Serum Bone Turnover Markers Research Articles

Silencing Hoxa2 reverses dexamethasone-induced dysfunction of MC3T3-E1 osteoblasts and osteoporosis in rats

Osteoporosis is damaging the health of women worldwide. Osteoporosis results from the imbalance between bone resorption and formation, which may be regulated by homeobox A2 (Hoxa2). However, the specific role and mechanism of Hoxa2 in osteogenesis and dexamethasone (Dex)-induced osteoporosis remain unknown. The present study investigated the effect of Hoxa2 on differentiation and osteoblastogenesis. Alkaline phosphatase staining and immunofluorescence staining were performed to evaluate the differentiation of MC3T3-E1 cells. Runt-related transcription factor 2 (Runx2), osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) in Dex stimulated osteoblastic MC3T3-E1 cells, and Dex-induced osteoporotic rats were estimated using western blot and quantitative polymerase chain reaction (qPCR). Serum markers of bone turnover were determined using enzyme-linked immunosorbent assay (ELISA). Trabecular bones of femur tissues were observed using hematoxylin and eosin (H&E) staining. Hoxa2 short hairpin RNA significantly promoted the differentiation of MC3T3-E1 cells and expression of Runx2 and OPG in Dex-treated MC3T3-E1 cells and osteoporotic rats but inhibited the expression of RANKL. Furthermore, silencing Hoxa2 resulted in the upregulation of bone alkaline phosphatase but suppressed the expression of tartrate-resistant acid phosphatase and C-terminal cross-linked telopeptides of type I collagen. Silencing Hoxa2 reversed the Dex-induced inhibition of osteoblastogenesis by modulating Runx2 and RANK-RANKL-OPG axis.

Longitudinal Analysis of Circulating Markers of Bone Turnover Across Multiple Decades in Osteoporotic Women

The objective of this study was to analyze changes in serum markers of bone turnover across multiple decades in osteoporotic women compared with nonosteoporotic controls, to determine their utility as potential predictors for osteoporosis. Early prediction of those at risk for osteoporosis can enable early intervention before the irreversible loss of critical bone mass. Serum samples were obtained from 20 women given the diagnosis of osteoporosis after age 46 years and 20 age-matched women with normal bone mineral density from 4 time points in their life (ages 25-31, 32-38, 39-45, and 46-60 years). Serum levels of bone turnover markers (propeptide of type I collagen, parathyroid hormone, bone-specific alkaline phosphatase, osteocalcin, C-terminal telopeptide of type I collagen, sclerostin, osteoprotegerin, osteopontin, and 25-OH vitamin D) were measured using commercially available arrays and kits. We used logistic regression to assess these individual serum markers as potential predictors of osteoporosis, and mixed-effects modeling to assess the change in bone turnover markers between osteoporotic and control groups over time, then performed fivefold cross-validation to assess the classification ability of the models. Markers of bone turnover, bone-specific alkaline phosphatase, C-terminal telopeptide of type I collagen, sclerostin, and osteocalcin were all independent predictors at multiple time points; osteopontin was an independent predictor in the 39- to 45-year age group. Receiver operating characteristic analyses demonstrated moderately strong classification ability at all time points. Sclerostin levels among groups diverged over time and were higher in the control group than the osteoporotic group, with significant differences observed at time points 3 and4. Serum markers of bone turnover may be used to estimate the likelihood of osteoporosis development in individuals over time. Although prospective validation is necessary before recommending widespread clinical use, this information may be used to identify patients at risk for developing low bone mineral density long before traditional screening would ostensibly take place. Diagnostic II.

Uncoupled bone remodeling is characteristic of bone damage in premenopausal women with new-onset systemic lupus erythematosus.

To investigate the mechanism underlying systemic lupus erythematosus (SLE)-related bone loss by evaluating the bone mineral density (BMD) and bone turnover markers (BTMs) in premenopausal patients with new-onset SLE without any treatment. BMD and BTMs of 106 premenopausal patients with new-onset SLE and 64 gender-, age- and body mass index (BMI)-matched healthy controls were analyzed. BMD was determined using dual energy X-ray absorptiometry (DXA). Serum BTMs were measured. Hip and lumbar spine BMD in premenopausal patients with new-onset SLE was significantly decreased compared with healthy controls. Higher rate of osteoporosis was observed in new-onset SLE patients (25% vs. 1%). Moreover, uncoupled bone remodeling evidenced by an increase in bone resorption marker β-CTX (685.9 ± 709.6 pg/mL vs. 395.4 ± 326.0 pg/mL, P < 0.05) and decrease in bone formation markers PINP (37.4 ± 33.0 ng/mL vs. 46.1 ± 20.9 ng/mL, P < 0.05) and OC (11.4 ± 9.8 ng/mL vs. 18.2 ± 8.6 ng/mL, P < 0.05) was observed in premenopausal patients with new-onset SLE compared with healthy controls. Univariate correlation analyses showed negative correlations between OC and SLE Disease Activity Index (SLEDAI), and positive correlations between β-CTX and SLEDAI. SLE patients positive for dsDNA, nucleosome showed lower OC and higher β-CTX. Premenopausal patients with new-onset SLE had decreased BMD and abnormal bone metabolism with increased β-CTX and decreased OC and P1NP levels, indicating uncoupled bone remodeling in new-onset SLE patients. Disease activity and abnormal immunity, especially the amount of antibodies in SLE patients, were strongly associated with abnormality of bone metabolism.

