Cross-linked Telopeptide Of type-I Collagen Research Articles

Microcystin-leucine-arginine impairs bone microstructure and biomechanics by activating osteoimmune response and inhibiting osteoblasts maturation in developing rats

Microcystin-LR (MC-LR) affects bone health in adult mice via osteo-immunomodulation. However, its effect on osteoblasts and bone development is unclear. This study investigated the effect of MC-LR on bone osteoimmune and osteoblasts in the developing period. 18 Four-week-old male Sprague Dawley rats were divided into two groups (n = 9 per group) and exposed to 0 (control) and 1 μg/kg b.w. MC-LR (exposure) by intraperitoneal injection for four weeks. The heart blood was collected for serological examination, and the femur for morphological, histopathological, and biomechanical analysis. MC-LR exposure significantly weakened bone microstructures (bone volume, bone volume/total volume, bone trabecular number, connectivity density) and biomechanics (maximum loads and maximum deflection) (P < 0.05). Besides, MC-LR decreased serum procollagen type І car-boxy-terminal propeptide, osteocalcin, bone morphogenetic protein-2, osteoprotegerin, and receptor activator of nuclear factor κB ligand, while elevating osteoclasts number, matrix metalloproteinase-9, β-catenin, Runt-related transcription factor 2, and osterix in bone, and bone alkaline phosphate, C-terminal cross-linked telopeptide of type-I collagen, tartrate-resistant acid phosphatase-5b in serum (P < 0.05). Moreover, MC-LR increased CD4+ T-cells, CD4+/CD8+, M1 and M2 macrophages, and cells apoptosis in the bone marrow, interleukin-6, interleukin-17, and tumor necrosis factor-α in serum, decreased serum interleukin-10 (P < 0.05). Overall, MC-LR can promote bone resorption by activating osteoclasts via osteoimmunology, which may involve macrophages besides lymphocytes. MC-LR may inhibit bone formation by stopping the osteoblasts at an immature stage. Thus, MC-LR weakened bone microstructure and biomechanics in developing period. Its risk on bone development needs further study.

Drinking Natural Mineral Water Maintains Bone Health in Young Rats With Metabolic Acidosis

IntroductionMetabolic acidosis affects bone health. It remains unclear whether drinking natural mineral water is better for maintaining bone health in the youth with metabolic acidosis.Materials and MethodsSixty young female rats (3-weeks-old) were randomly divided into three groups and drank purified water (PW, as control), bicarbonate-rich natural mineral water (Bic-NMW), or sulfate-rich natural mineral water (Sul-NMW), which, respectively, contained calcium (0.17, 155, and 175 mg/L), bicarbonate (0.1360, and 139 mg/L) and sulfate (0, 35.6, and 532 mg/L), for 16 weeks. In the last 3 weeks, metabolic acidosis was induced in 10 rats per group by adding NH4Cl (0.28 mM) to drinking water. The rats' blood, urine, and femur were collected for assessing acid-base status, calcium metabolism, bone microstructure, and strength. The difference between the three groups was determined using one-way ANOVA followed by the Student–Newman–Keuls test or Dunnett's T3 test.ResultsCompared with the PW rats, the Bic-NMW rats and the Sul-NMW rats had less urine net acid excretion (−1.51, 0.20 vs. 10.77, EQ/L), higher bone mineral density (442.50, 407.49 vs. 373.28, mg/mm3), growth cartilage width (271.83, 283.83 vs. 233.27, μm) and cortical trabecular area (9.33, 9.55 vs. 5.05, mm2), and smaller cortical marrow cavity area (5.40, 5.49 vs. 7.27, mm2) in the femur (P < 0.05). Besides, the Bic-NMW rats had less serum calcium (2.53 vs. 2.68, mmol/L) and C-terminal cross-linked telopeptide of type-I collagen (1.35 vs. 1.93, ng/mL), and higher serum calcitonin (0.61 vs. 0.39, μg/L), femoral trabecular thickness (0.10 vs. 0.09, μm), bone volume/total volume (0.42 vs. 0.34, %), cortical bone area (15.91 vs. 12.80, mm2), and ultimate stress (35.12 vs. 29.32, MPa) (P < 0.05). The Sul-NMW rats had more osteoclasts (22.50 vs. 11.54, cells/field) (P < 0.05).ConclusionsDrinking natural mineral water, especially bicarbonate-rich natural mineral water, is effective in improving bone health in young rats with metabolic acidosis. These benefits include maintaining bone mineral density, and improving bone microstructure and biomechanical properties via moderating metabolic acidosis.

