Sex steroid hormones regulate bone metabolism in men

[madman]

Role of sex steroids hormones in the regulation of bone metabolism in men: Evidence from clinical studies (2022)
Pawel Szulc, MD, Ph.D., Senior Research Fellow


Sex steroids regulate bone metabolism in young men during growth and consolidation. Their deficit during growth compromises longitudinal and radial growth of bones and has a negative impact on body height, bone width, peak areal bone mineral density (BMD), and bone microarchitecture. In older men, the deficit of sex steroid hormones (mainly 17b-estradiol) contributes to a high bone turnover rate, low BMD, poor bone microarchitecture, low estimated bone strength, accelerated bone loss, and rapid decline of bone microarchitecture. The role of 17b-estradiol is confirmed in the case of men with congenital estrogen receptor deficit and with congenital aromatase deficiency. 17b-estradiol inhibits bone resorption, whereas both hormones regulate bone formation. However, the associations are weak. Prospective data on the utility of blood 17b-estradiol or testosterone for fracture risk assessment are inconsistent. Men with hypogonadism have decreased BMD and poor bone microarchitecture. In men with hypogonadism, testosterone replacement therapy increases BMD and improves bone microarchitecture. In men with prostate cancer, androgen deprivation therapy (gonadoliberin analogs) induces rapid bone loss and severe deterioration of bone microarchitecture.

Hormones modulate bone turnover over the entire life. During growth, they control axial and radial bone growth. During aging, they regulate the decline of bone mass and microarchitecture. As age-related changes in sex steroid secretion vary between men and women, the growth of the skeleton and its decline during aging also differ between the sexes.




*Circulating sex steroid hormones
-Fractions
-Age-related changes in circulating concentrations of sex steroid hormones

*Growth

*Aging

*Sex steroids and bone in men e epidemiological studies

*Case reports of specific mutations

*Pharmacologically induced sex steroid deficiency

*Hypogonadism
-Hypogonadism in younger adult men
-Hypogonadism in older men

*Hormonal treatment of prostate cancer




Summary

Sex steroids regulate bone metabolism in boys during growth and in men during aging. Their deficit during growth compromises longitudinal and radial growth of bones and has a negative impact on body height, bone width, and peak BMD. The deficit during aging contributes to bone loss, a decline in bone microarchitecture, and a decrease in bone strength. However, the associations are weak, and abnormal bone status (e.g., accelerated bone decline) was found only in men with low levels of bioavailable or free sex steroids. Although 17b-estradiol seems to be the major sex steroid regulating bone metabolism in men, the variation of 17b-estradiol concentrations accounts only for 1.2-2.5% of the variation in BMD in men [152]. Moreover, prospective data on the associations of the blood 17b-estradiol or testosterone (including their bioavailable fractions) with fracture risk are limited and inconsistent [153-156]. Thus, the utility of the measurement of sex steroids for the assessment of bone status in men is limited. The inconclusive results may partly depend on the poor accuracy of older assays and on the inaccurate assessment of bioavailable and free fractions. We need more studies: 1. to define the threshold concentrations of sex steroids below which bone deterioration starts, and 2. to standardize the assessment of bioavailable fractions of circulating sex steroids.

 

[madman]

Fig. 1. Age dependency of two-dimensional bone geometry in girls (left) and boys (right). Results in adults from 29 to 40 years of age are indicated as bars (mean þ 2 SD). The best fit regression lines and maximal slopes of polynomial regressions are indicated: A) total cross-sectional area, B) cortical area, C) medullary area. Copyright: Reproduced from Neu CM et al. Osteoporosis International, 2001 12:538e547 (Ref. [29]) with permission from Springer Verlag.

