Association between bone turnover rate and bone microarchitecture in men: The STRAMBO study

Few data concern the relationship between bone turnover and microarchitecture in men. We investigated the association between levels of biochemical markers of bone turnover (BTM) and bone microarchitecture in 1149 men aged 19 to 85 years. Bone microarchitecture was assessed by high‐resolution peripheral quantitative computed tomography at the distal radius and tibia. Bone formation was assessed by serum osteocalcin, bone alkaline phosphatase, and N‐terminal extension propeptide of type I collagen. Bone resorption was assessed by serum C‐terminal telopeptide of type I collagen and urinary excretion of total deoxypyridinoline. BTM levels were high in young men and decreased until age 50 years. Urinary deoxypyridinoline (DPD) increased after age 70 years, whereas other BTMs remained stable. Before 50 years of age, only cortical volumetric bone mineral density (D_cort) correlated negatively with BTM levels. Between 50 and 70 years of age, D_cort and some microarchitectural parameters correlated significantly with BTM at the radius and tibia. After 70 years of age, higher BTM levels were associated with lower cortical thickness and D_cort at both the skeletal sites. At the distal radius, men in the highest BTM quartile had lower trabecular density, number (Tb.N), and thickness (Tb.Th) and more heterogeneous trabecular distribution compared with men in the lower quartiles. At the distal tibia, higher BTM levels were associated with lower Tb.N and Tb.Th in the central but not subendocortical area. Thus, in men, bone microarchitecture depends weakly on the current bone turnover rate until age 70. Thereafter, bone turnover seems to be a significant determinant of bone microarchitecture. © 2010 American Society for Bone and Mineral Research.     

Biochemical Markers of Bone Turnover in Men

Although osteoporosis in men has been recently recognized as a public health problem, the mechanisms leading to bone loss are still poorly understood. Longitudinal studies of bone mineral density suggest an acceleration of bone loss after 70 years of age. Histomorphometric data concerning age-related changes of bone turnover in men are limited, including few men over 70 years and have been restricted to the trabecular envelope of bone biopsies. Most measurements of biochemical markers of bone turnover have been performed in small cohorts of limited age range, and results obtained in large cohorts are scanty. Levels of markers of bone formation and of bone resorption are very high in men aged 20-30 years which corresponds to the late phase of formation of peak bone mass, and then declines, reaching their lowest levels between 50 and 60 years. Data on bone turnover markers in elderly men are discordant. Concentrations of bone formation markers remain stable, decrease slightly, or even increase marginally. Markers of bone resorption increase in some studies, mainly after 70 years of age, in line with acceleration of bone loss in this age range. This discordance between studies can result from different reasons. The increase of bone turnover may be limited to a subgroup of elderly men. In addition, urinary levels of bone resorption markers depend on the rate of bone turnover, on pre-renal and renal catabolism of peptides released from bone matrix, on glomerular filtration rate, as well as unit of expression of their results (per 24 hours per urinary creatinine mass, per glomerular filtrate volume). In elderly men, biochemical bone markers are negatively correlated with bone mineral density. Longitudinal studies are not yet available on the relationship among bone turnover markers, rate of bone loss, and fracture. In conclusion, in elderly men, age-related bone loss seems to result from increased bone resorption which is not matched by increased bone formation. Thus, antiresorptive therapy may be of interest in the prevention and treatment of osteoporosis in men. Further studies are necessary to determine if bone resorption markers predict the risk of fragility fractures in elderly men.     

