Biomarkers Of Bone Resorption Research Articles

Antioxidant Supplementation Does Not Affect Bone Turnover Markers During 60 Days of 6° Head-Down Tilt Bed Rest: Results from an Exploratory Randomized Controlled Trial.

Immobilization and related oxidative stress are associated with bone loss. Antioxidants like polyphenols, omega-3 fatty acids, vitamins, and micronutrients may mitigate these negative effects on bone metabolism through scavenging of free radicals. We hypothesized that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR) would reduce bone resorption and increase bone formation compared to nonsupplemented controls. This exploratory randomized, controlled, single-blind intervention study conducted in a parallel design included 20 healthy male volunteers (age, 34± 8 years; weight, 74± 6kg). The study consisted of a 14-day adaptation phase [baseline data collection (BDC)], followed by 60 days of HDBR and a 14-day recovery period (R). In the antioxidant group, volunteers received an antioxidant cocktail (741mg/d polyphenols, 2.1g/d omega-3 fatty acids, 168mg/d vitamin E, and 80μg/d selenium) with their daily meals. In the control group, volunteers received no supplement. Based on their body weight, all volunteers received an individually tailored and strictly controlled diet, consistent with DRIs. We analyzed biomarkers of calcium homeostasis, bone formation, and bone resorption during BDC, HDBR, and R, as well as for 30 days after the end of HDBR. Data were analyzed by linear mixed models. The antioxidant supplement did not affect serum calcium, parathyroid hormone, urinary C-telopeptide of type I collagen (CTX), urinary N-telopeptide of type I collagen, serum β-C-telopeptide of type I collagen (β-CTX), bone alkaline phosphatase, aminoterminal propeptide of type I collagen, osteocalcin, or urinary calcium excretion. In both groups, typical bed rest-related changes were observed. Supplementation of an antioxidant cocktail to a diet matching the DRIs did not affect bone resorption or formation during 60 days of HDBR in healthy young men. This trial was registered at clinicaltrials.gov as NCT03594799.

Amelioration of bone fragility by pulsed electromagnetic fields in type 2 diabetic KK-Ay mice involving Wnt/β-catenin signaling.

Type 2 diabetes mellitus (T2DM) results in compromised bone microstructure and quality, and subsequently increased risks of fractures. However, it still lacks safe and effective approaches resisting T2DM bone fragility. Pulsed electromagnetic fields (PEMFs) exposure has proven to be effective in accelerating fracture healing and attenuating osteopenia/osteoporosis induced by estrogen deficiency. Nevertheless, whether and how PEMFs resist T2DM-associated bone deterioration remain not fully identified. The KK-Ay mouse was used as the T2DM model. We found that PEMF stimulation with 2 h/day for 8 wk remarkably improved trabecular bone microarchitecture, decreased cortical bone porosity, and promoted trabecular and cortical bone material properties in KK-Ay mice. PEMF stimulated bone formation in KK-Ay mice, as evidenced by increased serum levels of bone formation (osteocalcin and P1NP), enhanced bone formation rate, and increased osteoblast number. PEMF significantly suppressed osteocytic apoptosis and sclerostin expression in KK-Ay mice. PEMF exerted beneficial effects on osteoblast- and osteocyte-related gene expression in the skeleton of KK-Ay mice. Nevertheless, PEMF exerted no effect on serum biomarkers of bone resorption (TRAcP5b and CTX-1), osteoclast number, or osteoclast-specific gene expression (TRAP and cathepsin K). PEMF upregulated gene expression of canonical Wnt ligands (including Wnt1, Wnt3a, and Wnt10b), but not noncanonical Wnt5a. PEMF also upregulated skeletal protein expression of downstream p-GSK-3β and β-catenin in KK-Ay mice. Moreover, PEMF-induced improvement in bone microstructure, mechanical strength, and bone formation in KK-Ay mice was abolished after intragastric administration with the Wnt antagonist ETC-159. Together, our results suggest that PEMF can improve bone microarchitecture and quality by enhancing the biological activities of osteoblasts and osteocytes, which are associated with the activation of the Wnt/β-catenin signaling pathway. PEMF might become an effective countermeasure against T2DM-induced bone deterioration.NEW & NOTEWORTHY PEMF improved trabecular bone microarchitecture and suppressed cortical bone porosity in T2DM KK-Ay mice. It attenuated T2DM-induced detrimental consequence on trabecular and cortical bone material properties. PEMF resisted bone deterioration in KK-Ay mice by enhancing osteoblast-mediated bone formation. PEMF also significantly suppressed osteocytic apoptosis and sclerostin expression in KK-Ay mice. The therapeutic potential of PEMF on T2DM-induced bone deterioration was associated with the activation of Wnt/ß-catenin signaling.