 

[madman]

Fig. 2. Levels of bone turnover markers in 596 men, aged 51-85 yr, according to the quartiles of serum bioavailable 17b-estradiol. Left panel - bone formation: A) osteocalcin (p < 0.001), B) bone alkaline phosphatase (p ¼ 0.02), C) N-terminal propeptide of type I collagen p < 0.02. Right panel - bone resorption: A) total deoxypyridinoline (p < 0.01), B) urinary b-isomerized C-terminal telopeptide of type I collagen (bCTX-I) (p < 0.001), C) serum bCTX-I p < 0.02. Copyright: Reproduced from Szulc P et al. J Clin Endocrinol Metab, 2001 86:192e199 (Ref. [25]) with permission from Oxford University Press

 

[madman]

Fig. 3. X-ray films of the hand and wrist of a 25-year-old man with congenital aromatase deficiency after 12 months of raloxifene treatment at a daily dose of 60 mg, with a corresponding bone age of 15.3 years, and the epiphyseal cartilages were still open (left panel), and after 12 months of transdermal estradiol at the dose of 25 mg twice weekly (right panel). A rapid increase in bone maturation, with the closure of the metacarpal and phalangeal epiphyses and corresponding bone age of 17 years, is evident after transdermal estradiol treatment (right panel). Copyright: Reproduced from Zirilli L et al. Bone, 2009 45:827-832 (Ref. [85]) with permission from Elsevier)

 

[madman]

Fig. 4. Percent change from baseline in (A) serum C-terminal telopeptide of type I collagen (CTX), (B) urinary N-terminal telopeptide of type I collagen (NTX), and (C) serum tartrate-resistant acid phosphatase 5b (TRACP5b) levels in the four study groups between the baseline and final visits. *p < 0.05, **p < 0.01, and ***p < 0.001 for change from baseline. The overall effect of 17b-estradiol (E, 37.5 mg/d) and testosterone (T, 5 mg/d) on the bone markers was analyzed using the two-factor ANOVA model in four groups of older men who underwent suppression of sex steroids using a gonadoliberin analog and aromatase inhibitor. Shown are the medians and interquartile ranges. Copyright: Reproduced from Sanyal A et al. J Bone Miner Res, 2008 23:705-714 (Ref. [99]) with permission from John Wiley and Sons

 

[madman]

Fig. 5. Comparison of the bone microarchitectural indices assessed by high resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius in 51 men with hypogonadism (light grey) and 40 healthy volunteers (dark grey). The selected panels demonstrate the results on the total and compartmental area (A-C), cortical bone (D, E), and trabecular bone (F-H) outcomes. Abbreviations: NS, not significant; CHH, congenital hypogonadotropic hypogonadism; KS, Kallmann syndrome. **p < 0.01; ****p < 0.0001. Copyright: Reproduced from Ostertag A et al. J Clin Endocrinol Metab, 2021 106:e3312-e3326 (Ref. [103]) with permission from Oxford University Press.

 

[madman]

Fig. 6. Effect of transdermal testosterone and transdermal testosterone patch treatment on urinary N-telopeptide (NTX)/creatinine (Cr) ratio, and serum parathyroid hormone (PTH), osteocalcin, and type I procollagen in men with hypogonadism (mean ± SE) The patients were initially (days 0-90) randomized to three groups: T patch (closed triangles), testosterone gel 50 mg/day (closed squares) and testosterone gel 100 mg/day (closed circles) (left panels of the graphs). Based on the serum testosterone, the dose of testosterone was adjusted upwards or downwards to 75 mg/day on day 90 if the serum testosterone concentration was below or above the adult male range, respectively: testosterone gel 50-75 mg/day (open squares), testosterone gel 100 to 75 mg/day (open circles) (right panels of each graph). Copyright: Reproduced from Wang C et al. Clinical Endocrinology, 2001 54:739-750 (Ref. [130]) with permission from John Wiley and Sons

 

[madman]

Fig. 7. Mean percentage increase (±SEM) in areal BMD of the lumbar spine (A), trochanteric (B), total hip (C), and intertrochanteric (D) regions in older men with low testosterone concentration who were treated with either testosterone (n = 24, T-only), testosterone and finasteride (n = 22, T + F), or placebo (n = 24) for 36 months. *p < 0.05 compared with baseline and placebo. Copyright: Reproduced from Amory JK et al. J Clin Endocrinol Metab, 2004 89:503-510 (Ref. [128]) with permission from Oxford University Press.