Growth hormone replacement may influence the biological action of thyroid hormone on liver and bone tissue

ObjectiveGrowth hormone (GH) replacement alters the peripheral interconversion of thyroxine (T4) and triiodothyronine (T3). However, little is known about the clinical impact of these alterations. We aimed to compare changes observed in the serum T3:T4 ratio with known biological markers of thyroid hormone action derived from different peripheral tissues. DesignWe prospectively studied twenty GH deficient men before and after GH replacement in a tertiary referral endocrine center. Serum biochemical measurements included insulin like growth factor-1 (IGF-1), thyroid hormones (free & total T3, free & total T4 and reverse T3) and TSH. Changes in thyroid hormone concentration were compared to alterations in hepatic and bone biomarkers of thyroid hormone action. ResultsGH replacement provoked a decline in serum free T4 concentration (−1.09 ± 1.99 pmol/L; p = 0.02) and an increase in free T3 (+0.34 ± 0.15 pmol/L; p = 0.03); therefore, the free T3:free T4 ratio increased from 0.40 ± 0.02 to 0.47 ± 0.02 (p = 0.002). Sex hormone binding globulin (SHBG) level was unchanged. However, a decline in serum ferritin (−26.6 ± 8.5 ng/mL; p = 0.005) correlated with a fall in freeT4. Alterations in lipid profile, including a rise in large HDL sub-fractions and Lp (a) (+2.1 ± 21.1 nmol/L; p = 0.002) did not correlate with thyroid hormone levels. Significant increases were recorded in serum bone turnover markers - procollagen type 1 amino-terminal propeptide +57.4%; p = 0.0009, osteocalcin +48.6%; p = 0.0007; c-terminal telopeptides of type 1 collagen +73.7%; p = 0.002. Changes in bone formation markers occurred in parallel with fluctuations in thyroid hormone. ConclusionGH-induced alterations in the thyroid axis are associated with complex, tissue specific effects on thyroid hormone action. Modulation of bone turnover markers suggests that GH may improve the biological action of thyroid hormone on bone.

Denosumab Reduces Lesional Fluoride Skeletal Burden on Na[18F]F PET-CT in Patients With Fibrous Dysplasia/McCune-Albright Syndrome.

ContextThe correlation between fibrous dysplasia/McCune–Albright syndrome (FD/MAS) skeletal disease burden on Na[18F]F positron emission tomography–computed tomography (PET-CT) and serum bone turnover markers (BTMs) was recently described. The effect of treatment on lesional fluoride burden in FD/MAS is unknown.ObjectiveTo investigate treatment response measurements in patients with FD/MAS who underwent Na[18F]F-PET-CT and treatment with antiresorptives.MethodsObservational case series at an academic center of expertise for rare bone diseases. Fifteen consecutive patients were observed with FD/MAS with baseline and follow-up Na[18F]F-PET-CT parameters of healthy bone and FD lesions, BTMs, and pain scores at start of denosumab (n = 8) treatment and non-denosumab patients (n = 7). On Na[18F]F-PET-CT the volumetric measures of FD burden (fluoride tumor volume [FTV]) and “fraction affected skeleton” (FAS) represented the portion of the skeleton affected. This was correlated with BTMs and pain.ResultsDisease activity decreased significantly, with FTV 361 cm3 to 97 cm3 (P = .018) in denosumab-treated patients, but not in non-denosumab patients (P = .249). Serum P1NP and alkaline phosphatase (ALP) decreased significantly: 82 ng/mL vs 55 ng/mL (P = .023) and 119 IU/L vs 84 IU/L (P = .020), respectively. In denosumab-treated patients pain scores improved leading to pain medication reduction. This correlated with lesional uptake, but healthy bone activity did not change. BTMs and FTV correlated positively (P1NP r = 0.730, P < .001; and ALP r = 0.406, P = .006), as did change in BTMs and FTV: P1NP (P = 0.032) and ALP (P = 0.024). FAS strongly correlated with treatment-induced decrease in ALP (P = .027) and P1NP (P = .009).ConclusionNa[18F]F-PET-CT captured treatment-induced lesional changes which correlated with BTMs and pain reduction. Therefore Na[18F]F-PET-CT can be used as an objective local parameter of response to denosumab treatment in FD/MAS.

