Are bone turnover markers associated with volumetric bone density,size, and strength in older men and women? The AGES–Reykjavik study

Summary

Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density.

Introduction

The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN).

Methods

A total of 1745 older individuals (773 men and 972 women, aged 66–92 years) from the Age, Gene/Environment Susceptibility (AGES)–Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression.

Results

Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1–10 %).

Conclusion

Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

     

Changes in serum levels of biochemical markers of bone turnover during 10 years among Japanese men and women: associated factors and birth-cohort effect. The Taiji Study

We aimed to clarify changes in biochemical markers of bone turnover (BTMs) over 10 years, associations with changes in bone mineral density (BMD), and birth-cohort effects in a Japanese community. We randomly selected 400 individuals (age, 40–79 years; 50 of each gender and age stratum) from a list of registered residents in 1993. We measured BMD of the spine and hip, and serum concentrations of total osteocalcin (OC), beta-C-terminal cross-linking telopeptide of type I collagen (beta-CTX), and N-terminal cross-linking telopeptide of type I collagen (NTX), in 1993 and 2003. Of the 400 subjects, 322 (153 men, 169 women) completed the 10-year follow-up. Mean change rates (standard deviation) for serum total OC, beta-CTX, and NTX over 10 years were –1.00 (3.74)%/year, 5.10 (22.48)%/year, and 0.40 (3.41)%/year, respectively, in men, and 0.02 (5.32)%/year, 5.53 (14.54)%/year, and 0.62 (3.26)%/year, respectively, in women. Change rates of BTMs were higher for women in their forties than for women in their fifties to seventies (P < 0.05), and higher in the menstrual transition group than in pre- and postmenopausal groups (P < 0.001). Changes in levels of BTMs over 10 years in women were significantly associated with change rates of BMDs at L2–L4 and total hip after adjusting for potential confounders. A significant birth-cohort effect was observed among women in their fifties. We concluded that change rates of BTMs during the 10 years were influenced by menstrual transition, age, and sex and associated with bone loss at L2–L4 and total hip.     

Radionuclide studies of bone metabolism: do bone uptake and bone plasma clearance provide equivalent measurements of bone turnover?

Quantitative radionuclide imaging using (18)F-fluoride positron emission tomography (18F-PET) or (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scans provides a novel tool for studying regional and whole skeleton bone turnover that complements the information provided by biochemical markers. Radionuclide bone scans can be quantified by measuring either tracer uptake or, if blood sampling is performed, bone plasma clearance. This study examines whether these two methods provide equivalent information about bone turnover. We examined data from two clinical trials of the bone anabolic agent teriparatide. In Study 1 twenty osteoporotic women had 18F-PET scans of the lumbar spine at baseline and after 6 months treatment with teriparatide. Bone uptake in the lumbar spine was expressed as standardised uptake values (SUV) and blood samples taken to evaluate plasma clearance. In Study 2 ten women had (99m)Tc-MDP scans at baseline, 3 and 18 months after starting teriparatide. Blood samples were taken and whole skeleton plasma clearance and bone uptake calculated. In Study 1 spine plasma clearance increased by 23.8% after 6-months treatment (P=0.0003), whilst SUV increased by only 3.0% (P=0.84). In Study 2 whole skeleton plasma clearance increased by 37.1% after 18-months treatment (P=0.0002), whilst the 4-hour whole skeleton uptake increased by only 25.5% (P=0.0001). During treatment the 18F- plasma concentration decrease by 20% and (99m)Tc-MDP concentration by 13%, and these latter changes were sufficient to explain the differences between the uptake and plasma clearance results. Measurements of response to treatment using bone uptake and plasma clearance gave different results because the effects of teriparatide on bone resulted in a sufficiently increased demand for radionuclide tracer from the skeleton that the concentration in the circulation decreased. Similar effects may occur with other therapies that have a large enough effect on bone metabolism. In these circumstances changes in bone plasma clearance give a truer impression of response to treatment than those in SUV or uptake.     