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study.

Simple SummaryCarfilzomib with dexamethasone is an important therapeutic option for patients with relapsed/refractory multiple myeloma. We sought to evaluate the effect of this regimen on the bone-related outcomes, which are associated with both quality of life and survival. Among 25 patients, less than one third experienced a new skeletal-related event during treatment, even in the absence of any bone-targeted agent. Interestingly, there was a significant decrease in serum biomarkers of bone resorption, which was at least partially due to the sRANKL/OPG ratio reduction. Furthermore, Kd produced an increase in markers of bone formation. Importantly, these changes were independent of myeloma response to treatment. Therefore, the combination of carfilzomib and dexamethasone improves bone metabolism and bone health in patients with advanced multiple myeloma.Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.

Bone resorption and dietary calcium in pregnancy-a window to future maternal bone health.

Pregnancy is characterized by increased bone turnover and reversible loss of bone mineral density (BMD) to meet fetal calcium demands. The long-term effect of bone turnover and maternal diet in pregnancy on maternal bone is not well established. We aimed to determine if an association exists between [1] bone resorption, [2] dietary calcium, and [3] serum 25-hydroxyvitamin D in pregnancy with maternal BMD 5-year postpartum. This is a prospective, longitudinal study of 107 women recruited to the ROLO low glycemic index dietary intervention trial in pregnancy and followed-up at 13, 28, and 34weeks' gestation and 5years' postpartum. At 13 and 28weeks' gestation, a biomarker of bone resorption, urine cross-linked N-telopeptide of type I collagen (uNTX), was measured. At the 5-year follow-up BMD was measured using dual-energy X-ray absorptiometry. Anthropometry, dietary intakes, and serum 25-hydroxyvitamin D were measured in pregnancy and at 5years. Multiple linear regression, controlling for confounders, was used for analysis. Mean BMD at 5years was 1.208g/cm2. In pregnancy, 24-34% reported dietary calcium intakes <800mg/day. Vitamin D deficiency (< 30nmol/L) was observed in 38-41% of women in pregnancy and in 29% of women at the 5-year follow-up. At 13 and 28weeks' gestation, uNTX levels greater than the median were associated with 0.060 and 0.050g/cm2 lower BMD 5years later, respectively. Dietary calcium <800mg/day in trimester 3 was associated with 0.072g/cm2 lower BMD 5years later. Vitamin D deficiency at 5years, but not in pregnancy, was associated with lower BMD. Higher bone resorption and low dietary calcium in pregnancy were associated with lower BMD 5years later. These findings could enable the identification of women at risk of declining of BMD in later life, but further research is needed. Adequate dietary calcium should be advised in the antenatal setting to promote lifelong maternal bone health.

Synergistic antitumor efficacy of radium-223 and enzalutamide in the intratibial LNCaP prostate cancer xenograft model.

