Use of data-independent acquisition mass spectrometry to identify an objective serum indicator of the need for osteoporotic therapeutic intervention.

Osteoporosis is characterized by weakened bone microstructure and loss of bone mass. Current diagnostic criteria for osteoporosis are based on the T-score, which is a measure of bone mineral density. However, osteoporotic fragility fractures can occur regardless of the T-score, underscoring the need for additional criteria for the early detection of patients at fracture risk. To identify indicators of reduced bone strength, we performed serum proteomic analysis using data-independent acquisition mass spectrometry with serum samples from two patient groups, one with osteoporosis but no fractures and the other with osteopenia and fragility fractures. Collective evaluation of the results identified six serum proteins that changed to a similar extent in both patient groups compared with controls. Of these, extracellular matrix protein 1 (ECM1), which contributes to bone formation, showed the most significant increase in serum levels in both patient groups. An ELISA-based assay suggested that ECM1 could serve as a serum indicator of the need for therapeutic intervention; however, further prospective studies with a larger sample size are necessary to confirm these results. The present findings may contribute to the provision of early and appropriate therapeutic strategies for patients at risk of osteoporotic fractures. SIGNIFICANCE: This study aimed to identify objective serum indicators of the need for therapeutic intervention in individuals at risk of osteoporotic fracture. Comprehensive proteome analyses of serum collected from patients with osteoporosis but no fractures, patients with osteopenia and fragility fractures, and controls were performed by data-independent acquisition mass spectrometry. Collective evaluation of the proteome analysis data and ELISA-based assays identified serum ECM1 as a potential objective marker of the risk of fragility fractures in patients with osteoporosis or osteopenia. The findings are an important step toward the development of appropriate bone health management methods to improve well-being and maintain quality of life.

Circulating MicroRNAs as Biomarkers of Osteoporosis and Fragility Fractures.

CONTEXT: Measurement of circulating microRNAs (miRNAs) as potential biomarkers of fragility fracture risk has recently become a subject of investigation. OBJECTIVE: Measure by next-generation sequencing (NGS), global miRNA expression in serum samples of osteoporotic subjects vs individuals with normal bone mineral density (BMD). DESIGN: Samples were collected from patients with different bone phenotypes and/or fragility fractures who did not receive any antiresorptive and/or bone-forming drug at the time of blood collection. SETTING: Samples and data were collected at 7 medical centers in Italy. PATIENTS: NGS prescreening: 50 osteoporotic patients vs 30 individuals with normal BMD. Droplet digital polymerase chain reaction (ddPCR) validation: 213 patients with different bone phenotypes, including the NGS-analyzed cohort. RESULTS: NGS identified 5 miRNAs (miR-8085, miR-320a-3p, miR-23a-3p, miR-4497, miR-145-5p) differentially expressed in osteoporosis cases without fractures vs controls. ddPCR validation confirmed lower c-miR-23a-3p expression in osteoporotic patients, with or without fracture, than in osteopenic and normal subjects and increased c-miR-320a-3p expression in osteoporotic patients with fracture and lower expression in osteoporotic patients without fracture. ddPCR analysis showed a significantly increased expression of miR-21-5p in osteoporotic patients, with or without fracture, than in osteopenic and normal subjects, not evidenced by the NGS prescreening. DISCUSSION: Our study confirmed levels of c-miR-23a-3p and c-miR-21-5p as able to distinguish osteoporotic patients and subjects with normal BMD. Increased levels of c-miR-320a-3p specifically associated with fractures, independently by BMD, suggesting c-miR-320a-3p as a prognostic indicator of fracture risk in osteoporotic patients, to be confirmed in prospective studies on incident fractures.

Serum irisin concentrations and osteoporotic vertebral fractures in women with rheumatoid arthritis: A cross-sectional study.

