Osteoporosis in hypogonadal men: Role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption, and low bone formation

Francis, Roger M.; Peacock, Munro; Aaron, Jean E.; Selby, Peter L.; Taylor, Geoffrey A.; Thompson, Janice L.; Marshall, D. H.; Horsman, A.

doi:10.1016/8756-3282(86)90205-x

Cited by 199 publications

(106 citation statements)

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confidence: 53%

“…In this study, calcitonin therapy was effective in reducing bone loss, and low calcitonin levels have been reported in another group of young hypogonadal men who had not undergone surgery [14]. Others have found low plasma 1,25 dihydroxyvitamin D levels and impaired calcium absorption in hypogonadal men [15].This combination of clinical and experimental evidence has led to the current prevailing view that gonadal androgens are the principal bone-active steroid hormones in males. However, recent evidence from several directions suggests that there is a significant effect of estrogens, and the role of adrenal androgens has also attracted interest.…”

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Sex Hormones and Osteoporosis in Men

et al. 1998

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Osteoporosis in men is a common disorder, the incidence of which is increasing. Bone is lost with advancing age in men as well as in women, leading to an increased risk of fracture after minimal trauma. Recent epidemiological data from North America suggests a lifetime risk of fracture of the hip, spine, or forearm of 13.1% in white men aged 50 [1]. Despite the considerable public health burden attributable to these fractures, our understanding of their pathogenesis is incomplete and there is no established treatment for osteoporosis in men.Androgen deficiency is thought to play an important role in many cases of male osteoporosis. Biochemical evidence of hypogonadism is found in about 20% of men with vertebral fractures [2] and up to 50% of men with hip fractures [3,4], often without other clinical features of gonadal failure. In cell culture studies using human osteoblastlike cells from both men and women [5][6][7], specific androgen receptors can be identified by nuclear and cytosolic binding assays (Table 1). Similarly, osteoblasts obtained from fresh femoral bone specimens can also metabolize the circulating androgen androstenedione to testosterone and 5␣-dihydrotestosterone (DHT) in both men and women [8] at rates dependent mainly on androstenedione concentration. Cells of osteoclast lineage may also have these properties, though this is less well established. Androgen receptors have also been directly demonstrated in osteoblasts and osteocytes around the growth plate [9]. Androgens may promote proliferation and differentiation of osteoblasts, inhibit osteoclast recruitment or affect osteoblast-to-osteoclast signaling.Animal studies have mostly been performed in orchiectomized (orch) male rats, though there are reservations about the appropriateness of this model because the rat skeleton grows throughout life. Replacement therapy with either testosterone or 5␣-DHT results in enhanced bone mass, though this remains lower than in control rats [10].In male humans, androgens have a marked effect on bone growth and peak bone mass via the growth hormone/ IGF-I axis; accordingly, androgen deficiency before puberty leads to lower bone mineral density (BMD) in both cortical and trabecular bone. Loss of androgens in later life is associated with increased bone resorption and loss of trabecular bone, but cortical bone mass is not greatly affected [11,12]. In a study of 12 men who had undergone judicial castration for ''sexual delinquency'' [13], bone turnover was increased and lumbar spine BMD fell significantly, with evidence of the most rapid loss in the first 5 years after castration. Rates of bone loss were as high as 7% per year, comparable to loss rates seen in early postmenopausal women. In this study, calcitonin therapy was effective in reducing bone loss, and low calcitonin levels have been reported in another group of young hypogonadal men who had not undergone surgery [14]. Others have found low plasma 1,25 dihydroxyvitamin D levels and impaired calcium absorption in hypogonadal men [15].This combination o...

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confidence: 52%

Sex Hormones and Osteoporosis in Men

et al. 1998

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“…Energy restriction is known to decrease bone mass density in adult rats (37), indicating that the decreased energy balance in pmch Ϫ/Ϫ rats could result in osteoporosis. Hypogonadism is another known inducer of osteoporosis (15,63). However, pmch Ϫ/Ϫ rats were already osteoporotic, while serum-free testosterone levels were indifferent compared with pmch ϩ/ϩ rats at PND 40, suggesting that loss of MCH signaling leads to osteoporosis independently of androgen deficiency.…”

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confidence: 99%

Pmchexpression during early development is critical for normal energy homeostasis

Mul

Berg³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Mul JD, Yi CX, van den Berg SAA, Ruiter M, Toonen PW, van der Elst MCJ, Voshol PJ, Ellenbroek BA, Kalsbeek A, la Fleur SE, Cuppen E. Pmch expression during early development is critical for normal energy homeostasis. Am J Physiol Endocrinol Metab 298: E477-E488, 2010. First published November 24, 2009 doi:10.1152/ajpendo.00154.2009.-Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch Ϫ/Ϫ rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch Ϫ/Ϫ rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries. melanin-concentrating hormone; hypothalamus; childhood obesity; rat knockout model CHILDHOOD OBESITY IS NOW WIDELY recognized as a severe public health issue (43). Treatment with drugs aimed at neural systems involved in the determination of the energy balance could potentially result in a lower energy balance during puberty as well as later in adulthood. Therefore, neuropeptides involved in body weight regulation during early development and puberty are attractive targets for anti-childhood obesity drugs.The neuronal metabolic systems in humans and primates develop prenatally, while in rodents these systems develop during the first 3 postnatal weeks (5, 21). This results in the activation and optimization of neuronal systems during early rodent development. A second important metabolic period is puberty, a period of major growth, hormonal changes, and sexual maturation. In the rat, puberty is characterized by different responses of young-adolescent [postnatal day (PND) 40] and young-adult (PND 60) male rats to environmental cues like stress and cold (17,18). In addition to these age-dependent behavioral differences, the amount of food consumed durin...

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“…Hypogonadism in men results in bone loss (13) and orchidectomy in male rats results in cortical and trabecular bone loss because of increased bone turnover. (14) The orchidectomy-induced cortical and trabecular bone loss in rats is prevented by treatment with testosterone.…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

Russell

Clarke

Cheong

et al. 2014

Journal of Bone and Mineral Research

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Androgen action via the androgen receptor (AR) is essential for normal skeletal growth and bone maintenance post-puberty in males; however, the molecular and cellular mechanisms by which androgens exert their actions in osteoblasts remains relatively unexplored in vivo. To identify autonomous AR actions in osteoblasts independent of AR signaling in other tissues, we compared the extent to which the bone phenotype of the Global-ARKO mouse was restored by replacing the AR in osteoblasts commencing at either the 1) proliferative or 2) mineralization stage of their maturation. In trabecular bone, androgens stimulated trabecular bone accrual during growth via the AR in proliferating osteoblasts and maintained trabecular bone post-puberty via the AR in mineralizing osteoblasts, with its predominant action being to inhibit bone resorption by decreasing the ratio of receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) gene expression. During growth, replacement of the AR in proliferating but not mineralizing osteoblasts of Global-ARKOs was able to partially restore periosteal circumference, supporting the concept that androgen action in cortical bone to increase bone size during growth is mediated via the AR in proliferating osteoblasts. This study provides further significant insight into the mechanism of androgen action via the AR in osteoblasts, demonstrating that it is dependent on the stage of osteoblast maturation.

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Osteoporosis in hypogonadal men: Role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption, and low bone formation

Cited by 199 publications

References 29 publications

Sex Hormones and Osteoporosis in Men

Sex Hormones and Osteoporosis in Men

Pmchexpression during early development is critical for normal energy homeostasis

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

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