Bone Turnover and Insulin-like Growth Factor I Levels Increase After Improved Glycemic Control in Noninsulin-dependent Diabetes Mellitus

It is unclear whether both bone resorption and formation are affected by glycemic control, and contribute to diabetic osteopenia. In this study, 20 patients with noninsulin-dependent diabetes mellitus (12 men and 8 postmenopausal women) and 20 healthy control subjects (10 men and 10 postmenopausal women) were examined at baseline and 2 months. The diabetic patients showed an improvement of glycemic control (decreased HbA_1c) at the second measurement. Analysis of variance showed that there was no effect of gender on the variables that increased with improved glycemic control, and therefore results are presented for both male and female subjects. Baseline values of serum osteocalcin, a marker of formation, were significantly lower in diabetic patients compared with healthy subjects (2.5 ± 1.3 versus 4.4 ± 1.4 ng/ml; P= 0.0006), but markers of bone resorption [urinary pyridinoline (PYD), deoxypyridinoline (DPD)] did not differ. Improved glycemic control in diabetic patients resulted in increased values of PYD (P= 0.012), DPD (P= 0.049), serum osteocalcin (P= 0.001), and serum insulin-like growth factor I (IGF-I, P= 0.003), but no change in serum parathyroid hormone or 25-hydroxyvitamin D. In diabetic patients there were inverse correlations for the percent change from baseline to improved glycemic control for osteocalcin and HbA_1c (r =−0.53; P= 0.016) and glucose (r =−0.46; P= 0.050). These data suggest that improved glycemic control is accompanied by an increase in bone turnover for male and female diabetic patients, possibly mediated by increased levels of circulating IGF-I. Received: 8 August 1997 / Accepted: 20 January 1998     

Age-related differences in hormonal and nutritional impact on lean anorexia nervosa bone turnover uncoupling

Introduction In anorexia nervosa (AN) patients osteoporosis occurs within a framework of multiple hormonal abnormalities as a result of bone turnover uncoupling, with decreased bone formation and increased bone resorption. The aim of study was to evaluate the hormonal and nutritional relationships with both of these bone remodeling compartments and their eventual modifications with age. Patients and measurements In a cohort of 115 AN patients (mean BMI:14.6 kg/m2) that included 60 mature adolescents (age: 15.5–20 years) and 55 adult women (age: 20–37 years) and in 28 age-matched controls (12 mature adolescents and 16 adults) we assessed: bone markers [serum osteocalcin, skeletal alkaline phosphatase (sALP), C-telopeptide of type I collagen (sCTX) and tartrate-resistant acid phosphatase type 5b (TRAP 5b)], nutritional markers [ body mass index (BMI, fat and lean mass), hormones (free tri-iodothyronine (T3), free T4, thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), 17 β estradiol, free testosterone index (FTI), dehydroepiandrosterone (DHEAS), insulin-like growth factor 1 (IGF-1), growth hormone (GH) and cortisol], plasma methoxyamines (metanephrine and normetanephrine) and calcium metabolism parameters [parathyroid hormone (PTH), Ca, vitamin D₃]. Results Osteocalcin reached similar low levels in both AN age subgroups. sCTX levels were found to be elevated in all AN subjects and higher in mature adolescents than in adult AN (11,567±895 vs. 8976±805 pmol/l, p<0.05). sALP was significantly lower only in mature adolescent AN patients, while there were no significant differences in the levels of TRAP 5b between AN patients and age-matched control groups. Osteocalcin correlated with sCTX in the control subjects (r=0.65) but not in the AN patients, suggesting the independent regulation of these markers in AN patients. Osteocalcin levels strongly correlated with freeT3, IGF-I, 17 β estradiol and cortisol, while sCTX correlated with IGF-I, GH and cortisol in both age subgroups of the AN patients. Other hormones or nutritional parameters displayed age-related correlations with bone markers, leading to different stepwise regression models for each age interval. In mature adolescent AN patients, up to 54% of the osteocalcin variance was due to BMI, cortisol and 17 β estradiol, while 54% of the sCTX variance was determined by GH. In adult subjects, freeT3 and IGF-I accounted for 64% of osteocalcin variance, while 65% of the sCTX variance was due to GH, FTI and methoxyamines. Conclusions We suggest a more complex mechanism of AN bone uncoupling that includes not only “classical” influence elements like cortisol, IGF-I, GH or 17 β estradiol but also freeT3, catecholamines and a “direct” hormone-independent impact of denutrition. Continuous changes of these influences with age should be considered within the therapeutic approach to AN bone loss.     