ABSTRACT: Irisin stimulates osteoblast differentiation increasing bone mass a decreasing in irisin levels might contribute to osteoporotic fractures in inflammatory diseases. To date, there is controverted whether irisin levels are associated with osteoporotic fractures in rheumatoid arthritis (RA). Therefore, we evaluate the association of serum irisin with osteoporotic Vertebral Fractures (VFs) in women with RA.A total of 148 women with RA was included in the study.Clinical characteristics and risk factors of VFs was evaluated. For measurement of bone mineral density we included the assessment of lumbar spine (AP L1-L4) and Femoral Neck by dual-energy X-ray absorptiometry (DXA). VFs were evaluated by lateral vertebral assessment (LVA) of the dorsal and lumbar regions using X-ray and digital vertebral morphometry by DXA, using the Genant scale. Serum irisin levels were measured by ELISA. A reference group of 97 women with non-rheumatic diseases were included to compare irisin levels.RA patients had a median age of 59 years and 41% had osteoporosis. Seventy three (49%) had VFs. Lower irisin levels were observed in RA patients compared to controls (94 ±â€Š74 vs 135 ±â€Š103, P < .001). Irisin concentrations were lower in RA + VFs than RA non-VFs (74 ±â€Š42 vs 113 ±â€Š92 ng/mL, P = .001). In the multivariable logistic regression analysis the low 50 percentile irisin levels < 73 ng/mL (OR:3.1, 95% CI:1.55-6.2, P = .001), and disease duration of RA (OR:1.04, 95% CI:1.001-1.08, P = .04) were associated with an increase in the risk of VFs.A decrease of irisin levels is associated to VFs in RA. These results are valuable to consider that RA patients with low levels of irisin are in a potential risk of VFs.

Serum calcium-phosphorus product for predicting the risk of osteoporotic vertebral compression fractures in elderly patients: a retrospective observational study.

BACKGROUND: This study retrospectively analyzed and evaluated the potential correlations of serum calcium, serum phosphorus, and calcium-phosphorus product (Ca-P product) with the incidence of osteoporotic vertebral compression fractures (OVCFs), with the aim of exploring whether the Ca-P product can be used as a serological indicator to predict the risk of OVCFs. METHODS: This study randomly enrolled 400 elderly patients in our hospital with OVCFs and 400 patients with hip and knee arthroplasty due to femoral head necrosis or osteoarthritis from August 2013 to April 2021. Age, sex, past medical history, and admission biochemical indicators, including albumin, blood urea nitrogen, serum creatinine, serum calcium and serum phosphorus, were collected for statistical analysis. RESULTS: Albumin, serum calcium, serum phosphorus, Ca-P product, corrected serum calcium and corrected Ca-P product were lower in the OVCF group than in the non-OVCF group (P < 0.05). Multivariate logistic regression analysis showed that low values of serum calcium, serum phosphorus, Ca-P product, corrected blood calcium, and corrected Ca-P product can all be risk factors for OVCF. The ROC curve showed that the Ca-P product and corrected Ca-P product were effective in predicting the risk of OVCFs. The predictive value of the Ca-P product was the best; the cutoff point was 29.88, the sensitivity was 0.72 and the specificity was 0.62. The cutoff point of the corrected Ca-P product was 30.50, the sensitivity was 0.74, and the specificity was 0.62. CONCLUSION: The Ca-P product and corrected Ca-P product can be used as serological indicators to predict the risk of OVCFs in elderly individuals. Early clinical interventions targeting this risk factor can further reduce the risk of OVCFs. Also, timely and regular testing of the serum calcium and phosphorus level is recommended and encouraged for this group of people.

Circulating serum microRNAs including senescent miR-31-5p are associated with incident fragility fractures in older postmenopausal women with type 2 diabetes mellitus.

