Sclerostin and Pref-1 have differential effects on bone mineral density and strength parameters in adolescent athletes compared with non-athletes

Summary

Excessive exercise can have detrimental effects on bone; however, the mechanisms leading to bone loss are not well understood. Sclerostin and preadipocyte factor (Pref)-1 are two hormones which inhibit bone formation. The present study demonstrates that these hormones may have differential effects in athletes as compared to non-athletes.

Introduction

Exercise activity is common in female adolescents, however, excessive exercise can have detrimental effects on bone mineral density (BMD). Mechanisms underlying this decrease in bone mass are not well understood. We investigated the effects of sclerostin, a potent inhibitor of bone formation via WNT signaling inhibition, and Pref-1, a suppressor of osteoblast differentiation, on BMD, bone turnover markers and bone strength in adolescent athletes.

Methods

We studied 50 adolescents between 15–21 years of age: 17 amenorrheic athletes (AA), 17 eumenorrheic athletes (EA), and 16 nonathletic controls (NA). We measured spine and hip BMD by dual energy x-ray absorptiometry and estimated failure load and stiffness at the distal radius and tibia using micro-finite element analysis. We also measured fasting sclerostin, Pref-1, N-terminal propeptide of type 1 procollagen, and C-terminal collagen cross-links levels.

Results

Sclerostin levels were higher in AA and EA compared with NA (AA: 0.42?±?0.15 ng/mL, EA: 0.44?±?0.09 ng/mL, NA: 0.33?±?0.14 ng/mL; p?=?0.047). In EA, sclerostin was positively associated with lumbar spine (LS) BMD and its Z-score (R?=?0.52, p?=?0.03 and R?=?0.55, p?=?0.02, respectively) whereas in NA, sclerostin was inversely associated with LS BMD (R?=??0.61, p?=?0.01). Pref-1 levels were similar in all three groups and there were significant inverse associations between Pref-1, BMD, and estimated bone strength in NA.

Conclusions

Sclerostin and Pref-1 may have differential effects on bone in adolescent athletes compared to non-athletes.     

Sclerostin serum levels in prostate cancer patients and their relationship with sex steroids

Summary

The role of sclerostin on bone metabolism and its relation to sex steroids in patients with prostate cancer (PC) is not well known. We found that sclerostin levels are significantly increased in PC patients, particularly in those with androgen deprivation therapy (ADT), and there is an inverse relationship between sclerostin levels and testosterone.

Introduction

Recent studies have evaluated sclerostin levels in bone diseases as osteoporosis. However, there are few data in PC patients, particularly in patients with hypogonadism related to ADT. The aim of the present study was to compare serum sclerostin levels in ADT/non-ADT-treated PC patients and healthy controls and to evaluate their relationship with sex steroids and bone metabolism.

Methods

We performed a cross-sectional study involving 81 subjects: 25 ADT-treated PC patients, 34 PC patients without ADT treatment, and 22 healthy controls. We measured serum sclerostin levels, bone turnover markers, bone mineral density (BMD) in all individuals, and sex steroids levels in PC patients.

Results

Serum sclerostin levels were significantly higher in PC patients compared to those in control subjects. ADT-treated patients had significantly higher sclerostin levels than PC patients without ADT treatment: ADT 64.52?±?27.21 pmol/L, non-ADT 48.24?±?15.93 pmol/L, healthy controls 38.48?±?9.19 pmol/L, p?<?0.05. In PC patients, we found a negative relationship between serum sclerostin levels and androgens after age adjustment (total testosterone: r?=??0.309, p?=?0.029; bioavailable testosterone: r?=??0.280, p?=?0.049; free testosterone: r?=??0.299, p?=?0.035). We did not observe any relationship between sclerostin levels and bone turnover markers or BMD in any group.

Conclusions

Circulating sclerostin levels are significantly increased in patients with PC and particularly in those receiving ADT. The inverse relationship between serum sclerostin and testosterone in these patients suggests that androgens are key regulators of bone metabolism in this population.     

Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months

Summary

In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months.

Introduction

This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass and to assess a potential effect of denosumab or teriparatide treatment for 3 months.