Glucose variability and low bone turnover in people with type 2 diabetes.

Type 2 diabetes (T2D) is related to an increased fracture risk and low bone turnover. However, the mechanisms are not elucidated. In the present study we investigate the association between glycemic variability and bone turnover markers. 100 participants with T2D and 100 age and gender matched controls were included in this cross-sectional study. All participants with T2D were equipped with a continuous glucose monitoring (CGM) sensor for 3days (CGMS iPro Continuous Glucose Recorder; Medtronic MiniMed). The dawn glucose levels were defined as a morning period starting 1h before breakfast ending 1h post ingestion. On all participants serum (s)-C-terminal cross-linked telopeptide of type-I collagen (CTX), s-procollagen type 1 amino terminal propeptide (P1NP), and s-sclerostin were measured. Participants with T2D displayed significantly lower levels of the bone resorption marker s-CTX and the bone formation marker s-P1NP compared to controls. S-CTX was significantly negatively associated with the mean amplitude of glycemic excursions (MAGE) and the dawn glucose levels whereas s-P1NP only was significantly negatively associated with the dawn glucose levels while it was borderline significantly associated with MAGE (p=0.05). S-CTX and s-P1NP were significantly lower among the 50% with the highest dawn glucose levels compared to the 50% lowest dawn glucose levels also after adjustment for age, gender, glycated hemoglobin A1c (HbA1c), and body mass index (BMI). We observed that the amplitude of glycemic excursions and rise in dawn glucose was negatively associated with bone turnover markers. Future research is needed to determine whether reduction of the amplitude of glycemic excursions increase bone turnover markers.

Effects of a whey protein pre-meal on bone turnover in participants with and without type 2 diabetes-A post hoc analysis of a randomised, controlled, crossover trial.

Whey protein may improve bone turnover and have anti-osteoporotic effects. The aim of the present randomised, controlled, crossover trial was to evaluate the effects of a whey protein pre-meal on bone turnover in people with type 2 diabetes and controls. Two groups, matched on sex, age and body mass index, comprising 12 participants with and 12 participants without type 2 diabetes were randomly given a pre-meal of whey protein (20g) or water, which was consumed 15min before a fat-rich meal or a fat-rich meal supplemented with 20g whey protein. During a 360-min period, postprandial responses in bone turnover were examined. Osteocalcin, P-procollagen type 1 amino terminal propeptide (P1NP), C-terminal cross-linked telopeptide of type-I collagen (CTX) and parathyroid hormone (PTH) were lower at baseline and PTH, osteocalcin and P1NP were lower during the entire postprandial phase in participants with type 2 diabetes than in participants without type 2 diabetes. We observed similar postprandial responses in bone turnover markers between persons with and without type 2 diabetes. We observed no effect of the whey protein or the water pre-meal on bone turnover markers. The changes were unrelated to secretion of hormones of the gut-bone axis. Osteocalcin, P1NP, CTX and PTH all decreased following meal ingestion. We observed no convincing effect of a whey protein pre-meal on bone turnover. However, these results confirm that people with type 2 diabetes have low bone turnover and that the decreased bone formation markers are also extend into the postprandial responses.

Overweight and underweight are risk factors for vertebral fractures in patients with type 2 diabetes mellitus.

The aim of this cross-sectional study was to examine the association between body mass index (BMI) and the prevalence of vertebral fracture (VF) in Japanese patients with type 2 diabetes (T2DM). A total of 798 patients with T2DM were enrolled. VF was determined semi-quantitatively using lateral X-ray films. The association between BMI quartiles (Q1: ≤ 21.2kg/m2, Q2: 21.3-23.4kg/m2, Q3: 23.5-25.8kg/m2, Q4: 25.9≤ kg/m2) and the presence of VF was examined. Multiple logistic regression analyses adjusted for age, sex, diabetes duration, hemoglobin A1c (HbA1c), estimated glomerular filtration rate, and albumin showed that Q1, Q3, and Q4 were significantly associated with an increased VF risk compared to Q2, which served as a reference [Q1; odds ratio (OR) = 1.91, 95% confidence interval (CI) 1.24-2.95, p = 0.004, Q3; OR = 1.65, 95% CI 1.07-2.55, p = 0.023, and Q4; OR = 2.18, 95% CI 1.39-3.41, p < 0.001]. Moreover, these associations remained significant after additional adjustment for femoral neck T-score, a bone resorption marker, urinary N-terminal cross-linked telopeptide of type-I collagen, and use of insulin and thiazolidinedione. Our study shows for the first time that both overweight and underweight were associated with the bone mineral density (BMD)-independent risk of VF in patients with T2DM. Therefore, body weight control should be considered as a protective measure against diabetes-related bone fragility.

