Serum C-terminal Cross-linking Telopeptide Research Articles

Water extract of Uncaria sinensis suppresses RANKL-induced bone loss by attenuating osteoclast differentiation and bone resorption

BackgroundThe hooks and stems of Uncaria sinensis have been used to mitigate cardiovascular and central nervous system disorders in Asia traditional medicine. Regulation of osteoclast differentiation and activity is a major target for preventing and treating pathological bone diseases. MethodsTartrate-resistant acid phosphatase (TRAP) activity and the number of TRAP-stained multinucleated cells were used to examine receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. The activation of RANKL-induced signaling pathways and the expression of transcription factors were investigated by western blot analysis and quantitative real-time polymerase chain reaction. The bone resorption activity of osteoclast was studied using a plate coated with hydroxyl-apatite. Trabecular bone destruction was investigated using a RANKL-induced trabecular bone loss mouse model. ResultsWe found that water extract of the hooks and stems of U. sinensis (WEUS) inhibits RANKL-induced differentiation of murine bone marrow macrophages and RAW264.7 cells into osteoclasts. WEUS inhibited the activation of NF-κB and the expression of nuclear factor of activated T-cells, cytoplasmic 1. In addition, WEUS suppressed the bone resorbing activity of mature osteoclasts without affecting their survival. Furthermore, oral administration of WEUS suppressed RANKL-induced bone loss with a significant amelioration of trabecular bone micro-structures. WEUS also reduced RANKL-induced increase in serum TRAP5b activity and C-terminal cross-linked telopeptide of type I collagen levels. ConclusionThe present study demonstrates that WEUS has a pharmacological activity that inhibits osteoclast-mediated bone destruction by suppressing osteoclast differentiation and function. These results suggest that U. sinensis could be a promising herbal candidate for preventing and treating bone diseases such as osteoporosis.

Management of oral bisphosphonates treatment by rheumatologists and determinants of therapeutic changes: a case-vignette-based study.

Persistence to oral bisphosphonates, the most commonly prescribed anti-osteoporotic treatments, is low. The aim of this study was to evaluate the role of rheumatologists on the treatment patterns, and to assess the determinants of treatment changes. We used the methodology of case vignettes with the participation of 142 rheumatologists. Three baseline clinical vignettes were presented: (1) the physician was asked to indicate the most appropriate period to schedule the next visit over 5years, (2) the physician was tested about parameters for follow-up (including traps), and (3) various results (both clinical, biological, densitometric, and radiological) were given by random and analyzed as determinants of treatment changes. The study allowed assessment of 426 virtual clinical cases. Clinical examinations, patient's height, inquiries about falls, and adherence to treatment were deemed necessary in >90% of cases. Bone mineral density was measured in 22, 40, and 71% of cases at 2, 3, and 5years, respectively. Dental follow-up was recommended in less than 25% of cases. Only 4.2% of patients were maintained on the same treatment at 5years, and a change of treatment (stop or switch) occurs in 20-30% of cases at each visit. Significant determinants were adherence to treatment, serum C-terminal crosslinking telopeptide of type 1 collagen (CTX) value, change in patient's height, and the occurrence of an incident vertebral fracture. Our study shows that maintenance of oral bisphosphonate in postmenopausal women managed by rheumatologists is low; there are few determinants of these changes and more information on appropriate follow-up could help in patients' management.

Biosensors For the Measurement of C-Terminal Telopeptide of Type I Collagen (CTX-I)

In the last few years, research on the use of biochemical markers of bone turnover has greatly improved. Among the several available bone turnover markers, monitoring serum C-terminal cross-linked telopeptides is one of the most accurate one. Manual and automated immunoassays are available for the measurement of CTX, which show high analytical performance. However, they are very expensive, time-consuming and require technical experts to perform the CTX assay. Different research groups have proposed novel immunosensing methods to detect CTX biomarker. It is a hope that the development of a rapid and inexpensive point-of-care device can aid in monitoring the bone metabolism more frequently, which can be helpful in indicating the early stages of bine loss.

Plasma homocysteine level is a risk factor for osteoporotic fractures in elderly patients.