The effects of antiepileptic drugs on bone health: A systematic review

PurposeEpilepsy may be treated with antiepileptic drugs (AEDs), which have been reported to decrease bone mineral density (BMD). Current data is conflicting and variable, and little is known with regard to how duration of AED use or specific AEDs, such as CYP-450 enzyme-inducing (EIAEDs) versus non-enzyme inducing (NEIAEDs) drugs affect BMD. We sought to systematically review BMD changes due to AED use to identify trends in reporting. MethodsA literature search via Medline (PubMed), EMBASE, and Cochrane databases was performed. Peer-reviewed articles were identified that reported on BMD measurements in conjunction with AEDs. ResultsTwenty-six studies met inclusion criteria. Long-term therapy was shown across multiple, well-controlled studies to have the most significant BMD loss. Carbamazepine had the most frequent reporting of unfavorable effects on bone health and Lamotrigine seemed to show the most bone-protective qualities. Serum biochemical markers of bone turnover did not significantly correlate with measured BMD changes. ConclusionThe present study provides evidence that long-term AED therapy is the most significant risk factor for BMD loss. Furthermore, there was little compelling evidence to support that EIAEDs, as a class, were more harmful to bone than NEIAEDs, which has been previously suggested in multiple studies. Early clinical concern for significant loss of BMD may not be warranted as lower BMD was less likely to be observed during the initial years of AED therapy. Furthermore, serum markers of bone turnover are not clinically reliable in assessing BMD changes in patients taking AEDs.

The use of bone turnover markers for monitoring the treatment of osteoporosis in postmenopausal females undergoing total knee arthroplasty: a prospective randomized study

BackgroundOsteoporosis (OP) and osteoarthritis (OA) commonly coexist in postmenopausal females. The decrease in bone density and increase in bone resorption in postmenopausal females with OP may consequently affect the surgical outcome of total knee arthroplasty (TKA). However, clinicians often ignore monitoring the treatment of OP in the perioperative management of TKA. Bone turnover marker (BTM) can timely and accurately reflect bone metabolism to monitor the treatment of OP. The purpose of this study was to investigate the effect of BTM monitoring to guide the treatment of OP in postmenopausal females undergoing TKA.MethodsPostmenopausal females with OP who underwent primary unilateral TKA were randomly divided into two groups (monitoring group and control group), given oral medication (alendronate, calcitriol, and calcium), and followed for 1 year. In the monitoring group, serum BTMs (C-telopeptide of type I collagen (CTX-I), N-terminal propeptide of type I procollagen (PINP), and 25(OH)D) were assessed preoperatively and repeated postoperatively; alendronate was withdrawn when CTX-I and PINP reached the reference interval; and calcitriol and calcium were withdrawn when 25(OH)D reached the reference interval. In the control group, oral medication was implemented for a uniform duration of 3 months. During the 1-year follow-up, the mean maximum total point motion (MTPM) of the tibial component, bone mineral density (BMD), visual analog scale (VAS) score, range of motion, and Oxford Knee Score (OKS) score were obtained.ResultsIn the monitoring group, BTM monitoring prolonged the medication duration, but did not cause more adverse reactions than in the control group. The mean MTPM values at 6 m and 12 m in the monitoring group were lower than those in the control group, and the BMD at 12 m in the monitoring group was significantly higher than that in the control group. Patients in the monitoring group had lower VAS scores at 6 m and higher OKS scores at 6 m and 12 m than those in the control group.ConclusionIn postmenopausal females with osteoporosis undergoing primary TKA, the application of BTM monitoring to guide the treatment of osteoporosis can enhance bone density, maintain prosthesis stability, and improve surgical outcome.Trial registrationChiCTR ChiCTR-INR-17010495. Registered on 22 January 2017

Relevant genetic variants are common in women with pregnancy and lactation-associated osteoporosis (PLO) and predispose to more severe clinical manifestations.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare skeletal disorder characterized by early-onset osteoporosis typically manifestating with vertebral compression fractures or transient osteoporosis of the hip. We hypothesized that genetic variants may play a role in the development of PLO. This study aimed to analyze the presence of genetic variants and a potential association with the clinical presentation in PLO. 42 women with PLO were included from 2013 to 2019 in a multicenter study in Germany. All cases underwent comprehensive genetic analysis based on a custom-designed gene panel including genes relevant for skeletal disorders. The skeletal status was assessed using dual-energy X-ray absorptiometry (DXA). Subgroups were further analyzed by serum bone turnover markers (n=31) and high-resolution peripheral computed tomography (HR-pQCT; n=23). We detected relevant genetic variants in 21 women (50%), with LRP5, WNT1 and COL1A1/A2 being the most commonly involved genes. The mean number of vertebral compression fractures was 3.3±3.4 per case with a significantly higher occurrence in the subgroup with genetic variants (4.8±3.7 vs. 1.8±2.3, p=0.02). Among the total cohort, DXA Z-scores were significantly lower at the lumbar spine compared to the femoral neck (p=0.002). HR-pQCT revealed a pronounced reduction of trabecular and cortical thickness, while trabecular number was within the reference range. Eighteen women (43%) received a bone-specific therapy (primarily teriparatide). Overall, a steep increase in bone mass (+37.7%) was observed after 3years. In conclusion, pregnancy and lactation represent skeletal risk factors, which may unmask hereditary bone disorders leading to PLO. These cases were affected more severely. Nevertheless, a timely diagnosis and adequate treatment can ensure a substantial recovery potential even without specific therapy. Patients with genetically induced low bone turnover (e.g.; LRP5, WNT1) may especially benefit from osteo-anabolic medication.