Study of bone mineral density in Chinese patients with complete androgen insensitivity syndrome

<正> Objective:To explore the characteristics of bone mineral density(BMD)and treatment inChinese patients with complete androgen insensitivity syndrome(CAIS).Methods:Fourteen cases of CAIS were studied retrospectively through analyzing and compa-ring BMD of pre-and post-gonadectomy with healthy Chinese men and women.BMD at the lum-bar spine and the femur were measured by dual energy X-ray absorptiometry(DXA).Results:There were 10 cases of CAIS having pre-gonadectomy DXA,in which 6 cases hadvery significantly reduced lumbar 2-4 BMD[(0.92±0.08)g/cm~2]comparing with both healthymen and women(P<0.01),5 cases had significantly reduced femur neck BMD[(0.89±0.12)g/cm~2]comparing with healthy men(P<0.05).There were 7 cases having 12 post-gonadectomyDXA,in which all lumbar 2-4 BMD[(0.954-0.06)g/cm~2]were reduced very significantly com-paring with both healthy men and women(P<0.01),femur neck BMD[(0.91±0.08)g/cm~2]were also reduced significantly comparing with healthy men(P<0.01)and women(P<0.05).Conclusion:There were different degrees of osteopenia in patients of CAIS,especially inlumbar vertebra.This suggests that both estrogen and androgen play important roles in the ac-quirement and maintenance of peak bone mass.     

Familial resemblance of bone turnover rate in men aged 40 and over—the MINOS study

Familial resemblance of bone mineral density (BMD) is well known in both sexes. Fewer data concern the familial resemblance of bone turnover markers (BTMs) and bone size in men. Our aim was to assess the correlation of BMD, bone size, BTM levels and hormones regulating bone turnover in 50 pairs of brothers aged ≥ 40 and 50 pairs of unrelated men matched for age, weight and height. BMD was measured at the lumbar spine, hip, forearm and whole body. We measured serum osteocalcin (OC), bone-specific alkaline phosphatase (bone ALP), N-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX-I) as well as urinary free and total deoxypyridinoline (DPD) and CTX-I. After adjustment for age, weight, bioavailable 17β-estradiol, and parathyroid hormone, all the BTMs (except bone ALP) were significantly correlated in the brothers (ICC = 0.36–0.64). Most of these correlations were significantly stronger than in the unrelated men. Bone size correlated significantly between the brothers (ICC = 0.55–0.65). These correlations were significantly stronger than in the unrelated men. BMD correlated between the brothers at most of the skeletal sites and, for some of them, more strongly than in the unrelated men. Serum levels of LDL-cholesterol and triglycerides were significantly correlated in the brothers, but not more strongly than in the unrelated men. BTM levels correlated independently in the brothers aged ≥ 40, when their shared environment was limited. These data suggest a substantial hereditary determinism of the BTM levels in men.     

Early changes in biochemical markers of bone turnover and their relationship with bone mineral density changes after 24?months of treatment with teriparatide

Summary

We report the changes in biochemical markers of bone formation during the first 6?months of teriparatide therapy in postmenopausal women with osteoporosis according to previous antiresorptive treatment. Prior therapy does not adversely affect the response to teriparatide treatment. Similar bone markers levels are reached after 6?months of treatment.

Introduction

The response of biochemical markers of bone turnover with teriparatide therapy in subjects who have previously received osteoporosis drugs is not fully elucidated. We examined biochemical markers of bone formation in women with osteoporosis treated with teriparatide and determined: (1) whether the response is associated with prior osteoporosis therapy, (2) which marker shows the best performance for detecting a response to therapy, and (3) the correlations between early changes in bone markers and subsequent bone mineral density (BMD) changes after 24?months of teriparatide.

Methods

We conducted a prospective, open-label, 24-month study at 95 centers in 10 countries in 758 postmenopausal women with established osteoporosis (n?=?181 treatment-na?ve) who had at least one post-baseline bone marker determination. Teriparatide (20 ??g/day) was administered for up to 24?months. We measured procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (b-ALP), and total alkaline phosphatase (t-ALP) at baseline, 1 and 6?months, and change in BMD at the lumbar spine, total hip and femoral neck from baseline to 24?months.