ObjectiveTo study the relationship of plasma homocysteine (Hcy), bone turnover biomarkers (BTB), and bone mineral density (BMD) with osteoporotic fracture (OPF) in elderly people.MethodsEighty-two patients (aged 65 years or older) admitted to our orthopedics department between October 2014 and May 2015 were randomly divided into three groups: 1) OPF group: 39 cases with the mean age 81.82±5.49 years, which included 24 females and 15 males; 2) high-energy fracture (HEF) group: 22 cases with the mean age 78.88±5.75 years, which included 16 females and six males; 3) non-bone-fracture group: 21 cases with mean age 79.75±5.47 years without bone fracture, which included 14 females and seven males. Plasma Hcy, BTB, and BMD were measured. Analysis of variance and multiple regression analysis were used in the statistical analysis.ResultsThere was no significant difference in either age or sex among the three groups. There were significant differences in plasma Hcy and hip BMD between the OPF and HEF groups; there was also significant difference in plasma Hcy, 25-(OH) Vit D, and hip BMD between the OPF and non-fracture groups. There was no difference in lumbar spine BMD between the OPF group and the other two groups. There was no significant difference in plasma Hcy, 25-(OH) Vit D, hip or lumbar spine BMD between the HEF and non-fracture group. There was no significant difference in procollagen type I N-propeptide of type I collagen, serum C-terminal cross-linking telopeptide of type I collagen, and parathyroid hormone among the three groups. Plasma Hcy was linearly correlated with age and serum C-terminal cross-linking telopeptide of type I collagen, but not correlated with either hip or lumbar spine BMD or any other BTBs.ConclusionIn this study, we found that the plasma Hcy level in elderly patients with OPF is higher than that of nonosteoporotic patients. It is not correlated with BMD, but positively correlated with bone resorption markers. An increased Hcy level appears to be a risk factor for OPFs in elderly people.

Abstract P2-08-24: High levels of serum C-terminal crosslinking telopeptide of type 1 collagen at baseline are associated with poor prognosis for breast cancer patients

Abstract Background: It has been demonstrated that adjuvant treatment using bisphosphonate may reduce recurrence among breast cancer patients. However, these improved prognoses of patients are reportedly limited to breast cancers of estrogen receptor (ER)-positive and postmenopausal women. Although the mechanisms of the effects of bisphosphonate remain unknown, this finding seems to represent support for the hypothesis that suppression of bone resorption by bisphosphonate results in favorable prognoses at least for patients in this subset. In order to determine the prognostic significance of bone resorption in breast cancer patients, we investigated these markers c-terminal crosslinking telopeptide of type I collagen (1CTP) and N-telopeptide of type I collagen (NTX). Patients and Methods: 469 breast cancer patients were recruited who were operated on Hyogo College of Medicine and histologically confirmed to have invasive carcinoma. Serum 1CTP and NTX were measured preoperatively with the two-antibody radioimmunoassay and enzyme-linked immunosorbent assay methods, respectively, and blood samples were obtained before treatment from patients who were treated with neoadjuvant chemotherapy or endocrine therapy. The area under receiver operating characteristic curves were applied and optimal cutoff values were set at 3.6ng/ml for 1CTP, and 10.55nmolBCE/L premenopausal and 14.05nmolBCE/L postmenopausal for NTX. The relationships between these bone turnover markers and various clinicopathological characteristics were evaluated with the chi square or Fisher's exact test. The log-rank test was used to compare relapse-free survival (RFS) in Kaplan-Meier plots. Associations of RFS were assessed with a Cox proportional-hazards model based on the results of univariate and multivariate analyses. Differences were considered statistically significant if p<0.05. Results: There were significantly more 1CTP-high patients among postmenopausal women and RFS of 1CTP-high patients was significantly worse than that of 1CTP-low patients (5-year RFS: 0.65 vs 0.86; p=0.0002). Similarly, NTX-high patients were significantly associated with postmenopausal status, but there was no significant association between NTX-high worse RFS (p=0.0976). Multivariate analysis of tumor size, lymph node metastasis and nuclear grade identified 1CTP (hazard ratio: 2.04, 95% confidence interval: 1.13-3.68; p=0.018) as a significant independent prognostic factor. Subset analyses of 1CTP showed that prognosis was consistently worse recognized for postmenopausal (p=0.0002), but not premenopausal (p=0.37) patients. Furthermore, prognosis for 1CTP-high patients was worse for the estrogen receptor (ER)-positive subset (p=0.0005) but not for the ER-negative subset (p=0.22). Conclusion and discussion: High levels of serum bone resorption markers at baseline were identified as significant unfavorable prognostic factors for breast cancer patients. The prognostic significance of 1CTP seems to be prominent for postmenopausal patients with ER-positive breast cancers. These findings suggest the use of bone-modifying agents as an adjuvant therapy may be beneficial for breast cancer patients, especially for patients with high serum levels of 1CTP. Citation Format: Imamura M, Nishimikai A, Yanai A, Miyagawa Y, Higuchi T, Ozawa H, Murase K, Takatsuka Y, Miyoshi Y. High levels of serum C-terminal crosslinking telopeptide of type 1 collagen at baseline are associated with poor prognosis for breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-24.

