Serum Biomarkers Of Bone Turnover Research Articles

S-Equol Ameliorates Menopausal Osteoarthritis in Rats through Reducing Oxidative Stress and Cartilage Degradation.

Osteoarthritis (OA) is a chronic degenerative disease leading to articular cartilage destruction. Menopausal and postmenopausal women are susceptible to both OA and osteoporosis. S-equol, a soy isoflavone-derived molecule, is known to reduce osteoporosis in estrogen-deficient mice, but its role in OA remains unknown. This study aimed to explore the effect of S-equol on different degrees of menopausal OA in female Sprague-Dawley (SD) rats induced by estrogen deficiency caused by bilateral ovariectomy (OVX) combined with intra-articular injection of mono-iodoacetate (MIA). Knee joint histopathological change; serum biomarkers of bone turnover, including N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (CTX-I) and N-terminal telopeptide of type I collagen (NTX-I); the cartilage degradation biomarkers hyaluronic acid (HA) and N-terminal propeptide of type II procollagen (PIINP); and the matrix-degrading enzymes matrix metalloproteinases (MMP)-1, MMP-3 and MMP-13, as well as the oxidative stress-inducing molecules nitric oxide (NO) and hydrogen peroxide (H2O2), were assessed for evaluation of OA progression after S-equol supplementation for 8 weeks. The results showed that OVX without or with MIA injection induced various severity levels of menopausal OA by increasing pathological damage, oxidative stress, and cartilage matrix degradation to various degrees. Moreover, S-equol supplementation could significantly reduce these increased biomarkers in different severity levels of OA. This indicates that S-equol can lessen menopausal OA progression by reducing oxidative stress and the matrix-degrading enzymes involved in cartilage degradation.

Clinical Indicators of Bone Deterioration in Alcoholic Liver Cirrhosis and Chronic Alcohol Abuse: Looking beyond Bone Fracture Occurrence.

Although previous studies indicated that chronic alcohol abuse (CAA) and alcoholic liver cirrhosis (ALC) are associated with increased bone fragility, understanding bone fragility determinants is still modest in these individuals. We used a comprehensive individualized clinical fracture risk assessment approach (vertebral osteodensitometry, femoral osteodensitometry and geometry, and serum bone turnover biomarkers) to compare adult male patients with ALC who have not previously had femoral or vertebral fractures (n = 39), patients with CAA (without liver cirrhosis, n = 78) who have not previously had femoral or vertebral fractures and healthy age- and sex-matched controls (n = 43). Our data suggested that intertrochanteric bone mineral density was significantly lower in ALC and CAA patients than in controls. Also, the trabecular bone score was considerably lower in ALC patients compared with CAA and control individuals. The most significant inter-group differences in femoral geometry were noted on the femoral shaft. Patients with ALC and CAA have a higher 10-year risk of major osteoporotic fractures compared to the controls. Analysis of bone turnover biomarkers showed increased osteoprotegerin and beta-C-terminal telopeptide serum concentrations and decreased insulin growth factor-1 concentrations in patients with ALC compared to CAA and control groups. Our data revealed that bone alterations are present in patients with ALC and CAA even if they did not sustain a nontraumatic bone fracture, but it is also indicative that current bone-assessing clinical methods are not entirely reliable. Thus, future studies should focus on developing a reliable integrative clinical tool that can be used to accurately predict and prevent bone fracture occurrences in patients with ALC and CAA.

A nomogram for predicting osteoarthritis based on serum biomarkers of bone turnover in middle age: A cross-sectional study of PTH and β-CTx.

The objective of this study was to investigate the diagnostic model of osteoarthritis by bone turnover markers in Chinese middle-aged subjects. The study was designed as a cross-sectional investigation with 305 participants aged 45 to 64. Radiographs of tibiofemoral knee joints were used for diagnose osteoarthritis. Radiographic grading, evaluated using the Kellgren and Lawrence grading scale (K-L), was scored by 2 experienced observers who were blinded to the source of subjects. An optimal model was developed by logistic regression. And the prognostic performance of the selected model was assessed by the area under the receiver operating characteristic curve. The prevalence of osteoarthritis was 52.29% (n = 137/262) in middle age. β-CTx levels tended to increase according to the K-L grades, whereas PTH levels significantly decrease. levels of 25(OH)D, β-CTx, and PTH were each significantly associated with osteoarthritis risk (P < .05). Based on the estimated parameters of the optimal model, a nomogram was constructed for predicting osteoarthritis. These data suggest that the combination of PTH and β-CTx could significantly improve the prognosis of osteoarthritis in middle age, and that the nomogram can assist primary physicians in the identification of high-risk men.