Characteristics of biochemical markers for bone formation in the elderly

Currently, several promising biochemical markers for bone metabolism have been postulated and expected to be applied to their clinical use. Among these markers, circulating levels of bone Gla-protein (BGP) and carboxyterminal peptide of type I procollagen (P1CP) have been established as non-invasive indices to assess bone turnover, especially bone formation. We investigated age-related effects on serum levels of both peptides and relationships between loss of bone mass and biochemical indices in the elderly. Fasting blood sample were obtained from 330 healthy volunteers to simultaneously measure serum BGP, serum P1CP and serum tartrate-resistant acid phosphatase (TRACP) as a marker for bone resorption. Serum BGP levels were found almost stable throughout life in men with a tendency to decrease in the elderly. Serum P1CP levels linearly decreased towards 50 to 60 years of age in men, followed by its constant increase with aging afterwards. Although a constant increase in serum P1CP levels were noted in women with aging, serum BGP levels were found remarkably elevated during menopausal periods of 50 to 70 years of age, followed by its wide distribution in the elderly. Both serum BGP and P1CP levels were elevated accompanied with age-related decrease in glomerular filtration rates in the elderly. In addition, a bone specific index, TRACP/BGP ratio consolidated the negative correlation between serum TRACP and % changes of bone mineral density (BMD). However, TRACP/P1CP ratio had nothing to do with % change of BMD. In conclusion, loss of bone mass could be predicted by bone specific indices, particularly in elderly women with widely distributed bone turnover. The data in this paper were reported in part in International Coference on Osteoporosis, Kobe, November 1991.     

Effect of age-related chronic immobility on markers of bone turnover.

The effects of acute immobilization on bone turnover are well known, but the effects of chronic hypomobility with aging have not been studied. In a cohort of 1064 frail elderly subjects, immobility was significantly associated with serum PINP but not serum CTx after adjusting for confounders. The effect of immobility may be more marked on bone formation than on bone resorption. INTRODUCTION: Accelerated bone turnover and rapid bone loss caused by acute immobilization is well recognized, but the effects of age-related chronic reduction in mobility on bone turnover have been less well studied. We assessed the associations between bone turnover and measures of mobility in a cohort of elderly subjects. MATERIALS AND METHODS: We measured serum levels of the aminoterminal propeptide of type I collagen (PINP), a marker of bone formation, and serum concentrations of the carboxyterminal telopeptide of type I collagen (CTx), a marker of bone resorption, as well as serum intact PTH, serum 25 hydroxyvitamin D (25OHD), mobility, and static balance in a well-characterized sample of 1064 elderly men and women living in residential aged care facilities. Serum creatinine, phosphate, albumin, and calcium were measured in a randomly selected subgroup of 447 subjects. RESULTS: The subjects were elderly and frail; their mean age was 86.0 years (range, 65-101 years); 69% used a walking aid; and 77% were vitamin D deficient (serum 25OHD level < 39 nM). Both serum PINP and CTx increased with age in both sexes. Elevated PINP or CTx was significantly correlated with high PTH, creatinine, and albumin in both genders, except for albumin in women. Age- and gender-adjusted serum CTx and PINP were significantly higher in those with poorer mobility and those with worse static balance. In multivariate analyses, higher serum PINP but not CTx was associated with poorer mobility and worse static balance. CONCLUSIONS: Our findings suggest that poor mobility contributes to the state of accelerated bone turnover usually seen in the elderly. The effect of chronic relative immobility may be more marked on bone formation than bone resorption.     

Biochemical Markers of Bone Turnover Reflect Femoral Bone Loss in Elderly Women

Although over 90% of hip fractures occur in patients over age 70, few data are available on femoral bone loss in this age group. To examine the relationship between biochemical markers of bone turnover and femoral bone loss in the elderly, 36 female and 17 male, healthy, community-dwelling elderly over age 65 (mean ± SD age: women 71 ± 4 years, men 75 ± 5 years) were followed for 3 years. Annual bone mineral density measurements of the hip and lumbar spine by dual-energy x-ray absorptiometry (DXA) were obtained and biochemical markers of bone resorption (urinary N-telopeptide crosslinks, free pyridinoline, total pyridinoline, total deoxypyridinoline, and hydroxyproline) and bone formation (serum osteocalcin, bone-specific alkaline phosphatase) were obtained at the end of year 3. In elderly women, longitudinal bone loss at the total hip was negatively correlated with markers of bone resorption (r =−0.39 to −0.52, P < 0.05), bone formation (r =−0.38, P < 0.05), and age (r =−0.39, P < 0.05). Markers of bone resorption were correlated with markers of bone formation (r = 0.63 to 0.74, P < 0.01). In multiple regression analysis, urinary N-telopeptide crosslinks (marker of resorption), serum osteocalcin (marker of formation), and serum parathyroid hormone explained 43% of the variability of bone loss at the total hip in women. These parameters were not related to bone loss in men. We conclude that femoral bone loss increases with age in women over 65. Measurements of specific biochemical markers of bone turnover are correlated with longitudinal bone loss in elderly women. These markers may help identify women at greatest risk for bone loss who would benefit most from therapeutic interventions. Received: 28 January 1996 / Accepted: 3 May 1996     

