Terminal Telopeptide Research Articles

The clinical importance of bone metabolic markers in detecting bone metastasis of lung cancer

The aim of this study was to evaluate the role of bone metabolic markers in clinical evaluation of bone metastasis of lung cancer. Sixty-five male patients with lung cancer were included in this trial, 77% of whom were diagnosed as having non-small cell lung cancer and 20% were small cell lung cancer. The presence of bone metastasis was investigated by whole-body bone scintigraphy via Tc-99m mostly (80%) and, in some cases, PET/CT (positron emission tomography and computerized tomography) which was performed for staging. Bone-specific alkaline phosphatase (BALP) and osteocalcin were measured in serum of the patients as markers of bone formation. N-terminal telopeptide (NTX) and β-form of C terminal telopeptide (β-CTX) were studied as bone destruction markers. The cases were divided into two groups according to the presence of bone metastasis. Twenty-three patients (35%) had bone metastasis. Serum levels of total ALP, BALP and NTX were significantly higher in the group with bone metastasis (p < 0.05). Osteocalcin and β-CTX levels were not significantly different between two groups. According to ROC-curve analysis, at the threshold value of 22.38 μg/L, the sensitivity of BALP was 60.87% and the specificity was 69.05%. Similarly, at the threshold value of 25.69 nmol BCE, the sensitivity of NTX was 90.24% and the specificity was 43.4%. Bone metabolic markers are considered noninvasive, useful and cost-effective. However, more prospective studies are needed in order to use them for evaluation of bone metastasis in lung cancer.

High sodium chloride intake exacerbates immobilization-induced bone resorption and protein losses

We examined, in immobilization, the effect of a diet high in sodium chloride (NaCl) on bone markers, nitrogen balance, and acid-base status. Eight healthy male test subjects participated in a 14-day head-down-tilt bed rest (HDBR) study. During the bed rest period they received, in a randomized crossover design, a high (7.7 meq Na(+)/kg body wt per day) and a low (0.7 meq Na(+)/kg body wt per day) NaCl diet. As expected, 24-h excretion of urinary calcium was significantly greater in the high-NaCl-intake HDBR phase than in the low-NaCl-intake HDBR phase (P < 0.001). High NaCl intake caused a 43-50% greater excretion of the bone resorption markers COOH- (CTX) and NH(2)- (NTX) terminal telopeptide of type I collagen in HDBR than low NaCl in HDBR (CTX/NTX: P < 0.001). Serum concentrations of the bone formation markers bone-specific alkaline phosphatase (bAP) and NH(2)-terminal propeptide of type I procollagen (PINP) were identical in both NaCl intake phases. High NaCl intake led to a more negative nitrogen balance in HDBR (P < 0.001). Changes were accompanied by increased serum chloride concentration (P = 0.008), reduced blood bicarbonate (P = 0.017), and base excess (P = 0.009) whereas net acid excretion was lower during high than during low NaCl intake in immobilization (P < 0.001). High NaCl intake during immobilization exacerbates disuse-induced bone and muscle loss by causing further protein wasting and an increase in bone resorption. Changes in the acid-base status, mainly caused by disturbances in electrolyte metabolism, seem to determine NaCl-induced degradation processes.

Interleukin-6: a growth factor stimulating collagen synthesis in human tendon

Human connective tissue, e.g., tendon, responds dynamically to physical activity, with collagen synthesis being increased after both acute and prolonged exercise or training. Markers of collagen synthesis and degradation as well as concentration of several potential growth factors have been shown to increase markedly in the peritendinous tissue around the human Achilles tendon following exercise. Of these potential growth factors interleukin-6 (IL-6) showed the largest fold increase, suggesting that IL-6 may be involved in transforming mechanical loading into collagen synthesis in human tendon tissue. In the present study the tissue levels of type I collagen turnover markers [procollagen type I NH(2)-terminal propeptide (PINP) and C-OOH terminal telopeptide of type I collagen (ICTP)] were measured by the use of microdialysis in peritendinous tissue of the Achilles tendon in 14 male volunteers, who had recombinant human IL-6 (rhIL-6) infused into the peritendinous tissue of the Achilles' tendon in one leg, with the other leg serving as control. Subjects were randomly assigned to either a resting group or an exercise group performing a 1-h treadmill run (12 km/h, 2% uphill) before infusion. In addition to IL-6, serum concentrations of collagen turnover markers PINP, ICTP, and COOH-terminal telopeptide of type I collagen (ICTX) were measured. The peritendinous concentration of PINP rose markedly in response to rhIL-6 infusion in both the exercise and the rest group, demonstrating that infusion of IL-6 significantly stimulates collagen synthesis in the peritendinous tissue in humans. Exercise alone did not result in an increased collagen synthesis. This indicates that IL-6 is involved in the collagen synthesis and supports the hypothesis that IL-6 is an important growth factor of the connective tissue in healthy human tendons.