Effects of competitive physical activity on serum irisin levels and bone turnover markers

BackgroundIrisin, a myokine, is a polypeptide derived from the cleavage of the extracellular domain of fibronectin domain-containing protein 5, a receptor that is present on different tissues (skeletal muscle, pericardium, myocardium, and brain), whose functions are not yet fully defined.PurposeThe main aim of our study was to evaluate the effect of competitive physical activity on serum irisin levels and bone turnover markers.MethodsFifteen male footballers and an equal number of subjects of the same age and gender, but with a predominantly sedentary lifestyle, had their serum levels of irisin and bone turnover markers measured. Bone mineral status was evaluated in both groups by quantitative bone ultrasound of the calcaneus. In addition, only in footballers, biochemical analyses were repeated after 3 months.ResultsWe did not observe significant differences in the serum levels of calcium, phosphorus, and parathyroid hormone between the two groups. The footballers had significantly higher quantitative bone ultrasound, 25-OH vitamin D, and creatinine values than the controls. There were also no significant differences in the bone alkaline phosphatase, carboxy-terminal telopeptide of type I collagen, osteoprotegerin, sclerostin or Dkk-1 values, while the irisin levels (+ 89%, p < 0.001) and RANKL were significantly higher in the footballers compared to those in the controls.ConclusionOur study shows that footballers have significantly higher serum irisin values than the general population. Irisin could be the "trait d’union" between bone health and physical activity.

Association of Bone Mineral Density to Cerebral Small Vessel Disease Burden.

To test the hypothesis that bone mineral loss is mechanistically related to cerebral small vessel disease (SVD), we investigated the relationship between bone mineral density and the prevalence and intensity of SVD among patients with stroke. We analyzed data of 1,190 consecutive patients with stroke who were >50 years of age and underwent both brain MRI and dual-energy x-ray absorptiometry from the stroke registry of Chung-Ang University Hospital in Seoul, Korea. The patients were categorized into 3 groups according to their bone mineral density (normal, osteopenia, and osteoporosis). White matter hyperintensities, silent lacunes, cerebral microbleeds, and extensive perivascular space were assessed from brain MRI. Multinomial logistic regression model was used to examine the association between osteoporosis and total SVD score. We also recruited 70 patients with stroke to study serum bone turnover markers and microRNAs related to both cerebral atherosclerosis and bone metabolism to understand bone and brain interaction. Osteoporosis was determined among 284 patients (23.9%), and 450 patients (37.8%) had osteopenia. As bone mineral density decreased, total SVD score and the incidence of every SVD phenotype increased except strictly lobar cerebral microbleeds. Multinomial logistic regression analysis showed that osteoporosis was independently associated with severe SVD burden. The levels of microRNA-378f were significantly increased among the patients with osteoporosis and maximal total SVD score and positively correlated with parathyroid hormone and osteocalcin. These findings suggest a pathophysiologic link between bone mineral loss and hypertensive cerebral arteriolar degeneration, possibly mediated by circulating microRNA.

Correlation between Serum Bone Turnover Markers and Estimated Glomerular Filtration Rate in Chinese Patients with Diabetes.