Results

Significant increases in formation markers occurred after 1?month of teriparatide regardless of prior osteoporosis therapy. The absolute increase at 1?month was lower in previously treated versus treatment-na?ve patients, but after 6?months all groups reached similar levels. PINP showed the best signal-to-noise ratio. Baseline PINP correlated positively and significantly with BMD response at 24?months.

Conclusions

This study suggests that the long-term responsiveness of bone formation markers to teriparatide is not affected in subjects previously treated with antiresorptive drugs.     

The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass—a randomized controlled 1-year trial

Summary  

Vitamin D is widely used in osteoporosis treatment, although the optimal dose is not known. This 1-year clinical study among 297 women aged 50–80 years old showed that a vitamin D₃ dose of 6,500 IU/day was not better than the standard dose of 800 IU/day in improving bone mineral density (BMD) in the hip and spine.     

The efficacy and tolerability of once-weekly alendronate 70 mg on bone mineral density and bone turnover markers in postmenopausal Chinese women with osteoporosis

Osteoporosis has become an important health problem in postmenopausal Chinese women. Bisphosphonates currently are the preferred therapy for treating osteoporosis. However, the use of daily regimen of alendronate in women at risk for osteoporosis has been relatively low in China because of its dosing inconvenience. To determine the efficacy and tolerability of once-weekly alendronate 70 mg in Chinese, a multicenter, randomized, double blind, placebo controlled study was performed in China. Five hundred and sixty postmenopausal women (≤85 years old) with osteoporosis were randomly assigned to receive either alendronate 70 mg or placebo once-weekly for 12 months. All women received calcium 500 mg daily and vitamin D 200 IU daily. A significant increase in lumbar spine BMD was already evident at 6 months of alendronate treatment (P < 0.001). The alendronate group showed significant increase (P < 0.001) in BMD at 12 months at both the spine and hip when compared with the placebo group (lumbar spine 4.87% vs. 0.4%, femoral neck 2.47% vs. 0.31%, trochanter 3.24% vs. 0.78%, total hip 2.56% vs. 0.28%, respectively). The percentage of women with ≥0% and ≥3% BMD increase in lumbar spine was significantly greater in women with alendronate than placebo (P < 0.001). Significant reduction in urine N-telopeptide (NTx) and serum bone-specific alkaline phosphatase were evident at 6 and 12 months, respectively, with alendronate treatment. No significant differences in the incidence of adverse experiences and upper gastrointestinal adverse experiences were seen. We conclude that once-weekly alendronate 70 mg is an effective and well-tolerated agent for the treatment of postmenopausal osteoporosis in Chinese women.     

Effect of training on muscle triacylglycerol and structural lipids: a relation to insulin sensitivity?

We studied whether endurance training impacts insulin sensitivity by affecting the structural and storage lipids in humans. Eight male subjects participated (age 25 +/- 1 years, height 178 +/- 3 cm, weight 76 +/- 4 kg [mean +/- SE]). Single-leg training was performed for 30 min/day for 4 weeks at approximately 70% of single-leg maximal oxygen uptake. After 8, 14, and 30 days, a two-step hyperinsulinemic-euglycemic glucose clamp, combined with catheterization of an artery and both femoral veins, was performed. In addition, a muscle biopsy was obtained from vastus lateralis of both legs. Maximal oxygen uptake increased by 7% in the trained leg (T), and training workload increased (P < 0.05) from 79 +/- 12 to 160 +/- 15 W. At day 8, glucose uptake was higher (P < 0.01) in the trained (0.8 +/- 0.2, 6.0 +/- 0.8, 13.4 +/- 1.2 mg x min(-1) x kg(-1) leg wt) than the untrained leg (0.5 +/- 0.2, 3.7 +/- 0.6, 10.5 +/- 1.5 mg x min(-1) x kg(-1) leg wt) at basal and the two succeeding clamp steps, respectively. After day 8, training did not further increase leg glucose uptake. Individual muscle triacylglycerol fatty acid composition and total triacylglycerol content were not significantly affected by training and thus showed no relation to leg glucose uptake. Individual muscle phospholipid fatty acids were not affected by training, but the content of phospholipid polyunsaturated fatty acids was higher (P < 0.06) after 30 than 8 days in T. Furthermore, after 30 days of training, the sum of phospholipid long-chain polyunsaturates was correlated to leg glucose uptake (r = 0.574, P < 0.04). Endurance training did not influence muscle triacylglycerol content or total triacylglycerol fatty acid composition. In contrast, training induced a minor increase in the content of phospholipid fatty acid membrane polyunsaturates, which may indicate that membrane lipids may have a role in the training-induced increase in insulin sensitivity.     

