The effect of one-year cross-sex hormonal treatment on bone metabolism and serum insulin-like growth factor-1 in transsexuals.
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The effects of treatment with estrogens and antiandrogens in male to female (M-->F) transsexuals and androgens in female to male (F-->M) transsexuals on their respective bone metabolism, bone mineral density (BMD), serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels were investigated. BMD and variables of bone turnover in serum were measured at baseline and after 3 months (except for BMD) and 1 yr of treatment in 56 M-->F and 35 F-->M transsexuals. Serum IGF-I, IGFBP-3, and propeptide of type I procollagen (P1CP) were measured at baseline and after 1 yr of treatment in 10 M-->F and 10 F-->M transsexuals. In M-->F, BMD increased significantly. Bone turnover decreased, as shown by a significant decline in levels of osteocalcin, alkaline phosphatase, P1CP, and fasting urinary calcium/creatinine and hydroxyproline/creatinine ratios. Serum IGF-I levels decreased significantly without significant changes in IGFBP-3 levels. In F-->M, BMD did not change. Bone formation increased, as suggested by an increase in alkaline phosphatase and a borderline increase in P1CP values. IGF-I levels increased significantly, whereas no significant changes were seen in IGFBP-3 levels. We conclude that in males, estrogens (in combination with antiandrogens) decrease bone turnover, with a subsequent increase in BMD and a decrease in serum IGF-I. In females, testosterone administration increases bone formation, but this is not reflected in an increased BMD, whereas serum IGF-I increases.Keywords:
Bone remodeling
Hyperinsulinemia
Bone remodeling
Tartrate-resistant acid phosphatase
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Background:The markers of bone remodelling, such as serum osteocalcin, may be used to assess osteoporosis and to predict the fracture risk in elderly persons, especially in women.The bone mineral density which reflects the bone mass and strength, also predicts osteoporotic related hip fractures.So, this work highlights the association between the bone turnover and the bone mass and strength. Aim:To assess the association between the biochemical markers of bone remodeling and osteocalcin with the bone mineral density in non osteoporotic and osteoporotic women among post menopausal subjects. Materials and Methods:Sixty postmenopausal women whose ages ranged from 55-65 years included in this study, were further divided into group 1 (thirty non osteoporotic subjects) and group 2 (thirty osteoporotic subjects).For all the subjects, serum osteocalcin was measured by ELISA.BMD was measured by the Dual Energy X-Ray Absorptiometry (DXA) scan.The women with osteoporosis were diagnosed, based on the T-score of the bone mineral density, by the DXA scan.The Student's "t" test was performed between the variables of both the groups and a correlation test was also performed between osteocalcin and BMD by using SPSS.
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Bone turnover is acutely suppressed after feeding or oral glucose. Insulin infusion suppresses bone turnover and might mediate this effect, but this is confounded by a possible direct effect of hypoglycemia. We examined the effect of euglycemic hyperinsulinemia and hypoglycemic hyperinsulinemia on bone turnover using an insulin clamp. Sixteen men participated in this double-blind crossover study. Clamp induction involved infusion of insulin (80 mU/m2·min) while maintaining euglycemia (5 mmol/liter) for 40 min with a variable rate dextrose infusion. Glucose was lowered to 2.5 mmol/liter (hypoglycemic clamp) or maintained at 5 mmol/liter (euglycemic clamp) for a further 105 min. Nine controls received a matched saline infusion. Measurements included serum C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide, osteocalcin, and PTH. Induction of hyperinsulinemia resulted in a reduction in PTH (27% ± 5; P < 0.01), but no significant change in bone turnover from baseline. Hypoglycemic clamp resulted in suppression of serum C-terminal telopeptide of type I collagen by 34% ± 3, procollagen type I N-terminal propeptide by 15% ± 1, osteocalcin by 5% ± 1, and PTH by a further 12% ± 5 (all P < 0.05). By contrast, there was no significant change in any marker of bone turnover during euglycemic clamp. Postprandial hyperinsulinemia is unlikely to explain the acute suppression of bone turnover with feeding. The reduction in bone turnover during hypoglycemia may be related to hypoglycemia itself, acute changes in PTH, or other hormones released in response to hypoglycemia.