Nutritional approach for inhibiting bone resorption in institutionalized elderly women with vitamin D insufficiency and high prevalence of fracture.

Nutritional approach to the deterioration of bone integrity and increased fracture risk appears to be particularly appropriate in elderly women living in nursing homes. To investigate the beneficial effect of the consumption of soft plain cheese on bone resorption markers in institutionalized elderly women. Prospective, randomized crossover controlled study. Six French nursing homes or other institutions for elderly. Institutionalized women ≥ 65 years old with low vitamin D status and calcium intake below 700 mg/day. Consumption of soft plain cheese made of semi-skimmed milk which was fortified by both vitamin D3 (+1.25 µg/100g) and milk extracted Ca, thus achieving a total Ca content of 151 mg/100g as compared to about 118 mg/100g for standard fresh cheese. Two servings were taken every day during the 6 weeks that preceded or followed a period of 6 weeks without soft plain cheese consumption. The primary end point was the change in serum carboxy terminal cross-linked telopeptide of type I collagen (CTX) selected as a marker of bone resorption. 29 women aged 73-94 yr were selected, 21 of them with mean age 87.2±6.1 years remained compliant. The intervention increased calcium and protein intakes by 51% (904±228 vs. 599±122 mg/d) and 33 % (74.2±17.1 vs. 55.6±12.7 g/d, mean±SD), respectively. The dietary intervention was associated with a statistically significant increase in serum levels of both 25OHD and IGF-I, while those of [corrected] CTX and TRAP5b were significantly reduced. Compliance was 93,4 %. The daily consumption of two servings of soft plain cheese was well accepted in terms of tastiness and appetite suited portion size. This randomized crossover controlled trial demonstrates that in elderly women living in nursing homes, the consumption of soft plain cheese increasing the supply of vitamin D, calcium and proteins, could reduce bone resorption and thereby reduce the risk of incidental fragility fractures in the long term.

Relative value of the lumbar spine and hip bone mineral density and bone turnover markers in men with ankylosing spondylitis

The purpose of this study is to evaluate bone mineral density (BMD) and bone turnover markers in men with ankylosing spondylitis (AS) and to determine their relationship with clinical features and disease activity. Serum carboxi terminal cross-linked telopeptide of type I collagen (CTX), osteocalcin (OC) levels, and BMD of lumbar spine and proximal femur were evaluated in 44 males with AS, 18-60 years of age, and compared with those of 39 age-matched healthy men. Men with AS had a significantly lower BMD at the femoral neck and total hip as compared to age-matched controls (all p < 0.01). Osteopaenia or osteoporosis was found in 59.5% AS patients at the lumbar spine and in 47.7% at the femoral neck. Mean serum levels of OC and CTX were similar in AS patients and controls. There were no significant differences in BMD and bone turnover markers when comparing subgroups stratified according to disease duration or presence of peripheral arthritis. No correlations were found between disease activity markers and BMD or OC and CTX. In a cohort of relatively young males with AS, we found a high incidence of osteopaenia and osteoporosis. Disease activity and duration did not show any significant influence on BMD or serum levels of OC and CTX.