Prognostic interest of bone turnover markers in the management of postmenopausal osteoporosis

ObjectiveThe aim was to review the literature dealing with the use of biochemical bone turnover markers (BTM) as predictors of bone loss and individual risk of fracture in postmenopausal osteoporosis.MethodsWe performed a generalized search in MEDLINE using Mesh Database from 1995 through 2009 with the following terms “biological markers” with “osteoporosis” or “bone resorption”, or “bone fracture”, “fracture risk”. From this research, 197 abstracts were read, 91 articles were screened then 43 original articles were selected.ResultsIn most of the selected articles, the upper limit of the premenopausal range was used as a cut-off definition for increased bone resorption. Based on this review, we found a moderate and positive relationship between baseline level of BTM and rate of bone loss, more particularly for high level of BTM over 2 SD, especially when high turnover is constant in repeated sampling. In addition, an increase in BTM levels is associated with an increase in the risk of hip and non-vertebral fractures in elderly women over 75 years old. This is especially demonstrated with bone resorption markers (e.g. uCTX) in the highest quartile with an 1.7 to 2.2 fold increase. The combination of data from bone mineral density (BMD) and bone resorption markers may improve fracture prediction.ConclusionThe measurement of BTM, together with the assessment of other risk factors including low BMD, will improve the prediction of risk facture, but there is a lack of practical guidelines.     

Cross-sectional evaluation of bone metabolism in men.

There are relatively few data concerning age-related changes of bone turnover in men. The aim of the study was to evaluate age-related changes of the levels of serum and urinary biochemical markers of bone metabolism in a large cohort of 934 men aged 19-85 years and to investigate their association with bone mineral density (BMD). Bone formation was evaluated using serum levels of osteocalcin (OC), bone alkaline phosphatase (BAP), and N-terminal extension propeptide of type I collagen (PINP). Bone resorption was evaluated by measurement of urinary excretion of beta-isomerized C-terminal telopeptide of collagen type I beta-CTX) of free deoxypyridinoline (fDpyr) and total Dpyr (tDPyr) and of the serum level of beta-CTX. Levels of biochemical bone markers were very high in young men and decreased rapidly until the age of 40 years and then more slowly until 60 years of age. After the age of 60 years, markers of bone formation remained stable while resorption markers showed a moderate and variable increase with aging. Serum and urinary beta-CTX levels were elevated only in about 5% of elderly men. The age-related increase of urinary excretion of tDpyr and of its free and peptide-bound fractions was related to the presence of elevated levels in a subgroup of about 15% of elderly men. Before 60 years of age, levels of biochemical bone markers were not correlated with BMD, whereas after 60 years of age, they were correlated negatively with BMD. After adjustment for age and body weight, BMD in men with the highest levels of biochemical bone markers (i.e., in the upper quartile) was 1.8-12.5% (i.e., 0.25-0.89 SD) lower than in men with levels of biochemical bone markers in the lowest quartile. In conclusion, bone turnover in men is high in young adults and decreases to reach a nadir at 55-60 years of age. After the age of 60 years, bone resorption markers--but not bone formation markers--increase in some men and are associated with lower BMD, suggesting that this imbalance is responsible for increasing bone loss in elderly men.     

Vitamin D status and bone turnover in women with acute hip fracture

Hypovitaminosis D is common in elderly women. Few data are available on vitamin D status and bone turnover in women with acute hip fracture. The aims of this study were to determine whether elderly Italian women with an acute hip fracture also had low vitamin D levels and an increase of bone turnover compared with elderly women with osteoporosis but without fractures. Seventy-four women with acute osteoporotic hip fracture and 73 women with postmenopausal osteoporosis were studied. All women were self-sufficient and had adequate sunlight exposure. To exclude the effect of trauma on serum 25-hydroxycolecalciferol levels and bone markers (bone alkaline phosphatase and C-terminal telopeptides of Type I collagen as indices of bone formation and bone resorption), blood samples were drawn within 24 hours of the fracture. Current data indicated that in our patients the prevalence of hypovitaminosis D is common although to a lesser extent than in women who are housebound. Women with acute hip fractures had a higher prevalence of vitamin deficiency defined as serum 25-hydroxycolecalciferol lower than 12 ng/mL, compared with women with osteoporosis. Moreover, the presence of fracture did not influence the rate of bone formation, whereas the increase in bone resorption could be attributed to an older age of women with acute hip fracture because of similar values of parathyroid hormone levels in the two groups.     

