U-Shaped Association Between Testosterone and Fractures

The occurence of fractures in an elderly population is a significant concern, so this study looked at the relation between the number of fractures and hormone levels, including testosterone. It found fractures were higher at both low and high levels of endogenous testosterone:

"Analysis of 3,307 community-dwelling men aged 76.8±3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG) and luteinising hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analysed probability of fracture and performed Cox regression adjusted for age, medical comorbidities and frailty.

"Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested non-linear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T,
"Mid-range plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk."

U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men
Bu B Yeap , Helman Alfonso , S A Paul Chubb , Jacqueline R Center , Jonathan Beilin , Graeme J Hankey , Osvaldo P Almeida , Jonathan Golledge , Paul E Norman , Leon Flicker
The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 5, May 2020, Pages 1489–1500, https://doi.org/10.1210/clinem/dgaa115

 

Interesting. I wonder if the higher T levels cause either more fractures due to more exposure to activities that can cause it (due to higher stamina) or if higher hematocrit can decrease blood flow to bones.

 

Whenever I see I u-shaped result, I'm a little suspicious. I'd like to see this study replicated.

 

We now know that low levels of testosterone does cause issues. High levels we don't know, high levels are definitely much better than low levels.
When I have my next wellness exam. I'm going to get another bone density test.

 

Thread 'Testosterone Treatment and Fractures in Men with Hypogonadism'

Jan 18, 2024

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2308836

Background

Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed.


Methods

In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a...

• madman
• traverse; testosteron; trt; fractures; bone health
• Replies: 2
• Forum: Testosterone and Men's Health Articles

 

I find the findings about high T very strange.​

​

Briefing Document: Association of Plasma Testosterone and SHBG with Fracture Incidence in Older Men​

Source: Yeap, B. B., et al. "U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men." J Clin Endocrinol Metab, vol. 105, no. 5, 2020, pp. 1489–1500.

Date: May 2020

Purpose: To assess the associations of various sex hormones with the incidence of any bone fracture or hip fracture in older men, aiming to understand the role of androgens versus estrogen in maintaining bone health during male aging.

Study Design: This was an observational study utilizing data from the Health In Men Study (HIMS) cohort.

• Participants: 3307 community-dwelling men from Perth, Western Australia, with a mean age of 76.8 ± 3.5 years at baseline (2001-2004). Men with known osteoporosis, previous bone fracture, Paget's disease, or receiving specific bone-affecting medications were excluded.
• Follow-up: Median follow-up period of 10.6 years, extending until December 31, 2016.
• Hormone Assays: Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) were quantified by liquid chromatography-tandem mass spectrometry (LC-MS). Sex hormone-binding globulin (SHBG) and luteinizing hormone (LH) were measured by immunoassay.
• Fracture Ascertainment: Incident fractures were determined via the Western Australian Data Linkage System (WADLS), linking to records from death, hospital, and emergency department registries. Fractures associated with falls were included, excluding pathological fractures.
• Outcomes: The primary outcomes were the incidence of any fracture and the incidence of hip fracture.
• Statistical Analysis: Cox proportional hazards regression was used, adjusted for age, medical comorbidities (e.g., smoking, alcohol, hypertension, diabetes, CVD, depression), frailty, BMI/waist, creatinine, and vitamin D. Nonlinear relationships were explored using restricted cubic splines.

Key Findings:

1. Testosterone (T) and Fracture Risk (U-Shaped Association):

• The study found a "U-shaped association of plasma T with incidence of any fracture... and hip fracture." This means that men with midrange plasma testosterone concentrations had the lowest risk of fractures.
• Specifically, men with T concentrations in the second (Q2) and third (Q3) quartiles had a significantly lower risk of any fracture compared to those in the lowest quartile (Q1):
• Q2 vs. Q1: Fully adjusted Hazard Ratio (HR) = 0.69 (95% CI 0.51–0.94, P = .020)
• Q3 vs. Q1: Fully adjusted HR = 0.59 (95% CI 0.42–0.83, P = .002)
• Similarly, for hip fracture:
• Q2 vs. Q1: Fully adjusted HR = 0.60 (95% CI 0.37–0.93, P = .043)
• Q3 vs. Q1: Fully adjusted HR = 0.52 (95% CI 0.31–0.88, P = .015)
• Men with T concentrations in the highest quartile (Q4) had a similar risk of both any fracture and hip fracture as those in the lowest quartile (Q1), reinforcing the U-shaped relationship. The risk was "not different in men with T concentrations in Q4 versus Q1."
• Calculated free testosterone (cFT) results mirrored total T for any fracture but not for hip fracture, suggesting "total T appears to be the more informative measure of circulating androgen."

1. Sex Hormone-Binding Globulin (SHBG) and Hip Fracture Risk:

• Higher SHBG concentrations were associated with an increased risk of hip fracture.
• Men with SHBG in the highest quartile (Q4) had a significantly increased risk of hip fracture compared to those in the lowest quartile (Q1):
• Q4 vs. Q1: Fully adjusted HR = 1.76 (95% CI 1.05–2.96, P = .033)
• This association "was largely unchanged when T was included in the fully adjusted model." This finding is consistent with other studies that have linked higher SHBG with increased fracture risk.

