Procollagen I N-terminal Propeptide Research Articles

The Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Liraglutide Regulates Sirtuin-1-Mediated Neutrophil Extracellular Traps to Improve Diabetes-Induced Bone Metabolism Imbalance

Background: Diabetes mellitus (DM) is a chronic metabolic disorder that disrupts normal bone remodeling. Objectives: This study aimed to investigate how the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (LIR) addresses bone metabolism imbalances induced by type-II diabetes. Methods: Type-II diabetic rat models were established through a single intraperitoneal injection of streptozotocin (STZ). Blood glucose levels were measured using a blood glucose meter, and insulin levels were assessed using an assay kit. Bone formation markers [alkaline phosphatase (ALP), osteocalcin (OCN), and procollagen I N-terminal propeptide (PINP)] and bone resorption markers [tartrate-resistant acid phosphatase (TRACP) and CTX-1] were monitored using assay kits. Bone marrow mesenchymal stem cells (BMSCs) were cultured in vitro under high-fat and high-glucose (HFHS) conditions to mimic diabetic bone metabolism dysregulation. Neutrophil extracellular traps (NETs) formation was examined through immunofluorescent staining and Western blot analysis. Results: Liraglutide was found to reduce STZ-induced NETs formation, as indicated by decreased expression of cit-H3 by 36.90% - 53.57%, myeloperoxidase (MPO) by 55.81% - 65.12%, NE by 53.95% - 65.17%, and PAD4 by 46.81% - 63.83%, alongside increased Sirtuin-1 (SIRT1) expression in femur tissue (70.71% - 91.19%). In vitro, LIR enhanced osteogenesis and inhibited apoptosis, effects that were partially reversed by SIRT1 knockdown. Additionally, SIRT1 knockdown partially restored LIR-induced reductions in oxidative stress, inflammation, and NETs formation. Conclusions: LIR mitigates diabetes-induced bone metabolism imbalance by inhibiting NETs formation through SIRT1 mediation.

Pharmacokinetics and pharmacodynamics of proposed denosumab biosimilar and reference denosumab in healthy male subjects.

e14500 Background: Denosumab is a human monoclonal antibody that binds to RANKL, preventing activation of its receptor RANK on the surface of osteoclasts and inhibiting osteoclastic bone resorption. This study was conducted to support demonstration of biosimilarity by evaluating similarity in pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity between GP2411, a proposed Sandoz denosumab biosimilar, and reference denosumab in healthy male subjects. Methods: This double-blind, three-arm, parallel-group, PK and PD study was conducted at two centres in Germany. Participants were randomised (1:1:1) to receive a single 35 mg s.c. dose of either GP2411, EU-authorised reference denosumab, or US-licensed reference denosumab and were followed-up for 39 weeks. A sub-therapeutic dose was chosen since it is more sensitive than therapeutic doses to detect potential PK and PD differences; PK and PD similarity established at the 35 mg dose supports extrapolation to therapeutic doses. The study enrolled 502 healthy male subjects, aged 28–65 years, with a body weight range of 50–90 kg. PK endpoints included the area under the serum concentration-time curve measured from the time of dosing and extrapolated to infinity (AUCinf), or to the last measurable concentration (AUClast), and maximum observed serum concentration (Cmax). PD endpoints were the area under the effect-time curve (AUEC) of the percentage change from baseline (%CfB) in serum carboxy-terminal crosslinked telopeptide of type I collagen (CTX), and CTX and procollagen I N-terminal propeptide (PINP) serum concentration per visit. Results: Overall, 499 healthy volunteers received one of the three treatments. PK and PD similarity was demonstrated between GP2411 and its reference biologic (EU-authorised and US-licensed), as the 90% CIs and 95% CIs of the geometric mean ratios for PK and PD parameters were fully contained within the prespecified equivalence margins [0.80, 1.25]. Changes from baseline to Week 39 in serum concentrations of CTX and PINP were similar between groups. Conclusions: PK and PD similarity between GP2411, a proposed Sandoz denosumab biosimilar, and reference denosumab were demonstrated in healthy male subjects. [Table: see text]

Impact of testosterone therapy on bone turnover markers in obese males with type 2 diabetes and functional hypogonadism

Methods Fifty-five obese males with type 2 diabetes mellitus and functional hypogonadism participated in a 2-year, double-blind, placebo-controlled study of testosterone undecanoate (TU). Bone turnover markers C-telopeptide of type I collagen (CTX) and procollagen I N-terminal propeptide (PINP) were assessed at baseline, 12 and 24 months. Bone mineral density (BMD) changes were evaluated after 24 months using dual-energy X-ray absorptiometry. Group T (n = 28) received TU both years. Group P (n = 27) received placebo first year and TU second year. Results CTX decreased in group P from 1055 (676–1344) to 453 (365–665) pmol/L (p < 0.001) and from 897 (679–1506) to 523 (364–835) pmol/L (p < 0.001) in T. PINP decreased by 4.30 ± 8.05 μg/L in group P (p = 0.030) and 4.64 ± 8.86 μg/L in T (p < 0.023) after first year of therapy. No femoral neck BMD changes were observed in 32 patients from both groups (n = 16 per group). Lumbar spine BMD increased (by 0.075 ± 0.114 g/cm2; p = 0.019) in group T following two years of treatment. Conclusions We observed decreased CTX, decreased PINP and increased lumbar spine BMD after two years of testosterone treatment. Clinical trials NCT03792321; retrospectively registered trial on 4 January 2019.