 

[madman]

Fig. 8. Volumetric bone mineral density (vBMD) in testosterone- and placebo-treated older men with low testosterone concentration. Shown are adjusted mean (95% CI) total (A-B), cortical (C-D) and trabecular (E-F) vBMD, measured by high resolution peripheral quantitative computed tomography at the radius and tibia in testosterone-(T, solid lines) and placebo- (P, dashed lines) treated men at baseline (week 0), week 66, and week 102. Copyright: Reproduced from Ng Tang Fui M et al. J Clin Endocrinol Metab, 2021 106:e3143-e3158 (Ref. [125]) with permission from Oxford University Press

 

[madman]

Fig. 9. Changes in areal bone mineral density assessed by DXA in men with prostate cancer during treatment with leuprolide or bicalutamide: A) total body, B) lumbar spine, C) total hip, D) femoral neck. Data presented as mean ± SE. p values are between-group comparisons of the percentage change from baseline to 12 months. Copyright: Reproduced from Smith MR et al. J Clin Oncol, 2004 22:2546-2553 (Ref. [142]) with permission from Wolters Kluwer Health, Inc.

 

[madman]

Practical points

*In men, sex steroid hormones regulate bone metabolism during growth (longitudinal growth, radial growth, consolidation) and during aging (slowdown of bone loss)

*The main sex steroid regulating bone metabolism in men is 17b-estradiol

*In older men, low 17b-estradiol level (mainly its bioavailable fraction) is associated with high bone turnover rate, low areal bone mineral density (BMD), poor bone microarchitecture, rapid bone loss, and rapid decline of bone microarchitecture

*Men with hypogonadism have decreased BMD and poor bone microarchitecture

*In men with hypogonadism, testosterone replacement therapy increases BMD and improves bone microarchitecture

*In men with prostate cancer, androgen deprivation therapy induces severe hypogonadism followed by rapid bone loss and deterioration of bone microarchitecture

 

[madman]

Research agenda

*The mechanisms of endocortical contraction in late puberty need further studies

*The assessment of the bioavailable fractions of blood sex steroid hormones should be better standardized

*We need more studies to define the threshold concentrations of sex steroids below which bone deterioration starts

*The impact of testosterone replacement therapy on fracture risk should be assessed in prospective studies

 

[madman]

*A proportion of androgens is aromatized into estrogens, partly in testicles and partly in peripheral tissues, mainly in adipocytes

*About 20% of serum 17b-estradiol originates from testicles and about 80% from peripheral aromatization

 

[madman]

Critical Role of Estrogens on Bone Homeostasis in Both Male and Female

Abstract: Bone is a multi-skilled tissue, protecting major organs, regulating calcium phosphate balance, and producing hormones. Its development during childhood determines height and stature as well as resistance against fracture in advanced age. Estrogens are key regulators of bone turnover in...

www.excelmale.com

Testosterone and Bone Health in Men

Abstract: Bone fracture due to osteoporosis is an important issue in decreasing the quality of life for elderly men in the current aging society. Thus, osteoporosis and bone fracture prevention is a clinical concern for many clinicians. Moreover, testosterone has an important role in maintaining...

www.excelmale.com

Hypogonadism and bone

Late Onset Hypogonadism (LOH): bone health Abstract Background. Bone health is underdiagnosed and undermanaged in men. Bone loss occurs in men with hypogonadism and in aging men. Thus, patients with a diagnosis of late-onset hypogonadism (LOH) are at risk of osteoporosis and osteoporotic...

www.excelmale.com

 

[madman]

Effects of Testosterone on Bone and Muscle

Effects of Testosterone on Bone and Muscle by Dr. Shailender Bhasin

www.excelmale.com

 

[madman]

Bone health in aging men

Bone health in aging men (2022) Karel David · Nick Narinx · Leen Antonio · Pieter Evenepoel · Frank Claessens · Brigitte Decallonne · Dirk Vanderschueren Abstract Osteoporosis does not only affect postmenopausal women but also aging men. The burden of disease is projected to increase with...

www.excelmale.com