Osteoporosis

[Michael Scally MD]

[OA] Golds G, Houdek D, Arnason T. Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health. Int J Endocrinol. 2017:4602129. https://www.hindawi.com/journals/ije/2017/4602129/

It is well recognized that bone loss accelerates in hypogonadal states, with female menopause being the classic example of sex hormones affecting the regulation of bone metabolism. Underrepresented is our knowledge of the clinical and metabolic consequences of overt male hypogonadism, as well as the more subtle age-related decline in testosterone on bone quality.

While menopause and estrogen deficiency are well-known risk factors for osteoporosis in women, the effects of age-related testosterone decline in men on bone health are less well known. Much of our knowledge comes from observational studies and retrospective analysis on small groups of men with variable causes of primary or secondary hypogonadism and mild to overt testosterone deficiencies.

This review aims to present the current knowledge of the consequences of adult male hypogonadism on bone metabolism. The direct and indirect effects of testosterone on bone cells will be explored as well as the important differences in male osteoporosis and assessment as compared to that in females.

The clinical consequence of both primary and secondary hypogonadism, as well as testosterone decline in older males, on bone density and fracture risk in men will be summarized. Finally, the therapeutic options and their efficacy in male osteoporosis and hypogonadism will be discussed.

 

[Michael Scally MD]

[OA] Novel Anabolic Treatments for Osteoporosis

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton.

Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors. Sclerostin is a Wnt antagonist that binds to Wnt co-receptors and prevents Wnt signal activation.

Teriparatide, a 1-34 amino terminal fragment of parathyroid hormone (PTH), and abaloparatide, a modified 1-34 amino terminal fragment of PTH-related peptide (PTHrp), induce IGF-I, increase bone mineral density (BMD), reduce the incidence of vertebral and non-vertebral fractures and are approved for the treatment of postmenopausal osteoporosis.

Romosozumab, a humanized anti-sclerostin antibody, increases bone formation, decreases bone resorption, increases BMD and reduces the incidence of vertebral fractures. An increased incidence of cardiovascular events has been associated with romosozumab, which is yet to be approved for the treatment of osteoporosis.

In conclusion, cell and molecular studies have formed the foundation for the development of new anabolic therapies for osteoporosis with proven efficacy on the incidence of new fractures.

Canalis E. MANAGEMENT OF ENDOCRINE DISEASE: Novel Anabolic Treatments for Osteoporosis. European Journal of Endocrinology. MANAGEMENT OF ENDOCRINE DISEASE: Novel Anabolic Treatments for Osteoporosis

 

[Michael Scally MD]

Body Composition and Circulating Estradiol Are the Main Bone Density Predictors

PURPOSE: Current fracture risk assessment options in men call for improved evaluation strategies. Recent research directed towards non-classic bone mass determinants have often yielded scarce and conflicting results. We aimed at investigating the impact of novel potential bone mass regulators together with classic determinants of bone status in healthy young and middle-aged men.

METHODS: Anthropometric measurements, all-site bone mineral density (BMD) and body composition parameters assessed by dual-energy X-ray absorptiometry and also serum concentrations of
(1) the adipokines leptin and resistin,
(2) vitamin D and parathormone (PTH),
(3) sex hormone binding globulin (SHBG), total testosterone and estradiol (free testosterone was also calculated) and
(4) C-terminal telopeptide of type I collagen (CTx)
were obtained from 30 apparently healthy male volunteers aged 20-65 years enrolled in this cross-sectional study.

RESULTS: Only lean mass (LM) and total estradiol independently predicted BMD in men in multiple regression analysis, together explaining 49% (p </= 0.001) of whole-body BMD variance. Hierarchical regression analysis with whole-body BMD as outcome variable demonstrated that the body mass index (BMI) beta coefficient became nonsignificant when LM was added to the model. Adipokines, fat parameters, testosterone (total and free), SHBG, PTH and vitamin D were not independently associated with BMD or CTx.

CONCLUSIONS: The present study shows that LM and sex hormones-namely estradiol-are the main determinants of bone mass in young and middle-aged men. The effects of BMI upon BMD seem to be largely mediated by LM. Lifestyle interventions should focus on preserving LM in men for improved bone outcomes.