105 Background: Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces DNA double-strand breaks in cancer cells, osteoblasts and osteoclasts. It is used for treating men with castration-resistant prostate cancer (CRPC) and bone metastases. Enzalutamide (enza) is a second-generation androgen receptor inhibitor also used for treating the same patient population, and the combination of Ra-223 and enza is currently being investigated in clinical trials. We evaluated the antitumor efficacy of Ra-223 and enza in the LNCaP intratibial model mimicking prostate cancer metastasized to bone. Previously, additive or synergistic antitumor effects were not observed when Ra-223 was combined with abiraterone and prednisone in the LNCaP model (Suominen et al., AACR 2020). Methods: LNCaP prostate cancer cells were inoculated into the right tibia of male NOD.scid mice. The mice were randomized (n = 9/group) based on serum PSA and treated with vehicle, Ra-223 (330 kBq/kg, i.v., Q4W x 2), enza (30 mg/kg, p.o., QD) or with a combination treatment of Ra-223 and enza, for 28 days. Serum PSA levels were analyzed at the end of the study and compared to the pre-treatment levels. Serum bone formation and resorption biomarkers, PINP and CTX, respectively, were measured during the study. Tumor-induced abnormal bone area and Ra-223 uptake were determined by X-ray and gamma counter, respectively. The healthy tibiae were evaluated by microCT. Results: Combination treatment showed synergistic antitumor efficacy as observed by lower PSA levels when compared to the vehicle, Ra-223 or enza monotherapies (p = 0.04, p = 0.008 and p = 0.002, respectively). A statistical interaction between Ra-223 and enza treatments was found (p = 0.003), confirming the synergistic effect. In combination treatment, the serum PSA change relative to pre-treatment levels was 18% of the vehicle. Accordingly, a decreasing trend (p = 0.08) in tumor-induced abnormal bone changes was associated with the combination treatment in the tumor-bearing tibiae (46% of the vehicle), whereas no changes in total bone structure/quality were observed in the healthy tibiae. Compared to monotherapies, the combination treatment had the most prominent lowering effect on the bone metabolism biomarkers PINP and CTX during the study. Concurrent administration of enza with Ra-223 did not affect Ra-223 uptake in tumor-bearing tibiae. Conclusions: Compared to Ra-223 and enza monotherapies, the combination treatment demonstrated synergistic antitumor efficacy by decreasing PSA levels in the LNCaP intratibial model. Despite of prominent effects on tumor growth, the combination treatment was not observed to compromise bone health in the healthy tibiae. In conclusion, these preclinical results support the ongoing phase 3 trials PEACE III (NCT02194842) &amp; ESCALATE (NCT04237584) of this combination.

U.S. Montmorency Tart Cherry Juice Decreases Bone Resorption in Women Aged 65-80 Years.

Pre-clinical studies have demonstrated that tart cherries, rich in hydroxycinnamic acids and anthocyanins, protect against age-related and inflammation-induced bone loss. This study examined how daily consumption of Montmorency tart cherry juice (TC) alters biomarkers of bone metabolism in older women. Healthy women, aged 65–80 years (n = 27), were randomly assigned to consume ~240 mL (8 fl. oz.) of juice once (TC1X) or twice (TC2X) per day for 90 d. Dual-energy x-ray absorptiometry (DXA) scans were performed to determine bone density at baseline, and pre- and post-treatment serum biomarkers of bone formation and resorption, vitamin D, inflammation, and oxidative stress were assessed. Irrespective of osteoporosis risk, the bone resorption marker, tartrate resistant acid phosphatase type 5b, was significantly reduced with the TC2X dose compared to baseline, but not with the TC1X dose. In terms of indicators of bone formation and turnover, neither serum bone-specific alkaline phosphatase nor osteocalcin were altered. No changes in thiobarbituric acid reactive substances or high sensitivity C-reactive protein were observed in response to either TC1X or TC2X. We conclude that short-term supplementation with the higher dose of tart cherry juice decreased bone resorption from baseline without altering bone formation and turnover biomarkers in this cohort.

Circulating MiR-21 expression is upregulated after 30days of head-down tilt bed rest.

Circulating miRNAs (c-miRNAs) have potential as biomarkers of cellular activity, and they may play a role in cell-to-cell communication. The purpose of this study was to examine c-miRNA and bone marker responses to a 30-day six-degree head-down bed rest protocol at an ambient 0.5% CO2. Eleven participants (6 males/5 females, 25-50years) had fasting blood draws taken 3days before and immediately after completing the 30-day bed rest protocol at the Institute for Aerospace Medicine in Germany. Serum relative expression of miRNAs associated with bone function (miR-21-5p, -100-5p, -125b-5p, -126-3p) were analyzed using qPCR, and serum bone markers were quantitated using ELISA. Serum bone markers, sclerostin, and calcium significantly increased (p ≤ 0.036), and total hip aBMD significantly decreased (p = 0.003) post bed rest. Serum miR-21-5p relative expression was significantly upregulated (p = 0.018) post bed rest. Fold changes in miR-126-3p (r = 0.82, p = 0.002) and miR-21-5p (r = 0.62, p = 0.042) were positively correlated with absolute change in serum calcium. There were no sex differences in miRNA responses; women had greater percent increases in TRAP5b (37.3% vs. 16.9% p = 0.021) and greater percent decreases in total hip aBMD (- 2.15% vs. - 0.69%, p = 0.034) than men. c-miR-21-5p has potential as a biomarker of bone resorption and bone loss in an unloading condition. The upregulation of miR-21-5p may reflect an increase in osteoclast activity after bed rest, which is corroborated by the increase in TRAP5b.