D-Pinitol Improved Glucose Metabolism and Inhibited Bone Loss in Mice with Diabetic Osteoporosis.

Diabetic osteoporosis (DO) has been increasingly recognized as an important complication of diabetes. D-pinitol, a natural compound found in various legumes, is known for its anti-diabetic function, but its effect on DO has not been investigated. Two doses of pinitol (50 and 100 mg/kg Bw/d) were administered orally to experimentally induce the DO mouse model for 5 weeks. The results indicated that pinitol suppressed fasting blood glucose levels and tended to enhance impaired pancreatic function. Pinitol also suppressed serum bone turnover biomarkers, and improved dry femur weight, cancellous bone rate, and bone mineral content in the DO mice. Based on the inositol quantification using GC-MS in serum, liver, kidney, and bone marrow, the pinitol treatment significantly recovered the depleted D-chiro-inositol (DCI) content or the decreased the ratio of DCI to myo-inositol caused by DO. In short, our results suggested that pinitol improved glucose metabolism and inhibited bone loss in DO mice via elevating the DCI levels in tissues.

Obacunone inhibits RANKL/M-CSF-mediated osteoclastogenesis by suppressing integrin- FAK-Src signaling.

Disrupted osteoblastogenesis or aberrant activation of osteoclastogenesis usually results in the break of bone homeostasis thus causing bone-associated diseases like osteoporosis. Obacunone, as a natural compound present in citrus fruits, has been demonstrated for various biological activities including anti-cancer and anti-inflammatory properties. However, the role of obacunone in regulating osteoclastogenesis has not been elucidated so far. Here, using in vitro cell models of RANKL (Receptor activator of nuclear factor-kB ligand) and M-CSF (Macrophage-colony-stimulating factor)-induced osteoclastogenesis, we showed that obacunone inhibited osteoclast differentiation in RAW264.7 cells and bone marrow macrophages (BMMs), as evidenced by obacunone dose-dependent reduction in numbers of osteoclasts and downregulated expressions of osteoclastogenesis-associated key genes. The anti-osteoclastic properties of obacunone were associated with downregulated expressions of Integrin α1 and attenuated activation of Focal adhesion kinase (FAK) and Steroid receptor coactivator (Src) signaling. Functional Integrin α1 blockade or FAK-Src inhibition suppressed RANKL/M-CSF-induced osteoclastogenesis, while Integrin α1 overexpression or FAK/Src activation partially attenuated obacunone's effects on suppressing RANKL/M-CSF-induced osteoclast differentiation. Furthermore, in vivo administration of obacunone displayed super therapeutic effects in attenuating ovariectomy-induced bone loss in mice, as indicated by decreases in serum biomarkers of bone turnover, restoring of femur fracture maximum force, and reversing of the worsened bone-related parameters in ovariectomized animals. Taken together, these findings demonstrate that obacunone has pharmacological activities to suppress osteoclast differentiation through modulating the Integrin-FAK-Src pathway, and suggest that obacunone is a therapeutic candidate for the treatment and prevention of bone diseases such as osteoporosis.

Associations Between Inflammatory Mediators and Bone Outcomes in Postmenopausal Women: A Cross-Sectional Analysis of Baseline Data from the Prune Study.