Research on biochemical indexes of bone metabolism in bipolar disorder: A cross-sectional study with newly diagnosed, drug-naïve patients

BackgroundIn recent years, the metabolic abnormalities associated with bipolar disorder (BD) have attracted people's attention. However, clinical studies on bone metabolism in individuals with BD are unavailable. This study was designed to assess biochemical indexes of bone metabolism and related influencing factors. MethodsWe measured bone turnover markers (BTMs), including procollagen Ⅰ N-terminal propeptide (PⅠNP), osteocalcin (OC) and C-terminal cross-linking telopeptide of type I collagen (CTX-I), and index of calcium and phosphorus metabolism in 100 drug-naïve individuals with BD (DSM-5) and 91 healthy volunteers. Besides, sociodemographic and clinical assessment were collected. Between-group comparisons and within subgroup analysis were performed. ResultsThe PⅠNP (t = 3.715, p < 0.001), OC (t = 2.117, p = 0.036), parathyroid hormone (PTH, t = 3.877, p < 0.001), vitamin D (t = 2.065, p = 0.041), insulin (t = 4.208, p < 0.001) and insulin resistance (t = 2.888, p = 0.004) levels in the drug-naive BD group was significantly higher than those in the healthy control (HC) group. The level of calcium (t = −2.124, p = 0.035) in the drug-naive BD group was significantly lower than that of the HC group. But OC and vitamin D loses statistical significance after Bonferroni correction. However, there was no significant difference in the CTX-I level between the two groups. There are gender differences in the level of BMTs in individuals with BD, but this phenomenon was not found in the HC subgroup. It is shown that diagnosed BD, gender, age and BMI may affect the PINP levels through multiple linear regression analysis. ConclusionThe biochemical indexes of bone metabolism in drug-naive individuals with BD were more active than that of the healthy controls in a sample from the Chinese Han nationality. The finding provides new evidence for our understanding of bone metabolism in individuals with BD.

3-Hydroxybutyrate administration elevates plasma parathyroid hormone in a pilot human randomized, controlled, cross over trial.

Ketone bodies, in particular 3-hydroxybutyrate (3OHB), are known to possess important energetic and signaling capacities. There is a growing block of evidence, that ketogenic dieting (KD), fasting, and sodium glucose transporter 2 inhibitor (SGLT2i) treatment are associated with hyperparathyroidism and negative bone health. We aimed to study the effect of exogenous 3OHB administration on bone metabolism, specifically the effect on parathyroid hormone (PTH) and calcium/phosphate homeostasis. A randomized, controlled, cross over study with two arms: i) saline infusion and ii) 3OHB infusion. The study was conducted at Aarhus University Hospital. We examined eight healthy human subjects aged 50-70years. Continuous intravenous DL-3OHB-NaCl infusion or 0.9% NaCl was administered for 390min. The study was designed to test the impact of 3OHB on PTH, calcium-phosphate, C-terminal Telopeptide (CTX), and Procollagen I N-terminal Propeptide (PINP). The study was a post hoc study. The PTH concentration increased by 25% with a concomitant drop in phosphate of 30% in the 3OHB group. 3OHB infusion increased concentrations of CTX by 5%, without changes in PINP and albumin corrected calcium concentrations. In conclusion, 3OHB administration increases PTH concentration and markers of bone resorption. These findings suggest a possible negative effect on bone health, which needs to be determined in future studies.

The Effect of Caloric Restriction with and without n-3 PUFA Supplementation on Bone Turnover Markers in Blood of Subjects with Abdominal Obesity: A Randomized Placebo-Controlled Trial.

