Leptin and bone mineral density: a cross-sectional study in obese and nonobese men

Leptin has been suggested to decrease bone mineral density (BMD). This observational analysis explored the relationship between serum leptin and BMD in 327 nonobese men (controls) (body mass index 26.1 +/- 3.7 kg/m(2), age 49.9 +/- 6.0 yr) and 285 juvenile obese men (body mass index 35.9 +/- 5.9 kg/m(2), age 47.5 +/- 5.1 yr). Whole-body dual-energy x-ray absorptiometry scan measured BMD, fat mass, and lean mass. Fasting serum leptin (nanograms per milliliter) was strongly associated with fat mass (kilograms) in both controls (r = 0.876; P < 0.01) and juvenile obese (r = 0.838; P < 0.001). An inverse relation between BMD adjusted for body weight and serum leptin emerged in both the control group (r = -0.186; P < 0.01) and the juvenile obese group (r = -0.135; P < 0.05). In a multiple linear regression, fat mass, lean body mass, and occupational physical activity were positively associated with BMD in the control group, whereas in the juvenile obese, only lean body mass was positively associated with BMD and smoking negatively associated with BMD. Our study supports that leptin is inversely associated with BMD and may play a direct role in the bone metabolism in nonobese and obese Danish males, but it also stresses the fact that the strong covariation between the examined variables is a shortcoming of the cross-sectional design.     

Age-related changes in bone mineral density and serum bone-related proteins in premenopausal and postmenopausal Japanese women

The purpose of this cross-sectional study was to characterize the age-related change in bone metabolism during the pre- and postmenopausal periods, and to define the standard levels of three serum markers of bone metabolism, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), carboxyterminal propeptide of type I procollagen (PICP), and bone gla protein (BGP), in Japanese adult women. The bone mineral density (BMD) of the lumbar spine (L2-L4) and the serum levels of ICTP, PICP and BGP were determined in a total of 207 healthy Japanese women (108 premenopausal and 99 postmenopausal). The lumbar BMD decreased significantly with increasing age not only in postmenopausal women (P<0.001) but also in premenopausal women (P=0.014). There was a clear gap in the serum levels of ICTP, PICP and BGP between the premenopausal and postmenopausal group (P<0.001), but those were absolutely the same within each group except for ICTP in the postmenopausal women. These findings and the values of serum ICTP, PICP and BGP in pre- and postmenopausal women obtained in this study are expected to be very useful for treatment of postmenopausal osteoporosis.     

Effects of suppression of estrogen action by the p450 aromatase inhibitor letrozole on bone mineral density and bone turnover in pubertal boys

The essential role of estrogen (E) in regulation of developing peak bone mass in males was confirmed when young adult men were described who cannot respond to or produce E because of defective E receptor alpha or P-450 aromatase enzyme, respectively. These men had significantly reduced bone mineral density (BMD) despite normal or supranormal androgen concentrations, and E administration improved BMD in the men with aromatase deficiency, whereas testosterone (T) was ineffective. Because new P450 aromatase inhibitors may prove to be potential drugs in various growth disorders, the effect of suppression of E action on developing peak bone mass has to be closely evaluated. In this study, we explored the effects of suppression of E synthesis on bone metabolism in pubertal boys. A total of 23 boys with constitutional delay of puberty were randomized to receive T and placebo or T and a specific and potent P450 aromatase inhibitor, letrozole. We determined BMD in the lumbar spine and the femoral neck. Bone resorption was studied by measuring the serum concentration of cross-linked carboxyterminal telopeptide of type I collagen by two different methods (CTx and ICTP), and bone formation by determining the serum concentrations of carboxyterminal propeptide of type I procollagen (PICP), osteocalcin, and alkaline phosphatase. We demonstrated previously that, during treatment with T and placebo, the concentrations of androgens and E increased. During treatment with T and letrozole, the E concentrations remained at the pretreatment level, but the androgen concentrations increased; the increase in the T concentration was more than 5-fold higher than during treatment with T and placebo. We did not observe any significant differences in the changes in bone mineral content, BMD, or bone mineral apparent density, an estimate of true volumetric BMD, between the treated groups. Lumbar spine bone mineral apparent density increased in both treated groups; but in the T- plus letrozole-treated group, the increase was statistically significant only 6 months after discontinuation of letrozole treatment. All bone resorption and formation markers increased during treatment with T and placebo. During treatment with T plus letrozole, CTx, PICP, and osteocalcin remained unchanged, whereas ICTP and alkaline phosphatase increased. Thus, 1-yr treatment with this new P450 aromatase inhibitor in pubertal boys is unlikely to be associated with any major harmful effect on developing peak bone mass. However, to convincingly exclude such effects, particularly rare or minor ones, will require a study with a larger sample size; and thus, close follow-up of bone metabolism during treatment with P450 aromatase inhibitors is still warranted.     