Subchondral bone loss following orthodontically induced cartilage degradation in the mandibular condyles of rats

Osteoarthritis (OA) is a degenerative joint disease generally characterized by progressive cartilage degradation and subchondral bone changes. Subchondral bone changes have been proposed to initiate or accompany with cartilage degradation in OA. The purpose of this study was to characterize cartilage damage, subchondral bone remodeling, and the possible mechanism involved in these morphological changes in our reported rat model with OA-like lesions in the mandibular condyle. In experimental groups, the dental occlusion was orthodontically disturbed. By histological analysis, transmission electron microscopy (TEM), micro-CT scanning and serum tests, changes in condylar cartilage and subchondral bone were analyzed at 8 and 12 weeks after treatment. The mRNA and protein levels of bone pro-resorptive and pro-formative factors by chondrocytes were investigated. Increased degraded cartilage areas and obvious cartilage calcification were observed in 8- and 12-week treated (EXP) groups compared to the age-matched controls. Subchondral bone loss, characterized as decreased bone mineral density (BMD), bone volume fraction (BV/TV) and trabecular thickness (Tb.Th), but increased trabecular separation (Tb.Sp), was observed in the 12-week but not the 8-week EXP group, respectively, versus their age-matched controls. The subchondral bone loss in the 12-week EXP group was accompanied with decreased new bone formation rate, but increased serum carboxy terminal telopeptides (CTXs), and increased osteoclast numbers and proportion of surface area in the subchondral bone regions. Increased mRNA and protein levels of M-CSF, VEGF, RUNX and RANKL/OPG ratio, but decreased OPG, were found in condylar cartilage in the 12-week EXP group versus its age-matched controls, and those of RANKL/OPG ratios were significantly higher in the 12-week EXP group than the 8-week EXP. In addition, increased mRNA levels of VEGF, RUNX and RANKL/OPG ratio, but decreased OPG, were also found in condylar cartilage in the 8-week EXP group versus its age-matched controls (All P < 0.05). This study demonstrated that obvious subchondral bone loss followed cartilage degradation in the mandibular condyles in the present rat models and suggested that the imbalance of chondrocyte-secreted regulatory factors within the degraded cartilage may play a role in the osteoclastogenesis, and thus leading to the subchondral bone loss in OA.

Osteolytic lesions marker in multiple myeloma

The degradation product of collagen type I carboxy terminal telopeptide (ICTP) represents a new biochemical parameter that reflects the changes in the resorption properties of skeletal system. Affection of the skeleton is one of the most important characteristics of multiple myeloma (MM). We estimated significance of ICTP as osteolysis predictor and overall survival in comparison with standard prognostic parameters β(2)-microglobulin and C-reactive protein (CRP), in patients with MM. With our results, we have shown significant difference in serum level of ICTP (P = 0.009) between patients with and without osteolysis on conventional radiography. It was proved that ICTP is the most significant predictor of osteolysis (P = 0.09), while CRP is the most significant risk factor for overall survival (P < 0.01). Being highly significant predictor of osteolysis, ICTP can be used for identification of patients with MM who had increased risk for developing osteolytic lesions.

Serum Carboxy Terminal Telopeptide of Type I Collagen (ICTP) Predicts Progression of Left Ventricular LV Remodeling After Reperfused AMI

Background: Extracellular matrix (ECM) reformation is an essential in the remodeling process following AMI. The aim of this study was to determine whether early assessment of serum ICTP, which reflects ECM reformation and degradation,levels may predict LV remodeling after AMI. Methods and Results: At discharge and 6 months after first reperfused AMI serum ICTP,log BNP,H-FABP levels and LV end diastolic volume index (LVEDVI) measured by gated SPECT were evaluated. Patients were divided according to the delta LVEDVI (LVEDVI at discharge-LVEDVI at 6 months after AMI) in 2 groups:group1 (non progressive group;n=43) with delta LVEDVI<10ml/m2 and group 2 (progressive group;n=8) with delta LVEDVI>10ml/m2.