1. Estradiol (E2) and Other Hormones:

• "DHT, E2, and LH were not associated with fracture."
• This finding regarding E2 is notable, as it "differs from previous studies" and runs "contrary to previous studies and the reasons for this are unclear." The authors postulate that "in older men, circulating E2 may not be fully indicative of E2 exposure in specific tissues."
• LH was not associated with fracture risk, indicating that "circulating T not LH appears to influence fracture risk in older men."

Main Themes/Most Important Ideas:

• Midrange Testosterone is Optimal for Bone Health in Older Men: The study provides strong evidence for a U-shaped association between plasma testosterone and fracture risk. This implies that both very low and very high testosterone levels may increase fracture risk in older men, with a "sweet spot" in the middle of the normal range offering the best protection against fractures. This is a significant departure from studies that primarily focused on the risks associated with low T.
• Androgens, Not Estrogen, as Primary Biomarker for Fracture Risk in Older Men: The study concludes that "Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk." The lack of association between E2 and fracture risk, despite estrogen's known role in bone metabolism (including T's aromatization to E2), suggests that circulating E2 levels in older men might not accurately reflect tissue-level E2 exposure or its impact on bone.
• SHBG as an Independent Risk Factor for Hip Fracture: Elevated SHBG is independently associated with an increased risk of hip fracture, reinforcing its role as a significant hormonal factor in male bone health, possibly by influencing androgen availability at the tissue level.
• Implications for Clinical Practice and Future Research: The findings suggest that future randomized controlled trials for testosterone treatment in older men should "recruit men with baseline T in the lowest quartile of values, and explore whether the degree to which exogenous T is aromatized at the tissue level predicts its beneficial effect on bone." This highlights the complexity of testosterone's role and the need to consider its metabolism and binding in future interventions.

Limitations:

• Observational Study: Causality cannot be established.
• "Healthy Survivor" Effect: Participants were community-dwelling men who had already participated in an earlier study, potentially leading to a healthier cohort and possibly lower fracture rates than the general population.
• Single Baseline Hormone Measurement: Hormonal status was assessed at one point, not longitudinally.
• Underestimation of Fractures: Fractures not requiring emergency department visits or hospital admissions (e.g., many vertebral fractures) were likely missed, potentially undercounting the overall fracture incidence.
• Lack of Bone Mineral Densitometry Data: The study did not include bone mineral density measurements, which could have provided further insight into the mechanisms.
• Homogeneous Cohort: Participants were predominantly Caucasian, limiting generalizability to other ethnicities or women.

Strengths:

• Large Sample Size and Long Follow-up: Allowed for a substantial number of fracture events, enhancing the precision of the analysis.
• Accurate Hormone Assays: Used mass spectrometry for T, DHT, and E2, which is superior for measuring low hormone concentrations.
• Comprehensive Covariate Adjustment: Adjusted for numerous potential confounding factors, including age, medical comorbidities, and frailty.
• Robust Outcome Ascertainment: Utilized a comprehensive data linkage system for fracture identification.

Conclusion:

This study provides compelling evidence for a U-shaped association between plasma testosterone levels and fracture risk in older men, indicating that midrange T levels are associated with the lowest incidence of both any fracture and hip fracture. Furthermore, high SHBG levels are associated with an increased risk of hip fracture. Contrary to some previous research, circulating estradiol was not found to be associated with fracture risk in this cohort. These findings underscore the importance of circulating androgen levels, particularly total testosterone and SHBG, as crucial biomarkers for bone health and fracture risk in aging men, warranting careful consideration in clinical assessment and guiding future therapeutic research.

 

What was the purpose of this study?​

The study aimed to investigate the relationship between different sex hormones (testosterone, dihydrotestosterone, estradiol), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) with the incidence of bone fractures, specifically any fracture and hip fracture, in older men. The researchers sought to understand whether androgens, distinct from estrogen, play a crucial role in maintaining bone health during male aging, which has implications for understanding osteoporosis.

Who participated in this study, and how were the data collected?​

The study analyzed data from 3307 community-dwelling men from Perth, Western Australia, with a mean age of 76.8 ± 3.5 years. These men were part of the Health In Men Study (HIMS) cohort. Blood samples collected between 2001-2004 served as the baseline for hormone measurements (testosterone, DHT, estradiol, SHBG, LH) using mass spectrometry and immunoassay. Incident fractures were identified over a median follow-up period of 10.6 years using the Western Australian Data Linkage System, which links records from various health registries.

What were the key findings regarding testosterone and fracture risk?​

The study found a "U-shaped" association between plasma testosterone (T) concentrations and the incidence of both any fracture and hip fracture. This means that men with midrange plasma T concentrations had the lowest risk of fractures. Both very low and very high testosterone levels were associated with an increased risk of fractures. Specifically, men with T in the second and third quartiles had significantly lower hazard ratios for fractures compared to those in the lowest quartile.