The Association Between Osteocalcin and Chronic Inflammation in Patients with Type 2 Diabetes Mellitus

Osteocalcin acts as an endocrine hormone to regulate energy homeostasis. Although several in vivo and in vitro studies suggest that osteocalcin is involved in chronic inflammation, the association between osteocalcin and chronic inflammation in humans is unknown. In this cross-sectional study, 246 patients with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of bone turnover markers with chronic inflammation parameters such as high-sensitive C-reactive protein (hsCRP), ferritin, and leukocyte subtype counts. Bone-specific alkaline phosphatase (BAP), total osteocalcin (OC), undercarboxylated OC (ucOC), and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) were measured. Multiple regression analysis adjusted for age, duration of diabetes, body mass index, estimated glomerular filtration rate, and hemoglobin A1c showed that serum OC levels were significantly and negatively associated with hsCRP, ferritin, basophil count, and monocyte count (β = - 0.18, p = 0.013; β = - 0.22, p = 0.031; β = - 0.14, p = 0.038; and β = - 0.17, p = 0.012, respectively). Moreover, serum ucOC levels were significantly and negatively associated with hsCRP, ferritin, total leukocyte count, neutrophil count, and monocyte count (β = - 0.24, p = 0.007; β =- 0.37, p = 0.003; β = - 0.21, p = 0.007; β = - 0.24, p = 0.002; and β = - 0.20, p = 0.011, respectively). The ratio of ucOC to OC was significantly and negatively associated with ferritin (β = - 0.31, p = 0.014). However, neither BAP nor uNTX was associated with any chronic inflammation parameters. This is the first study to show that serum OC and ucOC levels were negatively associated with chronic inflammation parameters such as hsCRP, ferritin, and leukocyte subtypes in patients with T2DM. Therefore, OC could be a therapeutic target for protecting against chronic inflammation.

Bone health in long-term gastric cancer survivors: A prospective study of high-dose vitamin D supplementation using an easy administration scheme

Bone disease in long-term survivors after gastric cancer resection has received little research attention. This study aimed to investigate bone health after curative resection of gastric cancer and the consequences of high-dose vitamin D supplementation in patients with low levels of 25-(OH)-vitamin D. Disease-free patients at least 24months after gastric cancer resection represented the study cohort. Serum markers of bone metabolism were assessed at baseline and at 3 and 12months. Bone mineral density and presence of fractures were assessed by X-ray at baseline. Patients with 25-(OH)-vitamin D ≤30ng/mL at baseline received 16,000IU of vitamin D3 every 10days during the 1-year follow-up. Forty patients were included in the study. Mean time from surgery was 48.9 (24-109)months. Vitamin D insufficiency and secondary hyperparathyroidism were observed in 38 and 20 patients, respectively. Densitometry showed osteoporosis in 14 women and seven men and prevalent fractures in 12 women and six men at baseline. After 3months of vitamin D supplementation, 35 patients reached values of 25-(OH)-vitamin D over 30ng/mL. After 12months, 38 patients were in the normal range of 25-(OH)-vitamin D. At the same time, iPTH levels and markers of bone turnover (C-terminal cross-linked telopeptide of type-I collagen, serum concentrations of bone-specific alkaline phosphatase and osteocalcin) significantly decreased after vitamin D intervention. Oral administration of high doses of vitamin D is easily implemented and restored 25-(OH)-vitamin D and iPTH values, which are frequently disturbed after gastric cancer resection.