Evaluation of the predisposing factors and involved outcome of surgical treatment in bisphosphonate-related osteonecrosis of the jaw cases including bone biopsies.

ObjectivesThis study examined the statistical relevance of whether the systemic predisposing factors affect the prognosis of surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ). All cases had undergone bone biopsies to determine the characteristics of the mechanisms of BRONJ by optical microscopy.Materials and MethodsThe data included 54 BRONJ cases who underwent surgery and in whom bone biopsies were performed. The results of surgery were evaluated and the results were classified into 3 categories: normal recovery, delayed recovery, and recurrence after surgery. The medical history, such as diabetes mellitus, medication of steroids, malignancies on other sites was investigated for an evaluation of the systemic predisposing factors in relation to the prognosis. The three factors involved with the medication of bisphosphonate (BP) were the medication route, medication period, and drug holiday of BP before surgery. The serum C-terminal cross-linking telopeptide (CTX) value and presence of microorganism colony in bone biopsy specimens were also checked. Statistical analysis was then carried out to determine the relationship between these factors and the results of surgery.ResultsThe group of patients suffering from diabetes and on steroids tended to show poorer results after surgery. Parenteral medication of BP made the patients have a poorer prognosis after surgery than oral medication. In contrast, the medication period and drug holiday of BP before surgery did not have significance with the results of surgery nor did the serum CTX value and presence of microorganism colony. Necrotic bone specimens in this study typically showed disappearing new bone formation around the osteocytic lacunae and destroyed Howship's lacunae.ConclusionAlthough many variables exist, this study could in part, predict the prognosis of surgical treatment of BRONJ by taking the patient's medical history.

Lentivirus-TAZ Administration Alleviates Osteoporotic Phenotypes in the Femoral Neck of Ovariectomized Rats

Background: Osteoporosis is characterized by impairment of bone mass, strength, and microarchitecture, leading to the susceptibility to fragility fractures, especially in femoral neck region. Transcriptional coactivator with PDZ-binding motif (TAZ) facilitates osteogenesis while suppressing adipogenesis via regulation of transcriptional activities of runt-related transcription factor 2 and peroxisome proliferator-activated receptor γ. Here, we validated the role of TAZ in vivo using an ovariectomized (OVX) rat model of osteoporosis. Methods: Serum alkaline phosphatase, triglyceride, cholesterol and urinary hydroxyproline were measured on an automatic analyzer using diagnostic reagent kits. Serum OCN and C-terminal cross-linked telopeptides of type I collagen were measured using ELISA. Bone mineral density was measured using dual-energy X-ray scanner. Mechanical parameters were detected by three-point bending assays. Bone volume per tissue volume (BV/TV), trabecular thickness (Tb. Th), trabecular number (Tb. No), and trabecular separation (Tb. Sp) were measured by MicroCT. The mRNA and protein levels were quantified by Realtime PCR and Western Blotting respectively. Results: After injections of lentivirus overexpressing TAZ into the femoral neck region, bone mineral density, ultimate force, stiffness, BV/TV, Tb. Th, and Tb. No were significantly increased, whereas Tb. Sp was dramatically decreased. In the TAZ-overexpression region in the femoral neck of OVX rats, the mRNA levels of Runx2 and osteocalcin were obviously elevated, whereas that of PPARγ and adipocyte protein 2 were downregulated. Conclusion: Lentivirus-mediated TAZ gene therapy alleviated the osteoporotic phenotypes in the femoral neck of OVX rats, providing an alternative strategy for the treatment of postmenopausal osteoporosis and prevention of osteoporotic fracture.

