The vitamin D receptor is highly expressed in the gastrointestinal tract where it transacts gene expression. With current limited understanding of the interactions between the gut microbiome and ...vitamin D, we conduct a cross-sectional analysis of 567 older men quantifying serum vitamin D metabolites using LC-MSMS and defining stool sub-Operational Taxonomic Units from16S ribosomal RNA gene sequencing data. Faith's Phylogenetic Diversity and non-redundant covariate analyses reveal that the serum 1,25(OH)
D level explains 5% of variance in α-diversity. In β-diversity analyses using unweighted UniFrac, 1,25(OH)
D is the strongest factor assessed, explaining 2% of variance. Random forest analyses identify 12 taxa, 11 in the phylum Firmicutes, eight of which are positively associated with either 1,25(OH)
D and/or the hormone-to-prohormone 1,25(OH)
D/25(OH)D "activation ratio." Men with higher levels of 1,25(OH)
D and higher activation ratios, but not 25(OH)D itself, are more likely to possess butyrate producing bacteria that are associated with better gut microbial health.
Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and ...androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution.
Central hypogonadism is a clinical condition, characterized by sexual symptoms and low serum testosterone levels, due to an impaired function of the hypothalamus or pituitary gland. Testosterone ...replacement therapy (TRT) is the standard treatment for hypogonadism, but it has some disadvantages. TRT is not a good option in men wishing to preserve fertility, nor in men with (a high risk of) prostate cancer, polycythemia, thrombophilia and severe cardiovascular disease. In this review, we discuss alternative treatments for central hypogonadism. If reversible causes are present, non-pharmacological interventions can be therapeutic. Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Clomiphene citrate and tamoxifen seem to be a safe alternative for the treatment of functional central hypogonadism in men, as several studies reported a significant increase in testosterone levels with these drugs. However, their use is off-label and data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. For this reason, clomiphene citrate and tamoxifen should not be used in routine clinical practice to treat sexual symptoms in men with central hypogonadism.
Context:
Public health authorities around the world recommend widely variable supplementation strategies for adults, whereas several professional organizations, including The Endocrine Society, ...recommend higher supplementation.
Methods:
We analyzed published randomized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health.
Conclusions:
The extraskeletal effects of vitamin D are plausible as based on preclinical data and observational studies. However, apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly, causality remains yet unproven in randomized controlled trials (RCTs). The greatest risk for cancer, infections, cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D (25OHD) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis, estimated from serum 1,25-dihydroxyvitamin D and PTH, calcium absorption, or bone mass, can be normalized by 25OHD levels above 20 ng/mL. Moreover, vitamin D supplementation (800 IU/d) in combination with calcium can reduce fracture incidence by about 20%. Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women. Based on calculations of the metabolic clearance of 25OHD, a daily intake of 500–700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore, the recommendations for a daily intake of 1500–2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects, as suggested by The Endocrine Society Task Force, are premature. Fortunately, ongoing RCTs will help to guide us to solve this important public health question.
Background
Evidence regarding functional hypogonadism, previously referred to as ‘late‐onset’ hypogonadism, has increased substantially during the last 10 year.
Objective
To update the European ...Academy of Andrology (EAA) guidelines on functional hypogonadism.
Methods
Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system.
Results
The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well‐validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%‐50% represent relative contraindications for TRT. Prostate‐specific antigen and digital rectal examination of the prostate should be undertaken in men >40 years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial.
Conclusion
TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long‐term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision‐making.
Structural gender differences in bone mass – characterized by wider but not thicker bones – are generally attributed to opposing sex steroid actions in men and women. Recent findings have redefined ...the traditional concept of sex hormones as the main regulators of skeletal sexual dimorphism. GH–IGF1 action is likely to be the most important determinant of sex differences in bone mass. Estrogens limit periosteal bone expansion but stimulate endosteal bone apposition in females, whereas androgens stimulate radial bone expansion in males. Androgens not only act directly on bone through the androgen receptor (AR) but also activate estrogen receptor-α or -β (ERα or ERβ) following aromatization into estrogens. Both the AR and ERα pathways are needed to optimize radial cortical bone expansion, whereas AR signaling alone is the dominant pathway for normal male trabecular bone development. Estrogen/ERα-mediated effects in males may – at least partly – depend on interaction with IGF1. In addition, sex hormones and their receptors have an impact on the mechanical sensitivity of the growing skeleton. AR and ERβ signaling may limit the osteogenic response to loading in males and females respectively, while ERα may stimulate the response of bone to mechanical stimulation in the female skeleton. Overall, current evidence suggests that skeletal sexual dimorphism is not just the end result of differences in sex steroid secretion between the sexes, but depends on gender differences in GH–IGF1 and mechanical sensitivity to loading as well.
The choice of a vitamin D–binding protein assay is key in calculating free 25-hydroxyvitamin D levels. The results of this analysis support the use of total 25-hydroxyvitamin D as a marker of vitamin ...D status, regardless of race or GC genotype.