Differences in biochemical bone markers by diabetes type and the impact of glucose

BackgroundDiabetes mellitus is associated with an increased fracture risk, however the fracture risk is 7 fold increased in patients with type 1 diabetes (T1D) and 1.4 fold increased in patients with type 2 diabetes (T2D) with decreased and increased bone mineral density, respectively. Oral ingestion of glucose causes an acute decrease in bone turnover markers, and thus glucose levels may affect bone turnover in diabetes. ObjectiveThe aim was to examine disparities in bone turnover markers between patients with T1D and T2D and evaluate the effect of glucose on bone turnover. MethodsA cross-sectional study was conducted. Patients diagnosed with T1D (n=98) or T2D (n=96) were included from the outpatient clinics at two University Hospitals. All individuals had normal renal function. Glucose and bone turnover markers were measured in non-fasting blood samples. ResultsP-procollagen type 1 amino terminal propeptide (P1NP), p-osteocalcin (OC), and s-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL) were lower in patients with T2D compared to T1D, and s-osteoprotegerin (OPG) was higher in T2D. P-C-terminal cross-linked telopeptide of type-I collagen (CTX), p-fibroblast growth factor-23 (FGF-23), p-sclerostin, and p-undercarboxylated osteocalcin (ucOC) were similar in between the two groups of patients. Increasing non-fasting glucose levels were inversely related to p-CTX, p-P1NP, p-OC, and p-ucOC and directly related to s-OPG in simple linear and multiple linear regressions adjusted for factors influencing bone turnover markers including HbA1c. ConclusionBone turnover markers were lower in patients with T2D compared to T1D. Acute blood glucose alterations may change bone turnover mediated by OPG and have detrimental effects on bone health in diabetes.Trial registration number: ClinicalTrials.govNCT01870557.

Increased serum alkaline phosphatase levels correlate with high disease activity and low bone mineral density in patients with axial spondyloarthritis

ObjectivesRecent studies report an association between serum alkaline phosphatase (ALP) levels and inflammation. The present study examined the relationship between ALP and disease activity, bone mineral density (BMD), and radiological damage in axial spondyloarthritis (SpA). MethodsA total of 115 patients who fulfilled the ASAS axial SpA criteria were enrolled. Serum ALP, bone-specific ALP (BALP), serum cross-linked telopeptide of type-I collagen (sCTX), and inflammatory markers were measured. Clinical parameters, BMD, grade of sacroiliitis, and the modified Stoke AS Spinal Score (mSASSS) were also assessed. The Ankylosing Spondylitis Disease Activity Score (ASDAS) was also calculated. The associations between serum ALP, disease activity score, BMD, and radiologic damage were evaluated. ResultsThe mean serum ALP level was 77 ± 26U/l. Serum ALP levels increased in 14 patients (13%). Serum ALP levels increased along with ASDAS-CRP after adjusting for age and sex (p = 0.004), and were significantly correlated with ASDAS-ESR and ASDAS-CRP (p = 0.001 and p < 0.001, respectively), negatively correlated with BMD in the lumbar spine and femoral neck (p = 0.003 and 0.046, respectively), and positively correlated with sacroiliitis grade and the mSASSS (p < 0.001 and p < 0.002, respectively). BALP and sCTX were not associated with disease activity or BMD. Multivariate analysis showed that serum ALP was independently associated with ASDAS-CRP (p = 0.010). ConclusionsIncreased serum ALP levels were associated with high disease activity, low BMD, and higher structural damage scores in SpA patients.

Relationships between dimethylarginine and the presence of vertebral fractures in type 2 diabetes mellitus

Although previous studies suggested that nitric oxide (NO) could affect bone metabolism, little is known about whether asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is associated with the risk of osteoporotic fractures. A cross-sectional study was carried out to examine the associations of serum dimethylarginines with bone mineral density (BMD), bone turnover markers, and the presence of vertebral fractures in 226 men and 152 postmenopausal women with type 2 diabetes. In subjects with vertebral fractures, there was significantly higher serum ADMA in men (0.61 ± 0.20 [mean ± SD] vs 0.55 ± 0.19 μm, P = 0.030) and symmetric dimethylarginine (SDMA) in postmenopausal women (0.72 ± 0.37 vs 0.56 ± 0.16 μm, P < 0.001) than in those without fractures. In men with vertebral fractures, serum ADMA was negatively correlated with Z-score at one-third radius (multiple regression β = -0.28, p = 0.016), and SDMA was positively correlated with serum osteocalcin (β = 0.38, P = 0.044) and urinary N-terminal cross-linked telopeptide of type-I collagen (β = 0.40, P = 0.027). In addition, serum ADMA in men and SDMA in postmenopausal women were positively associated with the presence of vertebral fractures after adjusting for age, duration of diabetes, and lumbar BMD (multiple logistic regression odds ratio [OR] = 1.36, P = 0.044 and OR = 1.78, P = 0 .006, respectively). We report, for the first time, that serum dimethylarginines may be independent risk factors for prevalent vertebral fractures in patients with type 2 diabetes.

