Assessment of bone turnover in postmenopausal osteoporosis by measurement of serum bone Gla-protein.
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Providing enough calcium for milk production stresses calcium homeostasis in lactating mammals. A universal response to these demands for calcium appears to be the mobilization of maternal skeletal reserves, and bone loss during lactation has been well documented. However, the regulation of calcium and skeletal metabolism during lactation remains enigmatic. Our study was designed to examine mineral and bone metabolism in lactating mice. We found that mice lose bone rapidly at all sites during lactation. Bone mineral density as determined by dual-energy x-ray absorptiometry was 20 to 30% lower at the spine, femur, and total body in lactating compared with either age-matched virgin or pregnant mice. The decrease in bone mineral density was accompanied by dramatic reductions in bone volume and changes in trabecular architecture. Bone loss was also accompanied by increases in bone turnover as determined by biochemical markers and histomorphometry. PTHrP levels were elevated during lactation and correlated positively with markers of bone resorption and negatively with bone mass at all sites. Estrogen levels were low during lactation and correlated negatively with bone resorption markers. Finally, estrogen and pamidronate treatment lowered rates of bone resorption to baseline virgin levels and mitigated, but did not prevent, bone loss. These data suggest that the combination of estrogen deficiency and elevations in circulating PTHrP during lactation act to stimulate bone resorption and promote bone loss.
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Serum osteocalcin (OC) and bone-specific alkaline phosphatase (B-ALP), reflecting bone formation, and urinary pyridinoline cross-link (Pyr) excretion, reflecting bone resorption, have been measured in 27 patients with hyperthyroidism and 30 age-matched controls using direct and novel immunoassays. Hyperthyroid patients had higher (P < 0.001) levels of all 3 markers compared with control values: Pyr, 246 +/- 181 nmol/mmol creatinine vs. 40 +/- 12 (+515%); OC, 55 +/- 23 vs. 23 +/- 7.4 micrograms/L (+139%); and B-ALP, 22 +/- 17 vs. 10.0 +/- 5.0 micrograms/L (+120%). OC and Pyr levels were elevated above the normal range in most patients and were significantly correlated with serum free T3 concentrations (r = 0.53; P < 0.01 and r = 0.76; P < 0.001; for OC and Pyr, respectively). B-ALP levels were elevated in 11 of the 27 patients and did not correlate with serum thyroid hormone concentrations. After therapy for hyperthyroidism, Pyr and OC levels returned to normal within 1 month, whereas B-ALP transiently increased after 1 month before falling to baseline levels. The relapse of hyperthyroidism observed in 1 patient was associated with a steep increase in bone markers. These results indicate that Pyr, measured using a new and convenient immunoassay, is a highly sensitive marker for altered bone metabolism in hyperthyroidism. The increases in OC and B-ALP were less impressive, suggesting an imbalance between resorption and formation with subsequent rapid bone loss in untreated hyperthyroidism. OC and B-ALP also appear to reflect different aspects of osteoblast metabolism during the treatment of hyperthyroid patients.
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Objective To characterize bone remodeling by establishing type 2 diabetic osteoporosis rat model.Methods Female Wistar rats were randomly divided into sham operation group(NS);bilateral ovariectomy group(NOVX);diabetic sham operation group(DS) and diabetic ovariectomized group(DOVX).Ovariectomy was performed in both control and diabetic rats after type 2 diabetic models had been made.Venous blood samples were collected at 0、4、 8 and 12wks after ovariectomy,fasting plasma glucose(FPG)、fasting insulin(FINS)、estrogen(E2) and specific bone turnover markers such as alkaline phosphatase(B-ALP),tartrate-resistant acid phosphatase(TRACP5b) were all measured.BMD were measured,osteoblast and osteoclast cell were isolated and cultured from rats of all groups.Results At 0wks,FPG had significantly increased when DOVX′ 13.1±4.9 mmol/L compared with NS′ 4.4±0.6 mmol/L(all P0.05).at 4wks,BMD had significantly decreased when DOVX′ 0.073±0.012 g/cm2 compared with DS′ 0.098±0.016 g/cm2(P0.05).at 4、8 and 12wks,there was no differences in plasma B-ALP levels when DOVX rats compared with NS rats.at 4 and 8wks,compared with NS rats,DOVX rats had significantly increased plasma TRACP5b concentration(all P0.05).For the activity of osteoblast,there wasno differences when DOVX compared with NS,NOVX and DS group.osteoclast numbers was significantly increased in DOVX rats than those in NS rats(P0.05).Conclusion There was active bone resorption and relatively slow bone formation in osteoporosis rats with type 2 diabetes mellitus.