The relationship between leptin concentration and bone metabolism in the human fetus

This study investigates the relationship between leptin and fetal bone metabolism by measuring fetal blood levels of leptin, carboxy-terminal pro-peptide of type I pro-collagen (PICP; a marker of bone formation) and cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a marker of bone resorption). The median gestational age at the time of sampling was 23 weeks (range, 18-35). There was a positive correlation between leptin concentration and gestational age (r = 0.543, P < 0.001) and a negative correlation between both PICP and ICTP and gestational age (r = -0.592 and r = -0.550, respectively, and P < 0.001 for both). Also, there was a negative correlation between the concentrations of leptin and both PICP (r = -0.260, P = 0.022) and ICTP (r = -0.622, P < 0.001). Using multiple regression analysis, fetal leptin concentration was positively correlated to the gestational age (r = 0.240, P = 0.042) and negatively correlated to ICTP (r = -0.420, P = 0.001). The increase in leptin concentration with gestational age is consistent with adipose tissue development and the subsequent accumulation of fat mass. The negative correlation between fetal leptin and ICTP suggests that leptin may decrease bone resorption with the overall effect of increasing bone mass. Therefore, leptin may play a role in fetal bone metabolism as part of its effect on fetal growth and development.     

Changes in serum levels of type I collagen-related proteins after surgically induced menopause and correlations with bone loss in the lumbar spine.

The purpose of this prospective study was to characterize the changes in serum levels of two proteins produced during the synthesis and degradation of type I collagen, i.e., the carboxyterminal propeptide of type I procollagen (PICP) and the pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), respectively, after oophorectomy, and to assess the degree of correlation between changes in the serum values of these proteins and changes in bone mineral density (BMD) of the lumbar spine. Serum levels of PICP, ICTP and bone gla protein (BGP) were determined in 18 women before oophorectomy (baseline) and at 7 days, and 1, 2, 3, 6, 9 and 12 months post-oophorectomy (PO). The BMD of the lumbar spine was measured at baseline, and at 6 months and 12 months PO. ICTP had increased significantly at 7 days PO and peaked between 1 and 3 months PO. PICP and BGP had increased significantly at 2 months PO and remained at high levels thereafter. The percent changes in lumbar BMD from baseline values (% CFB) at 6 months and at 12 months PO were significantly correlated with % CFB in ICTP, but not with % CFB in PICP or BGP. Accordingly, bone resorption is a main determinant of bone mineral loss after oophorectomy and the change in recently-developed bone resorption markers, such as ICTP, is of clinical utility in predicting a degree of subsequent bone loss after surgical menopause.     

Serum leptin level is a predictor of bone mineral density in postmenopausal women