Multiple myeloma: changes in serum C‐terminal telopeptide of collagen type I and bone‐specific alkaline phosphatase can be used in daily practice to detect imminent osteolysis*

Objective: Monitoring of bone disease in multiple myeloma is becoming increasingly important because bone-protecting treatment with bisphosphonate is becoming restricted after the awareness of osteonecrosis of the jaw. Despite the potential of biochemical markers of bone remodeling to monitor dynamic bone turnover, they are not used in everyday practice. Here, we investigate their usefulness to detect imminent progressive osteolysis in relapsing patients with multiple myeloma. Methods: In an unselected cohort of 93 patients, we measured the bone resorption markers C-terminal telopeptide of collagen type I (CTX-I), C-terminal cross-linked telopeptide of type-I collagen generated by MMPs (ICTP), N-terminal cross-linked telopeptide of type-I collagen (NTX-I), and the bone formation marker bone-specific alkaline phosphatase (bALP) monthly for 2 yr. Retrospectively, we identified 40 cases where patients had progressive disease. We investigated how the bone markers developed prior to disease progression. Results: We observed that CTX-I and bALP changed significantly before progressive disease were recognized. More interestingly, these changes differed depending on whether concurrent progressive osteolysis was present. In patients with progressive osteolysis, there was a large increase in bone resorption which was not compensated by increased bone formation. In contrasts, patients with stable bone disease had only a slight increase in bone resorption which was compensated by concurrent increased bone formation. By calculating a patient-specific CTX-I/bALP ratio, we quantified the risk a patient experiences if the ratio increases. Conclusion: By analyzing patient-specific changes in the ratio of CTX-I/bALP, we might tailor treatment with bone-protecting agents in the individual patient.

Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus

Although recent animal studies have shown that undercarboxylated osteocalcin acts as a hormone regulating glucose metabolism and fat mass, little is known about the relationships in humans. We reported here for the first time that undercarboxylated osteocalcin were associated with glucose/fat metabolism in patients with type 2 diabetes. Recent studies have shown that undercarboxylated osteocalcin (ucOC) acts as a hormone regulating glucose metabolism and fat mass. We investigated the relationship between ucOC as well as other bone turnover markers [serum OC, bone-specific alkaline phosphatase (BAP), and urinary N-terminal cross-linked telopeptide of type-I collagen] versus serum levels of glucose, fasting serum C-peptide, and adiponectin as well as the amount of fat mass in type 2 diabetes. A total of 180 men and 109 postmenopausal women were consecutively recruited, and radiographic and biochemical characteristics were collected. Fat mass was measured by dual X-ray absorptiometry (DXA) and computed tomography (CT). In men, ucOC negatively correlated with percent trunk fat (%trunk fat; by DXA) and visceral/subcutaneous fat ratio (by CT) as well as fasting plasma glucose and HbA(1c) (at least p < 0.05). Multiple regression analysis showed that these associations were still significant independent of age, duration of diabetes, body stature, and renal function as well as glucose or fat metabolism, whereas BAP, another bone formation marker, did not correlate with any variable. On the other hand, although ucOC also negatively correlated with %fat and %trunk fat as well as HbA(1c) (at least p < 0.05) in postmenopausal women, we found no significant association in multiple regression analysis. These findings suggest that ucOC is associated with plasma glucose level and fat mass in men with type 2 diabetes.

Baseline serum total adiponectin level is positively associated with changes in bone mineral density after 1-year treatment of type 2 diabetes mellitus

Although recent clinical studies have shown that serum adiponectin level was negatively associated with bone mineral density (BMD), serum adiponectin action on bone metabolism in humans is still unclear. We investigated the relationships between serum levels of total and high–molecular weight (HMW) adiponectin and its ratio (HMW-total ratio) vs chronological changes in BMD at the lumbar spine, femoral neck (FN), and one third of the radius after 1-year treatment of type 2 diabetes mellitus in 32 Japanese patients. Serum total adiponectin, but not HMW adiponectin or HMW-total ratio, was significantly and positively correlated with percentage change in FN-BMD ( r = 0.35, P < .05). Multiple regression analysis adjusted for age, duration of diabetes, sex, body height, body weight, waist circumference, serum creatinine, and hemoglobin A 1c showed that serum total adiponectin was still significantly and positively correlated with percentage change in FN-BMD ( r = 0.65, P < .01). On the other hand, no significant relationships were found between serum levels of hemoglobin A 1c, pentosidine, bone formation markers (bone-specific alkaline phosphatase and osteocalcin), or a bone resorption marker (urinary N-terminal cross-linked telopeptide of type-I collagen) vs percentage change in BMD at any site. These findings suggest that serum total adiponectin could be clinically useful for predicting BMD change during treatment of type 2 diabetes mellitus. Adiponectin might protect against BMD reduction in patients with type 2 diabetes mellitus.