Effects of Long-Term Odanacatib Treatment on Bone Gene Expression in Ovariectomized Adult Rhesus Monkeys: Differentiation From Alendronate.

Similar efficacy of the cathepsin K inhibitor odanacatib (ODN) and the bisphosphonate alendronate (ALN) in reducing bone turnover markers and increasing bone mineral density in spine and hip were previously demonstrated in ovariectomized (OVX)-monkeys treated for 20 months in prevention mode. Here, we profiled RNA from tibial metaphysis and diaphysis of the same study using Affymetrix microarrays, and selected 204 probe sets (p < 0.001, three-group ANOVA) that were differentially regulated by ODN or ALN versus vehicle. Both drugs produced strikingly different effects on known bone-related genes and pathways at the transcriptional level. Although ALN either reduced or had neutral effects on bone resorption-related genes, ODN significantly increased the expression of osteoclast genes (eg, APC5, TNFRSF11A, CTSK, ITGB3, and CALCR), consistent with previous findings on the effects of this agent in enhancing the number of nonresorbing osteoclasts. Conversely, ALN reduced the expression of known bone formation-related genes (eg, TGFBR1, SPP1, RUNX2, and PTH1R), whereas ODN either increased or had neutral effects on their expression. These differential effects of ODN versus ALN on bone resorption and formation were highly correlative to the changes in bone turnover markers, cathepsin K (Catk) target engagement marker serum C-terminal cross-linked telopeptide (1-CTP) and osteoclast marker tartrate resistant acid phosphatase isoform 5b (TRAP5b) in the same monkeys. Overall, the molecular profiling results are consistent with the known pharmacological actions of these agents on bone remodeling and clearly differentiate the molecular mechanisms of ODN from the bisphosphonates.

Folic Acid and Vitamin B12 Supplementation Lowers Plasma Homocysteine but has no Effect on Serum Bone Turnover Markers in Elderly Women: A Randomized, Double-blind, Placebo-controlled Trial

Abstract An elevated homocysteine level is a newly recognized risk factor for osteoporosis. Older individuals may have elevated homocysteine levels due to inadequate folate intake and/or lower absorption of vitamin B 12 . The aim of this study was to determine whether there is an impact of folic acid and vitamin B 12 supplementation on homocysteine levels and, subsequently, on bone turnover markers in older women with mildly to moderately elevated homocysteine levels. It is hypothesized that supplementation with folic acid and vitamin B 12 will improve homocysteine levels and, in turn, positively modify bone turnover markers in this population. This randomized, double-blind, placebo-controlled trial included 31 women (65 to 93 years) with homocysteine levels greater than 10 μ mol/L. Participants were randomly assigned to receive either a daily folic acid (800 μ g) and vitamin B 12 (1000 μ g) (n = 17) or a matching placebo (n = 14) for 4 months. The results showed significantly lower homocysteine concentrations in the vitamin group compared to the placebo group (10.6 vs 18.5 μ mol/L, P = .007). No significant difference in serum alkaline phosphatase or C-terminal cross-linking telopeptide of type I collagen was found between the vitamin and placebo groups before or after supplementation. The use of folic acid and vitamin B 12 as a dietary supplement to improve homocysteine levels could be beneficial for older women, but additional research must be conducted in a larger population and for a longer period to determine if there is an impact of supplementation on bone turnover markers or other indicators of bone health.

Impact of oral antidiabetic agents on bone metabolism.

Impact of oral antidiabetic agents on bone metabolism.

The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone remodeling markers in patients with rheumatoid arthritis