Hypoestrogenism triggers increased production of inflammatory mediators, which contribute to bone loss during postmenopausal osteoporosis. This study aimed to investigate the association between circulating inflammatory markers and bone outcomes in postmenopausal women. We conducted a cross-sectional, secondary analysis of baseline data from participants who completed a 12-month randomized controlled trial, The Prune Study (NCT02822378), which included healthy postmenopausal women (n=183, 55-75 years old) with bone mineral density (BMD) T-score between 0.0 and -3.0 at any site. BMD was measured using dual-energy X-ray absorptiometry, and bone geometry and strength were measured using peripheral quantitative computed tomography. Blood was collected at baseline to measure (1) serum biomarkers of bone turnover, including procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide and (2) inflammatory markers, including serum high-sensitivity C-reactive protein (hs-CRP) and plasma pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1, using enzyme-linked immunosorbent assay. The associations between bone and inflammatory outcomes at baseline were analyzed using correlation and regression analyses. Serum hs-CRP negatively correlated with P1NP (r=-0.197, p=0.042). Plasma IL-1β, IL-6, IL-8, and TNF-α negatively correlated with trabecular bone score at the lumbar spine (all p<0.05). In normal-weight women, plasma IL-1β, IL-6, and IL-8 negatively correlated (p<0.05) with trabecular and cortical bone area, content, and density at various sites in the tibia and radius. Serum hs-CRP positively predicted lumbar spine BMD (β=0.078, p=0.028). Plasma IL-6 negatively predicted BMD at the total body (β=-0.131, p=0.027) and lumbar spine (β=-0.151, p=0.036), whereas plasma TNF-α negatively predicted total hip BMD (β=-0.114, p=0.028). At baseline, inflammatory markers were inversely associated with various estimates of bone density, geometry, and strength in postmenopausal women. These findings suggest that inflammatory markers may be an important mediator for postmenopausal bone loss.

Dietary intake of pistachios or mixed nuts results in higher systemic antioxidant capacity with minimal effects on bone in adolescent male rats.

Nutrition is a key determinant of bone health and attainment of peak bone mass. Excess oxidative stress induces bone loss while increasing antioxidant capacity promotes protective effects on bone. Nuts are rich in antioxidants; therefore, we tested the hypothesis that compared to a control diet high in fat (40 % energy) and cholesterol, diets containing isocaloric amounts of pistachios (8·1 % g/g) or mixed nuts (7·5 % g/g) for 8 weeks would result in greater bone health in male adolescent (3 weeks; a state of continued skeletal growth) Sprague-Dawley rats. We found no difference in bone mechanical properties among groups. Tibial apparent density was ~5 % higher in the pistachio and mixed nuts groups v. control (P < 0·05) with no clear difference detected for the femur. Expressions of genes known to impact bone turnover and serum bone turnover biomarkers were unaffected by either diet relative to control. Serum antioxidant capacity was ~2-fold higher in the pistachio and mixed nuts groups compared with control (P < 0·05) but were similar between groups. Therefore, pistachios and mixed nuts may increase tibial density, in part, due to increasing antioxidant capacity. Longer dietary interventions may be necessary to elicit detectable changes in other bones (e.g. femur) and to detect potential mechanisms for the possible bone protective effects of nuts.

The Impact of an Adapted Physical Activity Program on Bone Turnover, Physical Performance and Fear of Falling in Osteoporotic Women with Vertebral Fractures: A Quasi-Experimental Pilot Study.

Physical activity has been indicated as a potential strategy to counteract osteoporosis (OP). This study of post-menopausal women with osteoporotic vertebral fractures investigated the effect of an adapted physical activity (APA) program on two serum bone turnover biomarkers (Bone Alkaline Phosphatase, B-ALP and C-terminal telopeptide of type 1 collagen, CTX-1), functional capacity (6-Minutes Walking Test, 6MWT), and risk and fear of falls (Tinetti and Falls Efficacy scale). The APA group (n = 12) performed a 1-h group session twice per week for 6 months whereas the control group (n = 9) was asked to maintain their current lifestyle. The exercise program did not affect the serum concentrations of B-ALP and CTX-1 biomarkers measured at the baseline and after 6 months in women of the APA group. Moreover, at the end of intervention no significant differences in serum concentrations for either biomarker was observed between the two study groups. Interestingly, when compared to the control group, women in the APA group showed significant improvement in the functional capacity measures by 6MWT (p = 0.037) and a decrease of the risk and fear of falls as indicated by the Tinetti test (p = 0.043). Based on these findings, exercise could provide new perspectives for the care and management of OP.

Changes in Vertebral Marrow Fat Fraction Using 3D Fat Analysis & Calculation Technique Imaging Sequence in Aromatase Inhibitor-Treated Breast Cancer Women.