Hyperinsulinemia
Bone remodeling
N-terminal telopeptide
Glucose clamp technique
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Excess GH secretion, as occurs in acromegaly, is associated with abnormalities in bone turnover markers and bone mineral density (BMD). GH administration in GH deficient patients causes an increase in bone turnover. IGF-I mediates many of the metabolic actions of GH, although GH may have direct effects upon bone. In patients with acromegaly who are treated with a GH receptor antagonist, selective blockade of the GH receptor results in a decrease in circulating IGF-I levels in the majority of cases. We hypothesized that, in acromegaly, antagonism of GH receptors would result in a decrease in serum markers of bone turnover, including serum procollagen I carboxy-terminal propeptide (PICP), osteocalcin and N-telopeptide (NTx).Twenty-seven patients with acromegaly were enrolled as part of a multicentre 12-week trial of a GH receptor antagonist and were randomized to placebo (n = 7) or 10, 15 or 20 mg of pegvisomant (n = 20).Serum markers of bone turnover were determined at baseline and 12 weeks.Baseline bone turnover markers were above the upper limit of normal in 23%, 19% and 32% of subjects for osteocalcin, PICP and NTx, respectively. During the 12-week placebo-controlled period, there were significant decreases in serum markers of bone formation, osteocalcin (-2.2 +/- 0.44 vs. placebo +0.01 +/- 0.39 nmol/l, P = 0.009) and PICP (-23.6 +/- 9.6 vs. placebo +18.1 +/- 12.8 micro g/l, P = 0.022) and a serum marker of bone resorption, NTx (-4.4 +/- 1.4, placebo +1.0 +/- 0.3 nm, P = 0.024).Using a specific GH receptor antagonist, we found that normalization of IGF-I is associated with rapid reductions in markers of both bone formation and resorption, and that these processes remain coupled. These data confirm the highly significant effects of GH and IGF-I in modulating bone turnover. The independent contributions of GH and IGF-I to these effects and the long-term effects on BMD in this population remain to be determined.
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N-terminal telopeptide
Pegvisomant
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The effect of long-term diabetes mellitus on bone and mineral metabolism was studied in BB rats. Diabetic rats were treated with 1 U of long-acting insulin every other day for 12 wk and compared with nondiabetic littermates. Urinary calcium excretion was increased > 10-fold, but serum total and diffusible calcium remained normal. Serum concentrations of both 1α,25-dihydroxyvitamin D3 and vitamin D–binding protein were significantly decreased in diabetic rats. The intestinal calbindin-D 9K concentration was decreased by nearly 50%, and active duodenal calcium absorption was totally abolished. Trabecular bone volume measured in the tibial metaphysis was decreased by 44%, and the osteoblast and osteoid surfaces were <10% of values observed in control rats, whereas the osteoclast surface was unchanged by diabetes. The daily bone formation (bone mineral apposition rate) measured by labeling twice with calcein was decreased by 86% in diabetic rats. The serum concentration of osteocalcin, a biochemical marker of osteoblast function, was similarly decreased (mean ± SE 23 ± 3 and 62 ± 4 μg/L in diabetic [n = 15] and nondiabetic [n = 15] rats, respectively). Serum osteocalcin was significantly correlated with the serum concentration of insulinlike growth factor I (r = 0.89, P < 0.001). Bone strength measured as the energy needed to fracture the femur was markedly decreased (5.3 ±1.4 and 8.4 ± 1.3 N · m · degree in diabetic and nondiabetic rats, respectively; P < 0.01). These histological, chemical, and biomechanical data clearly indicate that long-standing diabetes in BB rats results in severe low-turnover osteoporosis probably related to decreased osteoblast recruitment and/or function.