Moderate Ingestion of Alcohol Is Associated With Acute Ethanol-Induced Suppression of Circulating CTX in a PTH-Independent Fashion

The "J shape" curve linking the risk of poor bone health to alcohol intake is now well recognized from epidemiological studies. Ethanol and nonethanol components of alcoholic beverages could influence bone remodeling. However, in the absence of a solid underlying mechanism, the positive association between moderate alcoholic intake and BMD remains questionable because of confounding associated social factors. The objective of this work was to characterize the short-term effects of moderate alcohol consumption on circulating bone markers, especially those involved in bone resorption. Two sequential blood-sampling studies were undertaken in fasted healthy volunteers (age, 20-47 yr) over a 6-h period using beer of different alcohol levels (<0.05-4.6%), solutions of ethanol or orthosilicic acid (two major components of beer), and water +/- calcium chloride (positive and negative controls, respectively). Study 1 (24 subjects) assessed the effects of the different solutions, whereas study 2 (26 subjects) focused on ethanol/beer dose. Using all data in a "mixed effect model," we identified the contributions of the individual components of beer, namely ethanol, energy, low-dose calcium, and high-dose orthosilicic acid, on acute bone resorption. Markers of bone formation were unchanged throughout the study for all solutions investigated. In contrast, the bone resorption marker, serum carboxy terminal telopeptide of type I collagen (CTX), was significantly reduced after ingestion of a 0.6 liters of ethanol solution (>2% ethanol; p <or= 0.01, RM-ANOVA), 0.6 liters of beer (<0.05-4.6% ethanol; p < 0.02), or a solution of calcium (180 mg calcium; p < 0.001), but only after calcium ingestion was the reduction in CTX preceded by a significant fall in serum PTH (p < 0.001). Orthosilicic acid had no acute effect. Similar reductions in CTX, from baseline, were measured in urine after ingestion of the test solutions; however, the biological variability in urine CTX was greater compared with serum CTX. Modeling indicated that the major, acute suppressive effects of moderate beer ingestion (0.6 liters) on CTX were caused by energy intake in the early phase (approximately 0-3 h) and a "nonenergy" ethanol component in the later phase (approximately 3 to >6 h). The early effect on bone resorption is well described after the intake of energy, mediated by glucagon-like peptide-2, but the late effect of moderate alcohol ingestion is novel, seems to be ethanol specific, and is mediated in a non-calcitonin- and a non-PTH-dependent fashion, thus providing a mechanism for the positive association between moderate alcohol ingestion and BMD.

Serum concentrations of formation (PINP) and resorption (Ctx) bone turnover markers in rheumatoid arthritis

Joint inflammation in rheumatoid arthritis (RA) induces local periarticular osteoporosis. Generalised bone mineral density (BMD) decrease concerns approximately 50% of rheumatic patients. Both types of bone mass depletion can issue from cytokine-induced (TNF-α, IL-1, IL-6) osteoclasts’ activation, osteoprotegerin and its ligand’s (RANKL) function disorders, patients’ immobilisation and glucocorticosteroid (GCS) intake, as well as from hormonal alterations in postmenopausal women, predominate among RA individuals. The aim of the study was to compare serum concentrations of marker of bone formation—serum aminoterminal propeptide of type I collagen (PINP), and bone resorption, carboxy (C) terminal telopeptide (Ctx), bone turnover markers in RA and osteoarthritis (OA) patients and in RA groups of different disease activity, different degree of joint damage and the history of GCS intake. A total of 50 RA female patients and 50 women with knee OA were included in the study. Blood for morphology and biochemistry laboratory tests was taken. Joint X-rays to establish OA and RA diagnosis and the degree of RA progression, as well as DEXA BMD measurements were performed. PINP and Ctx concentrations were assessed. In RA patients the number of swollen and painful joints, the duration of morning stiffness, visual analogue scale values and Waaler–Rose’s test activity were recorded. The Disease Activity Index (DAS 28) was counted from the appropriate formula. No differences in bone turnover markers’ concentrations were noted neither between RA and OA patients nor between the RA group when compared to the one without the history of GCS use. Bone turnover markers’ concentrations in RA were proportional to the number of swollen and painful joints. However, no correlation was found between the markers’ concentrations and RA activity assessed by DAS 28 or by laboratory means. Ctx concentrations were higher in patients at II degree joint damage according to Larsen and Dale’s than at more advanced stages. Ctx concentrations decreased with the disease duration. Serum morphogenesis and resorption markers’ concentrations change in course of RA indicating the decrease in bone metabolic activity with the disease duration and progression. High RA activity and severity correlate with increased markers’ levels—the resorption one. The influence of GCS on bone metabolism in RA requires further study.