Was estradiol (E2) associated with fracture risk in this study?​

Unlike some previous studies, this research found no significant association between circulating estradiol (E2) levels and the incidence of any fracture or hip fracture in older men, even after adjusting for confounding factors. This suggests that in this cohort, circulating androgen, rather than estrogen, was a more direct biomarker for hormone effects on bone driving fracture risk.

What was the role of Sex Hormone-Binding Globulin (SHBG)?​

Higher levels of Sex Hormone-Binding Globulin (SHBG) were significantly associated with an increased risk of hip fracture. Men in the highest quartile of SHBG had a higher hazard ratio for hip fracture compared to those in the lowest quartile. This finding is consistent with other studies that have also linked higher SHBG to increased fracture risk in men.

How do these findings compare to previous research on sex hormones and fractures in men?​

The study's findings differ from some previous research, particularly concerning estradiol. While some past studies suggested an association between lower E2 and increased fracture risk, this study did not find such a link. However, the association of higher SHBG with increased fracture risk aligns with other major studies like MrOS US and MrOS Sweden. The U-shaped association of testosterone with fracture risk, where midrange levels are optimal, is a distinct finding compared to studies that only reported an increased risk with low testosterone. The larger cohort size and extended follow-up in this study may contribute to these more precise findings.

What are the clinical implications of these results for older men?​

The results suggest that maintaining midrange plasma testosterone levels might be beneficial for reducing fracture risk in older men. For older men with low-normal circulating testosterone without clear hypogonadism, the study implies that testosterone treatment could improve bone mineral density, though a randomized controlled trial specifically powered for fracture outcomes is still needed. Furthermore, future research should explore how the aromatization of exogenous testosterone into estradiol at the tissue level influences its beneficial effects on bone. The study also highlights SHBG as an important hormonal factor associated with fracture risk.

What were the limitations of this study?​

Several limitations were acknowledged. As an observational study, it cannot establish causality. The cohort might have a "healthy survivor" effect because participants had engaged in previous study waves. Hormone levels were measured from a single baseline blood sample, not serially over time. The overall incidence of fractures was relatively low, and vertebral fractures might be undercounted due to their potentially asymptomatic nature or non-hospital presentation. The study also lacked bone mineral densitometry data and was primarily conducted on Caucasian men, limiting the generalizability to other ethnicities or women.

 

From another study:

We did not expect these results, because most previous studies showed that testosterone improved many measures of bone structure and quality. In studies involving men with severe hypogonadism, testosterone treatment increased areal and volumetric bone mineral density1-4 and improved many structural and mechanical measures of trabecular bone on magnetic resonance microimaging.5-7 In the Testosterone Trials, which involved older men with hypogonadism, testosterone treatment for 1 year increased volumetric bone mineral density and estimated bone strength on quantitative CT.10

Because we did not expect these results, we did not design the trial to assess possible mechanisms by which testosterone would increase the incidence of fractures, so we can only speculate about possible mechanisms. Although previous studies showed that testosterone treatment in men with hypogonadism improved many measures of bone structure, especially of trabecular bone, one study showed that testosterone treatment in men with severe hypogonadism decreased cortical bone volume fraction and cortical bone axial thickness, a measure of bone strength.7

The fact that testosterone was associated with increased fracture risk among middle-aged and older men with hypogonadism should be considered in the context of potential benefits and other risks of testosterone treatment in these men. The Testosterone Trials showed that testosterone treatment improved sexual function26 and mood26 and increased hemoglobin levels27 in older men. In the present trial, testosterone was not associated with an increased risk of major adverse cardiovascular events but was associated with increased risks of atrial fibrillation, pulmonary embolism, and acute kidney injury.15
The Fracture Trial had many strengths, including enrolling more than 5000 men who had two low morning testosterone values, as well as a randomized, placebo-controlled design and a median duration of observation for more than 3 years — a large and long trial of testosterone treatment. Other strengths were the prespecified design to inquire about fractures at every visit, collection of information about reported fractures, and adjudication of the reported fractures centrally by an experienced adjudicator.16,17

This trial also had limitations. Participants were not evaluated for organic causes of hypogonadism, so it is not known whether some men with such causes were included. Adherence to administration of testosterone or placebo was suboptimal, although it was similar in the two trial groups. The increase in serum testosterone concentrations during treatment was less than in some other studies, but the lesser increase could not explain an increase in fractures. Information about falls was not assessed, except in participants who reported fractures. Physical activity and risk taking were also not assessed. Bone density and structure were not evaluated, so the effect of testosterone on these measures cannot be compared with the results in previous studies.

We found that among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo.

TRAVERSE: https://www.nejm.org/doi/full/10.1056/NEJMoa2308836

 

It would be interesting to see how many of the men were TRT. And what they're bone strength was before starting TRT.

 

It would be interesting to see how many of the men were TRT. And what they're bone strength was before starting TRT.

The TRAVERSE study had guys on Androgel although most were only over 400 ng/dL and not like most of us with T levels higher than that. @madman would know more.

 

The TRAVERSE study had guys on Androgel although most were only over 400 ng/dL and not like most of us with T levels higher than that. @madman would know more.

@madman when using Androgel does your T level usually peek at over 1000 ng/dL ?