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of Clinical Endocrinology & Metabolism (August 2015) with the title of "Plasma DPP4 activities are associated with osteoporosis in postmenopausal women with normal glucose tolerance" by Zheng et al (1).The authors prepared an outstanding study in the field of bone metabolism on the topic of dipeptidyl peptidase-4 (DPP4) activities and osteoporosis.However, the article raises some important points about this effect.The authors mentioned that increased DPP4 activities are associated with osteoporosis, regardless of decrease in the active fasting glucagon-like peptide-1 level.Gastric inhibitory polypeptide (GIP) is released from the K cells of the upper intestine, and secreted GIP is rapidly inactivated by DPP-4 (2).Bollag et al (3) reported that GIP receptors are present in bone and osteoblast-like cells, and collagen type 1 expression and alkaline phosphatase activity in osteoblastic-like cells are increased by GIP.Intermittent injection of GIP significantly increased bone mineral density in ovariectomized rats (4).Zhong et al ( 5) demonstrated the presence of GIP receptors in osteoclasts, in which GIP seems to suppress bone resorption and the resorptive activity of mature osteoclasts.Using GIP receptor knockout mice, Xie et al ( 6) demonstrated a reduction in bone formation, deteriorated bone microstructure, and biomechanical properties and an increase in bone resorption with a low bone mass.On the other hand, GIP-overexpressing transgenic mice caused elevated bone density (7).We would like to emphasize that increased DPP4 activity-induced GIP reduction may have a role in increased DPP4-associated osteoporosis.In this study, the authors did not report any information about the GIP levels.We think that it would be more reasonable if the authors add the data of the above-mentioned suggestions, which would strengthen their study.Finally, we would like to congratulate Zheng et al (1) on their outstanding study.
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Gastric inhibitory polypeptide
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Abstract Background: Anorexia nervosa (AN) is a condition of severe undernutrition associated with low bone mineral density (BMD) in adolescent females with this disorder. Although primarily a disease in females, AN is increasingly being recognized in males. However, there are few or no data regarding BMD, bone turnover markers or their predictors in adolescent AN boys. Hypotheses: We hypothesized that BMD would be low in adolescent boys with AN compared with controls associated with a decrease in bone turnover markers, and that the gonadal steroids, testosterone and estradiol, and levels of IGF-I and the appetite regulatory hormones leptin, ghrelin, and peptide YY would predict BMD and bone turnover markers. Methods: We assessed BMD using dual-energy x-ray absorptiometry and measured fasting testosterone, estradiol, IGF-I, leptin, ghrelin, and peptide YY and a bone formation (aminoterminal propeptide of type 1 procollagen) and bone resorption (N-telopeptide of type 1 collagen) marker in 17 AN boys and 17 controls 12–19 yr old. Results: Boys with AN had lower BMD and corresponding Z-scores at the spine, hip, femoral neck, trochanter, intertrochanteric region, and whole body, compared with controls. Height-adjusted measures (lumbar bone mineral apparent density and whole body bone mineral content/height) were also lower. Bone formation and resorption markers were reduced in AN, indicating decreased bone turnover. Testosterone and lean mass predicted BMD. IGF-I was an important predictor of bone turnover markers. Conclusion: AN boys have low BMD at multiple sites associated with decreased bone turnover markers at a time when bone mass accrual is critical for attainment of peak bone mass.