对长期低钙摄入幼鼠的骨骼的研究——Ⅲ 低钙时幼鼠的骨钙素水平

本文研究低钙摄入、维生素D供给正常时幼鼠血中骨钙素水平,以了解低钙时成骨细胞活性。实验采用60只21～23日Wistar断乳幼鼠,随机分为四组:A组,正常钙与VitD摄X组;B组,中度低钙组;C组,重度低钙组;D组,VitD缺乏组。定期监测血25-(OH)D_3水平。于实验中期(3周),末期(6周)分别处死1/2幼鼠,取血与左股骨标本。测血骨钙素水平,以股骨钙与股骨长计算股骨含钙指数。实验建立低钙与低VitD动物模型。结果发现严重低钙幼鼠股骨生长显著落后,VitD缺乏幼鼠股骨生长与正常组相似。低钙与VitD缺乏幼鼠股骨含钙指数均明显低于正常组,低钙组更严重。低钙组幼鼠血骨钙素水平略高于正常组,VitD缺乏幼鼠血骨钙素有增高趋势;提示低钙时股骨增生的成骨细胞活性低下,VitD缺乏幼鼠骨生长受阻程度不如低钙组明显,推测VitD缺乏与低钙时对成骨细胞的作用机理不同。本文研究证实低钙对生长期骨骼的影响远远超过临床估计。     

Bone gla: Protein in blood derived directly from human bone tissue

Summary In order to find out whether the concentration of bone gla-protein (BGP) is elevated in blood derived directly from bone tissue compared to peripherically sampled blood a peroperative model was used. Blood was collected simultaneously from an armvein and from the osteotomized surface of the bone during total hip replacement in 18 patients Peripheral blood was also collected before the anaesthetic procedure. The anaesthetic and/or the operative procedure slightly decreased the level of BGP in the peripheral blood during this short time interval, but serum BGP was not different in the bone-marrow derived blood and in the peripheral blood taken simultaneously. These data suggest that BGP released from bone into the circulation is rapidly cleared from the marrow and that peripheral serum BGP is a valid index of the bone-derived levels of BGP.     

Diurnal Variation in Total and Undercarboxylated Osteocalcin: Influence of Increased Dietary Phylloquinone