Chloroquine ameliorates bone loss induced by d-galactose in male rats via inhibition of ERK associated osteoclastogenesis and antioxidant effect.

Chloroquine (CQ); a lysosomotropic agent used for decade ago as anti-malarial, was tested against aging induced osteoporosis. Osteoporosis in male rats was induced using d-galactose (D-gal) as a reducing sugar at a dose of 200 mg/kg/day; i.p. Osteoporotic rats were orally treated with CQ (10 mg/kg/day) for four successive weeks. Bone densitometry of tibia and femur were evaluated. Bone formation biomarkers; osteoprotegrin (OPG), bone specific alkaline phosphatse (BALP), and osteocalcin (OCN), and bone resorption biomarker; receptor activator of nuclear factor kappa-B ligand (RANKL), cathepsin-k (CTSK), tartrate-resistant acid phosphatase (TRAP) were estimated. Moreover, the expression of extracellular regulated kinase (ERK) in bone was determined. CQ ameliorated the bone detrimental changes induced by d-galactose. It enhanced bone health as revealed by measurement of bone densitometry, halted the activation of receptor activator of nuclear factor kappa-B ligand (RANKL) and reduced bone manifestation of ERK. Furthermore, CQ treatment abated serum cathepsin-k (CTSK) and serum tartrate-resistant acid phosphatase (TRAP) thus inhibited osteoclastogenesis and consequently restored the RANKL/OPG ratio. CQ demonstrated an antioxidant effect in bone where it increased both Catalase (CAT) and Superoxide dismutase (SOD). These CQ preserving effect in rats treated with d-galactose were confirmed by the histopathological examination. The present study points to the potential therapeutic effect of CQ as anti-osteoporotic agent possibly through its antioxidant effects and suppression of ERK associated osteoclastogenesis.

Associations between bone turnover markers and bone mineral density in older adults.

To examine the associations between bone turnover markers (BTMs) and bone mineral density (BMD) in older adults aged 60-85 years. A total of 1124 men (mean age, 69.1 years) and 1203 women (mean age, 70.7 years) from the National Health and Nutrition Examination Survey 1999-2002 were included in this cross-sectional analysis. Independent variables were serum bone-specific alkaline phosphatase (sBAP) and urinary N-telopeptide (uNTx), which are biomarkers of bone formation and resorption, respectively. Outcome variable was lumbar BMD. The associations of sBAP and uNTx levels with lumbar BMD was examined using multivariable linear regression models. sBAP was negatively associated with lumbar BMD in each multivariable linear regression model, and this negative association was stable in both men and women men (men: β = -0.0028, 95% CI: -0.0046 to -0.0010; women: β = -0.0039, 95% CI: -0.0054 to -0.0023). On the other hand, uNTx was negatively associated with lumbar BMD after adjustment of relevant covariables (β = -0.0328, 95% CI: -0.0523 to -0.0133). However, in the subgroup analysis stratified by gender, this negative association remained only in older women (β = -0.0491, 95% CI: -0.0751 to -0.0231). Our study suggested that elevated sBAP and uNTX levels correlated with decreased lumbar BMD, especially in older women. This finding indicated that maintaining BTMs at low levels may be beneficial to bone health for older adults.

Effects of acute synovitis experimentally induced by amphotericin-b on the biomarkers of camel joint structures

The major objective of this study was to evaluate the effects of acute synovitis on the joint structures (bone, articular cartilage and synovial membrane) through the evaluation of biomarkers of bone, cartilage and synovial membrane in dromedary camels. Acute synovitis was experimentally induced by injecting amphotericin-B (20 mg in 4 ml sterilised distilled water) in the intercarpal joints of eight dromedary camels (treatment group) and other eight camels were used as a control group. Synovial fluid samples were collected prior to injection and 7, 14, 21 and 28 days post injection. Inflammatory biomarkers (Prostaglandin E2) and biomarkers of bone (bone alkaline phosphatase, osteocalcin and pyridinum cross-links) and cartilage (Chondroitin sulfate 846 epitope, C-terminal propeptide of type II procollagen, sulfated glycosaminoglycans and hyaluronan) were determined in the synovial fluid samples. The results showed significant elevations in the inflammatory, articular cartilage and bone biomarkers in the synovial fluid from the treatment group compared to the controls. Elevations of bone resorption and formation biomarkers were late in compare to cartilage biomarkers. This study proved that amphotericin B is an appropriate drug to induce synovitis in the camel joints when injected intra-articular. According to the results of biomarker analysis, it can be concluded that cartilage degradation proceeds bone degradation in camel joint with synovitis. Within articular cartilage tissue, proteoglycan synthesis proceeds type II collagen formation.