Objective Diabetes is a growing global public health concern with many significant disease complications. Multiple studies show that bone turnover markers (BTMs) are decreased in diabetes patients, indicating impaired bone metabolism in diabetes patients. A recent study also showed that in diabetes patients, BTMs are correlated with urine albumin to creatinine ratio, an indicator of nephropathy. However, whether BTMs are correlated with estimated glomerular filtration rate (eGFR) in diabetes remains unknown. This retrospective study accessed correlations between serum BTMs and eGFR in Chinese patients with diabetes and compare levels of BTMs and eGFR between diabetic patients and healthy individuals. Methods This study analyzed data from 221 diabetic patients (include type1 and type 2 diabetes) and 155 healthy individuals. Serum BTM levels and eGFR were compared between diabetic patients and healthy individuals. Pearson correlation analysis was used to assess correlations between BTMs and eGFR. Multiple logistic regression analysis adjusted for gender and age was performed to measure odd ratio (OR) and 95% confidence interval (95% CI) of BTMs on diabetes. Results Patients with diabetes had significant lower 25-hydroxyvitamin D (25(OH)D) levels (15.07 ± 6.20 ng/mL) than healthy group (17.89 ± 6.41 ng/mL) (P < 0.05). For patients with diabetes, eGFR was negatively correlated with osteocalcin (OC) (r = −0.434, P < 0.05), procollagen type 1 intact N-terminal propeptide (P1NP) (r = −0.350, P < 0.05), and β-carboxy-terminal cross-linking telopeptide of type I collagen (β-CTX) (r = −0.179, P < 0.05) levels. For healthy people, eGFR was negatively correlated with 25(OH)D (r = −0.290, P < 0.05) levels. Multiple logistic regression analysis adjusted for age and gender (mean age of diabetes was 64.9 years and the percentage of female was 66.9%, mean age of healthy people was 48.4 years and the percentage of female was 37.4%) showed that 25(OH)D (OR = 0.909, 95%CI = 0.862 − 0.959, P < 0.05) was protective factors for diabetes. Conclusions In the stage of diabetic nephropathy, bone turnover may accelerate. It is important to detect BTMs in the stage of diabetic nephropathy.

MiR-29c-3p reduces bone loss in rats with diabetic osteoporosis via targeted regulation of Dvl2 expression.

The aim of this study was to investigate the influence of micro ribonucleic acid (miR)-29c-3p on rats with diabetic osteoporosis (DOP) and its underlying mechanism. A total of 30 specific pathogen-free (SPF)-grade male Wistar rats aged 6-week-old were randomly selected and divided into three groups according to different intervention means, including: NC group (control rats only injected with normal saline), DOP group (rats with DOP induced by injection of streptozotocin), and ME group (DOP rats injected with miR-29c-3p agonist for 4 consecutive weeks). The changes in blood glucose and body weight were recorded in the rats of each group every week. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the content of bone turnover markers (BTMs) in serum, such as alkaline phosphatase (ALP), osteocalcin (OC), and procollagen type I N-terminal propeptide (PINP). The variations in serum calcium (Ca) and phosphorus (P) levels in the abdominal aorta were determined using an atomic absorption spectrometer in the three groups. Meanwhile, bone mineral density (BMD) of femur and lumbar vertebra (L1-L4) were examined. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the changes in messenger RNA (mRNA) expressions of miR-29c-3p and Disheveled 2 (Dvl2) in the bone tissues of intervened rats. In addition, the staining and expression changes of Dvl2 protein in bone tissues were determined via immunohistochemistry. The rats in NC group had normal behavioral activities, normally increased body weight, sensitive responses, as well as normal and stable blood glucose. In DOP group, the rats manifested clinical symptoms of diabetes mellitus (DM) (i.e., polydipsia, polyphagia, polyuria, and weight loss), lackluster hairs, decreased behavioral activities, slow responses, and blood glucose at a concentration higher than 16.7 mmol/L. However, the blood glucose rose first, and then, declined and it was maintained at a level higher than normal concentration in ME group. Meanwhile, the rate of weight loss significantly decreased. The results of qRT-PCR indicated that the relative expression level of miR-29c-3p in bone tissues of DOP group was remarkably lower than that in NC group (p<0.01). However, it was significantly higher in ME group than that in DOP group (p<0.05). DOP group exhibited significantly upregulated serum BTMs (ALP, CTX-1, OC, TRACP-5b, and PIPN) when compared with NC group (p<0.05) and ME group (p<0.05). Furthermore, femoral BMD decreased in DOP group (p<0.05) while increased in ME group, showing statistically significant difference between the two groups (p<0.05). Immunohistochemistry results indicated that the bone tissues of DOP rats were deeply stained, and protein expression of Dvl2 protein was significantly higher in comparison with NC group. The bone tissues were lightly stained in ME group, and the protein expression of Dvl2 was lower than that in DOP group. Besides, qRT-PCR results demonstrated that the mRNA expression changes of Dvl2 were consistent with its protein expression trends. MiR-29c-3p reduces bone loss in rats with DOP via targeted regulation of Dvl2 expression.

Bone Mineral Density and Bone Turnover 10 Years After a Single 5 mg Dose or Two 5-Yearly Lower Doses of Zoledronate in Osteopenic Older Women: An Open-Label Extension of a Randomized Controlled Trial.