Methods

Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤?2.0) and their age-matched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n?=?50; Dmab control group, n?=?25) and (b) women with more severe disease (LS or FN BMD T-score ≤?2.8) and their age-matched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n?=?25; TPTD control group, n?=?25).

Results

At baseline, irisin levels were inversely correlated with age (partial coefficient (r _p )?=??0.24; p?=?0.009), parathyroid hormone (PTH) (r _p ?=??0.30; p?=?0.001), and creatinine (r _p ?=??0.23; p?=?0.016) in univariate analysis, and were lower in women with (n?=?26; 41.6?±?2.7 ng/dL) than without previous osteoporotic fracture(s) (n?=?99; 51.0?±?1.6 ng/dL; p?=?0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p?=?0.04, CI ?16.1 to ?0.4 and p?=?0.002, CI ?0.3 to ?0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months.

Conclusions

Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified.     

SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer

Summary

Fractures are increased among prostate cancer patients. No data have been reported in patients with prostate cancer about the relation between serum sex hormone-binding globulin (SHBG) and bone metabolism. We found that SHBG levels were inversely related to bone mass and vertebral fractures in this population.

Introduction

Fractures are increased among prostate cancer patients, especially those on androgen deprivation therapy (ADT), but few data are available on the role of SHBG in their bone status. Our objective was to analyze the relation between serum SHBG and bone metabolism in prostate cancer patients.

Methods

This is a cross-sectional study including 91 subjects with prostate cancer (54 % with ADT). We measured serum levels of SHBG and sex steroids, bone mineral density (BMD) by dual-energy X-ray absorptiometry, and prevalent radiographic vertebral fractures.

Results

SHBG levels were inversely related to BMD (femoral neck: r?=??0.299, p?=?0.00; total hip: r?=??0.259, p?=?0.019). Subjects with osteoporosis had higher SHBG concentrations than patients without osteoporosis (60.97?±?39.56 vs 44.45?±?23.32 nmol/l, p?=?0.022). Patients with SHBG levels in the first quartile (>57.6 nmol/l) had an odds ratio (OR) for osteoporosis of 2.59 (95 % CI, 1.30–5.12; p?=?0.009) compared with patients with lower SHBG levels. In patients with SHBG >57.6 nmol/l, the OR for vertebral fractures was 2.34 (95 % CI, 1.15–4.78; p?=?0.034). The calculated OR was higher after adjustment for age (OR, 5.16; 95 % CI, 1.09–24.49; p?=?0.039), estrogens (OR, 6.45; 95 % CI, 1.44–28.95; p?=?0.023), and androgens (OR, 5.51; 95 % CI, 1.36–22.37; p?=?0.017).

Conclusions

In prostate cancer patients, SHBG levels were inversely related to bone mass and vertebral fractures. Determination of the serum SHBG level may constitute a useful and straightforward marker for predicting the severity of osteoporosis in these patients.     

Skeletal health in adult patients with classic galactosemia

Summary

This study evaluated bone health in adults with galactosemia. Associations between bone mineral density (BMD) and nutritional and biochemical variables were explored. Calcium level predicted hip and spine BMD, and gonadotropin levels were inversely associated with spinal BMD in women. These results afford insights into management strategies for these patients.

Introduction

Bone loss is a complication of galactosemia. Dietary restriction, primary ovarian insufficiency in women, and disease-related alterations of bone metabolism may contribute. This study examined relationships between clinical factors and BMD in patients with galactosemia.

Methods

This cross-sectional sample included 33 adults (16 women) with classic galactosemia, mean age 32.0?±?11.8 years. BMD was measured by dual-energy X-ray absorptiometry, and was correlated with age, height, weight, fractures, nutritional factors, hormonal status, and bone biomarkers.

Results

There was a significant difference in hip BMD between women and men (0.799 vs. 0.896 g/cm², p?=?0.014). The percentage of subjects with BMD-Z <?2.0 was also greater for women than men [33 vs. 18 % (spine), 27 vs. 6 % (hip)], and more women reported sustaining fractures. Bivariate analyses yielded correlations between BMI and BMD-Z [at the hip in women (r?=?0.58, p?<?0.05) and spine in men (r?=?0.53, p?<?0.05)]. In women, weight was also correlated with BMD-Z (r?=?0.57, p?<?0.05 at hip), and C-telopeptides (r?=??0.59 at spine and ?0.63 hip, p?<?0.05) and osteocalcin (r?=??0.71 at spine and ?0.72 hip, p?<?0.05) were inversely correlated with BMD-Z. In final regression models, higher gonadotropin levels were associated with lower spinal BMD in women (p?=?0.017); serum calcium was a significant predictor of hip (p?=?0.014) and spine (p?=?0.013) BMD in both sexes.