Aromatase inhibitor (AI) is a cornerstone drug for postmenopausal women with estrogen receptor-positive early-stage breast cancer. Fat-bone interactions within the bone marrow milieu are growing areas of scientific interest. Although AI treatment could lead to deterioration of the skeleton, the association between AI medication and subsequent marrow adiposity remains elusive. A total of 40 postmenopausal, early-staged, and hormone receptor-positive breast cancer patients who underwent treatment with adjuvant AIs and 40 matched controls were included. Marrow proton density fat fraction (PDFF) at the L1−L4 vertebral bodies using 3D Fat Analysis & Calculation Technique imaging (FACT) sequence at 3.0T, bone mineral density (BMD) by dual-energy X-ray absorptiometry, and serum bone turnover biomarkers were determined at baseline and at 6 and 12 months. We found that, in comparison to baseline, an increase of type I collagen cross-linked telopeptide was detected at 12 months (P <0.05). From baseline to 12 months, the PDFF measured using FACT was greatly increased. At 12 months, the median percent change of PDFF (4.9% vs. 0.9%, P <0.05) was significantly different between the AI treatments and controls. The same trend was observed for the marrow PDFF at 6 months relative to the respective values at baseline. Although BMD values were significantly reduced after 12 months in AI-treated women, changes in BMD vs. baseline condition were not significantly different between the AI-treated and control groups [Δ BMD −1.6% to −1.8% vs. −0.3% to −0.6%, respectively, P > 0.05]. In the AI-treated group, Δ PDFF was associated with Δ BMD at the lumbar spine (r = −0.585, P < 0.001), but not in the controls. Taken together, over a 12-month period, spinal marrow fat content assessed with FACT sequence significantly increased in postmenopausal women with hormone-receptor-positive breast cancer receiving AI treatment.

Inhibition of TGF‐β Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta

ABSTRACTOsteogenesis imperfecta (OI), is a genetic disorder of bone fragility caused by mutations in collagen I or proteins involved in collagen processing. Previous studies in mice and human OI bones have shown that excessive activation of TGF‐β signaling plays an important role in dominant and recessive OI disease progression. Inhibition of TGF‐β signaling with a murine pan‐specific TGF‐β neutralizing antibody (1D11) was shown to significantly increase trabecular bone volume and long bone strength in mouse models of OI. To investigate the frequency of dosing and dose options of TGF‐β neutralizing antibody therapy, we assessed the effect of 1D11 on disease progression in a dominant OI mouse model (col1a2 gene mutation at G610C). In comparison with OI mice treated with a control antibody, we attempted to define mechanistic effects of 1D11 measured via μCT, biomechanical, dynamic histomorphometry, and serum biomarkers of bone turnover. In addition, osteoblast and osteoclast numbers in histological bone sections were assessed to better understand the mechanism of action of the 1D11 antibody in OI. Here we show that 1D11 treatment resulted in both dose and frequency dependency, increases in trabecular bone volume fraction and ultimate force in lumbar bone, and ultimate force, bending strength, yield force, and yield strength in the femur (p ≤ 0.05). Suppression of serum biomarkers of osteoblast differentiation, osteocalcin, resorption, CTx‐1, and bone formation were observed after 1D11 treatment of OI mice. Immunohistochemical analysis showed dose and frequency dependent decreases in runt‐related transcription factor, and increase in alkaline phosphatase in lumbar bone sections. In addition, a significant decrease in TRACP and the number of osteoclasts to bone surface area was observed with 1D11 treatment. Our results show that inhibition of the TGF‐β pathway corrects the high‐turnover aspects of bone disease and improves biomechanical properties of OI mice. These results highlight the potential for a novel treatment for osteogenesis imperfecta. © 2021 Sanofi‐Genzyme. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Evaluation of arterial stiffness in maintenance hemodialysis patients using pulse wave analysis and serum biomarkers of bone turnover