Normative data of the urinary bone resorption biomarkers for osteoporosis DPD, CTx and NTx among females in Manipur and its correlation with bone mineral density measured by DEXA scan

Introduction: Osteoporosis has become a major public health problem affecting more than 100 million people worldwide. Standard diagnosis depends on measuring bone mineral density (BMD) using a dual energy X-ray absorptiometry (DEXA). Bone turnover markers are metabolic products that mediate bone metabolism and can provide information regarding bone formation or resorption before the structural changes of bone occur. BMD and bone markers complement each other, and provide comprehensive information about a patient’s bone status and bone activity. Aim: To find the correlation between selected urinary bone turnover markers and bone mineral density measured by DEXA scan. Materials and Methods: A cross sectional study was conducted among 2700 pre and post-menopausal women with intact ovaries aged between 21 to 70 years in three districts of Manipur. Performance of three urinary markers of bone turnover, i.e., Deoxypyridinoline (DPD), N-telopeptide (NTx) and C-telopeptide (CTx) were assessed and correlated with the bone mineral density (T-score) measured by DEXA scan. Results: Significant correlation was found between DEXA T-score and NTx (r=0.070, p= Conclusion: It can be concluded that there is significant correlation between DEXA T-score and NTx, but not for DPD and CTx. Clinical Significance: In the management of osteoporosis, bone markers can be used for determining the response to anti-resorptive treatment, amongnst which NTx of collagen-I may be suggested to assess bone resorption for Manipuri women. Keywords: Cross sectional study, DEXA, Deoxypyridinoline, C- telopeptide, N- telopeptide, Osteoporosis.

Initial displacement of the intra-articular surface after articular fracture correlates with PTA in C57BL/6 mice but not "superhealer" MRL/MpJ mice.

Posttraumatic arthritis (PTA) occurs commonly after articular fracture and may arise, in part, from joint surface incongruity after injury. MRL/MpJ (MRL) "super-healer" mice are protected from PTA compared to C57BL/6 (B6) mice following articular fracture. However, the relationship between the initial displacement of the articular surface, biologic response, and susceptibility to PTA after fracture remains unclear. The objective of this study was to assess whether joint incongruity after articular fracture, as measured by in vivo micro-computed tomography (microCT), could predict pathomechanisms of PTA in mice. B6 and MRL mice (n = 12/strain) received a closed articular fracture (fx) of the left tibial plateau. Articular incongruity was quantified as bone surface deviations (BSD) for each in vivo microCT scan obtained from pre-fx to 8 weeks post-fx, followed by histologic assessment of arthritis. Serum concentrations of bone formation (PINP) and bone resorption (CTX-I) biomarkers were quantified longitudinally. Both strains showed increases in surface incongruity over time, as measured by increases in BSD. In B6 mice, acute surface incongruity was significantly correlated to the severity of PTA (R 2 = 0.988; p = .0006), but not in MRL mice (R 2 = 0.224; p = .220). PINP concentrations significantly decreased immediately post-fx in B6 mice (p = .023) but not in MRL mice, indicating higher bone synthesis in MRL mice. MRL/MpJ mice demonstrate a unique biologic response to articular fracture such that the observed articular bone surface displacement does not correlate with the severity of subsequent PTA. Clinical Relevance: Identifying therapies to enhance acute biologic repair following articular fracture may mitigate the risk of articular surface displacement for PTA.

Bone Geometry, Density, Microstructure, and Biomechanical Properties in the Distal Tibia in Patients With Primary Hypertrophic Osteoarthropathy Assessed by Second-Generation High-Resolution Peripheral Quantitative Computed Tomography.