Conclusions

Bone density in adults with galactosemia is low, indicating the potential for increased fracture risk, the etiology of which appears to be multifactorial.     

Comparison of two commercially available ELISAs for circulating sclerostin

Summary

This study investigates the performance and correlation of sclerostin measurements by two commercially available sclerostin ELISAs from TECOmedical and Biomedica. We found that the correlation between the results of two sclerostin assays is strong.

Introduction

Circulating sclerostin levels may provide insight into the pathophysiology of metabolic bone diseases such as osteoporosis. However, recent studies suggest that commercially available assays give different results. We compare the analytical performance of the two most used commercially available sclerostin ELISAs from TECOmedical and Biomedica.

Methods

Sclerostin levels were assessed in 20 paired serum, EDTA, and heparin plasma convenience samples from hospitalized patients. In addition, sclerostin was measured in serum samples from 34 patients with metabolic bone diseases and from 10 patients with chronic kidney disease (CKD). Samples from three healthy donors were used to determine stability and intra- and inter- assay precision.

Results

The average serum sclerostin concentration of all patients (n?=?64) was 0.713?±?0.58 ng/mL with the Biomedica assay and 0.734?±?0.43 ng/mL with the TECO assay (p?<?0.05). The results correlated strongly (r?=?0.9; p?<?0.0001), with Passing-Bablok regression showing a linear relationship but with a slight systematic and proportional difference between both assays. Sclerostin levels were about 30 % higher in plasma than in serum for both assays, while no significant difference was seen between EDTA and heparin plasma. Intra- and inter- precision were <10 % for TECO and <20 % for Biomedica. Samples were stable for up to three freeze-thaw cycles with both assays.

Conclusions

The two commercially available ELISAs for measuring circulating levels of sclerostin are comparable. However, given the small but statistically significant systematic and proportional differences between both assays, results and reference ranges will be assay-specific. Results will also be specific to serum or plasma.     

Alterations of bone microstructure and strength in end-stage renal failure

Summary

End-stage renal disease (ESRD) patients have a high risk of fractures. We evaluated bone microstructure and finite-element analysis-estimated strength and stiffness in patients with ESRD by high-resolution peripheral computed tomography. We observed an alteration of cortical and trabecular bone microstructure and of bone strength and stiffness in ESRD patients.

Introduction

Fragility fractures are common in ESRD patients on dialysis. Alterations of bone microstructure contribute to skeletal fragility, independently of areal bone mineral density.

Methods

We compared microstructure and finite-element analysis estimates of strength and stiffness by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 33 ESRD patients on dialysis (17 females and 16 males; mean age, 47.0?±?12.6 years) and 33 age-matched healthy controls.

Results

Dialyzed women had lower radius and tibia cortical density with higher radius cortical porosity and lower tibia cortical thickness, compared to controls. Radius trabecular number was lower with higher heterogeneity of the trabecular network. Male patients displayed only a lower radius cortical density. Radius and tibia cortical thickness correlated negatively with bone-specific alkaline phosphatase (BALP). Microstructure did not correlate with parathyroid hormone (PTH) levels. Cortical porosity correlated positively with “Kidney Disease: Improving Global Outcomes” working group PTH level categories (r?=?0.36, p?<?0.04). BMI correlated positively with trabecular number (r?=?0.4, p?<?0.02) and negatively with trabecular spacing (r?=??0.37, p?<?0.03) and trabecular network heterogeneity (r?=??0.4, p?<?0.02). Biomechanics positively correlated with BMI and negatively with BALP.

Conclusion

Cortical and trabecular bone microstructure and calculated bone strength are altered in ESRD patients, predominantly in women. Bone microstructure and biomechanical assessment by HR-pQCT may be of major clinical relevance in the evaluation of bone fragility in ESRD patients.     

Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients

Summary

In female nursing home patients, homoarginine was associated with lower bone turnover, higher bone density, lower mortality and, by trend, with muscle strength.

Introduction

Homoarginine, a cationic amino acid, may be relevant for muscusloskeletal health because it inhibits alkaline phosphatases (AP) and is involved in nitric oxide and energy metabolism. We aimed to evaluate whether homoarginine serum concentrations are associated with bone density and metabolism, muscle strength, fractures and mortality.

Methods

We examined a cohort of female nursing home patients that underwent quantitative bone ultrasound (QUS) measurements and assessments of knee extensor strength. Measurements of serum homoarginine, C-terminal telopeptide cross-links (β-CTxs) and osteocalcin were also performed at baseline. Thereafter, patients were followed-up with respect to fractures and mortality.

Results

Serum homoarginine concentrations were determined in 506 female study participants (mean age: 83.9?±?6.0 years). Homoarginine was inversely correlated with β-CTxs (r?=??0.26; p?<?0.001) and osteocalcin (r?=??0.21; p?<?0.001), and these associations remained significant in multiple regression analyses. Multivariate regression analyses showed that homoarginine is significantly associated with calcaneus stiffness (beta coefficient?=?0.11; p?=?0.020) and by trend with knee extensor strength (beta coefficient?=?0.09; p?=?0.065). During a mean follow-up time of 27?±?8 months, we recorded 119 deaths (23.5%) and 63 fractures (12.5%). In multivariate analyses, homoarginine was associated with significantly reduced risk of mortality and the combined endpoint of fractures and mortality.

Conclusions

Whether homoarginine metabolism is critically involved into the pathogenesis of musculoskeletal diseases and fatal events warrants further studies.     

Circulating activin-A is elevated in postmenopausal women with low bone mass: the three-month effect of zoledronic acid treatment

Summary

Activin-A is expressed in bone and seems to regulate osteoclastogenesis. In this study, serum activin-A was increased in postmenopausal women with low bone mass and was positively correlated to age and negatively to lumbar spinal bone mineral density (BMD). Serum activin-A levels did not change 3 months after zoledronic acid infusion.

Introduction

The aims of the study were to evaluate prospectively the circulating activin-A levels in postmenopausal women with low bone mass and explore possible correlations with clinical and laboratory data, as well as the 3-month effect of zoledronic acid infusion.

Methods

Postmenopausal women with low bone mass assigned to receive zoledronic acid infusion (Patients, n?=?47) and age-matched, postmenopausal women with normal bone mass (Controls, n?=?27) were recruited on an outpatient basis. Main outcome measurement was serum activin-A levels.

Results

Serum activin-A was higher in patients at baseline compared to controls (p?<?0.001) and activin-A in the serum of patients and controls was positively correlated with age (Spearman’s coefficient of correlation [rs]?=?0.325; p?=?0.005) and negatively with lumbar spinal (LS) BMD (rs?=??0.425; p?<?0.001). In multiple linear regression analysis, only age (B?=?8.93; 95 % CI?=?4.39–13.46; p?<?0.001) was associated with serum activin-A levels at baseline, independent from group (patients or controls), previous anti-osteoporotic treatment, LS BMD and follicle-stimulating hormone. Circulating activin-A levels were not affected 3 months after zoledronic acid infusion.

Conclusions

Serum activin-A is increased in postmenopausal women with low bone mass compared with postmenopausal women with normal bone mass and is positively correlated to age and negatively to LS BMD.     

Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women

Summary

Higher serum uric acid (UA) was associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in postmenopausal women. Furthermore, UA suppressed osteoclastogenesis and decreased production of reactive oxygen species in osteoclast precursors, indicating UA may have beneficial effects on bone metabolism as an antioxidant.

Introduction

UA is known to play a physiological role as an antioxidant, and oxidative stress has detrimental effects on bone metabolism. In the present study, we investigated the association of serum UA level with the osteoporosis-related phenotypes and its direct effect on bone-resorbing osteoclasts using in vitro systems.

Methods

This is a large cross-sectional study, including 7,502 healthy postmenopausal women. Bone mineral density (BMD) and serum UA concentrations were obtained from all subjects. Data on bone turnover markers and lateral thoracolumbar radiographs were available for 1,023 and 6,918 subjects, respectively. An in vitro study investigated osteoclastogenesis and reactive oxygen species (ROS) levels according to UA treatment.