Inhibition of markers of bone resorption by consumption of vitamin D and calcium-fortified soft plain cheese by institutionalised elderly women

Acceleration of bone remodelling increases the risk of fragility fractures. The objective of the present study was to explore in elderly women whether a vitamin D and Ca-fortified dairy product providing about 17-25 % of the recommended intakes in vitamin D, Ca and proteins would reduce secondary hyperparathyroidism and bone remodelling in a way that may attenuate age-related bone loss in the long term. Thirty-seven institutionalised women, aged 84.8 (sd 8.1) years, with low serum 25-hydroxyvitamin D (5.5 (sd 1.7) ng/ml) were enrolled into a multicentre open trial to consume during 1 month two servings of soft plain cheese made of semi-skimmed milk providing daily 686 kJ (164 kcal), 2.5 microg vitamin D, 302 mg Ca and 14.2 g proteins. The primary endpoint was the change in serum carboxy terminal cross-linked telopeptide of type I collagen (CTX), selected as a marker of bone resorption. Thirty-five subjects remained compliant. Mean serum changes were: 25-hydroyvitamin D, +14.5 % (P = 0.0051); parathyroid hormone (PTH), - 12.3 % (P = 0.0011); CTX, - 7.5 % (P = 0.01); tartrate-resistant acid phosphatase isoform 5b (TRAP 5b), - 9.9 % (P < 0.0001); albumin, +6.2 % (P < 0.0001); insulin-like growth factor-I (IGF-I),+16.9 % (P < 0.0001); osteocalcin, +8.3 % (P = 0.0166); amino-terminal propeptide of type 1 procollagen (P1NP),+19.3 % (P = 0.0031). The present open trial suggests that fortified soft plain cheese consumed by elderly women with vitamin D insufficiency can reduce bone resorption markers by positively influencing Ca and protein economy, as expressed by decreased PTH and increased IGF-I, respectively. The rise in the bone formation marker P1NP could be explained by a protein-mediated increase in IGF-I. Thus, such a dietary intervention might uncouple, at least transiently, bone resorption from bone formation and thereby attenuate age-related bone loss.

Serum concentrations of formation (PINP) and resorption (Ctx) bone turnover markers in rheumatoid arthritis

Joint inflammation in rheumatoid arthritis (RA) induces local periarticular osteoporosis. Generalised bone mineral density (BMD) decrease concerns approximately 50% of rheumatic patients. Both types of bone mass depletion can issue from cytokine-induced (TNF-alpha, IL-1, IL-6) osteoclasts' activation, osteoprotegerin and its ligand's (RANKL) function disorders, patients' immobilisation and glucocorticosteroid (GCS) intake, as well as from hormonal alterations in postmenopausal women, predominate among RA individuals. The aim of the study was to compare serum concentrations of marker of bone formation--serum aminoterminal propeptide of type I collagen (PINP), and bone resorption, carboxy (C) terminal telopeptide (Ctx), bone turnover markers in RA and osteoarthritis (OA) patients and in RA groups of different disease activity, different degree of joint damage and the history of GCS intake. A total of 50 RA female patients and 50 women with knee OA were included in the study. Blood for morphology and biochemistry laboratory tests was taken. Joint X-rays to establish OA and RA diagnosis and the degree of RA progression, as well as DEXA BMD measurements were performed. PINP and Ctx concentrations were assessed. In RA patients the number of swollen and painful joints, the duration of morning stiffness, visual analogue scale values and Waaler-Rose's test activity were recorded. The Disease Activity Index (DAS 28) was counted from the appropriate formula. No differences in bone turnover markers' concentrations were noted neither between RA and OA patients nor between the RA group when compared to the one without the history of GCS use. Bone turnover markers' concentrations in RA were proportional to the number of swollen and painful joints. However, no correlation was found between the markers' concentrations and RA activity assessed by DAS 28 or by laboratory means. Ctx concentrations were higher in patients at II degree joint damage according to Larsen and Dale's than at more advanced stages. Ctx concentrations decreased with the disease duration. Serum morphogenesis and resorption markers' concentrations change in course of RA indicating the decrease in bone metabolic activity with the disease duration and progression. High RA activity and severity correlate with increased markers' levels-the resorption one. The influence of GCS on bone metabolism in RA requires further study.