Fragility fractures are an important hallmark of aging and an increasingly recognized complication of Type 2 diabetes (T2D). T2D individuals have been found to exhibit an increased fracture risk despite elevated bone mineral density (BMD) by dual x-ray absorptiometry (DXA). However, BMD and FRAX-scores tend to underestimate fracture risk in T2D. New, reliable biomarkers are therefore needed. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity. Serum miRNA-classifiers were recently found to discriminate T2D women with and without prevalent fragility fractures with high specificity and sensitivity (AUC > 0.90). However, the association of circulating miRNAs with incident fractures in T2D has not been examined yet. In 168 T2D postmenopausal women in the AGES-Reykjavik cohort, miRNAs were extracted from baseline serum and a panel of 10 circulating miRNAs known to be involved in diabetic bone disease and aging was quantified by qPCR and Ct-values extracted. Unadjusted and adjusted Cox proportional hazard models assessed the associations between serum miRNAs and incident fragility fracture. Additionally, Receiver operating curve (ROC) analyses were performed. Of the included 168 T2D postmenopausal women who were on average 77.2 ±â€¯5.6 years old, 70 experienced at least one incident fragility fracture during the mean follow-up of 5.8 ±â€¯2.7 years. We found that 3 serum miRNAs were significantly associated with incident diabetic fragility fracture: while low expression of miR-19b-1-5p was associated with significantly lower risk of incident fragility fracture (HR 0.84 (95% CI: 0.71-0.99, p = 0.0323)), low expression of miR-203a and miR-31-5p was each significantly associated with a higher risk of incident fragility fracture per unit increase in Ct-value (miR-203a: HR 1.29 (95% CI: 1.12-1.49), p = 0.0004, miR-31-5p HR 1.27 (95% CI: 1.06-1.52), p = 0.009). Hazard ratios of the latter two miRNAs remained significant after adjustments for age, body mass index (BMI), areal bone mineral density (aBMD), clinical FRAX or FRAXaBMD. Women with miR-203a and miR-31-5p serum levels in the lowest expression quartiles exhibited a 2.4-3.4-fold larger fracture risk than women with miR-31-5p and miR-203a serum expressions in the highest expression quartile (0.002 ≤ p ≤ 0.039). Women with both miR-203a and miR-31-5p serum levels below the median had a significantly increased fracture risk (Unadjusted HR 3.26 (95% CI: 1.57-6.78, p = 0.001) compared to those with both expression levels above the median, stable to adjustments. We next built a diabetic fragility signature consisting of the 3 miRNAs that showed the largest associations with incident fracture (miR-203a, miR-31-5p, miR-19b-1-5p). This 3-miRNA signature showed with an AUC of 0.722 comparable diagnostic accuracy in identifying incident fractures to any of the clinical parameters such as aBMD, Clinical FRAX or FRAXaBMD alone. When the 3 miRNAs were combined with aBMD, this combined 4-feature signature performed with an AUC of 0.756 (95% CI: 0.680, 0.823) significantly better than aBMD alone (AUC 0.666, 95% CI: 0.585, 0.741) (p = 0.009). Our data indicate that specific serum microRNAs including senescent miR-31-5p are associated with incident fragility fracture in older diabetic women and can significantly improve fracture risk prediction in diabetics when combined with aBMD measurements of the femoral neck.

Circulating MicroRNA Expression, Vitamin D, and Hypercortisolism as Predictors of Osteoporosis in Elderly Postmenopausal Women.

BACKGROUND: MicroRNAs (miRNA) identified as critical molecular regulators for bone development, function, and modeling/remodeling process and could be predictable for osteoporotic fractures in postmenopausal elderly women. AIM: The potential diagnostic role of circulating miRNAs, miR-148a and miR-122-5p, in the pathogenesis of osteoporosis and its association with bone markers, hypercortisolism, and vitamin D deficiency were explored in postmenopausal elderly women with osteoporosis. METHODS: A total of 120 elderly women aged 50-80 years old were recruited in this study, of which only 100 eligible women with amenorrhea of at least 12 consecutive months or surgical menopause participated in this study. Based upon bone mineral density (BMD) measurements, the participants were classified according into two groups: normal (n = 45; T score of ≥-1.0) and osteoporosis (n = 55; T score: ≤-2.5). Circulating miRNAs, miR-148a and miR-122-5p, were estimated by real-time RT-PCR analysis. In addition, bone markers, hypercortisolism, and vitamin D deficiency were colorimetrically and ELISA immune assay estimated. The potential role of miR-148a, miR-122-5p, cortisol, and vitamin D in the diagnosis of osteoporosis was predicted using the analysis of the respective area under the receiver operating characteristic curve (AUC-ROC). RESULTS: The expressed level of miR-148a significantly increased and miR-122-5p significantly decreased in the serum of osteoporotic patients compared to healthy controls. In addition, a significant increase in the levels of cortisol, s-BAP, and CTx and significant decrease in the levels of T-BMD, the levels of OC, and s-Ca were also identified. All parameters significantly correlated with fracture risk parameters; BMD, and T score lumbar spine (L2-L4). Thus, the data showed AUC cut off values (miR-148a; 0.876, miR-122-5p; 0.761) were best evaluated for clinical diagnosis of patients with osteoporosis and that AUC cut off values of 0.748 for cortisol and 0.635 for vitamin D were the best cut off values, respectively, reported for the prediction of osteoporosis clinical diagnosis. CONCLUSION: In this study, expressed miRNAs miR-148a and miR-122-5p and changes in the levels of both cortisol and vitamin D status are significantly associated with bone loss or osteoporosis. Thus, circulation miRNAs alone or in combination with cortisol and vitamin D status might be considered predictable biomarkers in the diagnosis or the pathogenesis of osteoporosis in elderly postmenopausal women; however, more studies are recommended.