Occurrence of erectile dysfunction, testosterone deficiency syndrome and metabolic syndrome in patients with abdominal obesity. Where is a sufficient level of testosterone?

Aim

The aim of this study was to determine the prevalence of erectile dysfunction (ED), testosterone deficiency syndrome (TDS), and metabolic syndrome in patients with abdominal obesity (AO) and the prevalence of morbidity at different levels of testosterone (TST).

Background

Male sex hormones play an important role in ED and variety of TDS and may have influence on the development of metabolic syndrome. The number of men with AO which constitutes a serious health risk is continuously growing. Currently, there are different views that TST levels are already insufficient, and the patient should benefit from treatment.

Objectives

This study examined the association between ED, testosterone level and metabolic syndrome in men with AO.

Design, setting, and participants

The study was carried out in an outpatient urology center of Urology Clinic and Obesity Center of the Clinic of Internal Medicine. There were 167 participants??men with AO which were examined as part of preventive examination.

Methods

Hormonal, a complete urological and internal evaluation was carried out in every patient.

Results and limitations

We found some degree of ED in 73% (122/167) in men with AO. The TST levels below 14?nmol/l had of these 122 patients 84 patients (68.9%) and 49 patients (40.2%) below 10?nmol/l. In this group of patients, we found 103/167 patients (61.7%) with metabolic syndrome. When we compared TST level and morbidity, we found significantly more patients with diabetes mellitus (DM), hypertension and dyslipidemia in group with TST below 10?nmol/l. We also found difference in the levels of HDL cholesterol and triglycerides in the group of patients with TST 10?C14 and over 14?nmol/l.

Conclusion

Patients over 40?years of age with AO and ED should also be examined for TDS and metabolic syndrome. In this group of patients we found that 113/167 patients (67.6%) had total TST below 14?nmol/l, and sufficient level of TST seems to be above this level.     

Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome?

The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [(18)F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 +/- 5.2 and 23.2 +/- 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P < 0.001), relative to global brain. Insulin's effect was less in ventral striatum and prefrontal cortex in the insulin-resistant subjects (mean +/- SD for right ventral striatum 3.2 +/- 3.9 vs. 7.7 +/- 1.7, P = 0.017). We conclude that brain insulin resistance exists in peripheral insulin resistance, especially in regions subserving appetite and reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.     

Anti-Müllerian hormone and inhibin B levels reflect altered Sertoli cell function in men with metabolic syndrome

The aim of the present study was to investigate the Sertoli cell markers inhibin B and anti-Müllerian hormone (AMH) in men with metabolic syndrome (MS). Twenty patients with MS according to the criteria of the International Diabetes Federation and 20 non obese age-matched men were investigated. The levels of testosterone, sex hormone binding globulin (SHBG), gonadotropins, inhibin B and AMH were measured in all of them. In obese patients with MS total testosterone (15.74 ± 6.95 versus 27.84 ± 12.80 nmol l(-1), P = 0.001), SHBG (21.71 ± 11.08 versus 38.80 ± 17.51 nmol l(-1), P = 0.001) and free testosterone (430.35 ± 237.40 versus 613.85 ± 303.65 pmol l(-1), P = 0.040) were significantly lower than in the controls. Interestingly, the inhibin B (103.64 ± 56.77 versus 149.88 ± 68.31 pg ml(-1), P = 0.025) and AMH levels (30.84 ± 13.14 versus 43.14 ± 9.66 pmol l(-1), P = 0.002) were also significantly lower in MS group in comparison to the other participants. The lowest levels of AMH were found in patients with MS and carbohydrate disturbances. The decreased concentrations of testosterone, inhibin B and AMH in patients with MS could reflect an impaired Leydig and Sertoli cell function. Further studies in men with obesity, insulin resistance and diabetes type 2 could reveal more information about the interrelations between the metabolic disturbances and reproductive function in men.     