High serum IGFBP-2 is predictive of increased bone turnover in aging men and women.

Elevated serum IGFBP-2 is associated with lower BMD in men and women. It is unknown whether IGFBP-2 serves as a negative regulator of bone metabolism by decreasing bone formation or increasing bone resorption. Studying an age-stratified community-based sample of 344 men and 276 women, IGFBP-2 was the strongest predictor of increased bone resorption among the IGF/IGFBPs studied. INTRODUCTION: Serum insulin-like growth factor binding protein-2 (IGFBP-2), which increases with age, is a predictor of low BMD among aging men and women. However, it is unknown whether IGFBP-2 negatively influences bone metabolism by decreasing bone formation or increasing bone resorption. Few have examined the relation between the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) with bone turnover markers. MATERIALS AND METHODS: In an age-stratified, random sample of the community, we examined the association between serum IGF-I, IGF-II, IGFBP-1, -2, and -3, and bone turnover markers before and after adjustment for potential confounders (age, body mass index, bioavailable estradiol and testosterone, and sex hormone binding globulin). Analyses were stratified by sex and menopausal status. RESULTS: We studied 344 men (age range, 23-90 yr) and 276 women (age range, 21-93 yr; 166 postmenopausal) not on oral contraceptives or hormone replacement. Among the IGF/IGFBPs assessed, IGFBP-2 was the strongest and most consistent predictor of bone turnover in men and women. After adjustment for potential confounders, IGFBP-2 was positively associated with osteocalcin (OC) and urine and serum N-teleopeptide (NTX) in men (r = 0.20, 0.26, and 0.23, respectively; p < 0.001), serum C-telopeptide (CTX) in premenopausal women (r = 0.28; p < 0.01), and OC, urine NTX, and serum CTX in postmenopausal women (r = 0.24, 0.33, and 0.19, respectively; p < 0.05). CONCLUSIONS: Higher serum IGFBP-2, which is predictive of lower BMD, is associated with increased markers of bone resorption, independent of age, body mass, and sex hormones. The association between IGFBP-2 and markers of bone formation may reflect coupling with increased bone resorption, which is not adequate to maintain BMD.     

Association of bone turnover markers with volumetric bone loss,periosteal apposition,and fracture risk in older men and women: the AGES-Reykjavik longitudinal study

Summary

Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk.

Introduction

We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study.

Methods

The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4–12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type.

Results

Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk.

Conclusion

This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

     

Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis

Introduction  The aim was to analyse data on the use of biochemical bone turnover markers (BTM) in postmenopausal osteoporosis. Methods  We carried out a comparative analysis of the most important papers concerning BTM in postmenopausal osteoporosis that have been published recently. Results  The BTM levels are influenced by several factors. They are moderately correlated with BMD and subsequent bone loss. Increased levels of bone resorption markers are associated with a higher risk of fracture. Changes in the BTM during the anti-osteoporotic treatment (including combination therapy) reflect the mechanisms of action of the drugs and help to establish their effective doses. Changes in the BTM during the anti-resorptive treatment are correlated with their anti-fracture efficacy. Conclusion  Biological samples should be obtained in a standardised way. BTM cannot be used for prediction of the accelerated bone loss at the level of the individual. BTM help to detect postmenopausal women who are at high risk of fracture; however, adequate practical guidelines are lacking. BTM measurements taken during the anti-resorptive therapy help to identify non-compliers. They may improve adherence to the anti-resorptive therapy and the fall in the BTM levels that exceeds the predefined threshold improves patients’ persistence with the treatment. There are no guidelines concerning the use of BTM in monitoring anti-osteoporotic therapy in postmenopausal women.     