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Individual susceptibility to glucocorticoid-induced osteoporosis is difficult to predict clinically. We recently characterized expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in human osteoblasts. This enzyme generates active cortisol (or prednisolone) from inactive cortisone (or prednisone) and regulates glucocorticoid action in vitro. We, thus, hypothesized that osteoblastic 11beta-HSD1 mediates susceptibility to glucocorticoid-induced osteoporosis. Twenty healthy males ingested 5 mg prednisolone twice daily for 7 d, and relationships between changes in bone turnover markers and urinary measures of corticosteroid metabolism were examined. The bone formation markers osteocalcin and N-terminal propeptide of type I collagen decreased in all subjects (P < 0.001), but resorption markers were unchanged. The extent of fall in formation markers correlated with baseline 11beta-HSD1 activity with high activity predicting the greatest fall [for osteocalcin d 4 and 7, r = -0.58 and -0.56 (P < 0.01); for N-terminal propeptide of type I collagen d 4, r = -0.51 (P < 0.05)]. There was no correlation with measures of glucocorticoid inactivation or total corticosteroid metabolite production. Urinary measures of 11beta-HSD1 activity predict the response of bone formation markers to glucocorticoids, and this appears to reflect increased generation of active glucocorticoids within osteoblasts. Measures of 11beta-HSD1 activity may predict individual susceptibility to glucocorticoid-induced osteoporosis, and these data should facilitate the development of bone-sparing glucocorticoids.
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Idiopathic osteoporosis in younger individuals could be related to reduced bone formation rather than increased bone resorption, and disturbances in GH or insulin-like growth factor (IGF)-I production could be involved in its pathogenesis. In the present study, men with idiopathic osteoporosis were compared with healthy men, with respect to bone histomorphometry and to serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2 and IGFBP-3, and 24-h urinary excretion of GH. Mean wall thickness was reduced in the patients (48.3 +/- 7.2 vs. 61.7 +/- 5.4 microns, P < 0.001). Also, resorption depth was decreased, albeit to a lesser degree (54.4 +/- 3.8 vs. 60.7 +/- 5.3 microns, P < 0.01), thus creating a pronounced negative balance (-6.04 +/- 9.8 vs. 0.96 +/- 3.2 microns, P < 0.05). In the patients, serum concentrations of IGFBP-3 were reduced, compared with controls, with a 46% lower mean value; whereas levels of IGF-I, IGF-II, IGFBP-2, and GH were similar in the two groups. Thus, there was a significant negative balance caused by a pronounced decrease in wall thickness in men with idiopathic osteoporosis. The finding of low IGFBP-3 levels in these patients is interesting, in view of previous clinical and experimental findings, but its pathophysiological significance remains to be determined.
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Growth hormone (GH) replacement improves target organ sensitivity to PTH, PTH circadian rhythm, calcium and phosphate metabolism, bone turnover, and BMD in adult GH-deficient (AGHD) patients. In postmenopausal women with established osteoporosis, GH and insulin like growth factor-1 (IGF-1) concentrations are low, and administration of GH has been shown to increase bone turnover and BMD, but the mechanisms remain unclear. We studied the effects of GH administration on PTH sensitivity, PTH circadian rhythm, and bone mineral metabolism in postmenopausal women with established osteoporosis.Fourteen postmenopausal women with osteoporosis were compared with 14 healthy premenopausal controls at baseline that then received GH for a period of 12 mo. Patients were hospitalized for 24 h before and 1, 3, 6, and 12 mo after GH administration and half-hourly blood and 3-h urine samples were collected. PTH, calcium (Ca), phosphate (PO(4)), nephrogenous cyclic AMP (NcAMP), beta C-telopeptide of type 1 collagen (betaCTX), procollagen type I amino-terminal propeptide (PINP), and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured. Circadian rhythm analysis was performed using Chronolab 3.0 and Student's t-test and general linear model ANOVAs for repeated measures were used where appropriate.IGF-1 concentration was significantly lower in the women with established osteoporosis compared with controls (101.5 +/- 8.9 versus 140.9 +/- 10.8 mug/liter; p < 0.05) and increased significantly after 1, 3, 6, and 12 mo of GH administration (p < 0.001). Twenty-four-hour mean PTH concentration was higher in