Results

After adjusting for multiple confounders, serum UA levels were positively associated with BMD at all sites (all p?<?0.001). Compared with the participants in the highest UA quartile, the odds for osteoporosis were 40 % higher in those in the lowest quartile. The serum UA levels were inversely related to both serum C-terminal telopeptide of type I collagen and osteocalcin levels (p?<?0.001 and p?=?0.004, respectively). Consistently, subjects with vertebral fracture had lower serum UA levels, compared with those without it (p?=?0.009). An in vitro study showed that UA decreased osteoclastogenesis in a dose-dependent manner and reduced the production of ROS in osteoclast precursors.

Conclusion

These results provide epidemiological and experimental evidence that serum UA may have a beneficial effect on bone metabolism as an antioxidant in postmenopausal women.     

Relationship of thoracic kyphosis and lumbar lordosis to bone mineral density in women

Summary

The relationship between spinal curvature and bone mineral density (BMD) in women was examined. Significant relationships were observed between spinal curvature and BMD in both pre- and postmenopausal women. Excessive spinal curvature may be associated with low bone mass in premenopausal women.

Introduction

The purpose of this study was to examine the associations between spinal measurements of thoracic and lumbar curvatures and bone mineral density in pre- and postmenopausal women.

Methods

The data for this study were obtained from the Texas Woman’s University Pioneer Project. Female participants (n?=?242; premenopausal n?=?104, postmenopausal n?=?138) between the ages of 18 and 60 years were evaluated on multiple health measures. Thoracic and lumbar curvatures were measured with a 24-in. (60 cm) flexicurve. Bone mineral density was assessed via dual-energy X-ray absorptiometry (Lunar DPX IQ, version 4.6e). Pearson correlations and logistic regression analysis were used to examine the associations between the obtained spinal curvature measurements and bone mineral density. Significance was set at p?<?.05.

Results

Significant correlations were observed for the femoral neck and lumbar spine bone mineral density with thoracic and lumbar curve in premenopausal women (r?=??.344 to???.525; p?<?.001). Slightly weaker, but significant, correlations were observed for femoral neck and lumbar spine in relation to thoracic and lumbar curve in postmenopausal women (r?=??.288 to ?.397; p?<?.01). Premenopausal women with thoracic curvature greater than 4 cm had a greater risk of having low bone mass compared to premenopausal women with less than 4 cm of curvature (odds ratio?=?3.982, 95 % CI?=?1.206, 13.144).

Conclusions

The observed negative relationship suggests that as either thoracic or lumbar curvature increases, the regional bone mineral density decreases in both pre- and postmenopausal women.     

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study

Summary

Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug.

Introduction

The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1–34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis.

Methods

Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N?=?65) or quarterly intravenous IBN (N?=?122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared.

Results

Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9?±?7.4 years, body mass index 23.8?±?3.8 kg/m², BMD L1–L4 0.741?±?0.100 g/cm², and TBS 1.208?±?0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 %?±?6.3 vs. +2.9 %?±?3.3 and +4.3 %?±?6.6 vs. +0.3 %?±?4.1, respectively; P?<?0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r ²?=?0.04) with no correlation between the changes in BMD and TBS over 24 months.

Conclusions

In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.     

Effects of cinacalcet on bone mineral density and bone markers in hemodialysis patients with secondary hyperparathyroidism

Background

Cinacalcet markedly reduces the serum intact parathyroid hormone (PTH) level of hemodialysis (HD) patients with secondary hyperparathyroidism. Parathyroidectomy also reduces the serum intact PTH level of HD patients and it increases their bone mineral density (BMD). However, there is little information about the effect of cinacalcet on BMD or on the associations between bone markers and BMD in HD patients.

Methods

We performed a 1-year cohort study of 25 HD patients who had a serum intact PTH level above 300 pg/ml during treatment by conventional therapies, such as with active vitamin D, and cinacalcet was prescribed for 14 of them. BMD of the femoral neck and the serum levels of two circulating bone markers, alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BSAP), were measured before and after treatment. The other 11 HD patients without cinacalcet treatment were defined as control group.