Bilha SC, Branisteanu D, Buzduga C, et al. Body composition and circulating estradiol are the main bone density predictors in healthy young and middle-aged men. Journal of endocrinological investigation 2018. Body composition and circulating estradiol are the main bone density predictors in healthy young and middle-aged men

 

[Michael Scally MD]

Testosterone and Male Osteoporosis

Male osteoporosis is not a rare public health issue. The prevalence of hypogonadism increases with aging, and the gradual onset of moderate hypogonadism is the most common cause of male osteoporosis.

Decreased testosterone levels with aging can directly or indirectly increase the risk of male osteoporosis and fractures. However, testosterone deficiency is not a universal feature of elderly men, and the association of testosterone with osteoporosis is not as strong as that of estrogen with osteoporosis in females; the effect of testosterone on male osteoporosis and treatment of osteoporosis is still controversial.

Although many data and results have been released, the mechanism by which testosterone affects bone formation and resorption is not fully understood yet. Therefore, this review aims to present current knowledge about testosterone and male osteoporosis.

Shin D-E, Ahn T-K, Kim J-W, Oh C-H, Choi S. Testosterone and Male Osteoporosis. Clinical Reviews in Bone and Mineral Metabolism 2018. https://doi.org/10.1007/s12018-018-9245-0

 

[Michael Scally MD]

Evidence of a Causal Effect of Estradiol on Fracture Risk in Men

Context - Observational studies indicate that serum estradiol (E2) is more strongly associated with bone mineral density (BMD) than serum testosterone (T) while both E2 and T associate with fracture risk in men.

Objective - To evaluate the possible causal effect of serum E2 and T on fracture risk in men.

Design, Setting, and Participants - A Mendelian Randomization (MR) approach was undertaken using individual-level data of genotypes, BMD as estimated by quantitative ultrasound of the heel (eBMD), fractures (n=17,650), and relevant covariates of 175,583 unrelated men of European origin from the UK Biobank. The genetic instruments for serum E2 and T were taken from the most recent large scale GWAS meta-analyses on these hormones in men.

Results - MR analyses demonstrated a causal effect of serum E2 on eBMD and fracture risk. A 1 SD (or 9.6 pg/ml) genetically instrumented decrease in serum E2 was associated with a 0.38 SD decrease in eBMD (p-value 9.7 x 10-74) and an increased risk of any fracture (OR 1.35, 95% CI, 1.18-1.55), non-vertebral major osteoporotic fractures (OR 1.75, 95% CI, 1.35-2.27) and wrist fractures (OR 2.27, 95% CI, 1.62-3.16).

These causal effects of serum E2 on fracture risk were robust in sensitivity analyses and remained unchanged in stratified analyses for age, BMI, eBMD, smoking status, and physical activity. MR analyses revealed no evidence of a causal effect of T levels on fracture risk.

Conclusion - Our findings provide the first evidence of a robust causal effect of serum E2, but not T, on fracture risk in men.

Nethander M, Vandenput L, Eriksson AL, Windahl S, Funck-Brentano T, Ohlsson C. Evidence of a Causal Effect of Estradiol on Fracture Risk in Men. The Journal of Clinical Endocrinology & Metabolism 2018. Evidence of a Causal Effect of Estradiol on Fracture Risk in Men | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic

 

[Michael Scally MD]

[OA] How to manage osteoporosis before the age of 50.

This narrative review discusses several aspects of the management of osteoporosis in patients under 50 years of age. Peak bone mass is genetically determined but can also be affected by lifestyle factors. Puberty constitutes a vulnerable period. Idiopathic osteoporosis is a rare, heterogeneous condition in young adults due in part to decreased osteoblast function and deficient bone acquisition.

There are no evidence-based treatment recommendations. Drugs use can be proposed to elderly patients at very high risk. Diagnosis and management of osteoporosis in the young can be challenging, in particular in the absence of a manifest secondary cause. Young adults with low bone mineral density (BMD) do not necessarily have osteoporosis and it is important to avoid unnecessary treatment.

A determination of BMD is recommended for premenopausal women who have had a fragility fracture or who have secondary causes of osteoporosis: secondary causes of excessive bone loss need to be excluded and treatment should be targeted. Adequate calcium, vitamin D, and a healthy lifestyle should be recommended. In the absence of fractures, conservative management is generally sufficient, but in rare cases, such as chemotherapy-induced osteoporosis, antiresorptive medication can be used.