Previous studies showed that the control of inflammation by biological therapies has a positive effect on bone in inflammatory diseases. The objective of this study was to assess the effects on bone mineral density (BMD) and bone remodeling of an anti-IL-6 monoclonal antibody (tocilizumab (TCZ)) in patients with rheumatoid arthritis (RA). MethodsOne hundred and three patients (75% women, 52±12years) with active RA were treated with TCZ 8mg/kg + methotrexate (MTX) every 4 weeks during 48 weeks. Hip and lumbar spine BMDs were measured at baseline and after 48 weeks by dual energy X-ray absorptiometry (DXA). Pro-collagen serum type I N-terminal propeptide (PINP), serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), and serum levels of total Dickkopf-1 (Dkk-1) and sclerostin were assessed at baseline, 12 and 48 weeks. ResultsBMD was available for 76 patients at baseline and at the end of the study. There was no change in lumbar spine and hip BMD over 48 weeks. Serum PINP increased from baseline by 22% (P≤0.001) and 19% (P≤0.001) at week 12 and week 48, whereas serum CTX-I remained stable. Serum DKK-1 significantly decreased from baseline by −31% (P≤0.001) and −25% (P=0.025) at week 12 and 48. Similar results were observed in the patients receiving low doses of oral corticosteroids. ConclusionIn this 1-year prospective open study, patients with active RA receiving TCZ and MTX had no change in BMD, a decrease in serum DKK-1 and an increase in bone formation marker.

Loading Dose Ibandronate Versus Standard Oral Ibandronate in Patients With Bone Metastases From Breast Cancer

IntroductionIn this phase II trial, the efficacy and safety of loading-dose I.V. ibandronate in patients with breast cancer with bone metastases were evaluated. Patients and MethodsThirty-four patients were randomized to receive a loading dose of 12 mg I.V. ibandronate on day 1 then oral ibandronate 50 mg daily (arm A), or standard oral therapy of 50 mg ibandronate daily from day 1 (arm B). The primary end point was percentage change in serum C-terminal crosslinking telopeptide of type I collagen (S-CTX) from baseline by day 5 of study. Secondary/exploratory end points included percentage change in other bone turnover markers (N-terminal cross-linking telopeptides of type I collagen [NTX], procollagen type I N propeptide, bone alkaline phosphatase) and change in average bone pain score. ResultsThere was a significantly greater reduction in S-CTX at day 5 in arm A compared with arm B (median difference, 15.82%; P = .005). There was also a significantly greater reduction in urine NTX/creatinine at day 5 (P = .009) and at the end of weeks 1 to 8 (averaged; P = .006). Average bone pain score was lower in arm A at the end of 8 weeks (P = .012). There were no additional adverse events after administration of 12 mg I.V. loading dose of ibandronate. ConclusionA 12-mg dose of I.V. ibandronate rapidly reduced markers of bone turnover and can be administered without additional toxicity.

Sirtuin 1 activity in peripheral blood mononuclear cells of patients with osteoporosis.

BackgroundSirtuin 1 (SIRT1) is a class III histone deacetylase that may play a critical role in several biological functions, including lifespan, stress, and inflammation. Our main objective was to evaluate SIRT1 activity in peripheral blood mononuclear cells (PBMCs) in patients with osteoporosis and to analyze the relationship between the SIRT 1 activity and markers of inflammation and bone remodelling.Material/MethodsWe performed a prospective monocentric study of patients with osteoporosis and measured the nuclear and cytoplasmic activities of SIRT1 in PBMCs. Levels of proinflammatory cytokines were assessed in culture supernatants of PBMCs isolated from the osteoporosis patients. The level of serum C-terminal cross-linking telopeptide of type I collagen (CTX), a marker of bone resorption, was measured in the serum of osteoporosis patients.ResultsSixteen women with osteoporosis were included. A statistically significant correlation between the cytoplasmic and nuclear SIRT 1 activities was found in PBMCs of patients with osteoporosis. Although non-significant, we observed a negative trend between nuclear SIRT 1 activity and the rate of serum CTX and a positive trend between IL-6 and CTX levels in patients with osteoporosis.ConclusionsThis study shows that the cytoplasmic and nuclear SIRT 1 activities are measurable in circulating PBMCs of patients with osteoporosis and that these 2 activities are correlated. The potential role of inflammation in bone resorption in patients with osteoporosis was also studied.

A Meta-Analysis of Reference Markers of Bone Turnover for Prediction of Fracture

The aim of this report was to summarize the clinical performance of two reference bone turnover markers (BTMs) in the prediction of fracture risk. We used an updated systematic review to examine the performance characteristics of serum procollagen type I N propeptide (s-PINP) and serum C-terminal cross-linking telopeptide of type I collagen (s-CTX) in fracture risk prediction in untreated individuals in prospective cohort studies. We excluded cross-sectional studies. Ten potentially eligible publications were identified and six included in the meta-analysis. There was a significant association between s-PINP and the risk of fracture. The hazard ratio per SD increase in s-PINP (gradient of risk [GR]) was 1.23 (95 % CI 1.09-1.39) for men and women combined unadjusted for bone mineral density. There was also a significant association between s-CTX and risk of fracture, GR = 1.18 (95 % CI 1.05-1.34) unadjusted for bone mineral density. For the outcome of hip fracture, the association between s-CTX and risk of fracture was slightly higher, 1.23 (95 % CI 1.04-1.47). Thus, there is a modest but significant association between BTMs and risk of future fractures.