Intravenous zoledronate reduces fracture risk (5 mg at 18-month intervals) and prevents bone loss (doses of 1 to 5 mg for 3 to >5 years), but the duration of action of a single 5 mg dose and the effects of lower doses beyond 5 years are unknown. We report the second open-label extension (years 5 to 10) of a 2-year randomized, multidose, placebo-controlled, double-blinded trial. A total of 116 older women who completed 5 years of participation either continued observation without further treatment (zoledronate 5 mg and placebo at baseline) or received repeat doses of 1 or 2.5 mg zoledronate (zoledronate 1 mg and zoledronate 2.5 mg at baseline, respectively). Outcomes were spine, hip, and total body bone mineral density (BMD) and serum markers of bone turnover. After a single 5 mg dose of zoledronate, mean BMD at the lumbar spine and total hip was maintained at or above baseline levels for 9 and 10 years, respectively. The mean level of the bone resorption marker β-C-terminal telopeptide of type I collagen (β-CTX) was at least 25% lower than that in the placebo group for 9 years. In women administered 5-yearly doses of 2.5 mg zoledronate, mean BMD at the total hip and lumbar spine was maintained at or above baseline levels for 9 and 10 years, respectively. Redosing with 1 or 2.5 mg zoledronate at 5 years reduced bone turnover markers for 3 to 4 years. BMD increased for 3 to 4 years after redosing with 1 mg zoledronate. In the group given 5-yearly 2.5 mg zoledronate, β-CTX was at least 20% lower than that in the placebo group for 10 years. Both a single baseline 5 mg dose of zoledronate and 5-yearly doses of 1 and 2.5 mg zoledronate prevented bone loss at hip and spine for 8 to 10 years in older postmenopausal women. Clinical trials to evaluate the effects on fracture risk of these very infrequent and lower doses of zoledronate are justified. © 2021 American Society for Bone and Mineral Research (ASBMR).

Components of the Gut Microbiome That Influence Bone Tissue-Level Strength.

Modifications to the constituents of the gut microbiome influence bone density and tissue-level strength, but the specific microbial components that influence tissue-level strength in bone are not known. Here, we selectively modify constituents of the gut microbiota using narrow-spectrum antibiotics to identify components of the microbiome associated with changes in bone mechanical and material properties. Male C57BL/6J mice (4 weeks) were divided into seven groups (n=7-10/group) and had taxa within the gut microbiome removed through dosing with: (i) ampicillin; (ii) neomycin; (iii) vancomycin; (iv) metronidazole; (v) a cocktail of all four antibiotics together (with zero-calorie sweetener to ensure intake); (vi) zero-calorie sweetener only; or (vii) no additive (untreated) for 12 weeks. Individual antibiotics remove only some taxa from the gut, while the cocktail of all four removes almost all microbes. After accounting for differences in geometry, whole bone strength was reduced in animals with gut microbiome modified by neomycin (-28%, p=0.002) and was increased in the group in which the gut microbiome was altered by sweetener alone (+39%, p < 0.001). Analysis of the fecal microbiota detected seven lower-ranked taxa differentially abundant in animals with impaired tissue-level strength and 14 differentially abundant taxa associated with increased tissue-level strength. Histological and serum markers of bone turnover and trabecular bone volume per tissue volume (BV/TV) did not differ among groups. These findings demonstrate that modifications to the taxonomic components of the gut microbiome have the potential to decrease or increase tissue-level strength of bone independent of bone quantity and without noticeable changes in bone turnover. © 2021 American Society for Bone and Mineral Research (ASBMR).

Association between gut microbiota, bone metabolism, and fracture risk in postmenopausal Japanese women

IntroductionWe investigated the relationship between gut microbiota composition and osteoporosis/fracture risk in Japanese postmenopausal women using 16S rRNA gene sequencing, FRAX, bone mineral density, biochemical bone parameters, and a self-administered questionnaire. Variation in abundance of specific microbiota was found to be significantly associated with fracture risk and vitamin K levels.Gut microbiota data with respect to bone metabolism and fracture risk is limited. Vitamin K is produced by certain intestinal bacteria and has been reported to play a role in maintaining bone quality.PurposeWe investigated relationships among gut microbiota composition, bone metabolism, and fracture risk in postmenopausal Japanese women.MethodsBone mineral density (BMD) was evaluated in 38 postmenopausal women (mean age 62.9 years) using forearm dual-energy X-ray absorptiometry. We collected and analyzed serum bone turnover markers (vitamin K fraction and tartrate-resistant acid phosphatase 5b; TRACP-5b), gut microbiota profiling (16S rRNA gene sequencing), and self-administered questionnaire data, including fracture history and vitamin K intake. Vitamin K2, BMD, and TRACP-5b data were divided into high- and low-level groups using cutoff values of 0.06 ng/mL, 87.05%, and 420 mU/dL, respectively; the proportions of bacteria were analyzed. Fracture incidence and relative risk were investigated for each bacterium.ResultsThe genus Bacteroides was predominant in the high vitamin K2 group (29.73% vs 21.58%, P = 0.022). Fracture incidence was significantly higher in the low Bacteroides group, with a 5.6-times higher risk ratio of fracture history.The family Rikenellaceae was more abundant in the low BMD group and more abundant in the high TRACP-5b group (2.15% vs 0.82%, P = 0.004; 2.38% vs 1.12%, P = 0.013, respectively).ConclusionBacteroides and Rikenellaceae may be involved in bone metabolism and fracture risk. Further investigations of the underlying microbiota-related pathways in bone metabolism may reveal treatment strategies, and facilitate the prevention of osteoporosis.