Results

BMD significantly increased by 7.3 % during the 1 year of treatment in the cinacalcet group and decreased by 6.2 % during the same period in the control group, and cinacalcet therapy was independently associated with the changes in BMD after multiple regression analysis that included intact PTH (β = 7.57, P < 0.01). In the cinacalcet group, the serum ALP levels (R ² = 0.315, P < 0.05) and BSAP levels (R ² = 0.682, P < 0.01) levels were significantly negatively correlated with the changes in BMD, but the serum intact PTH levels were not significantly associated with the changes in BMD (R ² = 0.011, P = 0.72).

Conclusions

One year of treatment with cinacalcet increased the BMD of the femoral neck in the HD cohort, especially in the patients who had higher serum ALP and BSAP levels at baseline.     

High serum pentosidine but not esRAGE is associated with prevalent fractures in type 1 diabetes independent of bone mineral density and glycaemic control

Summary

Fracture risk in type 1 diabetes (T1D) is supposed to be underestimated by bone mineral density (BMD). Individuals with T1D had more prevalent fractures in a cross-sectional study. Serum levels of pentosidine, an advanced glycation end product, and poor glycaemic control were associated with prevalent fractures independent of BMD.

Introduction

Type 1 diabetes (T1D) is associated with increased fracture risk. Bone mineral density (BMD) underestimates the risk of fractures in some individuals. The accumulation of advanced glycation end products (AGEs) impairs bone matrix and reduces bone strength.

Methods

In a cross-sectional study, 128 men and premenopausal women with T1D were evaluated. We compared traditional risk factors for fractures, BMD, parameters of bone metabolism and AGEs in individuals with and without prevalent fractures. An independent association of serum AGE levels with prevalent fractures was investigated.

Results

Individuals with prevalent fractures exhibited a longer duration of T1D, higher HbA1c and more diabetic-related complications. BMD at the femoral neck (z-score ?0.76?±?0.94 vs. ?0.23?±?1.02; p?=?0.031) and total hip (z-score ?0.54?±?0.93 vs. 0.11?±?1.11; p?=?0.017) was lower in those with prevalent fractures. Individuals with fractures had higher pentosidine levels (164.1?±?53.6 vs. 133.2?±?40.4; p?=?0.002). The levels of N-ε-(carboxymethyl)-lysine (CML) and endogenous secretory receptor for AGEs (esRAGE) did not significantly differ. Multivariate logistic regression analysis adjusted for age, BMI, family history of fractures, smoking, vitamin D deficiency, BMD at lumbar spine, femoral neck and total hip identified pentosidine levels and HbA1c as independent factors associated with prevalent fractures (odds ratio 1.02, 95 % CI 1.00–1.03/pmol/ml increase of pentosidine; p?=?0.008 and odds ratio 1.93, 95 % CI 1.16–3.20 per percentage increase of HbA1c; p?=?0.011).

Conclusions

The pentosidine levels but not BMD are independently associated with prevalent fractures. Impaired bone quality in T1D may result from increased AGE formation.     

Influence of recency and duration of glucocorticoid use on bone mineral density and risk of fractures: population-based cohort study

Summary

Although systemic glucocorticoids are commonly used, it is difficult to obtain accurate exposure history. In 50,000 patients, we confirmed that glucocorticoids were associated with reductions in bone mineral density (BMD) and increases in fracture and documented that recent and prolonged durations of exposure were particularly associated with adverse events—dose information did not improve risk prediction.

Introduction

Systemic glucocorticoid use, defined as ever having taken supra-physiologic doses for 90-days or more, is a risk factor for low BMD and fractures. This definition does not distinguish recent (vs remote) exposure.

Methods

Within a population-based clinical BMD registry in Manitoba, Canada, we identified all adults over age 40 years tested between 1998 and 2007 and then undertook a cohort study. We identified all oral glucocorticoid dispensations from 1995 to 2009 and stratified exposure by timing (“recent” if within 12 months vs “remote”) and duration (short [<90 days] vs prolonged [≥90 days]). Osteoporosis-related risk factors and treatments and major fractures were obtained using administrative health data.