Osteoporosis in young men is most often of secondary origin and hypogonadism is a major cause; testosterone replacement therapy will improve BMD in these patients. Diabetes is characterized by major alterations in bone quality, implying that medical therapy should be started sooner than for other causes of osteoporosis. Primary hyperparathyroidism, hyperthyroidism, Cushing's syndrome and growth hormone deficiency or excess affect cortical bone more often than trabecular bone.

Rozenberg S, Bruyère O, Bergmann P, et al. How to manage osteoporosis before the age of 50. Maturitas. 2020;138:14-25. doi:10.1016/j.maturitas.2020.05.004 https://www.maturitas.org/article/S0378-5122(20)30261-9/pdf

 

[Michael Scally MD]

[OA] Androgens and Androgen Receptor Actions on Bone Health and Disease

Androgens are not only essential for bone development but for the maintenance of bone mass. Therefore, conditions with androgen deficiency, such as male hypogonadism, androgen-insensitive syndromes, and prostate cancer with androgen deprivation therapy are strongly associated with bone loss and increased fracture risk.

Here we summarize the skeletal effects of androgens-androgen receptors (AR) actions based on in vitro and in vivo studies from animals and humans, and discuss bone loss due to androgens/AR deficiency to clarify the molecular basis for the anabolic action of androgens and AR in bone homeostasis and unravel the functions of androgen/AR signaling in healthy and disease states. Moreover, we provide evidence for the skeletal benefits of androgen therapy and elucidate why androgens are more beneficial than male sexual hormones, highlighting their therapeutic potential as osteoanabolic steroids in improving bone fracture repair.

Finally, the application of selective androgen receptor modulators may provide new approaches for the treatment of osteoporosis and fractures as well as building stronger bones in diseases dependent on androgens/AR status.

Chen JF, Lin PW, Tsai YR, Yang YC, Kang HY. Androgens and Androgen Receptor Actions on Bone Health and Disease: From Androgen Deficiency to Androgen Therapy. Cells. 2019;8(11):1318. Published 2019 Oct 25. doi:10.3390/cells8111318 Androgens and Androgen Receptor Actions on Bone Health and Disease: From Androgen Deficiency to Androgen Therapy

 

[Michael Scally MD]

Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment

This book represents a comprehensive, clinically oriented text covering all aspects of male osteoporosis, from the basic concepts of bone physiology and regulation of bone remodeling in men, the causes and pathophysiological mechanisms responsible for the most frequent causes of osteoporosis, to diagnostic and screening protocols, as well as prevention and treatment approaches. It offers a broad overview of male osteoporosis by specialists involved in research and clinical practice and discusses the practical issues encountered.

Ferlin A, Migliaccio S, eds. Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment. Cham: Springer International Publishing; 2020. Male Osteoporosis | SpringerLink

 

[Michael Scally MD]

Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment

This book represents a comprehensive, clinically oriented text covering all aspects of male osteoporosis, from the basic concepts of bone physiology and regulation of bone remodeling in men, the causes and pathophysiological mechanisms responsible for the most frequent causes of osteoporosis, to diagnostic and screening protocols, as well as prevention and treatment approaches. It offers a broad overview of male osteoporosis by specialists involved in research and clinical practice and discusses the practical issues encountered.

Ferlin A, Migliaccio S, eds. Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment. Cham: Springer International Publishing; 2020. Male Osteoporosis | SpringerLink

Rochira V, Madeo B. Estrogens and Male Osteoporosis. In: Ferlin A, Migliaccio S, eds. Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment. Cham: Springer International Publishing; 2020:67-84. Estrogens and Male Osteoporosis

Estrogens play an important role on bone health in men since they are needed for the achievement of peak bone mass at puberty and prevent bone loss in adulthood. Recent advancements in the comprehension of estrogen action on bone have pointed out on the importance of relative estrogen deficiency in men with low serum testosterone as a major determinant of osteoporosis in hypogonadal men. The recent use of mass spectrometry for sex steroid measurements also in the setting of clinical laboratories will allow the monitoring of both hypogonadism and testosterone therapy having as endpoint the normalization of serum estradiol too in addition to serum testosterone.

 

[Michael Scally MD]

Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment

This book represents a comprehensive, clinically oriented text covering all aspects of male osteoporosis, from the basic concepts of bone physiology and regulation of bone remodeling in men, the causes and pathophysiological mechanisms responsible for the most frequent causes of osteoporosis, to diagnostic and screening protocols, as well as prevention and treatment approaches. It offers a broad overview of male osteoporosis by specialists involved in research and clinical practice and discusses the practical issues encountered.