Role of parathyroid hormone in mediating age-related changes in bone resorption in men

Osteoporosis in men is an important and growing public health problem. While there has been extensive work done on defining the mechanism(s) of the age-related increase in bone resorption in women, our knowledge regarding the pathogenesis of bone loss in elderly men is still incomplete. We previously demonstrated that the age-related increase in serum PTH contributes substantially to the increased bone resorption in elderly women, since suppression of PTH levels by an intravenous calcium infusion decreased bone resorption markers to a greater extent in elderly compared to premenopausal women. In the present study, we tested the hypothesis that the comparable increase in PTH levels in elderly men (age 70–78 years) was driving bone resorption to a greater extent in these men than in younger men (age 40–50 years). PTH secretion was suppressed by an intravenous calcium infusion and the corresponding changes in the bone resorption marker, urine N-telopeptide of type I collagen (NTx) were assessed. In contrast to our previous findings in pre- versus postmenopausal women, suppression of PTH secretion in elderly men did not result in a greater decrease in urine NTx excretion than in the younger men (change in NTx excretion in the elderly men, -2.79±1.99 nmol/mmol Cr, versus that in the younger men, –5.07±1.39 nmol/mmol Cr, P=0.356). Collectively, these data suggest that the relationship between the age-related increase in serum PTH levels and bone resorption differs between elderly men and women. Since both estrogen and testosterone can attenuate the bone resorbing effects of PTH, it is possible that this difference may be due to the much milder degree of sex steroid deficiency in elderly men as compared to postmenopausal women.     

Inverse association between bone turnover rate and bone mineral density in community-dwelling men >70 years of age: no major role of sex steroid status

Bone loss is accelerated in elderly men. Little is known about the pathophysiology of senile bone loss or about the role played by relative sex steroid deficiency in the determination of bone turnover in elderly men. In a population-based sample of 283 healthy, ambulatory men, aged 71-86 years, we sought to determine whether lower bone mineral density (BMD; using dual-energy X ray absorptiometry at the hip and the forearm) is associated with higher bone turnover, and we assessed the impact of sex steroid status on bone turnover. Indices of bone formation, serum osteocalcin (s-Oc), and bone-specific alkaline phosphatase (s-bAP) and indices of bone resorption, serum and urinary telopeptide of type I collagen (s-CTx and u-CTx), and urinary free deoxypyridinoline (u-Dpd) were intercorrelated (r = 0.29-0.76, p < 0.001). Bone turnover indices were negatively associated with BMD (r = -0.17 to -0.34, p < 0.01). In univariate analyses, there was a trend toward weak negative associations of bone turnover markers with serum free testosterone (FT), significant only for s-Oc and s-CTx (r = -0.16 and -0.14, p < 0.01), and with serum free estradiol (FE(2)), significant only for u-CTx and s-CTx (r = -0.18 and -0.19; p < 0.01). The lower quartile for FE(2) was associated with higher values of u-CTx (p = 0.003) and s-CTx (p < 0.001). However, in multivariate models, for the individual markers of bone turnover a negative association between estradiol (E(2)) or FE(2) and s-CTx was the only remaining (marginally) significant association (p < 0.05) for the relationship between sex steroids and any of the bone turnover indices assessed. In community-dwelling men age >70 years, bone turnover rate, as determined by biochemical markers, is a significant negative determinant of prevalent BMD. However, the findings do not support the view that relative differences in sex steroid status, as observed among healthy elderly men, have a major impact on bone turnover.     

Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.     

The role of androgens or growth factors in the bone resorption process in recent spinal cord injured patients: a cross-sectional study

STUDY DESIGN: This cross-sectional study compared the androgen and growth factor profiles and the bone turnover of patients with spinal cord injury (SCI) versus able-bodied controls (AB). OBJECTIVE: Determine whether androgens, GH, or either IGF-I or IGFBP-3, are implicated in bone turnover alteration in patients with recent SCI. SETTING: Propara Center, Montpellier, France.Methods:In all, 16 men (31.3 years) with complete SCI, seven paraplegics and nine tetraplegics, who had sustained injury an average of 3 months earlier, and 12 AB who served as controls (27.5 years) participated. Androgens, growth hormone and its mediators were investigated. The bone resorption process was evaluated by urinary and plasma type I collagen C-telopeptide (CTXu, CTXp), while bone formation was evaluated by osteocalcin (OC) and bone alkaline phosphatase. RESULTS: Total testosterone (TT) and the free androgen index (FAI) were significantly lower in the SCI patients, whereas FSH was significantly higher (P<0.05). These hormonal variations were not related to the level of neurological lesion. There was no significant difference in GH, IGF-I, or IGFBP-3 levels. CTXu and CTXp indicated high bone resorption activity in the SCI patients (P<0.05). Regarding bone formation markers, only OC was affected by neurological lesion (P<0.05). Basal hormone levels did not correlate with markers of bone turnover. CONCLUSION: The high bone resorption process observed in SCI patients did not seem directly related to testicular endocrine abnormalities or an altered growth factor profile. Nevertheless, the reduced TT and FAI levels could be aggravating factors in the development of acute bone loss.     