Serum Osteocalcin/Bone-Specific Alkaline Phosphatase Ratio Is a Predictor for the Presence of Vertebral Fractures in Men with Type 2 Diabetes

We examined whether or not BMD or bone markers were useful for assessing the risk of vertebral fractures in 248 Japanese men with type 2 diabetes. We analyzed the relationships between bone markers (osteocalcin [OC], bone-specific alkaline phosphatase [BAP], urinary N-terminal cross-linked telopeptide of type-I collagen) or BMD and HbA(1c), urinary C-peptide, insulin-like growth factor-I (IGF-I), parathyroid hormone, 1,25(OH)(2) vitamin D, and the presence of prevalent vertebral fractures. Multiple regression analysis adjusted for age, body height, weight, duration of diabetes, and serum creatinine showed that serum OC and OC/BAP ratio were correlated negatively with HbA(1c) (P < 0.01) and positively with IGF-I (P < 0.01). Multivariate logistic regression analysis adjusted for the above parameters showed that serum OC/BAP ratio was inversely associated with the presence of vertebral fractures (odds ratio = 0.695, P < 0.05). This association was still significant after additional adjustment for lumbar or femoral neck BMD. Our results suggest that poor diabetic control and lower IGF-I level are linked to impaired bone formation and resultant reduction in OC/BAP ratio in men with type 2 diabetes. The OC/BAP ratio could be clinically useful for assessing the risk of vertebral fractures independent of BMD in diabetic men.

Associations between components of the metabolic syndrome versus bone mineral density and vertebral fractures in patients with type 2 diabetes

The association of bone with the metabolic syndrome and its features, visceral fat accumulation or insulin resistance, remains unclear. We determined visceral and subcutaneous fat areas (V and S) by computed tomography on 187 men (28–83 years) and 125 postmenopausal women (46–82 years) with type 2 diabetes. Men whose V was 100 cm2 or more had significantly lower urinary N-terminal cross-linked telopeptide of type-I collagen (p=0.005), higher femoral neck bone mineral density (FN-BMD) (p=0.004), and lower prevalence of vertebral fractures (VFs) (p=0.04) than controls. Fat mass, V, S, and lean body mass positively correlated with FN-BMD in men and with lumbar (L) and FN-BMD in women. When adjusted for weight, these correlations became negative. Urinary C-peptide positively correlated with FN-BMD in both genders. Multivariate logistic regression analysis adjusted for age, height, weight, L-BMD, duration of diabetes, and diabetes therapies identified V in men and urinary C-peptide in women as factors inversely associated with the presence of VFs [odds ratio (OR)=0.61 per SD increase, p=0.04, and OR=0.32, p=0.01, respectively]. These findings suggest that, of the components of the metabolic syndrome, body fat in gravity and hyperinsulinemia could increase FN-BMD in diabetic subjects. Visceral fat in men and hyperinsulinemia in women may protect against VFs independent of weight, L-BMD, diabetes duration, or therapies.

Effect of exemestane on bone turnover markers and bone mineral density (BMD): 2 year results of the Dutch/Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.