Background Vascular stiffness is common among patients with end-stage renal disease (ESRD). Circulating markers of bone formation play an important role in evaluating bone-mineral disease state as well as in predicting the risk of developing vascular calcification and hence, arterial stiffness. Aims This study aimed to assess arterial stiffness in maintenance hemodialysis patients using pulse wave analysis as an index of central and peripheral arterial stiffness and serum procollagen type I N-terminal propeptide (P1NP) as a marker for bone turnover. Patients and methods Fifty ESRD patients aged 18 years old or more who have been assigned to regular long-term hemodialysis were included in this study and subjected to complete history taking and physical examination and laboratory investigations including lipid profile, fasting plasma glucose level (mg/dl), serum creatinine, blood urea (mg/dl), serum phosphorus (mg/dl), serum calcium (mg/dl), P1NP (ng/ml), serum parathyroid hormone (PTH) (pg/ml), and serum bone-specific alkaline phosphatase (BALP) (U/l), and aortic pulse wave velocity. Results There was significant positive correlation between P1NP and PTH (P≤0.01) and between BALP and serum PTH (P≤0.01). There was significant difference between patients with low and high augmentation index regarding BALP (P=0.018). Conclusion ESRD patients have a high prevalence of vascular stiffness assessed by pulse wave analysis. There is a significant correlation between BALP and PTH and between P1NP and PTH. There is a relation between markers of bone formation and vascular stiffness.

Vertebral Fractures in Type 2 Diabetes Patients: Utility of Trabecular Bone Score and Relationship With Serum Bone Turnover Biomarkers

Background: Patients with type 2 diabetes (T2D) have an increased risk for vertebral fracture (VF). The aim of this study is to determine the utility of trabecular bone score (TBS) in T2D patients with VF and the relationship of TBS with serum bone turnover biomarkers (SBTBs). Methodology: Postmenopausal T2D female patients were prospectively enrolled. All patients received: (1) dual-energy X-ray absorptiometry exam for bone mineral density (BMD), T-score, and TBS values; (2) lateral lumbar spine radiographs for VF assessment; and (3) SBTBs: bone specific alkaline phosphatase and Beta-C-Terminal telopeptides. BMD, T-score, TBS, and SBTBs were tested for association with VF. Results: The study included 285 T2D patients (mean age = 61.1 years) and 32 patients had VF (11.2%). TBS had the strongest association with VF in T2D patients (area under curve 0.775). The TBS cutoff values for VF are 1.279 in T-score ≥1 and 1.236 in T-score <−1. In patients without VF, all sites of BMD and TBS are significantly associated with SBTBs, but in patients with VF, no associations are found between SBTBs and all sites of BMD and TBS. Conclusions: TBS can assess bone quality in the spine. The low TBS cutoff values for T2D patients with VF imply T2D does impair bone quality. Thus, TBS should be incorporated in VF risk assessment in T2D patients. In addition, a dissociated relationship between BMD and TBS with SBTBs represents imbalanced bone turnover rate and results in bone fragility and VF.

Anthocyanin-rich extract from black rice (Oryza sativa L. Japonica) ameliorates diabetic osteoporosis in rats.

Diabetic osteoporosis (DOP) is a systemic endocrine-metabolic osteopathy which has the characteristics of bone mineral density (BMD) reduction and bone microstructural destruction. Although anthocyanin-rich extract from black rice (AEBR) was reported to have a beneficial effect on diabetic rats, no studies have been performed on whether black rice anthocyanins are beneficial for diabetic osteoporosis. Therefore, in this study, a streptozotocin-induced diabetic rat model was established to investigate the protective effect of AEBR on diabetes-induced osteoporosis and its possible mechanism. AEBR at three doses (0.5, 1.0, and 2.0 g kg-1 d-1) were administered by oral gavage to diabetic rats for 8 weeks. The blood glucose, BMD, bone histomorphometry parameters, serum bone turnover biomarkers, bone marrow adipocyte numbers, as well as osteoprotegerin (OPG), runt-related transcription factor 2 (RUNX 2), and receptor activator of nuclear factor-κ B ligand (RANKL) protein expression in bone and serum were detected. The results indicated that AEBR dose-dependently decreased the blood glucose, increased the BMD, and decreased the serum bone turnover markers. The bone microstructure and osteoclast numbers in bone tissues returned to normal in the high AEBR dosage group; at the same time, the AEBR dose-dependently suppressed bone marrow adipogenesis. The RUNX 2 as well as the OPG/RANKL ratio in diabetic rats' bone tissues increased significantly in the AEBR treatment group. Our results indicate that AEBR administration can ameliorate bone loss caused by diabetes; this is mainly attributed to its inhibition of bone turnover, suppression of bone marrow adipogenesis, and up-regulation of RUNX 2 and the OPG/RANKL expression ratio.