Assessment of Serum sRANKL, sRANKL/OPG Ratio, and Other Bone Turnover Markers with the Estimated 10-Year Risk of Major and Hip Osteoporotic Fractures in Rheumatoid Arthritis: A Cross-Sectional Study.

BACKGROUND: Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. METHODS: Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. RESULTS: The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). CONCLUSION: High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.

Serum microRNAs in osteoporotic fracture and osteoarthritis: a genetic and functional study.

The rising incidence of bone pathologies such as osteoporosis and osteoarthritis is negatively affecting the functional status of millions of patients worldwide. The genetic component of these multifactorial pathologies is far from being fully understood, but in recent years several epigenetic mechanisms involved in the pathophysiology of these bone diseases have been identified. The aim of the present study was to compare the serum expression of four miRNAs in women with hip fragility fracture (OF group), osteoarthritis requiring hip replacement (OA group) and control women (Ctrl group). Serum expression of miR-497-5p, miR-155-5p, miR-423-5p and miR-365-3p was determined in a sample of 23 OA women, 25 OF women and 52 Ctrl women. Data shown that women with bone pathologies have higher expression of miR-497 and miR-423 and lower expression of miR-155 and miR-365 than control subjects. Most importantly, miR-497 was identified as an excellent discriminator between OA group and control group (AUC: 0.89, p < 0.000) and acceptable in distinguishing from the OF group (AUC: 0.76, p = 0.002). Our data suggest that circulating miR-497 may represent a significant biomarker of OA, a promising finding that could contribute towards future early-stage diagnosis of this disease. Further studies are required to establish the role of miR-155, miR-423 and miR-365 in bone pathologies.

Serum levels of irisin in postmenopausal women with osteoporotic hip fractures.

OBJECTIVE: The purpose of this study was to evaluate the role of circulating serum levels of irisin in predicting hip fracture occurrence in a cohort of Chinese postmenopausal women. METHODS: This was a cross-section and case-control study. Four hundred and thirty postmenopausal women aged 50-90 years were included (215 with hip fractures and 215 age-matched cases without fracture). Clinical features, bone mineral density (BMD) and serum biomarkers levels including irisin were measured at baseline. Cox proportional hazards regression analysis was used to assess the correlation between irisin and fracture risk. RESULTS: The mean age of those participants was 68.7 (S.D. 11.7) and 53.0% were order than 65. The irisin serum levels were positively related to total body BMD and total hip BMD. Women with hip fractures showed lower mean serum levels of irisin compared normal control women (457.6 ± 172.6 ng/ml vs. 602.2 ng/ml; P < 0.001). The irisin levels in third and fourth quartiles were associated with the risk of hip fracture (the lowest quartile of irisin levels as the reference), and risk of fracture reduced by 67% (hazard ratio [HR] = 0.33; 95 %CI: 0.18-0.54; P < 0.001) and 84% (HR = 0.16; 95 %CI: 0.09-0.29; P < 0.001). The irisin levels in third and fourth quartiles were also associated with the risk of osteoporosis, and risk of fracture reduced by 55% (HR = 0.45; 95 %CI: 0.21-0.63; P = 0.003) and 73% (HR = 0.27; 95 %CI: 0.15-0.47; P < 0.001). CONCLUSION: Decreased serum levels of circulating irisin are associated with high risk of osteoporosis-related hip fractures and osteoporosis.