Abstract Abstract #1154 Background Aromatase inhibitors (AIs) given to women with early breast cancer may adversely affect bone metabolism. We studied the effect of exemestane (E) on bone mineral density (BMD) and bone turnover and compared it to the effect of tamoxifen (T) treatment in a group of women participating in the Dutch and Belgian Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. In this trial, postmenopausal women with hormone sensitive early breast cancer (n=3168) were randomised between 5 years E or 2½-3 years T followed by 2½-2 years of E.&amp;#x2028; Methods In this subprotocol, 87 women were followed for two years. Patients with bone diseases were excluded. Total hip and lumbar spine BMD were assessed at baseline and after 1 and 2 years. The bone resorption marker cross-linked telopeptide of type-I collagen (CTX) and the bone formation marker N-terminal propeptide of type I collagen (PINP) were measured in fasting serum at baseline and after 3, 6, 12 and 24 months.&amp;#x2028; Results At baseline, there was no difference in total hip (E: 0.85g/cm2, T: 0.80g/cm2; p=0.642) and lumbar spine BMD (E: 0.99g/cm2, T: 1.02g/cm2; p=0.545) between both groups. After 2 years, there were no significant changes in total hip BMD (E: 0.02 g/cm2 95%CI -0.05;0.08, p=0.849; T: 0.03 g/cm2, 95%CI -0.02;0.09, p=0.466) and in spine BMD (E: -0.02 g/cm2 95%CI -0.11;0.06, p=0.834; T: 0.02 g/cm2 95%CI -0.05;0.10, p=0.747). At baseline, there was no difference in serum CTX (E: 0.34ng/mL, T: 0.29ng/mL; p=0.271) and P1NP (E: 57ng/L, T:58ng/L, p=0.973) between both groups. After 2 years of treatment, serum CTX increased, although not significantly in the E group (20%, 95%CI -6%;54%, p=0.223) while it decreased significantly in the T group (-40%, 95%CI -23%;-53%, p&amp;lt;0.001). At 24 months, the CTX was 0. 44ng/mL (E) and 0. 18ng/mL (T). Serum P1NP did not change in the E group (-2%, 95%CI -20%;19%, p=0.837) but decreased significantly in the T group (-48%, 95%CI -36%;-58%, p&amp;lt;0.001). At 24 months, the P1NP was 55ng/L (E) and 28ng (T).&amp;#x2028; Conclusion Although there was a trend for an increase in bone resorption with E treatment, this was not significant and was not associated with a decrease in BMD. The magnitude of the reported negative effect of aromatase inhibitors on bone metabolism in studies using T as comparator treatment may be overestimated by the effect of T on bone turnover. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1154.

Combination of Obesity with Hyperglycemia is a Risk Factor for the Presence of Vertebral Fractures in Type 2 Diabetic Men

Although patients with type 2 diabetes show no bone mineral density (BMD) reduction, fracture risks are known to increase. It is unclear why the patients have an increased risk of fracture despite sufficient BMD. We investigated the relationships of body mass index (BMI), HbA(1c), and urinary C-peptide (uC-peptide) versus BMD, bone metabolic markers, serum adiponectin, and prevalent vertebral fracture (VF). A total of 163 Japanese type 2 diabetic men were consecutively recruited, and radiographic and biochemical data were collected. BMI was positively correlated with BMD at the whole body, lumbar spine, and femoral neck (P < 0.05) and negatively correlated with osteocalcin and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) (P < 0.01). HbA(1c) was negatively correlated with osteocalcin (P < 0.01) but not BMD at any site. Subjects were classified into four groups based on BMI and HbA(1c) (group LL BMI < 24 and HbA(1c) < 9, group LH BMI < 24 and HbA(1c) > or = 9, group HL BMI > or = 24 and HbA(1c) < 9, group HH BMI > or = 24 and HbA(1c) > or = 9). Serum adiponectin, osteocalcin, and uNTX were lower and the incidence of VF was higher despite sufficient BMD in the HH group. Multivariate logistic regression analysis adjusted for age, duration of diabetes, uC-peptide, and estimated glomerular filtration rate showed that the HH group was associated with the presence of a VF and multiple VFs (odds ratio [OR] = 3.056, 95% confidence interval [CI] 1.031-9.056, P = 0.0439, and OR = 5.415, 95% CI 1.126-26.040, P = 0.0350, respectively). Combination of obesity with hyperglycemia was a risk factor for VF despite sufficient BMD in diabetic men.

Serum insulin-like growth factor-I level is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus

Multivariate logistic regression analysis showed that serum IGF-I level was significantly lower in postmenopausal diabetic women with vertebral fractures than in those without fractures. Serum IGF-I level could be clinically useful for assessing the risk of vertebral fractures independent of BMD in postmenopausal women with type 2 diabetes. We investigated the relationships among serum IGF-I and C-peptide levels, BMD, and vertebral fractures in postmenopausal women with type 2 diabetes. A total of 131 postmenopausal women with type 2 diabetes were consecutively recruited, and radiographic and biochemical characteristics were collected. Either IGF-I or C-peptide was not correlated with BMD at any site or bone metabolic markers, such as osteocalcin (OC) and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX). However, serum IGF-I level was significantly lower in subjects with vertebral fractures than in those without fractures (mean +/- SD: 106.9 +/- 50.0 vs. 142.8 +/- 50.8 ng/ml, p = 0.0006). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and serum IGF-I adjusted for the parameters described above as independent variables, IGF-I was selected as an index affecting the presence of vertebral fractures [odds ratio = 0.436, 95% confidential interval 0.234-0.814 per SD increase, p = 0.0092]. This significance was almost the same after additional adjustment for lumbar BMD or C-peptide. Serum IGF-I level could be clinically useful for assessing the risk of vertebral fractures independent of BMD in postmenopausal women with type 2 diabetes.

