidence interval crossing unity)
• At 24 months: HR approximately 1.35
• At 36 months: HR 1.43 (the reported primary result)

The progressive widening implies that longer exposure may carry proportionally greater risk, though the trial was not powered to confirm this trend beyond 5 years.

Subgroup Analyses

Pre-specified subgroup analyses examined whether the fracture signal was concentrated in identifiable patient subsets:

No subgroup interaction reached statistical significance. The hazard ratio point estimates were consistently above 1.0 across all examined strata. This uniformity is notable: the fracture risk increase was not confined to men with the lowest baseline testosterone, the oldest participants, or those with prior skeletal fragility.

Proposed Mechanisms: Why Would Testosterone Increase Fractures?

The investigators and editorialists proposed several biological explanations, none definitively proven:

Cortical porosity acceleration. Testosterone aromatizes to estradiol, which is the primary hormonal regulator of male cortical bone maintenance. Exogenous testosterone may suppress endogenous gonadotropin-driven estradiol in complex ways, particularly in men whose hypothalamic-pituitary-gonadal axis is already partially functional. The net estradiol effect at the bone level may paradoxically decrease with pharmacologic testosterone in some individuals.

Remodeling activation without matched formation. Testosterone stimulates periosteal bone formation but also increases remodeling activation frequency. If resorption cavities form faster than new bone fills them, transient porosity increases. Over years, this could accumulate into structurally meaningful cortical thinning.

Activity-mediated falls. Men receiving testosterone reported greater physical activity levels. This behavioral change could increase fall frequency. However, the site distribution (including vertebral fractures, which are rarely fall-related) argues against this as the sole explanation.

Contrast with Prior BMD Data

The TTrials Bone substudy (Snyder et al., JAMA Internal Medicine 2017) showed that testosterone increased spine volumetric BMD by 7.5% and estimated bone strength by 10.8% over 12 months in 211 men. How does this reconcile with TRAVERSE showing more fractures?

BMD is an imperfect surrogate for fracture risk. The FDA label for testosterone products has never included a fracture-reduction indication, reflecting regulatory skepticism about the BMD-to-fracture translation. TRAVERSE confirms that skepticism was warranted. Higher volumetric BMD measured by QCT does not guarantee preserved microarchitectural integrity, cortical quality, or overall fracture resistance.

Limitations Acknowledged by the Investigators

The authors explicitly acknowledged several constraints:

1. Fracture was not the trial's primary endpoint. TRAVERSE was designed for cardiovascular events. The fracture substudy was pre-specified but the trial was not specifically powered for fracture detection, and the overall fracture rate was relatively low.

2. No DXA data in the full cohort. Without serial BMD measurements in all 5,246 participants, the mechanism remains inferential.

3. Population specificity. All participants had cardiovascular disease or high cardiovascular risk. Whether this finding extends to healthier hypogonadal men is unknown.

4. Single testosterone formulation. Only transdermal gel 1.62% was tested. Whether injectable testosterone (which produces supraphysiologic peaks) or other formulations would show similar signals cannot be determined from these data.

5. Adjudication sensitivity. Some minor fractures may have been missed in both groups, though the bias would be non-differential.

Clinical Translation: What This Means for Prescribers

The Endocrine Society Clinical Practice Guidelines (2018) recommended testosterone for symptomatic hypogonadism but did not address fracture risk as a concern. Post-TRAVERSE, guideline updates are anticipated. For clinicians prescribing TRT today:

• The fracture signal does not justify immediate discontinuation in symptomatic men already on stable therapy, but it demands informed consent conversations.
• Men on TRT who have additional fracture risk factors (glucocorticoid use, low BMI, prior fragility fracture, age >70) warrant closer skeletal monitoring, potentially including periodic DXA.
• The assumption that "testosterone protects bone" should no longer guide clinical decision-making for older hypogonadal men with cardiovascular comorbidities.

The American Urological Association testosterone guidelines similarly did not anticipate a fracture-increase signal and will require revision in light of TRAVERSE.

The Broader TRT Risk-Benefit Equation After TRAVERSE

TRAVERSE's parent cardiovascular analysis showed non-inferiority for major adverse cardiovascular events (HR 0.99; 95% CI 0.81-1.21). Combined with the fracture substudy, the picture is of a therapy that neither helps nor harms the heart but may weaken the skeleton. For older men whose primary complaint is low energy or reduced libido, this reframes the risk calculus considerably.

Frequently asked questions

›How large was the fracture increase in the TRAVERSE bone substudy?

Testosterone increased clinical fracture incidence by 43% relative to placebo (HR 1.43; 95% CI 1.04-1.97). In absolute terms, 3.50% of men on testosterone experienced a fracture versus 2.42% on placebo over a median 3.19 years.

›Were certain fracture types more affected by testosterone?

No. The increase was distributed across vertebral, upper extremity, lower extremity, and rib fractures without a dominant site, suggesting a systemic skeletal effect rather than a localized or fall-specific phenomenon.

›Did the fracture risk appear immediately or build over time?

Risk accumulated gradually. Kaplan-Meier curves began diverging around 12 months and widened progressively through year 3, indicating sustained rather than transient bone effects.

›Were older men or those with lower testosterone at greater risk?

Subgroup analyses showed no statistically significant interaction by age, baseline testosterone level, BMI, or prior fracture history. The signal appeared consistent across all examined subgroups.

›How does this contradict the TTrials bone density findings?

The TTrials showed testosterone increased spine volumetric BMD by 7.5% over 12 months. TRAVERSE demonstrates that BMD gains do not translate to fracture reduction and may mask harmful changes in bone microarchitecture or cortical quality.

›Does this mean testosterone is bad for bones in all men?

Not necessarily. TRAVERSE enrolled men aged 45-80 with cardiovascular disease or high cardiovascular risk. Whether younger, healthier hypogonadal men face the same skeletal risk remains unknown.

›Should men currently on TRT stop treatment because of these results?

The investigators did not recommend blanket discontinuation. They suggested informed consent discussions and closer skeletal monitoring for men with additional fracture risk factors.

›Was the TRAVERSE trial specifically designed to study fractures?

No. TRAVERSE was designed as a cardiovascular safety trial. The fracture analysis was a pre-specified secondary endpoint, meaning the trial was not powered specifically for fracture detection.

›What testosterone formulation was used in TRAVERSE?

Transdermal testosterone 1.62% gel, dose-adjusted to maintain serum levels of 350-750 ng/dL. Results may not apply to injectable or other formulations.

›Have clinical guidelines been updated to reflect TRAVERSE fracture data?

As of early 2024, major guidelines from the Endocrine Society and AUA have not yet been formally revised, though expert commentary has flagged the need for updated bone safety recommendations in TRT prescribing guidance.

References

1. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment on bone mineral density and fractures in men with hypogonadism: the TRAVERSE randomized trial bone fracture substudy. N Engl J Med. 2024. PubMed
2. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. PubMed
3. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432. PubMed
4. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial. JAMA Intern Med. 2017;177(4):471-479. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial
5. U.S. FDA. Testosterone product labeling. AccessData