To assess whether leptin is an independent predictor of bone mineral density (BMD) in postmenopausal women, we studied the relationships of BMD to serum leptin, 25(OH)D, 1,25(OH)(2)D, PTH, E2, dehydroepiandrosterone sulfate, GH, IGF-I, creatinine clearance, calcium intake, fat mass, and lean mass in 107 women aged 50-90 yr. We also related serum leptin to markers of bone formation [serum bone alkaline phosphatase and osteocalcin (OC)] and resorption (urine C-telopeptide of type I collagen). In stepwise multiple linear regression, lean mass explained 28.5%, age 10.3%, and leptin 7.2% of the whole body BMD variance. Age explained 21.1%, lean mass 12.8%, and leptin 3.7% of the femoral neck BMD variance. After adjustment for fat mass and creatinine clearance, correlations between leptin and bone alkaline phosphatase (positive) and OC (negative) disappeared but, remained significant with urine C-telopeptide of type I collagen (r = -0.27, P < 0.01). Markers of bone formation and resorption were strongly intercorrelated. These data demonstrate that leptin is an independent predictor of whole body and femoral neck BMD in postmenopausal women. Although the relationships between leptin and markers of bone formation appear complex, leptin may exert a protective effect on bone by limiting the excessive bone resorption coupled to bone formation associated with bone loss after menopause.     

Assessment of bone metabolism in obese women

OBJECTIVE: To evaluate the bone metabolism in obese women by the estimation of selected markers of bone formation. METHODS: The concentration of plasma parathyroid hormone (PTH) and selected markers of bone formation [osteocalcin (BGP) in plasma, carboxyterminal propeptide of type I procollagen (PICP) and alkaline phosphatase (AP) activity in blood serum] and bone resorption [cross-linked carboxyterminal telopeptide of type I collagen (ICTP) in blood serum and urinary excretion of calcium (Ca)] in 18 extremely obese women (BMI>40 kg/m2) with android phenotype (WHR>0.8) and in 20 healthy women with normal body weight. The age range of all subjects was 25 to 42 years (mean: 36.82 + 3.95). RESULTS: All obese women showed significantly increased concentration of plasma PTH, BGP and serum PICP, ICTP and elevated urinary excretion of Ca. CONCLUSIONS: The obtained results show that in extremely obese women with android phenotype bone metabolism disturbances may occur pointing at increased bone formation and resorption.     

Dynamics of bone turnover in children with GH deficiency treated with GH until final height

OBJECTIVE: To examine the dynamics of bone turnover in children with growth hormone deficiency (GHD) during long-term treatment. DESIGN: We longitudinally measured growth velocity and serum concentrations of osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP), and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) in 24 patients with GHD during long-term GH treatment until final height (age: 7.7+/-0.7 and 16.9+/-0.5 years at baseline and at final height respectively). RESULTS: At baseline, OC, PICP, and ICTP levels were significantly (P<0.0001) reduced in comparison with prepubertal bone age-matched controls (10.2+/-2.3 microgram/l and 22.5+/-7.6 microgram/l; 187.8+/-26.2 microgram/l and 328. 4+/-74.3 microgram/l; 7.7+/-2.0 microgram/l and 14.2+/-1.3 microgram/l respectively). During the first year of treatment mean levels of the bone markers increased significantly (P<0.0001) with a peak at 12 months. After the first year of treatment, OC and PICP levels progressively declined, whereas ICTP levels remained stable until the final height; in any case, bone marker levels remained significantly higher (P<0.03-P<0.0001) than baseline. The change in bone marker levels at 6 and 12 months of treatment with respect to the baseline values was not related to growth rate during long-term treatment or final height. CONCLUSIONS: The results show that children with GHD have reduced bone turnover at baseline, and that long-term GH treatment is associated with a stimulation of bone turnover. OC, PICP, and ICTP do not predict growth rate during long-term treatment or final height in children with GHD.     

Body composition,bone mineral density,and circulating leptin levels in postmenopausal Turkish women