The fear of prostate cancer in men with lower urinary tract symptoms: should symptomatic men be screened?

OBJECTIVE: To explore the concerns and worries in men with uncomplicated lower urinary tract symptoms (LUTS, but no evidence of prostate cancer) relating to their symptoms. PATIENTS AND METHODS: There is no current prostate cancer screening programme in the UK. Evidence suggests that men with LUTS have the same risk of prostate cancer as aged-matched asymptomatic men. However, most men with LUTS are 'screened' with a digital rectal examination (DRE) and prostate specific antigen (PSA) testing as part of routine assessment. Whether this screening offers any benefit to patients and whether national screening for prostate cancer and subsequent early treatment offer any long-term survival or quality of life benefit is uncertain. Thus 30 men with uncomplicated LUTS were qualitatively interviewed to explore their concerns and worries about their symptoms. Interviews were transcribed verbatim and subjected to content analysis using validated techniques. RESULTS: Of the 30 men, 22 (73%) expressed a fear of prostate cancer at the time of their initial presentation. This fear was independent of race, social class and symptom severity; older men were less worried. Of the 22, 15 (68%) stated that after reassurance their symptoms were less bothersome and easier to cope with. CONCLUSIONS: These findings suggest there is a considerable gain in health by explicitly addressing the concerns of prostate cancer in men with uncomplicated LUTS. Informing these men of their true risk of prostate cancer (before or after a DRE and PSA estimate) may alleviate much of the bother associated with their symptoms. Despite no evidence of any greater risk of prostate cancer than in asymptomatic men, symptomatic men should continue to be screened after appropriate counselling.     

Biochemical markers of bone turnover in diabetes patients—a meta-analysis,and a methodological study on the effects of glucose on bone markers

Summary

This study examined whether markers of bone turnover differ between individuals with and without diabetes. Bone markers showed heterogeneity between studies and were discrepant for markers of bone creation and markers of bone degradation. Bone markers may be of lesser value in diabetes due to heterogeneity.

Introduction

The aim of this meta-analysis was to compare existing literature regarding changes in bone markers among diabetics compared to healthy controls. To exclude that blood glucose levels among diabetes patients could influence the assays used for determining bone turnover markers, a methodological study was performed.

Methods

Medline at Pubmed Embase, Cinahl, Svemed+, Cochrane library, and Bibliotek.dk was searched in August 2012. The studies should examine biochemical bone turnover among diabetes patients in comparison to controls in an observational design. In the methodological study, fasting blood samples were drawn from two individuals. Glucose was added to the blood samples in different concentrations and OC, CTX, and procollagen type 1 amino terminal propeptide were measured after 0, 1, 2, and 3 h.

Results

Twenty-two papers fulfilled the criteria for the meta-analysis. From the pooled data in the meta-analysis, the bone markers osteocalcin (OC) (?1.15 ng/ml [?1.78,-0.52]) and C-terminal cross-linked telopeptide (CTX) (?0.14 ng/ml [?0.22, ?0.05]) were significantly lower among diabetes patients than non-diabetes patients, however other markers did not differ. All markers displayed very high heterogeneity by I2 statistics. In the methodological study, the addition of glucose did not significantly change the bone markers neither by level of glucose nor with increasing incubation time.

Conclusion

The dissociative pattern of biochemical bone markers of bone formation and bone resorption present in diabetes patients is thus not caused by glucose per se but may be modulated by unknown factors associated with diabetes mellitus.