the osteoporotic women (5.4 +/- 0.1 pM) than in healthy controls (4.4 +/- 0.1 pM, p < 0.001) and decreased after 1 (5.2 +/- 0.1 pM, p < 0.001), 3 (5.0 +/- 0.1 pM, p < 0.001), 6 (4.7 +/- 0.1 pM, p < 0.001), and 12 mo (4.9 +/- 0.1 pM, p < 0.05) of GH administration compared with baseline. NcAMP was significantly lower in osteoporotic women (17.2 +/- 1.2 nM glomerular filtration rate [GFR]) compared with controls (21.4 +/- 1.4 nM GFR, p < 0.05) and increased after 1 (24.2 +/- 2.5 nM GFR, p < 0.05), 3 (27.3 +/- 1.5 nM GFR, p < 0.001), and 6 mo (32.4 +/- 2.5 nM GFR, p < 0.001) compared with baseline. PTH secretion was characterized by two peaks in premenopausal women and was altered in postmenopausal women with a sustained increase in PTH concentration. GH administration also restored a normal PTH secretory pattern in the osteoporotic women. The 24-h mean adjusted serum calcium (ACa) concentration increased at 1 and 3 mo (p < 0.001) and PO(4) at 1, 3, 6, and 12 mo (p < 0.001). 1,25(OH)(2)D concentration increased after 3, 6, and 12 mo of GH (p < 0.05). An increase in urine Ca excretion was observed at 3 and 6 mo (p < 0.05), and the renal threshold for maximum tubular phosphate reabsorption rate (TmPO4/GFR) increased after 1, 3, 6, and 12 mo (p < 0.05). betaCTX concentration increased progressively from 0.74 +/- 0.07 mug/liter at baseline to 0.83 +/- 0.07 mug/liter (p < 0.05) at 1 mo and 1.07 +/- 0.09 mug/liter (p < 0.01) at 3 mo, with no further increase at 6 or 12 mo. PINP concentration increased progressively from baseline (60 +/- 5 mug/liter) to 6 mo (126 +/- 11 mug/liter, p < 0.001), with no further increase at 12 mo. The percentage increase in PINP concentration was significantly higher than betaCTX (p < 0.05).Our study shows that GH has a regulatory role in bone mineral metabolism. GH administration to postmenopausal osteoporotic women improves target organ sensitivity to PTH and bone mineral metabolism and alters PTH secretory pattern with greater increases in bone formation than resorption. These changes, resulting in a net positive bone balance, may partly explain the mechanism causing the increase in BMD after long-term administration of GH in postmenopausal women with osteoporosis shown in previous studies and proposes a further component in the development of age-related postmenopausal osteoporosis.
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BACKGROUND: There has been increasing evidence that the growth hormone (GH)-IGF-I axis plays an important part in the maintenance of bone mass. However, controversy still exists as to the effect of GH treatment on bone mineral density (BMD) in elderly patients with osteoporosis. OBJECTIVE: To investigate the effect of low-dose GH treatment on markers of body composition and bone turnover, serum concentrations of IGF-I and IGF-binding proteins (IGFBPs), and BMD at the radius and lumbar spine in eight elderly Japanese women with osteoporosis. METHODS: Participants were treated with GH as a single daily subcutaneous injection (0.125 IU/kg per week; 0.00595 mg/kg per day) for 48 weeks. RESULTS: Markers of bone formation and bone resorption were both increased up to 24 weeks of GH treatment. The bone formation markers remained increased during GH treatment, whereas the bone resorption markers returned to baseline values after 24 weeks of GH treatment. GH treatment caused a rapid (within 2 weeks) and sustained increase in serum IGF-I concentration. As for IGFBPs, serum concentrations of IGFBPs-2, -3 and -4 did not change significantly during GH treatment. In contrast, GH treatment caused a gradual increase in serum IGFBP-5 concentration, with a significant increase seen 48 weeks after the start of GH treatment. Radial BMD seemed to be increased during the late period of GH treatment, although the change was not significant. Lumbar BMD did not change during GH treatment. GH treatment caused a significant increase in hand grip strength. None of the GH-treated participants had new fractures and side effects such as edema and joint pain. Radial BMD was significantly increased after discontinuation of GH treatment for another 48 weeks and a similar tendency was observed at the lumbar spine (7.1+/-2.3% above pretreatment values for the radius and 3.6+/-2.0% for the lumbar spine). CONCLUSIONS: Low-dose GH treatment attenuated the decrease in muscle strength and bone mass in elderly women without side effects, although changes in nutrition and exercise might affect BMD. The present findings provide useful information regarding the use of low-dose GH treatment in elderly women with osteoporosis.
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