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L1 -L4 ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E2 (PGE2 ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (β-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE2 , biomarkers of bone resorption (β-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE2 level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR).

Clinical efficiency of combined pharmacotherapy of сoronary artery disease associated with postmenopausal osteoporosis

The aim of the study. To evaluate the clinical efficacy of combined pharmacotherapy with alendronate sodium and exogenous L-arginine on the background of basic treatment of patients with coronary artery disease (CAD) associated with postmenopausal osteoporosis (PMOP).Material and methods. A double open, prospective, monocentric clinical study in parallel groups involved 58 women in the postmenopausal period with a diagnosis of coronary artery disease: stable angina pectoris II-III FC, who had PMOP (age 71 (65; 77) years). By the method of block randomization, patients were divided into two groups: 1 group – 27 women who received standard basic therapy; 2 group – 31 women who were prescribed a combination of alendronate sodium and L-arginine hydrochloride according to the scheme on the background of basic treatment. The indices of daily ECG monitoring by Holter, structural and functional state of the heart and blood vessels assessment, levels of biomarkers (osteoprotegerin, osteocalcin, homocysteine, VEGF-A) assessment in patients were obtained at study entry and after 3 months of therapy.Results. According to the results of daily ECG monitoring in the dynamics of treatment in patients of both groups there was a significant decrease in the number of episodes of supraventricular arrhythmia per day (by 11.54% and 34.52%, respectively; p&lt;0.05) and the ratio of LF / HF in active and passive period. In patients of group 2 in contrast to group 1, there was also a significant decrease in the number of episodes of tachycardia per day (1.8 times; p&lt;0.05), an increase in RMSSD (by 74.36%; p&lt;0.05), a decrease in LF (by 54.69%; p&lt;0.05) and an increase in HF (by 73.71%; p&lt;0.05) in both active and passive periods. After 3 months of treatment in patients of the 2nd group showed a significant decrease in the IMC thickness of the right CA by 7.95%, the size of the LP by 16.83% compared to baseline (p&lt;0.05), while the 1st group no significant changes in these indicators were observed. Under the influence of treatment in patients of the 2nd group revealed a significant decrease in the level of VEGF-A (by 25.41%; p&lt;0.05), homocysteine (by 10.72%; p&lt;0.05), osteoprotegerin (2 times ; p&lt;0.05), while in patients of the 1st group there was a significant decrease only in the level of VEGF-A (by 20.09%; p&lt;0.05). In patients of group 2 compared with patients of group 1, after 3 months of treatment there were significantly fewer episodes of ventricular and supraventricular arrhythmias, smaller LF meaning, IMC, LA size and greater HF meaning, probably lower levels of osteocalcin, VEGF-A and osteoprotegerin.Conclusions. The use of combined therapy in patients with coronary artery disease, comorbid with PMOP, contributes to positive changes in the autonomic regulation of cardiac activity, structural adjustment of the heart and vascular endothelium, normalization of the balance of biomarkers of osteoreparation and bone resorption.

The Role of Recombinant Parathormone derivative in Bone healing. Making the Unfavorable, Favorable - A Systematic Review

Background: Teriparatide is a recombinant parathormone derivative encompassing the first 1-34 amino acids off PTH, which is said to contain potent anabolic capability. It is said to induce osteoblastogenesis thereby placing an essential role in bone healing. The aim of this systematic review is to evaluate the best available evidence from randomized controlled trials analyzing the effectiveness of teriparatide on bone regeneration and healing in osteoporotic patients and patients with fractures. Aim: This systematic review aims to assess whether Teriparatide enhances bone regeneration and healing in terms of improving clinical, radiographic, histologic parameters and Biomarkers of Bone formation and resorption. Materials and Methodology: A comprehensive search was done in databases such as ‘PubMed’, ‘Google Scholar and ‘Cochrane’ databases based on pre-determined eligibility criteria. Randomized control trials assessing the effectiveness of Teriparatide in Bone healing in fractures as well as osteoporosis were selected after thorough screening. Results: The selected 13 studies compared teriparatide to either placebo or another anti-resorptive drug. Out of the 13, 8 studies were done to evaluate the improvement and healing of bone in Osteoporotic patients whereas 5 studies were done on improvement in fracture healing. The studies evaluated outcome parameters such as Clinical and Radiological improvement, Biomarkers of Bone resorption and formation and Safety.6 studies assessed clinical parameters, 12 studies assessed radiological parameters, 7 studies assessed biomarkers, 11 studies assessed safety parameters by means of occurrence of any adverse effects. All the 8 studies done on osteoporotic patients showed a good improvement. Of the 5 studies on fracture healing, only 2 studies showed beneficial effects while the other 3 did not show any benefits. Conclusion: Teriparatide could have beneficial effects in bone healing in osteoporotic patients and is well tolerated. However, the results are inconclusive whether they have beneficial effects in treating fractures. More Homogenous Randomized control trials are required to ascertain whether teriparatide could improve bone healing.