Long-term Bisphosphonates for Osteoporosis: A Factor Effecting Fracture Pattern?

BACKGROUND: The incidence of fragility hip fractures, intracapsular and extracapsular, has been increasing worldwide. Fracture stability is important for treatment decision-making and is related to the expected rate of complications. It is unclear whether metabolic therapy explains the increased incidence of unstable fractures. OBJECTIVES: To investigate the possible association between treatment with bisphosphonates and the various patterns encountered with intertrochanteric hip fractures. METHODS: Patients with fragility hip fractures who were treated in our department between 2013 and 2014 were included in this study. They were classified into three groups: group 1 had a stable extracapsular fracture, group 2 had an unstable extracapsular fracture, and group 3 had an intracapsular fracture. Collated data included: osteoporosis preventive therapy and duration, fracture-type, history of previous fractures, and vitamin D levels. RESULTS: Of 370 patients, 87 were previously treated with bisphosphonates (18.3% prior to fracture in group 1, 38.3% in group 2, and 13.8% in group 3). Of those treated with bisphosphonates, 56.3% had an unstable fracture, 21.8% had a stable fracture, and the rest an intracapsular fracture. In contrast, only 27.9% of patients who were not treated with bisphosphonates had an unstable fracture and 30.0% had stable fractures. CONCLUSIONS: Our findings show a higher proportion of complex and unstable fractures among patients with fragility hip-fractures who were treated with bisphosphonates than among those who did not receive this treatment. The risk for complex and unstable fracture may affect the preferred surgical treatment, its complexity, length of surgery, and rehabilitation.

Acute Inflammatory Response in Osteoporotic Fracture Healing Augmented with Mechanical Stimulation is Regulated In Vivo through the p38-MAPK Pathway.

Low-magnitude high-frequency vibration (LMHFV) has previously been reported to modulate the acute inflammatory response of ovariectomy-induced osteoporotic fracture healing. However, the underlying mechanisms are not clear. In the present study, we investigated the effect of LMHFV on the inflammatory response and the role of the p38 MAPK mechanical signaling pathway in macrophages during the healing process. A closed femoral fracture SD rat model was used. In vivo results showed that LMHFV enhanced activation of the p38 MAPK pathway at the fracture site. The acute inflammatory response, expression of inflammatory cytokines, and callus formation were suppressed in vivo by p38 MAPK inhibition. However, LMHFV did not show direct in vitro enhancement effects on the polarization of RAW264.7 macrophage from the M1 to M2 phenotype, but instead promoted macrophage enlargement and transformation to dendritic monocytes. The present study demonstrated that p38 MAPK modulated the enhancement effects of mechanical stimulation in vivo only. LMHFV may not have exerted its enhancement effects directly on macrophage, but the exact mechanism may have taken a different pathway that requires further investigation in the various subsets of immune cells.

Serum Glycine Levels Are Associated With Cortical Bone Properties and Fracture Risk in Men.

CONTEXT: In a recent study a pattern of 27 metabolites, including serum glycine, associated with bone mineral density (BMD). OBJECTIVE: To investigate associations for serum and urinary glycine levels with BMD, bone microstructure, and fracture risk in men. METHODS: In the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (men, 69-81 years) serum glycine and BMD were measured at baseline (n = 965) and 5-year follow-up (n = 546). Cortical and trabecular bone parameters of the distal tibia were measured at follow-up using high-resolution peripheral quantitative computed tomography. Urinary (n = 2682) glycine was analyzed at baseline. X-ray-validated fractures (n = 594) were ascertained during a median follow-up of 9.6 years. Associations were evaluated using linear regression (bone parameters) or Cox regression (fractures). RESULTS: Circulating glycine levels were inversely associated with femoral neck (FN)-BMD. A meta-analysis (n = 7543) combining MrOS Sweden data with data from 3 other cohorts confirmed a robust inverse association between serum glycine levels and FN-BMD (P = 7.7 × 10-9). Serum glycine was inversely associated with the bone strength parameter failure load in the distal tibia (P = 0.002), mainly as a consequence of an inverse association with cortical cross-sectional area and a direct association with cortical porosity. Both serum and urinary glycine levels predicted major osteoporotic fractures (serum: hazard ratio [HR] per SD increase = 1.22, 95% CI, 1.05-1.43; urine: HR = 1.13, 95% CI, 1.02-1.24). These fracture associations were only marginally reduced in models adjusted by FRAX with BMD. CONCLUSIONS: Serum and urinary glycine are indirectly associated with FN-BMD and cortical bone strength, and directly associated with fracture risk in men.