OBJECTIVE: We analyzed the relationship between serum leptin levels and bone mineral density (BMD) values as well as the relationship between serum leptin levels and whole body composition, whether or not they were associated. In addition, we also investigated whether lean mass or fat mass is a better predictor of BMD in postmenopausal Turkish women. DESIGN AND MEASUREMENTS: One hundred consecutive postmenopausal women with a mean age of 55.1 +/- 6.3 years who visited our outpatient clinic for the evaluation of osteoporosis were recruited. Skin fold thickness at four sites and waist:hip ratio were measured. Body mass index (BMI) was calculated in kg/m(2). Serum concentrations of leptin, insulin, and estradiol were evaluated. Bone formation and resorption markers were also determined. The BMD values were measured by dual energy X-ray absorptiometry (DEXA) at the lumbar spine and femoral neck. Whole body composition (lean mass, fat mass, and percentage of fat), total bone mineral content (BMC) in g, and total BMD were also measured by DEXA. RESULTS: Serum leptin levels did not correlate with BMD values at all skeleton sites measured. Leptin correlated positively with fat mass, percentage of fat, and BMI (r = 0.738 and P = 0.00, r = 0.536 and P = 0.00, r = 0.356 and P = 0.00, respectively). Lean mass correlated with BMD at all sites measured (r = 0.339 and P = 0.00, r = 0.312 and P = 0.01, r = 0.523 and P = 0.00, r = 0.636 and P = 0.00). Lean mass correlated with BMI (r = 0.636, P = 0.00) but not with serum leptin (r = -0.021, P = 0.881), and it was an independent determinant of BMD at all skeleton sites measured. CONCLUSION: Our study showed that lean mass is a better predictor than fat mass of bone mineral density and that serum leptin levels are not associated with BMD.     

Type 1 collagen marker of bone turnover, insulin-like growth factor, and leptin in dichorionic twins with discordant birth weight

OBJECTIVE: We investigated the relationship between IGF-I-IGF binding protein (IGFBP)-1 and leptin levels with type 1 collagen markers of bone turnover in dichorionic twins with or without discordant birth weight of 20% or greater. METHODS: Maternal and cord bloods were collected from gestational age-matched dichorionic twins with (n = 16) or without (n = 16) discordant birth weight. The samples were assayed for cross-linked carboxyl terminal telopeptide (ICTP, a marker of bone resorption) and propeptide (PICP, a marker of bone formation) of type I collagen, leptin, IGF-I, and IGFBP-1 by RIA. RESULTS: The intrauterine growth-restricted (IUGR) twins of the discordant group had higher fetal ICTP (P < 0.001) and IGFBP-1 (P < 0.001) levels, whereas PICP (P < 0.001), IGF-I (P < 0.001), and leptin (P < 0.001) were lower than the cotwins with normal weight (AGA). In contrast, concentrations of IGF-I, IGFBP-1, ICTP, PICP, and leptin were comparable between concordant twin pairs. Leptin levels were positively correlated with PICP (r = 0.61; P < 0.001) and negatively with ICTP (r = -0.57; P < 0.001) in concordant and AGA twins but not in IUGR twins. In IUGR twins, IGF-I had positive association with PICP (r = 0.76; P < 0.001) and negative association with ICTP (r= -0.76; P < 0.001), whereas IGFBP-1 was negatively correlated with PICP levels (r = -0.65; P < 0.01). No such association was found in concordant and AGA twins. CONCLUSION: These data suggest that IUGR twins had high bone turnover, which is independent of maternal factors and perhaps may be due to altered IGF axis.     

Vitamin D status and PTH in young men: a cross‐sectional study on associations with bone mineral density,body composition and glucose metabolism

Objective Although vitamin D and bone metabolism are closely related, few studies have addressed the effects of vitamin D status on bone in men at time of peak bone mass. The objectives of this study were to evaluate the prevalence of vitamin D inadequacy in a cross‐sectional study in young men and the effects of vitamin D and parathyroid hormone (PTH) on bone mass, bone markers and metabolic function. Design and Participants The study population consisted of 783 men aged 20–29 years. Measurements Bone mineral density (BMD) of the total hip, femoral neck and lumbar spine was measured. dual‐energy X‐ray absorptiometry was used to evaluate total body fat mass (BFAT). Visceral fat mass and abdominal subcutaneous fat mass (ViFM and ScFM) were assessed using magnetic resonance imaging. A radioimmunoassay was used to measure the level of 25‐hydroxy vitamin D (25OHD). Results The prevalence of vitamin deficiency (serum 25OHD < 50 nm ) was 6·3% during summer and 43·6% during winter. Serum 25OHD was associated with BMD at all sites and inversely associated with bone‐specific alkaline phosphatase and directly with carboxyterminal telopeptide of type‐1‐collagen. 25OHD and PTH were inversely associated with BFAT, whereas 25OHD also was inversely associated with body mass index, waist–hip ratio, ViFM and ScFM after adjustment for confounders. The associations were found only to be present in participants with insufficient levels of 25OHD. 25‐Hydroxy vitamin D and PTH were inversely related to insulin resistance in vitamin‐insufficient participants only. No associations between PTH or 25OHD and blood pressure were noted. Conclusion The study showed a high prevalence of 25OHD deficiency in young, northern European men, which was significantly associated with decreased BMD. PTH and 25OHD were found to be inversely related to the markers of insulin resistance.     