Bone metabolism in obese rats programmed by early weaning

ObjectiveObesity and osteoporosis seem to have a common pathogenesis, especially because bone and adipose tissue have common origins. Since early weaning (EW) decreases adipogenesis and osteogenesis in neonate, further programming for obesity and hyperleptinemia, we hypothesized that these changes in adipogenesis could affect bone metabolism. Materials/MethodsLactating rats were separated into 3 groups: control — dams whose pups ate milk throughout lactation; mechanical EW (MEW) — dams were involved with a bandage interrupting suckling in the last 3days of lactation; pharmacological EW (PEW) — dams were bromocriptine-treated (0.5mg/twice a day via intraperitoneal injection) 3days before weaning. The adult offspring was subjected to dual-energy X-ray absorptiometry and bone tissue was also evaluated by computed tomography, microcomputed tomography and biomechanical tests, beyond serum analyses. ResultsMEW and PEW presented higher total bone mineral density (BMD), total bone mineral content, spine BMD and bone area in postnatal day 150 (PN150). In PN180, both groups also presented increase of these parameters and higher femur BMD and fourth lumbar vertebra (LV4) BMD, femoral head radiodensity and LV4 vertebral body radiodensity, trabecular number, stiffness and break load; lower trabecular separation, maximal deformation and break deformation, and also hyperleptinemia and higher visceral fat mass and 25-hydroxivitamin D, whereas parathyroid hormone was unchanged. Serum C-terminal cross-linked telopeptide of type I collagen was lower for both groups. ConclusionsSince both models program for obesity and increased bone mass, and leptin increases plasma vitamin D levels, probably leptin is the link between obesity and higher bone mass.

Exendin-4, a Glucagon-Like Peptide-1 Receptor Agonist, Prevents Osteopenia by Promoting Bone Formation and Suppressing Bone Resorption in Aged Ovariectomized Rats

Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have antiosteoporotic effects, especially in aged postmenopausal situation, has not been confirmed. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX)-induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 was administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks of treatment with exendin-4 slowed down body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased the urinary deoxypyridinoline (DPD)/creatinine ratio and serum C-terminal cross-linked telopeptides of type I collagen (CTX-I) and increased serum alkaline phosphatase (ALP), osteocalcin (OC), and N-terminal propeptide of type 1 procollagen (P1NP) levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio, but also promoted bone formation by increasing the expression of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous antiosteoporotic agents. In conclusion, these findings demonstrated for the first time the antiosteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis.

Folic acid and vitamin B12 supplementation lowers plasma homocysteine but has no effect on serum bone turnover markers in elderly women: a randomized, double-blind, placebo-controlled trial

An elevated homocysteine level is a newly recognized risk factor for osteoporosis. Older individuals may have elevated homocysteine levels due to inadequate folate intake and/or lower absorption of vitamin B12. The aim of this study was to determine whether there is an impact of folic acid and vitamin B12 supplementation on homocysteine levels and, subsequently, on bone turnover markers in older women with mildly to moderately elevated homocysteine levels. It is hypothesized that supplementation with folic acid and vitamin B12 will improve homocysteine levels and, in turn, positively modify bone turnover markers in this population. This randomized, double-blind, placebo-controlled trial included 31 women (65 to 93 years) with homocysteine levels greater than 10 μmol/L. Participants were randomly assigned to receive either a daily folic acid (800 μg) and vitamin B12 (1000 μg) (n = 17) or a matching placebo (n = 14) for 4 months. The results showed significantly lower homocysteine concentrations in the vitamin group compared to the placebo group (10.6 vs 18.5 μmol/L, P = .007). No significant difference in serum alkaline phosphatase or C-terminal cross-linking telopeptide of type I collagen was found between the vitamin and placebo groups before or after supplementation. The use of folic acid and vitamin B12 as a dietary supplement to improve homocysteine levels could be beneficial for older women, but additional research must be conducted in a larger population and for a longer period to determine if there is an impact of supplementation on bone turnover markers or other indicators of bone health.