Association Between Visit-to-Visit Fasting Plasma Glucose Variability and Osteoporotic Fractures in Nondiabetic Subjects.

CONTEXT: Although long-term glucose variability has been reported to be a risk factor associated with osteoporosis, there have been no previous studies between the relationship of glucose variability and fractures in people without diabetes. OBJECTIVE: We assessed visit-to-visit variations in fasting plasma glucose (FPG) as a prognostic factor in predicting osteoporotic fractures in individuals without diabetes. METHODS: Using a nationwide cohort database, we examined the impact of FPG on the development of osteoporotic fractures in men and women (aged ≥50 years). The primary outcomes were the number of total fractures and vertebral fractures. FPG variability was measured using standard deviation (FPG-SD), coefficient of variation (FPG-CV), and variability independent of the mean (FPG-VIM). RESULTS: Of the 92 929 participants, 5262 (5.7%) developed osteoporotic fractures during the mean follow-up of 8.4 years. Individuals in the highest quartile of FPG-SD showed an 11% and 16% increase in risk of total and vertebral fractures, respectively, compared with those in the lowest quartile after adjustment for mean FPG and other risk factors. Analyses using FPG-CV and FPG-VIM demonstrated similar results. Subgroup analyses and sensitivity analyses to explore potential heterogeneity showed consistent results. CONCLUSION: FPG variability may be a novel risk factor for osteoporotic fractures independent of risk factors in the general population without diabetes.

The Ability of Exercise to Mitigate Caloric Restriction-Induced Bone Loss in Older Adults: A Structured Review of RCTs and Narrative Review of Exercise-Induced Changes in Bone Biomarkers.

Despite the adverse metabolic and functional consequences of obesity, caloric restriction- (CR) induced weight loss is often contra-indicated in older adults with obesity due to the accompanying loss of areal bone mineral density (aBMD) and subsequent increased risk of fracture. Several studies show a positive effect of exercise on aBMD among weight-stable older adults; however, data on the ability of exercise to mitigate bone loss secondary to CR are surprisingly equivocal. The purpose of this review is to provide a focused update of the randomized controlled trial literature assessing the efficacy of exercise as a countermeasure to CR-induced bone loss among older adults. Secondarily, we present data demonstrating the occurrence of exercise-induced changes in bone biomarkers, offering insight into why exercise is not more effective than observed in mitigating CR-induced bone loss.

Interactions of Anemia, FGF-23, and Bone in Healthy Adults-Results From the Study of Health in Pomerania (SHIP).

CONTEXT: Osteoporosis and anemia are among the most common diseases in the aging population with an increasing prevalence worldwide. OBJECTIVE: As the bone-derived hormone fibroblast growth factor 23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover, and FGF-23 concentrations. DESIGN: We used data from more than 5000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX), and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Carboxy-terminal FGF-23 levels were measured in plasma in a subset of 852 subjects. RESULTS: Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than nonanemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover. CONCLUSION: Our data corroborate a close link between FGF-23 and anemia, which is related to poor bone quality in elderly people. We observed no direct association of FGF-23 with bone parameters. Further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.

Serum Spermidine as a Novel Potential Predictor for Fragility Fractures.