Results

A total of 12,818 of 52,070 (25 %) subjects had used glucocorticoids prior to BMD testing; the most common exposure was remote short (n?=?6453) vs recent prolonged (n?=?2896) vs recent short (n?=?2644) vs remote prolonged (n?=?825). Compared to 39,252 never-users, only recent prolonged glucocorticoid use was significantly associated with femoral neck T-score (ANCOVA-adjusted difference ?0.13, 95 % CI ?0.16 to ?0.10, p?<?0.001). There were 2,842 major (566 hip) fractures over median 5-year follow-up. Compared with never-users, only recent prolonged glucocorticoid use was significantly associated with BMD-independent increases in risk of incident major fracture (5.4 vs 7.7 %, adjusted HR 1.25, 95 % CI 1.07–1.45, p?=?0.004) and hip fracture (1.1 vs 1.8 %, adjusted HR 1.61, 95 % CI 1.18–2.20, p?=?0.003).

Conclusions

Recent and prolonged glucocorticoid use (but neither remote nor recent short courses) was independently associated with reduced BMD and increased risk of fractures. These findings should permit clinicians to identify a high-risk group of patients that might benefit from osteoporosis prevention.     

Association between high-molecular-weight adiponectin and bone mineral density in hemodialysis patients

Background

Chronic kidney disease-mineral and bone disorder is a regular complication seen in hemodialysis patients and leads to substantial increases in the fracture rate, morbidity, and mortality. Discovered a few years ago, several clinical studies have shown a negative correlation between adiponectin and bone mineral density (BMD) independently of confounding factors. The relationship between adiponectin and bone metabolism in hemodialysis patients has not been fully described yet. We conducted this study to investigate the relationship between serum adiponectin concentration and the BMD in hemodialysis patients.

Methods

We enrolled 92 hemodialysis patients who were receiving maintenance hemodialysis therapy at Towa Hospital. A peripheral blood sample was obtained, and standard biological data and the serum high-molecular-weight (HMW) adiponectin level were measured. BMD was assessed using dual-energy X-ray absorptiometry scans.

Results

In male hemodialysis patients, BMD was negatively related to age (r = ?0.299, P = 0.012), duration of hemodialysis therapy (r = ?0.31, P = 0.009), and log [HMW-adiponectin] (r = ?0.31, P = 0.009) and positively related to body weight (r = 0.332, P = 0.004) and BMI (r = 0.297, P = 0.013). In female hemodialysis patients, BMD was negatively related to age (r = ?0.499, P = 0.018) and log [HMW-adiponectin] (r = ?0.46, P = 0.030) and positively related to triglyceride (r = 0.491, P = 0.020).

The relationship between BPAQ-derived physical activity and bone density of middle-aged and older men

Summary

The bone-specific physical activity questionnaire (BPAQ) accounts for activities that affect bone but has not been used in studies with older adults. Relationships exist between the BPAQ-derived physical activity and bone density in healthy middle-aged and older men but not men with prostate cancer. Disease-related treatments detrimental to bone should be considered when administering the BPAQ.

Introduction

The bone-specific physical activity questionnaire (BPAQ) was developed to account for bone-specific loading. In this retrospective study, we examined the relationship between BPAQ-derived physical activity and bone mineral density (BMD) in middle-aged and older men with and without prostate cancer.

Methods

Two groups, 36 healthy men and 69 men with prostate cancer receiving androgen suppression therapy (AST), completed the BPAQ and had whole body, total hip, femoral (FN) and lumbar spine BMD assessed by dual-energy X-ray absorptiometry.

Results

Past (pBPAQ), current (cBPAQ) and total BPAQ (tBPAQ) scores for the healthy men were related to FN BMD (pBPAQ r?=?0.36, p?=?0.030; cBPAQ r _s?=?0.35, p?=?0.034; tBPAQ r?=?0.41, p?=?0.014), and pBPAQ and tBPAQ were related to total hip (r _s?=?0.35, p?=?0.035 and r _s?=?0.36, p?=?0.029, respectively) and whole body BMD (r _s?=?0.44, p?=?0.007 and r _s?=?0.45, p?=?0.006, respectively). In men with prostate cancer, the BPAQ was not significantly associated with BMD. In stepwise regression analyses, body mass and tBPAQ predicted 30 % of the variance in total hip BMD (p?=?0.003), cBPAQ predicted 14 % of the variance in FN BMD (p?=?0.002), and body mass, age and tBPAQ predicted 47 % of the variance in whole body BMD (p?Conclusions Although BPAQ-derived estimates of physical activity are related to bone status in healthy middle-aged and older men, the adverse effect of AST on bone appears to obscure this relationship in men with prostate cancer.     