The Effect of Physical Activity on Bone Biomarkers in People With Osteoporosis: A Systematic Review

BackgroundBone imbalance between anabolic and catabolic processes at the level of remodeling unit due to the prevalence of resorbing activity, represents a health problem of aging. The consequence is the negative balance of bone turnover that can lead to osteoporosis. Physical activity (PA) can play a central role in the comprehensive management of osteoporosis, since it induces the anabolism of bone tissue. Bone turnover biomarkers, reflecting the cellular activity linked to bone metabolism, can represent an evaluation tool to assess the efficacy of PA in the osteoporotic population. The aim of this systematic review, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, was to investigate the effects of PA interventions on bone biomarkers in people with osteoporosis.MethodsA comprehensive literature search of electronic databases was conducted through PubMed, Cochrane, Cinahl, Embase, Trip, to find randomized controlled trials (RCTs) investigating the topic of PA and bone turnover biomarkers in the osteoporosis population. In accordance with the Cochrane risk-of-bias tool, the quality of each study was assessed.ResultsOut of 992 identified articles, 136 full texts were screened. Only three RTCs matched the eligibility criteria. In one study, sub-maximal aerobic exercise improved Bone-specific alkaline phosphatase (bone formation biomarker) and Amino-terminal Crosslinked Telopeptide of type 1 collagen (bone resorption biomarker) in osteoporotic women. The other two studies showed a positive effect on total alkaline phosphatase (a non-specific bone formation biomarker) in women with osteoporosis.ConclusionThe systematic review revealed possible exercise benefits in terms of improving bone formation and decreasing bone resorption biomarkers in the osteoporotic population. However, these results should be interpreted with caution, especially due to the limited number and poor quality of the studies included. Further research is needed to estimate the influence of PA on bone biomarkers in the osteoporosis management.

Association between the Metabolome and Bone Mineral Density in Chinese

Background: Osteoporosis is a common metabolic bone disease, which always leads to osteoporotic fractures especially among the elderly. Biomarkers of bone mineral density (BMD) are helpful for prevention and early diagnosis of osteoporosis. This study aims to identify metabolomic biomarkers of low BMD. Methods: We included 701 participants who had BMD measures by dual-energy X-ray absorptiometry scans and donated fasting plasma samples from three clinical centers as a discovery set and another 278 participants from the fourth center as an independent replication set. We used a liquid chromatography-mass spectrometry-based metabolomics approach to profile the global circulating metabolites. Results: Among the 265 named metabolites identified in our study, six were associated with low BMD (FDR-adjusted P <0.05) in the discovery set and were successfully validated in the independent replication set. The circulating levels of five metabolites, i.e., inosine, hypoxanthine, PC(O-18:0/22:6), SM(d18:1/21:0) and isoleucyl-proline were associated with decreased odds of low BMD, and PC(16:0/18:3) level was associated with increased odds of low BMD. Per one standard deviation increase in a composite metabolite score of these six metabolites was associated with about half decreased odds of low BMD (odds ratio 0.59, 95% confidence interval: 0.52-0.68). Furthermore, introduction of a panel of metabolites selected by elastic net regression to a prediction model of classical risk factors and plasma biomarker of bone resorption substantially improved the prediction performance for low BMD (AUCs: 0.782 vs. 0.698, P =0.002). Conclusions: Metabolomics profiling may help identify novel biomarkers of low BMD and be helpful for early diagnosis of osteoporosis beyond the current clinical index. Funding Statement: This study was supported by the National Key R&D Program of China [2018YFC2001500 to J.S.], the National Natural Science Foundation of China [Key Program, 91749204 to J.S.], the National Natural Science Foundation of China [General Program, 81771491 to J.S.], the Project of Shanghai Subject Chief Scientist [2017BR011 to J.S.], Grants from the TCM Supported Project [18431902300 to J.S.] from the Science and Technology Commission of Shanghai Municipality, and the National Natural Science Foundation of China [General Program, 81972089 to Z.X.]. Y.Z. was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, Shanghai Municipal Science and Technology Major Project [2017SHZDZX01 to Y.Z.], and the National Natural Science Foundation of China [81973032]. Declaration of Interests: The authors have nothing to disclose. The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the ethics committee at each center and conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Bone turnover biomarkers in COPD patients randomized to either a regular or shortened course of corticosteroids: a substudy of the randomized controlled CORTICO-COP trial