CONTEXT: Metabolomics is an emerging tool that provides insights into the dynamics of phenotypic changes. It is a potential method for the discovery of novel serum markers of fracture. OBJECTIVE: To identify metabolite parameters that can be used as a proxy for osteoporotic fracture risk. DESIGN: Prospective study based on the Ansung cohort in Korea. SETTING: The general community. PARTICIPANTS: A total of 1504 participants with metabolomic analyses. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Fragility fractures. RESULTS: We measured 135 baseline metabolite profiles in fasting serum of the participants. The participants had a mean age of 60.2 years and were comprised of 585 (38.9%) men. During a mean 9-year follow-up, 112 osteoporotic fracture events occurred. Of all metabolites measured, only serum spermidine concentrations were positively associated with the risk of fracture (hazard ratio [HR] per 1 µM of spermidine 1.35, 95% confidence interval [CI] = 1.03-1.65, P = 0.020) after adjusting for age, sex, body mass index, diabetes, hypertension, smoking status, previous fracture history, and baseline tibial quantitative ultrasound. Participants with spermidine concentrations >1.57 µM had a 2.2-fold higher risk of fractures (95% CI 1.08-4.51, P = 0.030) compared with those with concentrations ≤1.57 µM after adjustment. In a subgroup analysis, women with baseline spermidine concentrations >1.57 µM also had a 2.4-fold higher risk of fracture than those with concentrations ≤1.57 µM (95% CI 1.02-5.48, P = 0.047). CONCLUSIONS: Increased baseline spermidine concentrations were associated with a risk of osteoporotic fracture during a mean 9-year follow-up. The biological significance of the metabolites in the musculoskeletal system could be a subject for future studies.

Prediction of Fracture Risk From Early-Stage Bone Markers in Patients With Osteoporosis Treated With Once-Yearly Administered Zoledronic Acid.

The prevention of fractures is the ultimate goal of osteoporosis treatments. To achieve this objective, developing a method to predict fracture risk in the early stage of osteoporosis treatment would be clinically useful. This study aimed to develop a mathematical model quantifying the long-term fracture risk after 2 annual doses of 5 mg of once-yearly administered zoledronic acid or placebo based on the short-term measurement of bone turnover markers or bone mineral density (BMD). The data used in this analysis were obtained from a randomized, placebo-controlled, double-blind, 2-year study of zoledronic acid that included 656 patients with primary osteoporosis. Two-year individual bone resorption marker (tartrate-resistant acid phosphatase 5b [TRACP-5b]) and lumbar spine (L2-L4) BMD profiles were simulated using baseline values and short-term measurements (at 3 months for TRACP-5b and 6 months for BMD) according to the pharmacodynamic model. A new parametric time-to-event model was developed to describe the risk of clinical fractures. Fracture risk was estimated using TRACP-5b or BMD and the number of baseline vertebral fractures. As a result, the fracture risk during the 2 years was successfully predicted using TRACP-5b or BMD. The 90% prediction intervals well covered the observed fracture profiles in both models. Therefore, TRACP-5b or BMD is useful to predict the fracture risk of patients with osteoporosis, and TRACP-5b would be more useful because it is an earlier marker. Importantly, the developed model allows clinicians to inform patients of their predicted response at the initial stage of zoledronic acid treatment.

Pentosidine and carboxymethyl-lysine associate differently with prevalent osteoporotic vertebral fracture and various bone markers.

Pentosidine (PEN) and carboxymethyl-lysine (CML) are well-recognized advanced glycation end products (AGEs). However, how these AGEs affect the pathophysiology of osteoporosis and osteoporotic fractures remains controversial. This cross-sectional study aimed to investigate the associations of PEN and CML with bone markers, bone mineral density (BMD), and osteoporotic fractures in postmenopausal women from the Nagano Cohort Study. A total of 444 Japanese postmenopausal outpatients (mean ± standard deviation age: 69.8 ± 10.2 years) were enrolled after the exclusion of patients with acute or severe illness or secondary osteoporosis. The relationships among urinary PEN and serum CML levels, various bone markers, lumbar and hip BMD, and prevalent vertebral and long-bone fractures were evaluated. PEN associated significantly with prevalent vertebral fracture after adjustment for other confounders (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.22-2.07; P < 0.001), but not with lumbar BMD. In contrast, a significant negative correlation was found between CML and lumbar BMD (r = - 0.180; P < 0.001), and this relationship was significant after adjustment for confounders (OR 0.84, 95% CI 0.76-0.93; P < 0.01). Although patients with prevalent vertebral fracture had significantly higher CML levels, the association between CML and prevalent vertebral fracture did not reach significance in the multivariate regression model. Both PEN and CML may play important roles in bone health for postmenopausal women, possibly via different mechanisms.