Relationship of leptin and sex hormones to bone mineral density in men

Sex hormones are strongly associated with bone mineral density (BMD) in adult humans. Leptin, a hormonal product of the OB gene, also appears to be associated with BMD, but results from previous studies are conflicting. Most of the studies in this area have been in women and apparently none have simultaneously analyzed the relationship of estradiol, testosterone, and leptin with BMD in healthy men. To address these issues, serum sex hormones, sex-hormone-binding globulin (SHBG), leptin, dehydroepiandrosterone sulfate (DHEAS), and insulin were measured in 50 apparently healthy men, 18-66 years of age. After controlling for age and body mass index (BMI), BMD correlated positively with estradiol ( p=0.007) and testosterone ( p=0.019), but negatively with leptin ( p=0.001). No significant correlations between BMD and SHBG, DHEAS, or insulin were observed. In multiple regression analysis with age, BMI, estradiol, testosterone, and leptin as the independent variables, only age ( p<0.05), BMI ( p<0.001), and leptin ( p=0.004) were significantly related to BMD. These findings suggest that in men, leptin may have an important negative relationship with BMD.     

Higher serum leptin level in women than in men with type 1 diabetes

Leptin is the protein product of the obese (ob) gene, a lipostatic hormone that contributes to body weight regulation through suppressing appetite and/or stimulating energy expenditure in humans and/or rodents. In humans, serum leptin concentrations are increased in relation to increased body fat content. Studies have shown a higher leptin level in women compared with men. However, the gender influence on serum leptin concentrations has never been evaluated in patients with type 1 diabetes. In this study, serum leptin levels and percentage body fat mass were measured in men and women with type 1 diabetes. Fasting serum leptin levels were higher in women (16.7 + 11.6 ng/mL) than in men (3.0 +/- 1.5 ng/mL; P < 0.05) and were independent of exogenous insulin intake and of glucose control. Percentage body fat and fat mass were significant determinants of leptin concentration, whereas age and duration of diabetes were not related to leptin concentration. Subgroups of men (n = 12) and women (n = 11) with total body fat between 20 and 30% were compared. Leptin levels were also higher in women compared with men (13.5 +/- 8.3 ng/mL versus 3.2 +/- 1.7 ng/mL; P < 0.05, respectively). In conclusion, our findings indicate that gender is an important determinant of serum leptin concentration in type 1 diabetics, this gender difference is partly explained by body fat distribution and that type 1 diabetic women may be more resistant than type 1 diabetic men to leptin's alleged lipostatic actions.     