A randomised study of the effects of anastrozole (A), letrozole (L) and exemestane (E) on bone turnover.

Abstract Abstract #1145 Background:&amp;#x2028; Aromatase inhibitors (AIs) reduce circulating oestrogen which increases bone turnover. L decreases circulating oestrogen levels to a greater degree than A. This study compares the effects of the non-steroidal aromatase inhibitors, A and L and the steroidal inactivator, E on bone turnover.&amp;#x2028; Patients and Methods:&amp;#x2028; This was an open, randomized pharmacodynamic study. Bone turnover markers were measured in 162 postmenopausal women with invasive ER +ve breast cancer. As part of their adjuvant hormone therapy, patients were randomized to receive either:&amp;#x2028; 16 weeks of A, 16 weeks of L or 16 weeks of E&amp;#x2028; Fasting blood and urine samples were collected at entry and after 12 and 16 weeks of each drug. Bone remodelling releases breakdown products of type 1 collagen including the terminal peptide fragments N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx). An increase in these indicates bone resorption. Increases in type 1 pro-collagen peptides (N-terminal – PINP) and bone specific alkaline phosphatase (ALP) indicate bone formation. These were measured as was parathyroid hormone (PTH) which is an indirect measure of overall bone turnover.&amp;#x2028; Results:&amp;#x2028; A vs E vs L&amp;#x2028; A, E and L significantly increased the bone turnover markers - PINP, CTX and bone ALP.&amp;#x2028; E showed a greater change in bone turnover but there were no significant differences between the drugs.&amp;#x2028; &amp;#x2028; &amp;#x2028; &amp;#x2028; E resulted in a greater increase in PINP and uNTX compared to the non-steroidal AIs however these were of borderline significance.&amp;#x2028; PINP, CTX and bone ALP all have significantly higher than zero percentage changes, regardless of drug or drug type.&amp;#x2028; Conclusions:&amp;#x2028; AIs cause a significant increase in both bone breakdown and bone formation.&amp;#x2028; There is no evidence to suggest E has less effects on bone turnover than A or L. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1145.

Cross-sectional association between urinary type II collagen C- terminal telopeptide concentration and radiographic spinal disc degeneration

Cross-sectional association between urinary type II collagen C- terminal telopeptide concentration and radiographic spinal disc degeneration

Impaired pyridinoline cross-link formation in patients with osteogenesis imperfecta

Patients with osteogenesis imperfecta (OI) show various degrees of bone fragility. Nevertheless, details of the mechanisms causing bone fragility remain unclear. We hypothesized that differences in pyridinoline cross-link formation at the N-and C-termini in type I collagen molecules partly contribute to bone fragility of OI. To verify this hypothesis, urinary N and C terminal telopeptides of type I collagen (uNTx and ubetaCTx, respectively) and urinary hydroxyproline (uHyp) were measured using second morning void urine samples obtained from OI patients and healthy control children. Ratios of uNTx and ubetaTx to uHyp (uNTx/uHyp and ubetaCTx/uHyp, respectively) of OI patients and healthy normal control children were analyzed. Ratios of uNTx to ubetaCTx (uNTx/ubetaCTx) were also analyzed. In OI patients, uNTx and ubetaCTx were lower than in healthy control children. Also, uNTx/uHyp and ubetaCTx/uHyp were significantly lower than in healthy children. Among OI patients, uNTx/uHyp and uNTx/ubetaCTx of type III OI were significantly lower than of either type I or type IV OI. These results show that pyridinoline cross-link formation is lower than in healthy control children and that pyridinoline cross-link formation at the N-and C-termini in type I collagen molecules might be differently disrupted in OI patients according to the severity of OI.