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.     

High bone turnover is an independent predictor of mortality in the frail elderly.

Osteoporotic fractures are associated with accelerated bone turnover and excess mortality. In a prospective study of 1112 frail subjects (79% female; mean age, 86 years), high bone turnover was an independent predictor of all-cause mortality. This association seemed to be mainly manifested in deaths from cardiovascular causes. INTRODUCTION: Osteoporotic fractures are associated with accelerated bone turnover and excess mortality. In a prospective cohort study of elderly men and women, we assessed whether the rate of bone turnover measured by markers of bone remodeling is a direct predictor of mortality. MATERIALS AND METHODS: We measured serum concentrations of the aminoterminal propeptide of type I collagen (PINP), a marker of bone formation, and of the carboxyterminal telopeptide of type I collagen (CTX-I), a marker of bone resorption, along with serum PTH and 25-hydroxyvitamin D [25(OH)D] levels in 1112 subjects (79% female; mean age, 86 years) living in residential care. Co-morbidity was measured using the Implicit Illness Severity Scale. Fracture data were validated by a radiology report. Mortality and causes of death were ascertained from death certificates. RESULTS: Over a median follow-up of 817 days, 559 (50.3%) subjects died. In univariate analyses, time to death from all causes was significantly (p < 0.01) associated with age (HR = 1.62 per 10 years), male sex (HR = 1.33), immobility (HR = 1.94), co-morbidity (HR = 0.31, mild versus severe), lower weight (HR = 0.83 per 10-kg increase), impaired cognitive function (HR = 2.14, severe versus normal), number of medications (HR = 1.05 each), hip fracture (HR = 2.26), log serum creatinine (HR = 1.67), log PTH (HR = 1.29), CTX-I (HR = 1.70, highest 25% versus lowest 75%), and PINP (HR = 1.46, highest 25% versus lowest 75%). In multivariate analysis adjusting for age, sex, immobility, co-morbidity, weight, cognitive function, number of medications, PTH, and hip fracture status, the highest quartile was significantly more likely to die than the rest for both serum CTX-I (HR = 1.39; 95% CI: 1.14-1.70; p = 0.002) and PINP (HR = 1.25; 95% CI: 1.02-1.52; p = 0.03). For individual causes of death, CTX-I was significantly associated with deaths from cardiac causes (HR = 1.78: 95% CI: 1.27-2.50; p < 0.001). CONCLUSIONS: We conclude that in the frail elderly, high bone turnover is associated with all cause mortality independently of age, sex, health status, serum PTH levels, and hip fracture status. The mechanism of the effect of bone turnover on mortality seems to be mainly manifested in deaths from cardiovascular causes.     

Gastric bypass in obese rats causes bone loss,vitamin D deficiency,metabolic acidosis,and elevated peptide YY

BackgroundMetabolic bone disease and bariatric surgery have long been interconnected. The objective of this study is to better understand the mechanisms of bone mass loss after Roux-en-Y gastric bypass (RYGB) surgery. We evaluated mineral homeostasis and bone mass in diet-induced obese (DIO) rats after RYGB or sham surgery.MethodsTwelve DIO male Sprague Dawley rats underwent RYGB (n = 8) or sham (n = 4) surgery at 21 weeks of age. Postoperatively, animals ate an ad libitum 40% fat, normal calcium diet and were euthanized 22 weeks later. Serum and urine chemistries, insulin, leptin, bone turnover markers (BTM), and calciotropic and gut hormones were measured before and 22 weeks after surgery. Femurs were analyzed using microcomputed tomography (µCT).ResultsCompared to sham, RYGB animals had lower serum bicarbonate, calcium, 25-hydroxyvitamin D, insulin, and leptin levels with higher serum parathyroid hormone, peptide YY, and urinary calcium at 43 weeks of age. Sham control rats gained weight and had coupled decreases in formation (P1NP and OC) and unchanged resorption (CTX) BTMs. Comparatively, RYGB animals had higher serum CTX and OC but even lower P1NP levels than controls. µCT revealed lower trabecular bone volume, number, and thickness and lower cortical bone volume, thickness, and moment of inertia relative to controls.ConclusionIn rats with DIO, long-term RYGB-associated bone resorption appears to be driven in part by vitamin D malabsorption and secondary hyperparathyroidism. Other mechanisms, such as chronic acidosis, changes in fat-secreted hormones, and persistently elevated gut-derived hormone peptide YY, may also contribute to observed bone mass differences. Further investigation of these potential contributors to bone loss may lead to new targets for skeletal maintenance after RYGB.     