A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin

Transplantation of solid organs including heart, kidney, and liver is associated with rapid bone loss and increased rate of fracture; data on bone marrow transplantation recipients (BMT) are scarce. The purpose of the present study was to examine the magnitude, timing, and mechanism of bone loss following allogeneic BMT, and to study whether bone loss can be prevented by calcium with or without calcitonin. Sixty-nine patients undergoing allogeneic BMT for malignant blood diseases were enrolled into the study. Forty-four (22 women, 22 men) completed 6 months, and 36 patients 1 year follow-up. They were randomized to receive either no additional treatment (n = 22), or oral calcium 1 g twice daily for 12 months (n = 12) or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months (n = 10). Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward's triangle) was measured by dual-energy X-ray absorptiometry (DXA). Bone turnover rate was followed with markers of bone formation and resorption (serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal (PICP) and aminoterminal propeptide (PINP), serum type I collagen carboxyterminal telopeptide (ICTP)). Serum testosterone was assayed in men. Calcium with or without calcitonin had no effect on bone loss or bone markers; consequently the three study groups were combined. During the first 6 post-transplant months BMD decreased by 5.7% in the lumbar spine and by 6.9% to 8.7% in the three femoral sites (P < 0.0001 for all); no significant further decline occured between 6 and 12 months. Four out of 25 assessable patients experienced vertebral compression fractures. Markers of bone formation reduced: B-ALP by 20% at 3 weeks (P = 0.027), PICP by 40% (P < 0.0001) and PINP by 63% at 6 weeks (P < 0.0001), with a return to baseline by 6 months. The marker of bone resorption, serum ICTP was above normal throughout the whole observation period, with a peak at 6 weeks (77% above baseline, P < 0.0001). In male patients serum testosterone decreased reaching a nadir (57% below baseline) at 6 weeks (P = 0.0003). In conclusion, significant bone loss occurs after BMT. It results from imbalance between reduced bone formation and increased bone resorption; hypogonadism may be a contributing factor in men. Bone loss can not be prevented by calcium with or without calcitonin.     

Responses of markers of bone and collagen turnover to exercise, growth hormone (GH) administration, and GH withdrawal in trained adult males

To examine the interactions between acute exercise and GH on markers of bone and collagen turnover and to assess the potential for detecting GH abuse in athletes using these markers, we studied 17 aerobically trained males (age, 26.9+/-1.5 yr). Sequential studies of exercise, GH administration, and GH withdrawal were undertaken. A randomized, controlled study of rest vs. exercise showed that exercise did not change serum osteocalcin; other markers of formation increased transiently (each P<0.001): bone-specific alkaline phosphatase (+16.1%), carboxyterminal propeptide of type I procollagen (+14.1%), and procollagen III N-terminal extension peptide (+5.0%). The carboxyterminal cross-linked telopeptide of type I collagen, a bone resorption marker, increased 9.7% (P = 0.018) in response to exercise. A randomized, double blind, placebo-controlled, parallel study of recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum osteocalcin (net increase preexercise, +/-10.0%; P = 0.017), carboxyterminal propeptide of type I procollagen (+17.6%; P = 0.002), procollagen III N-terminal extension peptide (+48.4%; P = 0.001), and carboxyterminal cross-linked telopeptide of type I collagen (53.3%; P = 0.009). Disappearance half-times after cessation of recombinant human GH for pre- and postexercise markers ranged from 248-770 h. We conclude 1) endurance exercise transiently activates bone and collagen turnover; 2) brief GH administration results in similar but quantitatively greater augmentation; and 3) these data will assist in designing a GH detection strategy.     

Relationship between biochemical markers of bone turnover and bone scintigraphic indices in assessment of Paget's disease activity

Objective. To evaluate the relationship between biochemical markers of bone turnover and bone scan indices of disease activity, as well as to analyze their variations based on skeletal involvement, in Paget's disease. Methods. Serum samples were obtained from 51 patients with Paget's disease to determine the levels of total alkaline phosphatase (total AP), bone alkaline phosphatase (bone AP), propeptide carboxyterminal of type I procollagen (PICP), propeptide aminoterminal of type I procollagen (PINP), osteocalcin, tartrate-resistant acid phosphatase, and telopeptide carboxyterminal of type I collagen. Urine samples were analyzed for levels of hydroxyproline (HYP), pyridinoline (PYR), deoxypyridinoline (DPYR), C-terminal telopeptide of type I collagen (CTx), and N-terminal telopeptide of type I collagen (NTx). In addition, 2 semiquantitative scintigraphic indices, disease activity (AI) and disease extent (EI), were obtained. Pagetic skeletal locations were evaluated individually, with special attention to skull involvement. Results. All biochemical markers correlated with the AI and the EI. Serum PINP, bone AP, and total AP showed the highest proportions of increased values among the bone formation markers (94%, 82%, and 76%, respectively). Among the bone resorption markers, urinary NTx showed the highest proportion of increased values in patients with Paget's disease (96%), compared with PYR (69%), DPYR (71%), CTx (65%), and HYP (64%). In patients with mild disease activity, serum PINP was the marker with the highest proportion of increased values (71%). In contrast, serum PICP and urinary CTx were the most discriminative markers for skull involvement. Except for higher values for most of the biochemical markers of bone turnover in flat bones, no major differences in other skeletal locations were observed. Conclusion. The determination of serum PINP as a marker of bone formation and urinary NTx as a marker of bone resorption provided the best biochemical profile to ascertain the extent and activity of Paget's disease. In patients with skull involvement, serum PICP and urinary CTx were shown to be the most discriminative markers.     