Retinol, retinol-binding protein 4, abdominal fat mass, peak bone mineral density, and markers of bone metabolism in men: the Northern Osteoporosis and Obesity (NO2) Study

The association between retinol and bone mineral density (BMD) in males after puberty has not been fully investigated previously. To investigate the association between retinol, retinol-binding protein-4 (RBP-4), BMD (g/cm(2)), abdominal fat mass, and markers of bone metabolism in young men. Longitudinal study. Seventy-eight healthy males with a mean age of 22.6+/-0.7 years at baseline. A follow-up was conducted in 73 of the participants 2.0+/-0.4 years later. Associations between serum concentrations of retinol and RBP-4, and BMD of the total body, lumbar spine, and hip, serum concentrations of osteocalcin, and carboxy terminal telopeptide of type 1 collagen (CTX), were investigated. Both retinol and RBP-4 showed an inverse relationship with that of osteocalcin (r=-0.23 to -0.25, P<0.05). Levels of RBP-4 (r=0.26, P=0.02) and osteocalcin (r=-0.23, P=0.04) were also related to abdominal fat mass, and the relationship between RBP-4, retinol, and osteocalcin disappeared after adjusting for this influence of abdominal fat mass. Neither retinol nor RBP-4 concentrations were associated with BMD at any site, CTX as baseline, or changes in BMD during the 2-year follow-up period. Levels of RBP-4 showed a strong association with levels of retinol (r=0.61, P<0.001). We found a negative association between the bone formation marker osteocalcin with retinol and RBP-4. The association disappeared when adjusting for the influence of abdominal fat mass. Neither retinol nor RBP-4 were associated with peak BMD in young men.

Thyroid hormone independent associations between serum TSH levels and indicators of bone turnover in cured patients with differentiated thyroid carcinoma.

It has been proposed that TSH has thyroid hormone-independent effects on bone mineral density (BMD) and bone metabolism. This concept is still controversial and has not been studied in human subjects in detail. We addressed this question by studying relationships between serum TSH concentration and indicators of bone turnover, after controlling for triiodothyronine (T(3)), free thyroxine (FT(4)), and non-thyroid factors relevant to BMD and bone metabolism. We also studied the contribution of the TSH receptor (TSHR)-Asp727Glu polymorphism to these relationships. We performed a cross-sectional study with 148 patients, who had been thyroidectomized for differentiated thyroid carcinoma. We measured BMD of the femoral neck and lumbar spine. FT(4), T(3), TSH, bone-specific alkaline phosphatase, procollagen type 1 aminoterminal propeptide levels, C-cross-linking terminal telopeptide of type I collagen, and urinary N-telopeptide of collagen cross-links were measured. Genotypes of the TSHR-Asp727Glu polymorphism were determined by Taqman assay. We found a significant, inverse correlation between serum TSH levels and indicators of bone turnover, which was independent of serum FT(4) and T(3) levels as well as other parameters influencing bone metabolism. We found that carriers of the TSHR-Asp727Glu polymorphism had an 8.1% higher femoral neck BMD, which was, however, no longer significant after adjusting for body mass index. We conclude that in this group of patients, serum TSH was related to indicators of bone remodeling independently of thyroid hormone levels. This may point to a functional role of the TSHR in bone in humans. Further research into this mechanism needs to be performed.

Vasomotor symptoms in infertile premenopausal women: a hitherto unappreciated risk for low bone mineral density