The Effect of Bisphosphonates on Managing Osteoporosis After Spinal Cord Injury: A Meta-Analysis.

The increased bone loss after spinal cord injury (SCI) is associated with an increase in the morbidity and mortality of fragility fractures, which can constitute a substantial cost to health care systems. Bisphosphonates (BPs) are now the principal class of medications used for osteoporosis. To demonstrate the effect of BPs on treating osteoporosis after SCI. A comprehensive search in PubMed, EMBASE, Web of Science and Cochrane Central databases was undertaken for randomized controlled trials (RCTs), exploring the effect of BPs on osteoporosis after SCI. The primary outcome measures were the BMD of different locations, serum bone turnover marker levels, serum biochemistry marker levels and adverse effect (AE) risks. The final search was performed in September 2019. Reporting was carried out according to PRISMA Guidelines. Six RCTs were included. A total of 147 patients met the inclusion criteria. BPs were found to statistically prevent bone loss in the total hip, femoral neck and trochanter at the 6- and 12-month follow-up points and to increase the BMD of the lumbar spine at the 12-month follow-up time point. BPs had no clear effect on serum PINP or serum calcium levels at the 12-month follow-up time point. BP therapy may prevent bone loss in the lumbar spine and hip when administered early after SCI and has relatively high safety.

Metabolomic Associations with Serum Bone Turnover Markers.

Bone is a dynamic tissue that is in a constant state of remodeling. Bone turnover markers (BTMs), procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptides of type I collagen (CTX), provide sensitive measures of bone formation and resorption, respectively. This study used ultra-high-resolution metabolomics (HRM) to determine plasma metabolic pathways and targeted metabolites related to the markers of bone resorption and formation in adults. This cross-sectional clinical study included 34 adults (19 females, mean 27.8 years), without reported illnesses, recruited from a US metropolitan area. Serum BTM levels were quantified by an ELISA. Plasma HRM utilized dual-column liquid chromatography and mass spectrometry to identify metabolites and metabolic pathways associated with BTMs. Metabolites significantly associated with P1NP (p < 0.05) were significantly enriched in pathways linked to the TCA cycle, pyruvate metabolism, and metabolism of B vitamins important for energy production (e.g., niacin, thiamin). Other nutrition-related metabolic pathways associated with P1NP were amino acid (proline, arginine, glutamate) and vitamin C metabolism, which are important for collagen formation. Metabolites associated with CTX levels (p < 0.05) were enriched within lipid and fatty acid beta-oxidation metabolic pathways, as well as fat-soluble micronutrient pathways including, vitamin D metabolism, vitamin E metabolism, and bile acid biosynthesis. P1NP and CTX were significantly related to microbiome-related metabolites (p < 0.05). Macronutrient-related pathways including lipid, carbohydrate, and amino acid metabolism, as well as several gut microbiome-derived metabolites were significantly related to BTMs. Future research should compare metabolism BTMs relationships reported here to aging and clinical populations to inform targeted therapeutic interventions.

Association of Visceral and Subcutaneous Fat Mass With Bone Density and Vertebral Fractures in Women With Severe Obesity

Introduction: The aim of this study was to evaluate the association of visceral and subcutaneous adipose tissue with bone mineral density (BMD), geometric indices of femoral neck strength and vertebral fractures in pre- and postmenopausal women with severe obesity. Methods: A cross-sectional study was conducted with pre- (n = 37) and postmenopausal (n = 21) women with body mass index higher than 40 kg/cm2. BMD at total body, lumbar spine, hip and forearm, presence of vertebral fractures, lean mass, visceral, and subcutaneous adipose tissue were assessed by DXA. Geometric indices of femoral neck strength were calculated by DXA. Serum bone turnover markers (CTX and osteocalcin) and 25(OH)D were also measured. Results: BMD at all studied sites was similar in pre- and postmenopausal women. In postmenopausal women, total subcutaneous adipose tissue was inversely associated with BMD at total femur (β = −0.009; 95% confidence interval [CI] −0.017; −0.002) and with strength index (β = −0.03; 95% CI −0.04; −0.01). In premenopausal women, visceral adipose tissue was inversely associated with cross-sectional moment of inertia (β = −0.95; 95%CI −1.89; −0.01). Vertebral fractures were highly prevalent in premenopausal (32%), and even more frequent among postmenopausal women (55%). Conclusion: Taken together, our results suggest that both visceral and subcutaneous fat may be detrimental for bone health in pre- and postmenopausal women, and that severe obesity may increase the risk of vertebral fractures, even in young women.

The effect of vitamin MK-7 on bone mineral density and microarchitecture in postmenopausal women with osteopenia, a 3-year randomized, placebo-controlled clinical trial.