Ferlin A, Migliaccio S, eds. Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment. Cham: Springer International Publishing; 2020. Male Osteoporosis | SpringerLink

Aversa A, Ilacqua A. Androgen Therapy. In: Ferlin A, Migliaccio S, eds. Male Osteoporosis: Gender Differences in Pathophysiology, Clinical Aspects, Diagnosis and Treatment. Cham: Springer International Publishing; 2020:177-82. Androgen Therapy

Male osteoporosis is a health problem of multifactorial origin. Bone mineral density evaluation by X-ray densitometry allows diagnosis, while stratification of risk fracture is usually done through useful diagnostic tools, i.e., FRAXc. Observational studies demonstrate that sex hormones are important regulators of bone turnover in men.

Serum estradiol levels are consistent predictors of bone turnover in men. Although correlation data do not prove causality, interventional studies underline that estradiol appears to be the dominant sex hormone regulating bone resorption, while both testosterone and estradiol may be important in maintaining bone formation in male population.

It remains to be elucidated to what extent sex hormones and, more specifically, inadequate testosterone levels, i.e., late-onset hypogonadism, may contribute to increased risk of osteoporotic fractures. Measurements of serum testosterone levels are routinely indicated to exclude secondary causes of male osteoporosis and to designate appropriately all candidates for testosterone treatment. The association with other anti-resorption drugs is somehow indicated in association with testosterone treatment in all cases of severe fracture risk.

 

[Michael Scally MD]

Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density

Previous observational studies have identified various risk factors associated with the development of osteoporosis, including sex hormone-binding globulin (SHBG). The aim of this study was to determine the potential causal effects of circulating SHBG concentrations on bone mineral density (BMD). Two-sample Mendelian randomization (MR) approach was applied in analyses.

From summary-level data of genome-wide association studies (GWAS), we selected 11 single-nucleotide polymorphisms (SNPs) associated with SHBG levels as instrumental variable, and used summary statistics for BMD at forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498) and heel (HL) (n = 394,929), and total-body BMD of different age-stages (15 or less, 15-30, 30-45, 45-60, 60 or more years old) (n = 67,358).

Inverse causal associations was observed between SHBG levels and FA BMD (Effect = - 0.26; 95% CI - 0.49 to - 0.04; P = 0.022), HL eBMD (Effect = - 0.09; 95% CI - 0.12 to - 0.06; P = 3.19 × 10-9), and total-body BMD in people aged 45-60 years (Effect = - 0.16; 95% CI - 0.31 to - 2.4 × 10-3; P = 0.047) and over 60 years (Effect = - 0.19; 95% CI - 0.33 to - 0.05; P = 0.006).

Our study demonstrates that circulating SHBG concentrations are inversely associated with FA and HL eBMD, and total-body BMD in people aged over 45 years, suggesting that the role of SHBG in the development of osteoporosis might be affected by chronological age of patients and skeletal sites.

Qu Z, Jiang J, Yang F, Huang J, Zhao J, Yan S. Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density: A Mendelian Randomization Study. Calcif Tissue Int. 2020 Oct 17. doi: 10.1007/s00223-020-00770-8. Epub ahead of print. PMID: 33068140. Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density: A Mendelian Randomization Study

 

[Michael Scally MD]

[OA] Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health

One of the complications from chronic hyperglycemia and insulin resistance due to type 2 diabetes mellitus (T2DM) on the hypothalamic-pituitary-gonadal axis in men is the high prevalence of hypogonadotropic hypogonadism (HH).

Both T2DM and hypogonadism are associated with impaired bone health and increased fracture risk but whether the combination results in even worse bone disease than either one alone is not well-studied.

It is possible that having both conditions predisposes men to an even greater risk for fracture than either one alone. Given the common occurrence of HH or hypogonadism in general in T2DM, a significant number of men could be at risk.

To date, there is very little information on the bone health men with both hypogonadism and T2DM. Insulin resistance, which is the primary defect in T2DM, is associated with low testosterone (T) levels in men and may play a role in the bidirectional relationship between these two conditions, which together may portend a worse outcome for bone.

The present manuscript aims to review the available evidences on the effect of the combination of hypogonadism and T2DM on bone health and metabolic profile, highlights the possible metabolic role of the skeleton, and examines the pathways involved in the interplay between bone, insulin resistance, and gonadal steroids.