Weight loss contributes to an increased risk of hip fracture, especially in postmenopausal women. Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation could diminish the adverse effect of weight loss on bone health. The aim of this randomized, placebo-controlled, double-blind parallel trial was to investigate the effect of caloric restriction and n-3 PUFA supplement intake on osteogenic markers (carboxylated osteocalcin (Gla-OC); procollagen I N-terminal propeptide (PINP)), as well as a bone resorption marker (C-terminal telopeptide of type I collagen (CTX-I)) in a serum of 64 middle aged individuals (BMI 25–40 kg/m2) with abdominal obesity. Bone remodeling, metabolic and inflammatory parameters and adipokines were determined before and after 3 months of an isocaloric diet (2300–2400 kcal/day) or a low-calorie diet (1200 kcal/day for women and 1500 kcal/day for men) along with n-3 PUFA (1.8 g/day) or placebo capsules. CTX-I and adiponectin concentrations were increased following 7% weight loss independently of supplement use. Changes in CTX-I were positively associated with changes in adiponectin level (rho = 0.25, p = 0.043). Thus, an increase in serum adiponectin caused by body weight loss could adversely affect bone health. N-3 PUFAs were without effect.

Effects of resveratrol supplementation on bone quality: a systematic review and meta-analysis of randomized controlled trials

BackgroundThe results from clinical trials have revealed that the effects of resveratrol supplementation on bone mineral density (BMD) and bone biomarkers are inconsistent. Our objective was to determine the effects of resveratrol supplementation on BMD and serum bone biomarkers.MethodsPubMed, Cochrane library, EMBASE, Web of science and Scopus were searched up to August 24, 2020. Two reviewers independently performed the articles search and screen according to defined selection criteria. The study quality of the randomized controlled trials (RCTs) was evaluated with the Cochrane scoring system. Heterogeneity among studies was examined by Cochrane Q test. Retrieved data were pooled after mean differences (MD) were computed between two groups for BMD and serum biomarkers. Subgroup analyses were performed to evaluate a potential difference in terms of dose of resveratrol and intervention duration. Sensitivity analysis was executed by omitting studies with imputed values in order to evaluate the influence of these studies on the overall results.ResultsTen eligible studies involving 698 subjects were included in this meta-analysis with 401 participants receiving resveratrol and 297 receiving placebo. Supplementation of resveratrol had no statistically significant effects on areal bone mineral density (aBMD) at lumbar spine (MD: -0.02, 95% CI: − 0.05, 0.01, p = 0.26, I2 = 6%), total hip BMD (MD: -0.01, 95% CI: − 0.04, 0.02, p = 0.65, I2 = 0%), and whole body BMD (MD: 0.00, 95% CI: − 0.02, 0.02, p = 0.74, I2 = 0%). Supplementation of resveratrol also did not result in significant change in bone serum markers, including serum alkaline phosphatase (ALP), bone alkaline phosphatase (BAP), osteocalcin (OCN), procollagen I N-terminal propeptide (PINP), C-terminal telopeptide of type I collagen (CTX) and parathyroid hormone (PTH). Subgroup analysis showed the effect of resveratrol supplementation on BMD and serum bone markers were similar in trails of different doses, intervention duration, and pathological conditions of the participants.ConclusionResveratrol supplementation did not show any significant effect on BMD or serum bone markers with the current evidence. Further investigation with more well-organized multicentre randomized trial is warranted.

Simvastatin reverses the harmful effects of high fat diet on titanium rod osseointegration in ovariectomized rats.

The objectives of the present study were to determine whether simvastatin (SIM) could reverse the harmful effects on titanium rod osseointegration in ovariectomized rats fed high-fat diet (HFD). Ovariectomized female Sprague-Dawley rats were randomly allocated to three groups and received SIM treatment plus HFD for 12 weeks. We then evaluated the microstructure parameters, histological parameters, biomechanical parameters, bone turnover, and blood lipid level. After 12 weeks of treatment, SIM can significantly improve bone formation around the titanium rod and osseointegration including higher values of maximum push-out force, bone area ratio (BAR), bone-to-implant contact (BIC), bone mineral density (BMD), bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), mean connective density (Conn.D) when compared with the HFD group. In addition, system administration of SIM showed positive effects on collagen type 1 cross-linked C-telopeptide (CTX-1), procollagen I N-terminal propeptide (PINP), total cholesterol (TC), triglycerides (TGL), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol. Compared with the HFD group, lower values of CTX-1, P1NP, TC, TGL and LDL were observed in the SIM+HFD group (P < 0.05). Our findings revealed that HFD may have an adverse effect on osseointegration in osteoporotic conditions, and the harmful effect of HFD on osseointegration could be reversed by SIM.