The efficacy of the bone markers osteocalcin and the carboxyterminal cross-linked telopeptide of type-I collagen in evaluating osteogenesis in a canine crural lengthening model

The aim of the present study was to determine the efficacy of the bone markers osteocalcin (OC) and carboxyterminal cross-linked telopeptide of type-I collagen (ICTP) in evaluating new bone formation in the dog, using commercially available immunoassay kits. Dogs were randomly divided into three groups and a circular external skeletal fixation system (CESF) was mounted on the tibia. In the first group a distraction osteogenesis procedure of the crus was performed. The second group received an osteotomy without crural lengthening, whereas the third group served as a sham-operated control. Bone formation was assessed using densitometric image analysis of crural radiographs. Despite significant differences in the amount of newly formed bone, this finding was not reflected in the plasma levels of OC and ICTP. In conclusion, OC and ICTP were not efficacious as markers of bone formation and resorption during osteogenesis in this canine model.

Long-Term Results of Total Parathyroidectomy without Autotransplantation in Patients with and without Renal Failure

The optimal surgical procedure for severe renal secondary hyperparathyroidism (sHPT) is still a point of controversy. Total parathyroidectomy (PTX) without auto-transplantation was abandoned for fear of an adynamic bone condition; however, in the case of autotransplantation recurrent sHPT is frequent and promotes atherosclerosis. We studied 11 hemodialysis patients (age 59±12 years) on dialysis for 18 (12–30) years in whom total PTX was performed due to severe sHPT (group I; intact PTH: 1,240±230 pg/ml), and 5 patients (age 55±10 years) without renal insufficiency who inadvertently received total PTX during thyroid surgery (group II). After total PTX (group I, 26±18 [9–59] months; group II, 252±188 [22^480] months) both groups showed no measurable intact PTH levels. Calcium homeostasis was maintained by oral substitution with calcium (group I, calcium dialysate of 2.0 mmol/l), vitamin D and calcitriol (serum parameters in groups I and II: calcium 2.4 and 2.2 mmol/l; phosphate 1.8 and 1.1 mmol/l; 25(OH)-vitamin D₃ 21 and 34 ng/ml; 1,25(OH)₂-vitamin D₃ 32 and 41 pg/ml, respectively). In group I, after total PTX there was a rapid and sustained improvement in bone pain with markedly enhanced physical activity and endurance. High turnover osteopathy markedly improved as indicated by declining levels of native osteocalcin (90±17 vs. 26±18 ng/ml), bone alkaline phosphatase (74±12 vs. 12±6 ng/ml), and carboxyterminal cross-linked telopeptide of type-I collagen (65±16 vs. 40±21 ng/ml) but increasing levels of carboxyterminal propeptide of type-I procollagen (120±36 vs. 148±41 ng/ml). Recalcification of bone was excellent as demonstrated by X-ray and confirmed by bone histology. Itching extravascular calcific deposits and calcifications of blood vessel and cardiac valves immediately stopped after total PTX. Moreover, 6 sHPT patients suffered from severe atherosclerotic lesions such as thoracic aortic aneurysm (n = 3) or abdominal aortic aneurysm (n = 3) which showed size progression before but not after total PTX when annually controlled by ultrasonography. In group II, even long after total PTX, there was no clinical, radiological, histological or biochemical evidence for low turnover osteopathy. In conclusion, our data indicate that substitution with vitamin D₃ metabolites and calcium can prevent deleterious bone effects of hypoparathyroidism in hemodialysis patients and in patients with normal kidney function and may compensate for the missing PTH action. Over this, a better survival rate is expected as a consequence of the beneficial effect of total PTX on the progression of atherosclerotic lesions. We suggest reconsideration of total PTX without autotransplantation in dialysis patients with severe sHPT who are not eligible for renal transplantation.