Studies of indirect and direct effects of hypervitaminosis A on rat bone by comparing free access to food and pair-feeding

Background: The most prominent features of hypervitaminosis A in rats are spontaneous fractures and anorexia. Since caloric restriction induces alterations in bone, some effects could be secondary to loss of appetite. To clarify the mechanisms behind vitamin A-induced bone fragility it is necessary to distinguish between direct and indirect effects.Materials and methods: In this study we compared rats fed high doses of vitamin A both with pair-fed controls, which were fed the same amount of chow as that consumed by the vitamin A group to keep food intake the same, and to controls with free access to food.Results: In contrast to the pair-fed animals, rats in the free access group fed high doses of vitamin A for 7 days had 13% lower food intake, 15% lower body weight, and 2.7% shorter femurs compared with controls. In addition, serum biomarkers of bone turnover were reduced. Peripheral quantitative computed tomography of the femurs showed that the bone mineral content, cross sectional area, and periosteal circumference were similarly reduced in the pair-fed and free access groups. However, bone mineral density (BMD) and cortical parameters were only significantly decreased in the free access group.Conclusions: Our data indicate that the major direct short-term effect of high doses of vitamin A on rat bone is a reduced bone diameter, whereas the effects on bone length, serum biomarkers of bone turnover, BMD, and bone cortex appear to be mainly indirect, caused by a systemic toxicity with loss of appetite, reduced food intake, and general effects on growth.

A High-Fat Diet Decreases Bone Mass in Growing Mice with Systemic Chronic Inflammation Induced by Low-Dose, Slow-Release Lipopolysaccharide Pellets

Background: Chronic inflammation is associated with increased bone resorption and is linked to osteopenia, or low bone mass. Obesity is also associated with low-grade chronic upregulation of inflammatory cytokines.Objective: This study investigated the effect of high-fat (HF) diet-induced obesity on bone structure changes in growing mice with existing systemic chronic inflammation induced by low-dose, slow-release lipopolysaccharide (LPS).Methods: Forty-eight 6-wk-old female C57BL/6 mice were randomly assigned to 4 treatment groups (n = 12/group) in a 2 × 2 factorial design-control (placebo) or LPS treatment (1.5 μg/d)-and consumed either a normal-fat (NF, 10% of energy as fat) or an HF (45% of energy as fat) diet ad libitum for 13 wk. Bone structure, serum biomarkers of bone turnover, and osteoclast differentiation were measured.Results: No alterations were observed in final body weights, fat mass, or lean mass in response to LPS treatment. LPS treatment increased serum concentration of tartrate-resistant acid phosphatase (TRAP, a bone resorption marker) and bone marrow osteoclast differentiation and decreased femoral and lumbar vertebral bone volume (BV):total volume (TV) by 25% and 24%, respectively, compared with the placebo. Mice fed the HF diet had greater body weight at the end of the study (P < 0.01) due to increased fat mass (P < 0.01) than did mice fed the NF diet. The HF diet increased serum TRAP concentration, bone marrow osteoclast differentiation, and expression of tumor necrosis factor α, interleukin 1β and interleukin 6 in adipose tissue. Compared with the NF diet, the HF diet decreased BV:TV by 10% and 8% at femur and lumbar vertebrae, respectively, and the HF diet was detrimental to femoral and lumbar vertebral bone structure with decreased trabecular number and increased trabecular separation and structure model index.Conclusion: Results suggest that HF diets and systemic chronic inflammation have independent negative effects on bone structure in mice.

Serum bone-turnover biomarkers are associated with the occurrence of peripheral and axial arthritis in psoriatic disease: a prospective cross-sectional comparative study