To the Editor:
It is unclear whether circulating free or bioavailable 25-hydroxyvitamin D is a better marker of vitamin D status than is total 25-hydroxyvitamin D, especially in racially diverse populations. Until recently, the only method to compare the levels was to estimate the level of free or bioavailable 25-hydroxyvitamin D from total 25-hydroxyvitamin D, vitamin D–binding protein (also known as gc-globulin, encoded by the
GC
gene), and albumin, with or without the
GC
genotype. Powe et al. reported that levels of vitamin D–binding protein, as measured on a monoclonal enzyme-linked immunosorbent assay (ELISA, R&D Systems), were lower in black . . .
Bone is a biomechanical tissue shaped by forces from muscles and gravitation. Simultaneous bone and muscle decay and dysfunction (osteosarcopenia or sarco-osteoporosis) is seen in ageing, numerous ...clinical situations including after stroke or paralysis, in neuromuscular dystrophies, glucocorticoid excess, or in association with vitamin D, growth hormone/insulin like growth factor or sex steroid deficiency, as well as in spaceflight. Physical exercise may be beneficial in these situations, but further work is still needed to translate acceptable and effective biomechanical interventions like vibration therapy from animal models to humans. Novel antiresorptive and anabolic therapies are emerging for osteoporosis as well as drugs for sarcopenia, cancer cachexia or muscle wasting disorders, including antibodies against myostatin or activin receptor type IIA and IIB (e.g. bimagrumab). Ideally, increasing muscle mass would increase muscle strength and restore bone loss from disuse. However, the classical view that muscle is unidirectionally dominant over bone via mechanical loading is overly simplistic. Indeed, recent studies indicate a role for neuronal regulation of not only muscle but also bone metabolism, bone signaling pathways like receptor activator of nuclear factor kappa-B ligand (RANKL) implicated in muscle biology, myokines affecting bone and possible bone-to-muscle communication. Moreover, pharmacological strategies inducing isolated myocyte hypertrophy may not translate into increased muscle power because tendons, connective tissue, neurons and energy metabolism need to adapt as well. We aim here to critically review key musculoskeletal molecular pathways involved in mechanoregulation and their effect on the bone-muscle unit as a whole, as well as preclinical and emerging clinical evidence regarding the effects of sarcopenia therapies on osteoporosis and vice versa.
•Simultaneous bone and muscle decay and dysfunction are seen in aging and disuse.•Mechanical, endocrine, nutritional and neural signals co-regulate bone and muscle.•Muscle-bone interactions further involve local growth factors and myokines.•Myostatin and activin receptor inhibition holds promise for sarco-osteoporosis.•We recommend an integrated view on the bone-muscle unit.
This multicenter trial evaluated zoledronic acid versus placebo in men with osteoporosis for a primary end point of new morphometric vertebral fracture over 24 months. Zoledronic acid was associated ...with a significantly reduced risk of vertebral fracture.
Osteoporosis is an important cause of morbidity and mortality among men.
1
,
2
Among persons older than 50 years of age, approximately 40% of all osteoporotic fractures worldwide occur in men.
3
Mortality after osteoporotic fracture is higher among men than among women.
2
,
4
Previous studies involving men with osteoporosis have focused on the surrogate outcomes of bone mineral density and bone-turnover markers,
5
–
9
but data from double-blind, randomized studies assessing antifracture efficacy are lacking. In addition, given the low awareness of the disease,
10
the development of guidelines for the detection and treatment of osteoporosis in men has been limited.
11
Hence, there . . .
Context:
Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, ...considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD.
Objectives:
Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD.
Design:
This study used a cross-sectional design.
Setting:
The general community in the United States, United Kingdom, and The Gambia were included in this study.
Participants:
Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included.
Exposures:
Total 25OHD concentration, race, and DBP (GC) genotype exposures were included.
Outcome Measures:
Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures.
Results:
Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured by monoclonal assay, mean DBP in African-ancestry subjects was approximately 50% lower than in whites, whereas DBP measured by polyclonal DBP antibodies or proteomic methods was not lower in African-ancestry. Calculated f25OHD (using polyclonal DBP assays) correlated strongly with directly measured f25OHD (r = 0.80–0.83). Free 25OHD, measured or calculated from polyclonal DBP assays, reflected total 25OHD concentration irrespective of race and was lower in African Americans than in US whites.
Conclusions:
Previously reported racial differences in DBP concentration are likely from monoclonal assay bias, as there was no racial difference in DBP concentration by other methods. This confirms the poor vitamin D status of many African-Americans and the utility of total 25OHD in assessing vitamin D in the general population.
We found no racial or genetic differences in serum vitamin D binding protein. Free 25OHD, directly measured or calculated from DBP (using polyclonal antibodies), was low in Afro-Americans, compared to US whites or blacks from The Gambia.
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