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Osteoid
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The effects of treatment with estrogens and antiandrogens in male to female (M-->F) transsexuals and androgens in female to male (F-->M) transsexuals on their respective bone metabolism, bone mineral density (BMD), serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels were investigated. BMD and variables of bone turnover in serum were measured at baseline and after 3 months (except for BMD) and 1 yr of treatment in 56 M-->F and 35 F-->M transsexuals. Serum IGF-I, IGFBP-3, and propeptide of type I procollagen (P1CP) were measured at baseline and after 1 yr of treatment in 10 M-->F and 10 F-->M transsexuals. In M-->F, BMD increased significantly. Bone turnover decreased, as shown by a significant decline in levels of osteocalcin, alkaline phosphatase, P1CP, and fasting urinary calcium/creatinine and hydroxyproline/creatinine ratios. Serum IGF-I levels decreased significantly without significant changes in IGFBP-3 levels. In F-->M, BMD did not change. Bone formation increased, as suggested by an increase in alkaline phosphatase and a borderline increase in P1CP values. IGF-I levels increased significantly, whereas no significant changes were seen in IGFBP-3 levels. We conclude that in males, estrogens (in combination with antiandrogens) decrease bone turnover, with a subsequent increase in BMD and a decrease in serum IGF-I. In females, testosterone administration increases bone formation, but this is not reflected in an increased BMD, whereas serum IGF-I increases.
Bone remodeling
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Patients with poorly controlled noninsulin dependent diabetes mellitus (NIDDM) are shown to have higher bone mass. However, the influence of changes in glycemic control on bone turnover is not known. To clarify whether metabolic improvement of poorly controlled NIDDM affects bone turnover, markers for glucose, mineral, and bone metabolism were assessed before and after glycemic control for 3 weeks in 78 poorly controlled NIDDM patients with initial hemoglobin A1c over 8%. Metabolic improvement caused a reduction in urinary calcium (Ca) and phosphate (Pi) and serum 1,25(OH)2D levels, and an increase in serum Pi without changes in serum Ca or parathyroid hormone levels. Bone resorption markers, urinary deoxypyridinoline (Dpd) and type I collagen carboxy-terminal telopeptide (CTx), as well as a bone formation marker, serum bone type alkaline phosphatase (BALP), were reduced. However, another bone formation marker, serum osteocalcin (OC), was low before treatment and was elevated after treatment. The decrease in Dpd, CTx and BALP, but not the increase in OC, correlated with each other and with the improvement in glycemic indices. In conclusion, metabolic improvement of poorly controlled NIDDM decreases bone turnover within a short period. Thus, glycemic control may protect NIDDM patients from bone loss. It is possible that serum OC is affected by hyperglycemia per se, and may not correctly reflect bone turnover.
Bone remodeling
Deoxypyridinoline
N-terminal telopeptide
Metabolic control analysis
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Bone remodeling
Procollagen peptidase
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Administration of insulin-like growth factor-I (IGF-I) or growth hormone (GH) is known to stimulate bone turnover and kidney function. To investigate the effects of IGF-I and GH on markers of bone turnover, eight adult GH-deficient patients (48 ± 14 yr of age) were treated with IGF-I (5 μg/kg/h in a continuous sc infusion) and GH (0.03 IU/kg/daily sc injection at 2000 h) in a randomized cross-over study. We monitored baseline values for three consecutive days before initiating the five-day treatment period, as well as the wash-out period of ten weeks. Serum osteocalcin, carboxyterminal and aminoterminal propeptide of type I procollagen (PICP and PINP, respectively) increased significantly within 2–3 days of both treatments (P < 0.02) and returned to baseline levels within one week after the treatment end. The changes in resorption markers were less marked as compared with formation markers. Total 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) rose significantly, whereas PTH and calcium levels remained unchanged during either treatment. Conclusions: Because the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF-I is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because PTH, calcium, and phosphate remained unchanged, IGF-I appears to stimulate renal 1α-hydroxylase activity in vivo.
Bone remodeling
Growth hormone treatment
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