High bone turnover persisting after vitamin D repletion: beware of calcium deficiency

Treatment of vitamin D deficiency with vitamin D is a common procedure when taking care of elderly patients, calcium supplementation being added only when calcium dietary intake is insufficient. Here, we report the case of a 58-year-old female who was referred to our unit because of suspicion of Paget's disease of the skull, based on elevated serum alkaline phosphatase and high skull methylene diphosphonate-technetium uptake. She had been prescribed cholecalciferol (100,000 IU/month) and calcium salts for the past 7 months after discovery of severe vitamin D deficiency by her primary care physician. No specific skull bone lesions were observed on both X-ray and computerized tomography. Serum calcium, phosphate and 25(OH) vitamin D levels were normal, while serum C-terminal cross-linked telopeptide, bone alkaline phosphatase and calcitriol were high and daily urinary calcium excretion was low. We found that she had not been compliant with the calcium prescription while vitamin D had been thoroughly taken. We suspected osteomalacia due to calcium deficiency. Both skull uptake and biological abnormalities normalised in few months after adding calcium supplementation to the vitamin D treatment, and spine bone mineral density increased by 9.5 % after 14 months of full treatment. The present case illustrates the necessity for adequate calcium intake during vitamin D repletion to normalise bone mineralisation and turnover and maintain the skeletal integrity.

Dose–response study of denosumab on bone mineral density and bone turnover markers in Japanese postmenopausal women with osteoporosis

The efficacy and safety of denosumab were evaluated in Japanese postmenopausal women with osteoporosis. Total hip and distal 1/3 radius bone mineral densities (BMDs) were increased, and lumbar spine BMD was increased in magnitude with increasing dose. Bone turnover markers significantly decreased compared with placebo. Denosumab was well tolerated in Japanese subjects. The efficacy and safety of three doses of denosumab were compared with a placebo over 12 months in Japanese postmenopausal women with osteoporosis. In this phase 2 multicenter, randomized, placebo-controlled study, 226 subjects were randomized and 212 subjects received at least 1 dose of investigational product, subcutaneously. All subjects also received daily supplements of at least 600 mg elemental calcium and 400 IU vitamin D from the beginning of screening through 12 months of treatment. Compared with placebo, denosumab (14, 60, and 100 mg) showed significant increases in percent BMD values of lumbar spine (5.25, 6.27, and 7.00) and total hip (3.90, 3.69, and 4.35) from baseline in 12 months. Distal 1/3 radius BMD was also significantly increased except at the 100-mg dose (1.82, 1.35, and 1.15). Denosumab significantly decreased the serum C-terminal crosslinking telopeptide of type 1 collagen and urinary N-terminal crosslinking telopeptide of type I collagen/urinary creatinine levels in 8 days, and bone alkaline phosphatase in 3 months. No new vertebral fracture was observed on spinal radiographs in either group. The overall incidences of adverse events were similar in the denosumab groups and the placebo group. No subject developed antibodies to denosumab. These results were similar to those obtained in the US phase 2 study. Denosumab 60 mg could be an effective dose for Japanese postmenopausal women with osteoporosis as was shown in the Caucasian population.

International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine Position on bone marker standards in osteoporosis

The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group on Bone Marker Standards (WG-BMS) has evaluated the clinical potential of bone turnover markers (BTMs) in the prediction of fracture risk and for monitoring treatment. Research evidence suggests that BTMs may provide information on fracture risk independently from BMD, so that fracture risk prediction might be enhanced by their inclusion in assessment algorithms. The potential use of BTMs to predict the response to treatments for osteoporosis in the individual patient is also of great interest. Treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. However, there is still a need for stronger evidence on which to base practice in both situations. IOF/IFCC recommends one bone formation marker (serum procollagen type I N propeptide, s-PINP) and one bone resorption marker (serum C-terminal cross-linking telopeptide of type I collagen, s-CTX) to be used as reference markers and measured by standardised assays in observational and intervention studies in order to enlarge the international experience of the application of markers to clinical medicine and to help resolve uncertainties over their clinical use.