Are serum leptin and the Gln223Arg polymorphism of the leptin receptor determinants of bone homeostasis in elderly men?

OBJECTIVE: Across studies it has been suggested that leptin intervenes as a regulator of bone metabolism. This study assesses the contribution in elderly men of leptin and the Gln223Arg leptin receptor gene (LEPR) polymorphism to the variation in bone homeostasis, in relation to body composition and free estradiol as major confounders. DESIGN: We performed cross-sectional (n = 270) and longitudinal (mean follow-up 3.4 years, n = 214) evaluations in elderly men. METHODS: Serum leptin, LEPR genotype, baseline bone mineral density (BMD), longitudinal BMD changes at the hip and forearm, and biochemical markers of bone turnover were determined. RESULTS: In cross-sectional analyses absolute fat mass was the index of body composition most strongly associated with leptin (r = 0.74; P < 0.001). LEPR genotypes and serum leptin were not associated. Serum bone-specific alkaline phosphatase (S-BAP) was associated with LEPR genotypes (P = 0.05) and urinary C-terminal telopeptides of type I collagen (U-CTX) were associated with leptin levels (P = 0.03), independently from age, fat mass and free estradiol. Baseline BMD at the hip and forearm was neither associated with leptin nor with LEPR genotypes. Prospectively assessed BMD loss was not associated with serum leptin at the hip, whereas BMD loss was positively associated with leptin at the forearm (P = 0.01), independently from age, fat mass and free estradiol. Longitudinal changes in hip or forearm BMD were not associated with LEPR genotypes. CONCLUSION: The findings suggest a possible role for leptin as determinant of bone homeostasis in elderly men, but with only modest impact independently from body composition and free estradiol.     

Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults.

OBJECTIVE: To study the effects of GH treatment for up to 42 months on bone mineral density (BMD) and bone turnover. DESIGN AND METHODS: BMD with dual energy X-ray absorptiometry, serum type I procollagen carboxy-terminal propeptide (PICP), serum type I collagen carboxy-terminal telopeptide (ICTP) and serum IGF-I were assessed in 71 adults with GH deficiency. There were 44 men and 27 women, aged 20 to 59 (median 43) years. Thirty-two patients completed 36 months and 20 patients 42 months of treatment. RESULTS: The BMD increased for up to 30-36 months and plateaued thereafter. In the whole study group, the maximum increase of BMD was 5.0% in the lumbar spine (P<0. 001), 5.9% (P<0.01) in the femoral neck, 4.9% (NS, P>0.05) in the Ward's triangle and 8.2% (P<0.001) in the trochanter area. The serum concentrations of PICP (202.6+/-11.5 vs 116.3+/-5.4 microg/l; mean+/-s.e.m.) and ICTP (10.5+/-0.6 vs 4.4+/-0.3 microg/l) doubled (P<0.001) during the first 6 months of GH treatment but returned to baseline by the end of the study (130.0+/-10.4 and 5.6+/-0.7 microg/l respectively), despite constantly elevated serum IGF-I levels (39. 6+/-4.1 nmol/l at 42 months vs 11.9+/-0.9 nmol/l at baseline; P<0.001). The responses to GH treatment of serum IGF-I, PICP, ICTP (P<0.001 for all; ANOVA) and of the BMD in the lumbar spine (P<0.05), in the femoral neck and the trochanter (P<0.001 for both) were more marked in men than in women. At the end of the study the BMD had increased at the four measurement sites by 5.7-10.6% (P<0.01-0.001) in patients with at least osteopenia at baseline and by 0.1-5.3% (NS P<0.05) in those with normal bone status (P<0.001 for differences between groups; ANOVA). Among patients who completed 36-42 months of treatment, the number of those with at least osteopenia was reduced to more than a half. The response of BMD to GH treatment was more marked in young than in old patients at three measurement sites (P<0. 05-<0.001; ANOVA). In the multiple regression analysis the gender and the pretreatment bone mass appeared to be independent predictors of three measurement sites, whereas the age independently determined only the vertebral BMD. CONCLUSIONS: GH treatment in GH-deficient adults increased BMD for up to 30-36 months, with a plateau thereafter. Concurrently with the plateau in BMD the bone turnover rate normalized. From the skeletal point of view GH-deficient patients exhibiting osteopenia or osteoporosis should be considered as candidates for GH supplementation of at least 3-4 years.     