Biochemical markers of bone formation reflect endosteal bone loss in elderly men--MINOS study

In the skeleton of elderly men, two opposite activities occur: bone loss at the endosteal envelope, which increases bone fragility, and periosteal apposition, which improves bending strength of bone. Both may contribute to serum bone formation markers although they have an opposite effect on bone fragility. The aim of this study was to determine if circulating bone formation markers reflect periosteal bone formation and endosteal bone remodelling in 640 men aged 55-85 years belonging to the MINOS cohort. We measured biochemical markers of bone formation (osteocalcin, bone alkaline phosphatase, N-terminal extension propeptide of type I collagen) and bone resorption (urinary and serum beta-isomerised C-terminal telopeptide of collagen type I, total and free deoxypyridinoline). Parameters of bone size (cross-sectional surface of third lumbar vertebral body measured by X-ray, projected areas of total hip, femoral neck, radius and ulna measured by dual-energy X-ray absorptiometry) increased with age (r = 0.20-0.32, P < 0.0001). In contrast, parameters related to bone loss (areal bone mineral density [aBMD], volumetric bone mineral density [vBMD] and cortical thickness) and determined mainly by bone resorption, decreased with ageing (r = -0.14 to -0.23, P < 0.005-0.0001). Men in the highest quartile of bone resorption markers had lower aBMD (3.8-10.2%, P < 0.05-0.0001), lower vBMD (3.9-13.0%, P < 0.05-0.0001), and lower cortical thickness (1.5-9.6%, P < 0.05-0.0001) than men in the lowest quartile. Markers of bone resorption were not significantly associated with estimates of bone size at any skeletal site. Markers of bone formation were not associated with estimates of periosteal formation after adjustment for covariates. In contrast, men in the highest quartile of the bone formation markers had significantly lower aBMD (4.0-11.7%, P < 0.05-0.0001), lower vBMD (4.2-16.3, P < 0.05-0.0001) and lower cortical thickness (4.0-7.4%, P < 0.05-0.0001) than men in the lowest quartile. In summary, serum levels of bone formation markers are negatively correlated with the estimates of endosteal bone loss. In contrast, they disclose no association with parameters reflecting periosteal apposition. Thus, in elderly men, bone formation markers reflect endosteal bone remodelling, probably because of the coupling between resorption and formation activities. In contrast, they do not reflect the periosteal bone formation, probably because the periosteal surface is smaller and has a slower remodelling rate than the endosteal surface.     

Inhibin and the regulation of bone mass

Inhibins A and B are gonadal peptide members of the transforming growth factor-β superfamily that serve as negative feedback regulators of pituitary follicle-stimulating hormone (FSH). Accumulating evidence suggests that bone turnover and bone loss increase in women before menopause and the decrease in serum estradiol levels. Increased FSH levels have been correlated with some of these perimenopausal changes, whereas decreased inhibins strongly correlate with increases in bone formation and resorption across the menopause transition, and predict lumbar bone mass in perimenopausal women, likely resulting from the direct inhibin suppression of osteoblast and osteoclast development. Interestingly, continuous exposure of mice to inhibin A in vivo is anabolic and protective against gonadectomy-induced bone loss. Together, these data suggest inhibins contribute to the endocrine regulation of bone metabolism via a bimodal mechanism of action such that cycling inhibin exposure suppresses bone turnover, and continuous exposure to inhibins is anabolic.