BackgroundA recent systematic review identified four candidate serum-soluble bone-turnover biomarkers (dickkopf-1, Dkk-1; macrophage-colony stimulating factor, M-CSF; matrix metalloproteinase-3, MMP-3; osteoprotegerin, OPG) showing possible association with psoriatic arthritis (PsA). We aimed to: (i) confirm and determine if these four biomarkers are associated with PsA; (ii) differentiate psoriasis cases with and without arthritis; and (iii) differentiate PsA cases with and without axial arthritis.MethodsA prospective cross-sectional comparative two-centre study recruited 200 patients with psoriasis without arthritis (PsC), 127 with PsA without axial arthritis (pPsA), 117 with PsA with axial arthritis (psoriatic spondyloarthritis, PsSpA), 157 with ankylosing spondylitis (AS) without psoriasis, and 50 matched healthy controls (HC). Serum biomarker concentrations were measured using ELISA. Multivariable regression and receiver operating characteristic analyses were performed.ResultsMMP-3 concentrations were significantly higher and M-CSF significantly lower in each arthritis disease group compared with HC (p ≤ 0.02). MMP-3 concentrations were significantly higher (adjusted odds ratio, ORadj 1.02 per ng/ml increase in concentration; p = 0.0004) and M-CSF significantly lower (ORadj 0.44 per ng/ml increase; p = 0.01) in PsA (pPsA and PsSpA combined) compared with PsC. Dkk-1 concentrations were significantly higher (ORadj 1.22 per ng/mL increase; p = 0.01), and OPG concentrations significantly lower (ORadj 0.20 per ng/mL increase; p = 0.02) in patients with axial arthritis (PsSpA and AS combined) than in those without (pPsA). Furthermore, Dkk-1 concentrations were significantly higher along a spectrum of increasing axial arthritis; Dkk-1 concentrations were higher in AS compared with PsSpA (ORadj 1.18 per ng/mL increase; p = 0.02). Receiver operating characteristic analysis showed MMP-3 to be the best single biomarker for differentiating PsA from PsC (AUC 0.70 for a cut-off of 14.51 ng/mL; sensitivity 0.76, specificity 0.60).ConclusionsMMP-3 and M-CSF are biomarkers for the presence of arthritis in psoriatic disease, and could therefore be used to screen for PsA in psoriasis cohorts. Dkk-1 and OPG are biomarkers of axial arthritis; they could therefore be used to screen for the presence of axial disease in PsA cases, and help differentiate PsSpA from AS. High concentrations of Dkk-1 in AS and PsSpA compared with HC, support previous reports that Dkk-1 is dysfunctional in the spondyloarthritides.

Role of APOE Gene in Bone Mineral Density and Incidence of Bone Fractures in Brazilian Postmenopausal Women

Osteoporosis is one of the major diseases that affects mostly postmenopausal women. Despite being a multifactorial disease, some genes have been shown to play an important role in osteoporosis. Bone mineral density (BMD) is still largely used to diagnose it, although many other biomarkers are used to better follow the disease onset. It has been shown that the apolipoprotein E (APOE) gene could be a biomarker for risk of fractures as well as to predict lower BMD in patients with osteoporosis. The human APOE gene encodes 3 protein isoforms called ApoE2, ApoE3, and ApoE4, resulting in 4 possible genotypes, because they are a product of a single nucleotide polymorphism found in this gene. So far, the APOE4 allele has been associated with low BMD in postmenopausal women and to incidence of bone breaking in older women. This study aimed to investigate the role of ApoE isoforms in a cohort of 413 postmenopausal Brazilian women. These patients were randomly recruited, clinically examined, and subjected to dual-energy X-ray absorptiometry to measure their BMD. Patients were further grouped as normal BMD (T-score < 0.5) or low BMD (T-score > 1.0, osteopenic or osteoporotic). Patients with osteopenia or osteoporosis were further genotyped for APOE alleles as well as tested for many serum bone turnover biomarkers. Our data showed that presence of the APOE3 allele was associated with both higher BMDs and higher serum concentrations of osteocalcin and alkaline phosphatase, biomarkers for bone formation. On the other hand, the APOE2 and APOE4 alleles were associated with lower BMD as well as higher levels of serum C-terminus collagen peptide and urinary deoxipyridinolines, biomarkers for bone resorption. However, these effects on lower BMD and bone resorption biomarkers observed in either APOE2 or APOE4 alleles were eliminated when patients' genotype carried the APOE3 allele. Codominance of the APOE3 allele was also associated with lesser cases of bone fractures in these patients within a 5-year follow-up. In conclusion, our data show that APOE4 may be associated with lower bone formation as well as increased risk of osteoporosis and bone fractures, whereas APOE3 seems to decrease lowering BMD in postmenopausal women, and its presence seemed to lower the incidence of bone breaking in patients with osteoporosis.