BackgroundLong-term treatment with corticosteroids causes loss of bone density, but the effects of using short-term high-dose systemic-corticosteroid therapy to treat acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are unclear. Our aim was to determine whether high-dose corticosteroid therapy affected bone turnover markers (BTMs) to a greater extent compared to low-dose corticosteroid therapy.MethodsThe CORTICO-COP trial (NCT02857842) showed that an eosinophil-guided corticosteroid intervention led to approximately 60% lower accumulated corticosteroid dose for hospitalized patients with AECOPD (low-dose group) compared with 5-day standard corticosteroid treatment (high-dose group). We compared the levels of BTMs C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) in 318 participants during AECOPD and at 1- and 3-month follow-up visits.ResultsCTX decreased and P1NP increased significantly over time in both treatment groups. There were no significant differences between the groups at 1- or 3-months follow-up for P1NP. A significant drop in CTX was seen at 3 months (down Δ24% from the baseline, p = 0.017) for the high dose group.ConclusionShort-term, high-dose systemic corticosteroid treatment caused a rapid suppression of biomarkers of bone resorption. Corticosteroids did not suppress biomarkers of bone formation, regardless of patients receiving low or high doses of corticosteroids. This therapy was, therefore, harmless in terms of bone safety, in our prospective series of COPD patients.Trial registrationClinicalTrials.gov Identifier: NCT02857842. Submitted August 2nd, 2016.

Association between non-alcoholic fatty liver disease-associated hepatic fibrosis and bone mineral density in postmenopausal women with type 2 diabetes or impaired glucose regulation

IntroductionTo evaluate the association of non-alcoholic fatty liver disease (NAFLD)-associated hepatic fibrosis with bone mineral density (BMD) in postmenopausal women with type 2 diabetes mellitus (T2DM) or impaired glucose regulation...

Blocking CCN2 preferentially inhibits osteoclastogenesis induced by repetitive high force bone loading

ABSTRACT Purpose/Aim: We recently found that blocking CCN2 signaling using a monoclonal antibody (FG-3019) may be a novel therapeutic strategy for reducing overuse-induced tissue fibrosis. Since CCN2 plays roles in osteoclastogenesis, and persistent performance of a high repetition high force (HRHF) lever pulling task results in a loss in trabecular bone volume in the radius, we examined here whether blocking CCN2 signaling would reduce the early catabolic effects of performing a HRHF task for 3 weeks. Materials and Methods: Young adult, female, Sprague-Dawley rats were operantly shaped to learn to pull at high force levels, before performing the HRHF task for 3 weeks. HRHF task rats were then left untreated (HRHF Untreated), treated in task weeks 2 and 3 with a monoclonal antibody that antagonizes CCN2 (HRHF+FG-3019), or treated with an IgG (HRHF+IgG), while continuing to perform the task. Non-task control rats were left untreated. Results: In metaphyseal trabeculae of the distal radius, HRHF Untreated and HRHF-IgG rats showed increased osteoblast numbers and other indices of bone formation, compared to controls, yet decreased trabecular bone volume, increased osteoclast numbers, and increased serum CTX-1 (a serum biomarker of bone resorption). HRHF+FG-3019 rats also showed increased osteoblast numbers and bone formation, but in contrast to HRHF Untreated and HRHF-IgG rats, showed higher trabecular bone volume, and reduced osteoclast numbers and serum CTX-1 levels (and statistically similar to Control levels). Conclusions: HRHF loading increased bone formation in each task group, yet blocking CCN2 dampened trabecular bone catabolism by reducing osteoclast numbers and activity.