Russo V, Chen R, Armamento-Villareal R. Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health: A Narrative Review. Front Endocrinol (Lausanne). 2021 Jan 18;11:607240. doi: 10.3389/fendo.2020.607240. PMID: 33537005; PMCID: PMC7848021. Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health: A Narrative Review

 

[Michael Scally MD]

Effect of Testosterone Treatment on Bone Microarchitecture and Bone Mineral Density

Context: Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown.

Objective: Determine the effect of testosterone treatment on bone microarchitecture using high resolution-peripheral quantitative computed tomography (HR-pQCT).

Design, setting, participants: Men>50 years were recruited from six Australian centres.

Interventions: Injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program.

Main outcomes: Primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (one centre). Secondary endpoints included other HR-pQCT parameters and bone remodelling markers. Areal BMD (aBMD) was measured by dual energy X-ray absorptiometry (DXA) in 601 men (five centres). Using a linear mixed model for repeated measures, the mean adjusted differences (MAD) [95% CI] at 12 and 24 months between groups are reported as treatment effect.

Results: Over 24 months, testosterone treatment, compared to placebo, increased tibial cortical vBMD), 9.33mgHA/cm 3[3.96;14.71],p<0.001 or 3.1%[1.2;5.0], radial cortical vBMD, 8.96mgHA/cm 3[3.30;14.62],p=0.005 or 2.9%[1.0;4.9], total tibial vBMD, 4.16mgHA/cm 3[2.14;6.19],p<0.001 or 1.3%[0.6;1.9] and total radial vBMD, 4.42mgHA/cm 3[1.67;7.16],p=0.002 or 1.8%[0.4;2.0].

Testosterone also significantly increased cortical area and thickness at both sites. Effects on trabecular architecture were minor. Testosterone reduced bone remodeling markers CTX, -48.1ng/L[-81.1;-15.1],p<0.001, and P1NP, -6.8μg/L[-10.9;-2.7], p<0.001. Testosterone significantly increased aBMD at the lumbar spine, 0.04 g/cm 2[0.03;0.05],p<0.001, and the total hip, 0.01g/cm 2[0.01;0.02],p<0.001.

Conclusions: In men>50 years, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.

Ng Tang Fui M, Hoermann R, Bracken K, Handelsman DJ, Inder WJ, Stuckey BGA, Yeap BB, Ghasem-Zadeh A, McLachlan R, Robledo KP, Jesudason D, Zajac JD, Wittert GA, Grossmann M. Effect of Testosterone treatment on bone microarchitecture and bone mineral density in men: a two-year RCT. J Clin Endocrinol Metab. 2021 Mar 8:dgab149. doi: 10.1210/clinem/dgab149. Epub ahead of print. PMID: 33693907. Effect of Testosterone treatment on bone microarchitecture and bone mineral density in men: a two-year RCT

 

[Drew dude]

[OA] Golds G, Houdek D, Arnason T. Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health. Int J Endocrinol. 2017:4602129. https://www.hindawi.com/journals/ije/2017/4602129/

It is well recognized that bone loss accelerates in hypogonadal states, with female menopause being the classic example of sex hormones affecting the regulation of bone metabolism. Underrepresented is our knowledge of the clinical and metabolic consequences of overt male hypogonadism, as well as the more subtle age-related decline in testosterone on bone quality.

While menopause and estrogen deficiency are well-known risk factors for osteoporosis in women, the effects of age-related testosterone decline in men on bone health are less well known. Much of our knowledge comes from observational studies and retrospective analysis on small groups of men with variable causes of primary or secondary hypogonadism and mild to overt testosterone deficiencies.

This review aims to present the current knowledge of the consequences of adult male hypogonadism on bone metabolism. The direct and indirect effects of testosterone on bone cells will be explored as well as the important differences in male osteoporosis and assessment as compared to that in females.

The clinical consequence of both primary and secondary hypogonadism, as well as testosterone decline in older males, on bone density and fracture risk in men will be summarized. Finally, the therapeutic options and their efficacy in male osteoporosis and hypogonadism will be discussed.

I am in my early 30's and have 3 herniated discs in my lower back from L3-S1. My L5-S1 went out when I was 25, and was the first one to go. My MRI shows that they are all medium in severity. I've been researching some NIH studies that used deca-durabolin or HGH for disc preservation. I want to attempt a combination of the 2 instead of just one or the other. I'm very curious what your opinion on this subject is.