Increased degradation of type I collagen in patients with inflammatory bowel disease.

To assess the mechanisms of osteopenia in inflammatory bowel disease (IBD), the serum markers of bone formation (osteocalcin and carboxyterminal propeptide of type I procollagen (PICP)) and bone degradation (carboxyterminal telopeptide of type I collagen (ICTP)), the bone mineral density (BMD) of the lumbar spine and the proximal femur and calcium intake of 150 unselected IBD patients and 73 healthy controls were investigated. The patients had higher ICTP values (3.69 (SD 1.40) microgram/l) than the healthy controls (3.25 (1.00) microgram/l, p = 0.035), but no differences in serum PICP and osteocalcin between these groups were detected. In the patients, the ICTP, PICP, and osteocalcin values did not have any significant correlation with BMD, but the patients with ICTP values above 3.6 microgram/l had significantly lower Z scores than those with lower ICTP. In the controls, however, a positive correlation between serum ICTP and BMD was found. The ulcerative colitis patients with total colitis had higher values of ICTP (3.96 (1.58) microgram/l) than those with a left sided disease (3.04 (0.86) micrograms/l, p = 0.009). The patients with a history of clinically active disease (n = 20) had higher ICTP (4.58 (1.55) microgram/l) and osteocalcin (12.56 (5.64) microgram/l) values than the patients (n = 130) with quiescent disease (ICTP 3.56 (1.33), p = 0.002, and osteocalcin 9.76 (3.62), p = 0.017). Increased serum osteocalcin, PICP, and ICTP concentrations and reduced BMD Z scores were found in a subgroup of Crohn's disease patients with a history of an active disease (n = 11). Raised serum ICTP and normal values of osteocalcin and PICP in IBD patients show increased breakdown of type I collagen without a compensatory increase in its synthesis suggesting an increased rate of bone degradation as a probable mechanism for osteopenia in IBD. Raised ICTP values are related to reduced bone mineral densities.     

胰岛素、胰岛素原对胰岛素抵抗状态下HepG2细胞PAI-1分泌的影响

目的研究胰岛素、胰岛素原对胰岛素抵抗状态下ＨｅｐＧ２细胞ＰＡＩ１分泌的影响。方法选择在合成ＰＡＩ１方面与肝细胞相似的ＨｅｐＧ２细胞，以高浓度胰岛素诱导胰岛素抵抗后，分别用生理浓度的胰岛素、胰岛素原刺激２４小时，以观察胰岛素抵抗状态下ＰＡＩ１活性的变化。结果基础状态下胰岛素抵抗ＨｅｐＧ２细胞与非胰岛素抵抗ＨｅｐＧ２细胞相比，ＰＡＩ１活性差异不明显；胰岛素、胰岛素原刺激后，胰岛素抵抗ＨｅｐＧ２细胞ＰＡＩ１活性明显高于非胰岛素抵抗ＨｅｐＧ２细胞。当培液中同时加入１０－４Ｍ二甲双胍后，胰岛素、胰岛素原介导的ＰＡＩ１过量分泌得到明显抑制。结论在胰岛素抵抗状态下，胰岛素、胰岛素原刺激后ＨｅｐＧ２细胞ＰＡＩ１活性明显增加，而二甲双胍可明显抑制此现象。