Vitamin K is a cofactor in the carboxylation of osteocalcin (OC) and carboxylated OC promotes mineralization of bone. Clinical studies suggest that vitamin K2 prevents bone loss. The aim of the study was to investigate the effect of vitamin K2 as an add-on to calcium and vitamin D supplementation on osteocalcin, bone mass, and microarchitecture in postmenopausal women. We conducted a randomized placebo-controlled double-blinded clinical trial, including 142 postmenopausal women with osteopenia who received vitamin K2 (375μg MK-7) or placebo daily for 3years. Both groups received vitamin D3 (38μg/day) and calcium (800mg/day). We measured bone turnover markers in serum and bone mineral density and microarchitecture by DXA and HRpQCT. Undercarboxylated osteocalcin decreased in the MK-7-group (- 65.2 ± 23.5%) (mean ± SD) compared with the placebo group (- 0.03 ± 38.5%), p < 0.01 after 1year. After 3years, aBMD decreased at all sites without differences between the MK-7 and placebo-treated women (p > 0.09). aBMD decreased at the total hip by 1.5 ± 2.5% and 2.4 ± 2.7% in the MK-7 and the placebo groups, respectively, at the femoral neck by 1.5 ± 3.5% and 1.0 ± 5.0% in the MK-7 and the placebo groups, respectively, and at the lumbar spine by 1.8 ± 3.9% and 1.1 ± 3.1% in the MK-7 and the placebo groups, respectively. Changes in bone turnover markers were also similar between the two groups.We have previously reported improved microarchitecture with MK-7 after 1year. However, changes in microstructure over 3years were similar between the two groups, as assessed by both HRpQCT and DXA trabecular bone score. Treatment with MK-7375μg daily as an add-on to calcium and vitamin D increased carboxylation of osteocalcin. However, treatment of postmenopausal women with osteopenia for 3years did not affect biochemical markers of bone turnover, bone mineral density, or bone microarchitecture. The study was registered at Clinicaltrial.gov : NCT01922804 .

Applied Value of Serum Bone Turnover Markers in Patients with Myeloma Bone Disease

To explore the clinical value of serum bone turnover markers including β-CrossLaps (β-CTx), N-MID Osteocalcin (Osteocalcin), and total procollagen type 1 amino-terminal propeptide (TP1NP) in patients with myeloma bone disease (MBD). A total of 55 MBD patients(MBD group) and 20 healthy volunteers(control group) were selected, and the serum was collected for detecting β-CTx, Osteocalcin and TP1NP by Roche analyzer of automated electrochemiluminescence. Meanwhile, the imaging techniques such as MRI and CT were used for evaluation of bone destruction and the damage extent in MBD patients. Measurement data is expressed as median (P25, P75) according to distribution characteristics of data. The detection results showed that concentrations of β-CTx in MBD patients and control group were 0.72(0.48, 1.28) ng/mL and 0.53(0.34, 0.61) ng/mL respectively, the β-CTx concentration in MBD patients was significantly higher than that in control group(P=0.002). The ratio β-CTx to TP1NP (%) in MBD patients and control group was 1.50 (1.05, 3.36) and 1.25 (0.86, 1.35) respectively, the ratio in MBD patients was significantly higher than that in control group (P=0.007). The serum β-CTx concentrations in MBD patients of localized bone destruction type and extensive bone destruction type were 0.41(0.31, 0.66) ng/mL and 1.14(0.72, 1.81) ng/mL respectively, the β-CTx concentration in MBD patients of extensive bone destruction type was significantly higher than that in MBD patients of localized bone destruction type (P＜0.001). The ratio of β-CTx to TP1NP(%) in MBD patients of localized and extensive bone destruction type was 1.30 (0.90, 2.49) and 1.98 (1.18, 3.76) respectively, the ratio in the MBD patients of extensive bone destruction type was significantly higher than that in MBD patients of localized bone destruction type (P=0.019). The serum osteocalcin concentrations in MBD patients of localized and extensive bone destruction type were 14.31 (8.82, 19.39) ng/mL and 21.52 (14.42, 47.76) ng/mL respectively, the osteocalcin concentration in MBD patients of extensive bone destruction type was higher than that in MBD patients of localized bone destruction type (P=0.008). The AUC of β-CTx was 0.88 (95% CI: 0.78-0.98)(P＜0.001), and the cut-off value was 0.69 ng/ml in the diagnosis of extensive bone injury for MBD patients, and the sensitivity and specificity were 80.65% and 83.33% respectively. The MBD patients show bone resorption hyperthyroidism and high bone turnover. The β-CTx and osteocalcin in serum bone turnover markers can effectively reflect the extent of bone damage in MBD patients, especially the β-CTx is more efficient for the diagnosis of MBD patients of extensive bone destruction type. However, β-CTx, osteocalcin and TP1NP are not relate with the MM disease progression.