A diurnal variation exists in blood levels of the vitamin K-dependent bone protein osteocalcin. However, it is not known whether the carboxylated and undercarboxylated constituents of osteocalcin also vary. Therefore, osteocalcin and undercarboxylated osteocalcin were measured in specimens collected every 4 hours over a 24-hour period in nine healthy subjects (five males, four females) ages 20–33 years who were consuming a mixed diet containing 100 μg of phylloquinone. Osteocalcin and undercarboxylated osteocalcin were measured by radioimmunoassay (RIA) before and after treatment with barium sulfate. Although the percent undercarboxylated osteocalcin did not change, a diurnal variation was observed in total osteocalcin, carboxylated osteocalcin, and undercarboxylated osteocalcin, with peak concentrations at 4 a.m. and the lowest concentrations between 12 p.m. and 4 p.m. The difference between the total osteocalcin peak and trough concentrations averaged 28 ± 7 (SEM)%. There were no gender differences in these rhythms. The effect of dietary phylloquinone as a modulator of these rhythms was evaluated in a randomized study by increasing phylloquinone intake to 420 μg/day with fortified corn oil, split between the lunch and dinner meals. Total and carboxylated osteocalcin fluctuations and concentrations were not affected by the dietary treatment. The diurnal variation in undercarboxylated osteocalcin was abolished with supplementation and concentrations at 8 a.m. (14 hours following supplementation) (2.3 ± 0.2 ng/ml) were significantly lower than the unsupplemented levels (2.7 ± 0.2 ng/mL, P= 0.006). The percentage of undercarboxylated osteocalcin was similarly decreased after supplementation (19.7 ± 1.3%) in relation to the mixed diet cycle (24.2 ± 1.6%, P= 0.006) at 8 a.m. on the second day. Dietary supplementation induced a fluctuation in percentage undercarboxylated osteocalcin with a decline in levels starting at approximately 12 a.m. Therefore, additional dietary phylloquinone does not appear to modulate the total osteocalcin diurnal rhythm, but can influence its undercarboxylated component. Received: 14 June 1996 / Accepted: 22 August 1997     

Diet,bone mass,and osteocalcin: A cross-sectional study

To determine the relationships among nutrient intake, bone mass, and bone turnover in women we have investigated these issues in a population-based, crosssectional, observational study in one county in central Sweden. A total of 175 women aged 28–74 at entry to the study were included. Dietary assessment was made by both a semiquantitative food frequency questionnaire and by four 1-week dietary records. Dual energy X-ray absorptiometry was performed at five sites: total body, L2–L4 region of the lumbar spine, and three regions of the proximal femur. Serum concentrations of osteocalcin (an osteoblast-specific protein reflecting bone turnover) were measured by a radioimmunoassay. Linear regression models, with adjustment for possible confounding factors, were used for statistical analyses. A weak positive association was found between dietary calcium intake as calculated from the semiquantitative food frequency questionnaire and total body bone mineral density (BMD) among premenopausal women. No association emerged between dietary calcium intake and sitespecific bone mass, i.e., lumbar spine and femoral neck, nor was an association found between dietary calcium intake and serum osteocalcin. BMD at some of the measured sites was positively associated with protein and carbohydrates and negatively associated with dietary fat. In no previous studies of diet and bone mass have dietary habits been ascertained so carefully and the results adjusted for possible confounding factors. Neither of the two methods of dietary assessment used in this study revealed any effect of calcium intake on BMD at fracture-relevant sites among these healthy, mostly middle-aged women. A weak positive association was found between calcium intake estimates based on the food frequency questionnaire and total body BMD. In this study population the preventive effect of high dietary calcium on osteoporosis is probably very weak. The independent significance of protein, carbohydrates, and fat is uncertain.     

Expression of the parathyroid hormone receptor and correlation with other osteoblastic parameters in fetal rat osteoblasts

Primary fetal rat calvarial cell cultures were examined for the expression of different osteoblastic parameters at the single cell level and in the whole population. The presence of the parathyroid hormone (PTH) receptor was studied by employing receptor autoradiography. After 3 days of culture, 10% of the cells expressed the PTH receptor. Immunolocalization of osteocalcin in 3-day-old cell cultures was found to be strongly correlated with the presence of the PTH receptor. Alkaline phosphatase (APase) localization in 3-day-old cultures correlated with only 69% of the PTH receptor expressing cells. Our results show that in 3-day-old rat calvarial cell cultures, only about 10% of the cells show markers of osteoblastic differentiation. The presence of the PTH receptor is strongly correlated with the presence of osteocalcin, but less with the presence of APase, indicating that it is the mature osteoblast that expresses the PTH receptor. After 7 days of culture, most receptor labeling, APase, and osteocalcin expression was found in multilayered areas of cells (nodules). Received: 28 February 1995 / Accepted: 27 July 1995     