To identify the prevalence of vasomotor symptoms (VMS) in a population of premenopausal infertile women and to determine whether VMS is associated with enhanced bone turnover and low bone mineral density (BMD). Cross-sectional study. Academic infertility practice. Eighty-two premenopausal infertile, but otherwise healthy, women attending for routine infertility care. Bone mineral density testing, general health and Profile of Mood States questionnaires, and serum samples (cycle d 1-3). Vasomotor symptoms, specifically hot flashes (HF) and night sweats (NS); BMD z score, BMD categorized as low (Z <or= -1.0) or normal (Z > -1.0); ovarian reserve assessment (biochemical and ovarian dimensions on transvaginal ultrasound); and serum markers of bone turnover (collagen N-terminal telo-peptide, tartrate-resistant acid phosphatase, and bone-specific alkaline phosphatase) and ovarian reserve (FSH, E(2), and inhibin B). Multivariable regression analyses determined the associations between VMS, BMD, and bone turnover (individual markers and composite turnover score). The prevalence of VMS was 12% in this relatively young population (mean [+/- SD] age [years], 34.53 +/- 4.32). Symptomatic women were statistically significantly more likely to report sleep disturbances and to exhibit evidence of low BMD, as well as to exhibit enhanced bone turnover and poorer ovarian reserve parameters. Multivariable logistic regression analyses confirmed the statistical significance of both HF and NS as independent correlates to low BMD after adjusting for age, body mass index, smoking status, menstrual regularity, and ovarian reserve status. Multivariable linear regression analyses demonstrated that NS, but not HF, predicted higher bone turnover at a statistically significant level after adjusting for age, smoking, menstrual regularity, and ovarian reserve. We demonstrate, in a premenopausal population of infertile women, evidence of morbid accompaniments to VMS, including sleep disturbances and evidence of low BMD. Our data further suggest a state of enhanced bone turnover in association with VMS, specifically in those experiencing NS. Declining ovarian reserve may be the common pathophysiological mechanism underlying VMS and low BMD in the symptomatic population and merits further investigation.

Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy

Reports of decreased serum 25-hydroxyvitamin D (25-OHD) and altered bone metabolism associated with antiepileptic drug (AED) treatment are inconsistent and predominantly restricted to adults. In this cross-sectional observational study, the aim was to evaluate the influence of AED treatment on vitamin D status and markers of bone turnover in children with epilepsy. In 38 children taking AEDs and 44 healthy control subjects, blood samples were collected to determine the levels of serum 25-OHD, intact parathyroid hormone (iPTH), calcium (Ca), phosphate (P), bone alkaline phosphatase (BAP), osteocalcin (OC) and C terminal telopeptide of type I collagen (ICTP). More than 75% of the patients were vitamin D deficient (serum 25-OHD<20 ng/mL) and 21% of the patients had an insufficient vitamin D status (serum 25-OHD=20-30 ng/mL). In the patients, the serum levels of OC (p = 0.002) and BAP (p < 0.001) were significantly increased, but ICTP (p = 0.002) concentrations were significantly decreased compared with the control group. When patients where divided into two groups according to their medication (mono- or polytherapy), significantly lower 25-OHD (p = 0.038) and ICTP (p = 0.005) levels and elevated BAP (p = 0.023) concentrations were found in patients under polytherapy. An association between 25-OHD and the measured bone markers could not be determined. Our results indicate that the prevalence of vitamin D deficiency in epilepsy patients under AED treatment is high, especially under polytherapy, and alteration markers of bone formation and resorption suggests an accelerated skeletal turnover. The routine monitoring of serum 25-OHD and vitamin D supplementation on an individual basis should be considered.

Old Rhesus Macaques Treated with Interleukin-7 Show Increased TREC Levels And Respond Well to Influenza Vaccination

Old age is accompanied by an increased incidence of infection and poorer responses to vaccination. In this proof of principle study, old female rhesus macaques (aged 18.5 to 23.9 years) were treated with recombinant simian interleukin-7 (IL-7) or saline, according to a two-phase regime. Treatment was not associated with bone loss as judged by plasma carboxy terminal telopeptide of type I collagen (ICTP) levels, nor with neutropenia. IL-7-treated animals showed an increase in the number of blood CD4(+) CD3(+) and CD8(+) CD3(+) T cells after both phases of treatment and a transient increase in the number of naïve (CD62L(+) CD45RA(+)) T cells for both CD4(+) and CD8(+) subsets after only the first treatment. Increases in TREC levels per T cell followed both phases of treatment, but were more prolonged after the second phase. Following vaccination with inactivated influenza strain A/PR/8/34, hemagglutination inhibition assays showed that half of the IL-7-treated animals showed a greater than eight-fold increase in antibody titer following the first challenge with the vaccine. In addition IL-7-treated animals showed higher numbers of central memory CD8(+) T cells compared to pretreatment levels with numbers greater than in the saline-treated group. Animals with the highest hemagglutination inhibition titers and the best proliferation against flu antigen were among those with the highest TREC per T cell levels after the second phase of treatment. Treatment of the elderly with IL-7 may provide an effective therapy to improve the immune system.