Obesity alters cortical and trabecular bone density and geometry in women

Summary

The goal in this study was to determine the relationship between body mass index and trabecular and cortical bone using quantitative computed tomography. A higher body mass index (BMI) was positively associated with trabecular and cortical bone parameters, and serum parathyroid hormone, and negatively associated with cortical volumetric bone mineral density (vBMD) and serum 25-hydroxy-vitamin D. When BMI is greater than 35 kg/m², adiposity affects vBMD and may explain the higher fracture risk in this population without low BMD.

Introduction

The influence of adult obesity on the trabecular and cortical bone, geometry, and strength has not been fully addressed. The goal in this study was to determine the relationship between body mass index and trabecular and cortical bone mass and geometry, over a wide range of body weights.

Methods

We examined 211 women (25–71 years; BMI 18–57 kg/m²) who were classified into three categories of BMI (kg/m²) including normal-weight (BMI?<?25), overweight and obese-class I (BMI 25–35) and obese-class II–III (BMI?>?35), and also by menopausal status. Volumetric bone mineral density (mg/cm³), trabecular, and cortical components as well as geometric characteristics at the 4%, 38%, and 66% from the distal tibia were measured by peripheral quantitative computed tomography, and serum was analyzed for parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25OHD).

Results

Higher BMI was associated with greater values of trabecular bone and cortical BMC and area and PTH (r?>?0.39, p?<?0.001), but lower cortical vBMD and 25OHD (r?>??0.27, p?<?0.001). When controlling for lower leg muscle area, fat area was inversely associated with cortical vBMD (r?=??0.16, p?<?0.05). Premenopausal obese women with both higher BMI and PTH had lower cortical vBMD (r?<??0.40, p?<?0.001). While age is a predictor for most bone variables, fat mass explains more variance for vBMD, and lean mass and 25OHD explain greater variance in geometric and strength indices (p?<?0.05).

Conclusions

Severe obesity (BMI?>?35) increases trabecular vBMD and in the presence of a higher PTH is associated with a lower cortical vBMD without compromising bone geometry and strength. Whether or not a lower cortical vBMD in obesity influences fracture risk over time needs to be further explored.     

Impaired bone mineralization accompanied by low vitamin D and secondary hyperparathyroidism in patients with femoral neck fracture

Summary

Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal bone mineral density (BMD) is rather low. Here, we have identified bone mineralization defects together with low serum 25-hydroxyvitamin D (25-(OH) D) levels as additional factors associated with femoral neck fractures.

Introduction

Osteoporotic fractures of the femoral neck are associated with increased morbidity and mortality. Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal BMD is rather low. To identify possible additional factors influencing femur neck fragility, we analyzed patients with femoral neck fracture.

Methods

We performed a detailed clinical and histomorphometrical evaluation on 103 patients with femoral neck fracture including dual-energy X-ray absorptiometry, laboratory parameters, and histomorphometric and bone mineral density distribution (BMDD) analyses of undecalcified processed biopsies of the femoral head and set them in direct comparison to skeletal healthy control individuals.

Results

Patients with femoral neck fracture displayed significantly lower serum 25-(OH) D levels and increased serum parathyroid hormone (PTH) compared to controls. Histomorphometric analysis revealed not only a decreased bone volume and trabecular thickness in the biopsies of the patients, but also a significant increase of osteoid indices. BMDD analysis showed increased heterogeneity of mineralization in patients with femoral neck fracture. Moreover, patients with femoral neck fracture and serum 25-(OH) D levels below 12 μg/l displayed significantly thinner trabecular bone.

Conclusion

Taken together, our data suggest that impaired bone mineralization accompanied by low serum 25-(OH) D levels is of major importance in the etiology of femoral neck fractures. Therefore, balancing serum 25-(OH) D levels and thereby normalizing PTH serum levels may counteract pronounced mineralization defects and might decrease the incidence of femoral neck fractures.