Bone remodelling in monoclonal gammopathies of uncertain significance,symptomatic and nonsymptomatic myeloma

Summary In order to characterize the abnormalities of bone remodelling in the various stages of plasma cell disorders, we studied 60 patients (29 monoclonal gammopathies of uncertain significance (MGUS), 13 stage I myeloma, 18 stage III myeloma). We carried out histomorphometric study of bone biopsies in 34 patients and measurement of osteocalcin and the calciuria/creatinine ratio.Bone remodelling was approximately normal (BV/TV: 21.2±7, ES: 4.1±2, OS: 16.5±10) in MGUS. Stage I myeloma was characterised by parallel increases in resorption surfaces and osteoid surfaces (BV/TV: 18±5, ES/BS: 7.4±3.5, OS/BS: 24.8±11.5), of the ca/cr ratio and osteocalcin. In stage III myeloma, resorption surfaces and the ca/cr ratio showed an even greater increase while osteoid surfaces, osteocalcin and trabecular bone volume decreased (BV/TV 13.6±6, ES/BS: 12.1±6, OS/BS: 13.6±8.3). Osteocalcin and osteoid surfaces were correlated (r=0.5). There was a positive correlation between osteocalcin and the number of plasmocytes in stage 1 myeloma (r=0.64) and a negative correlation in stage III myeloma (r=0.9).Bone remodeling was normal in MGUS; bone remodelling grew with a parallel increase of formation and resorption in stage I; bone resorption increased while bone formation decreased in stage III myeloma.     

Indicators of bone formation in weight lifters

Physical activity has been suggested to be one of the determinants of bone turnover and to prevent age-related bone loss. To examine this we measured the serum levels of osteocalcin (bone Gla-protein, BGP), C-terminal procollagen peptide (PICP), serum alkaline phosphatase, bone-specific alkaline phosphatase, and S-calcium as indices of bone formation in 19 actively performing and 15 ex-lifters. All were nationally or internationally ranked male athletes. Their values were compared with those from 38 age- and gendermatched controls. Actively performing weight lifters had 35% higher (P<0.05) serum concentration of osteocalcin than the controls. The ex-lifters did not differ from the agematched controls. Also serum calcium was elevated in active lifters (6%) (P<0.01) but not in ex-lifters. No difference was found for serum-ALP, B-ALP, or PICP in either of the groups. Our study indicates that in addition to an already documented and well-known higher bone mineral density in heavily exercising athletes, they have an indication of higher bone formation as measured by biochemical markers. In athletes who have retired from competitional training, however, the bone formation does not differ from that of more sedentary controls.     

Acute effects of high-dose chemotherapy followed by bone marrow transplantation on serum markers of bone metabolism

There is an interplay between the cells in the bone marrow and the surrounding bone tissue, but little is known about the effects of myeloablative treatment followed by bone marrow transplantation on bone metabolism. We have therefore investigated 24 patients undergoing bone marrow transplantation (14 autologous, 10 allogeneic) for hematological malignancies. Serum concentrations of parathyroid hormone (PTH), albumin-modified calcium, and biomarkers for bone turnover-osteocalcin, bone alkaline phosphatase (B-ALP), and carboxyterminal cross-linked telopeptide of type I collagen (ICTP)-were measured. The samples were collected before myeloablative treatment, on the day of bone marrow infusion and 1, 2, 3, and 12 weeks thereafter. A serum PTH peak was consistently seen the day after total body irradiation, but no long-term effects on PTH/calcium homeostasis were observed. Bone formation as reflected by serum osteocalcin and B-ALP decreased, with nadir levels 2 to 3 weeks after marrow infusion. A simultaneous increase in bone resorption (increased S-ICTP) occurred. Pretreatment values were not completely regained 12 weeks after transplantation. the findings indicate that bone tissue is affected by myeloablative treatment, and the changes in biomarkers imply a net loss of bone over the study period.