Pain prediction by serum biomarkers of bone turnover in people with knee osteoarthritis: an observational study of TRAcP5b and cathepsin K in OA

To investigate serum biomarkers, tartrate resistant acid phosphatase 5b (TRAcP5b) and cathepsin K (cath-K), indicative of osteoclastic bone resorption, and their relationship to pain and pain change in knee osteoarthritis (OA). Sera and clinical data were collected from 129 people (97 with 3-year follow-up) with knee OA from the Prediction of Osteoarthritis Progression (POP) cohort. Knee OA-related outcomes in POP included: WOMAC pain, National Health and Nutrition Examination Survey (NHANES) I (pain, aching and stiffness), subchondral sclerosis, and radiographically determined tibiofemoral and patellofemoral OA. Two putative osteoclast biomarkers were measured in sera: TRAcP5b and cath-K. Medial tibia plateaux were donated at knee arthroplasty for symptomatic OA (n=84) or from 16 post mortem (PM) controls from the Arthritis Research UK (ARUK) Pain Centre joint tissue repository. Osteoclasts were stained for tartrate resistant acid phosphatase (TRAcP) within the subchondral bone of the medial tibia plateaux. Serum TRAcP5b activity, but not cath-K-immunoreactivity, was associated with density of TRAcP-positive osteoclasts in the subchondral bone of medial tibia plateaux. TRAcP-positive osteoclasts were more abundant in people with symptomatic OA compared to controls. Serum TRAcP5b activity was associated with baseline pain and pain change. Our observations support a role for subchondral osteoclast activity in the generation of OA pain. Serum TRAcP5b might be a clinically relevant biomarker of disease activity in OA.

Prospective cohort study of the risk factors for stress fractures in Chinese male infantry recruits.

ObjectiveTo determine potential risk factors that could predict stress fractures over an 8-week basic military training in Chinese male infantry recruits.MethodsRecruits from three infantry units enrolled in this prospective study. At baseline, demographic data, personal history of stress fractures, mean duration of weekly exercise and smoking history were recorded on questionnaires and blood samples taken for analysis of bone turnover biomarkers and genetic factors.ResultsOf the 1516 male recruits who volunteered to participate in the study, 1398 recruits provided data for analysis. In total, 189 stress fracture cases were observed (incidence rate: 13.5%) during the 8-week training period. Recruits with stress fractures had a significantly higher incidence of prior fracture history and lower exercise level prior to enrolment compared with those without stress fractures. A significant difference in both allelic frequency and genotypic distribution of the growth differentiation factor 5 (GDF5) gene rs143383 polymorphism was observed between recruits with and without stress fractures. However, no difference in serum bone turnover biomarkers was detected between groups.ConclusionThis prospective, cohort study indicates that fracture history, lower exercise level and GDF5 rs143383 may be predictive risk factors for stress fractures in Chinese male infantry recruits.

Bone turnover biomarkers and risk of osteoporotic hip fracture in an Asian population

While epidemiologic studies suggest that bone turnover biomarkers may predict hip fracture risk, findings are inconsistent and Asian data are lacking. We conducted a matched case–control (1:1) study nested in the Singapore Chinese Health Study, a population-based prospective cohort of Chinese men and women (45–74years) recruited from 1993 to 1998 in Singapore. One hundred cases with incident hip fracture and 100 individually matched controls were randomly selected from 63,257 participants. Serum bone turnover biomarkers, namely bone alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), N-terminal and C-terminal crosslinking telopeptide of type I collagen (NTX-I and CTX-I) were measured using immunoassays. Hip fracture cases had significantly higher serum levels of OC, PINP, CTX-I and NTX-I than controls (p<0.05). There was a dose-dependent positive relationship between OC, PINP, CTX-I and NTX-I and risk of hip fracture (all Ps for trend≤0.006), where the risk was significantly increased by 4.32–8.23 folds for the respective BTM [Quartile (Q) 4 vs. Q1]. The odds ratio [OR (95% CI)] at the highest quartile (Q4) was 6.63 (2.02–21.18) for PINP and 4.92 (1.67–14.51) for CTX-I. The joint effect of PINP and CTX-I showed a 7-fold increase in risk (OR: 7.36; 95% CI: 2.53–21.41) comparing participants with higher levels of PINP (Q4) and CTX-I (Q3–Q4) to those with low levels of PINP (Q1–Q3) and CTX-I (Q1–Q2). Our data demonstrated that higher serum levels of bone turnover biomarkers were associated with increased risk of hip fracture in an Asian population.