The Effect of Daily Yogurt Supplementation on Inflammation and Bone Biomarkers

Abstract Objectives To evaluate the effect of daily yogurt intake on markers of inflammation and bone turnover in an 8wk RCT among Caribbean Latino adults with low-grade inflammation, at high-risk for osteoporosis (OP). Methods Eligible adults (n = 39) at-risk for OP (FRAX score) reporting &amp;lt;2 s/wk of yogurt intake, provided written informed consent, and participated in 1 study visit/wk for 12wks. Baseline (4wks) and intervention (8wks) assessment included health behavior questionnaires, 24-h dietary recalls (NDSR NCC, University of Minnesota, Minneapolis 2019), fecal collections (OMNIgene GUT), and venipunctures. Participants were randomly assigned to yogurt group (YG) [one 5-ounce container/d, 7/wk] or diet control group (DC). Each serving contained 5 grams protein, 8 grams fat, 16 grams carbohydrates, 170 kcal. Pre- and post-intervention blood evaluated osteocalcin (OC), Procollagen I N-Terminal Propeptide (PINP), and a panel of inflammatory biomarkers. Percent change in biomarkers between groups was assessed using unadjusted and adjusted generalized linear models. Relative abundance of yogurt starter cultures (Lactobacillus delbrueckii subsp. bulgaricus, Streptococcus thermophilus) was quantified in the feces by qPCR. Fold change in abundance was tested between groups by independent t-test. Results Participants were 69% women (all post-menopausal), sedentary, average 70y, BMI 30 kg/m2, and baseline CRP of 5 mg/L. Baseline characteristics were not significantly different between groups. YG presented with 10.7- and 3.8-fold greater abundance of L. bulgaricus and S. thermophilus, respectively, in feces compared to DC. In unadjusted models, PINP increased 18.2% and OC 14.8% in the YG compared to DC [−1.9% P = 0.007, 0.3% P = 0.047, respectively]. In adjusted models, % increase in PINP remained significant (P = 0.03) but was attenuated for OC (P = 0.13). Daily yogurt intake did not change inflammatory biomarkers, compared to DC (P ≥ 0.1). Conclusions Daily yogurt intake significantly increased bone formation biomarkers from baseline, suggesting that regular yogurt consumption may protect against OP, independent of inflammatory pathways. Funding Sources Yogurt in Nutrition Initiative grant by Danone Institute International, American Society for Nutrition, International Osteoporosis Foundation

Associations of LRP5 Gene With Bone Mineral Density, Bone Turnover Markers, and Fractures in the Elderly With Osteoporosis.

Objective: The study aimed to explore the associations of rs4988300 and rs634008 in the low-density lipoprotein receptor–related protein 5 (LRP5) gene with bone mineral density (BMD), bone turnover markers (BTM), and fractures in elderly patients with osteoporosis (OP).Methods: Our study included 328 unrelated OP patients with or without fractures. Genomic DNA was extracted for genotyping. BTM levels were assessed by electrochemiluminescence (ECL). Dual-energy X-ray absorptiometry (DXA) was employed to measure BMD in the lumbar spine (LS) and proximal femur. Basic features between the OP and fracture groups were analyzed using the t-test. The Chi-square test was performed to analyze the differences in allele and genotype frequencies. The associations of single-nucleotide polymorphisms (SNPs) with BMD and BTM in the subgroups were investigated by the analysis of covariance (ANCOVA) adjusted for confounding factors.Results: In both females and males, individuals with fractures exhibited higher BTM levels and lower BMD values than those with OP (P < 0.05). The allele and genotype frequencies of rs4988300 in the subgroups were significantly different (P < 0.05). In both females and males suffering from OP, participants with rs4988300 GG or rs634008 TT presented lower procollagen I N-terminal propeptide (PINP) levels (P < 0.05). Women with OP carrying rs4988300 GG exhibited lower BMD values at FN and TH (P < 0.05). In both females and males with fractures, individuals carrying rs4988300 GG genotype or rs634008 TT genotype exhibited lower PINP levels and BMD values at FN and TH than those with other genotypes (P < 0.05).Conclusions: Rs4988300 and rs634008 polymorphisms in the LRP5 gene are associated with bone phenotypes in the elderly with OP or fractures.

Effect of Vitamin D Supplementation on Bone Turnover Markers During HIV Pre-Exposure Prophylaxis Using Tenofovir Disoproxil Fumarate-Emtricitabine in Men Who Have Sex with Men

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) reduces bone mineral density in HIV-uninfected men who have sex with men (MSM). We hypothesized that PrEP with TDF-FTC would increase bone turnover markers (BTMs) at week 24 and that vitamin D supplementation from weeks 24 to 48 would blunt this increase. Participants were from a cohort of 398 MSM and transgender women who received daily TDF-FTC for PrEP. At week 24, a prospective intervention group initiated vitamin D3 4,000 IU daily. Concurrent controls were selected from the cohort who took ≤400 IU/day of vitamin D3 matched by age, race, and body mass index. The primary endpoint was the change in procollagen-I N-terminal propeptide (P1NP) from weeks 24 to 48. Paired t-tests were used to compare changes in BTMs between intervention and controls. Among 48 intervention-control pairs, median age was 33 years. At baseline, 68.9% of the intervention group and 77.3% of controls were vitamin D sufficient (≥20 ng/mL, p = .94). P1NP, C-telopeptide, parathyroid hormone (PTH), and 25-OH vitamin D3 did not increase significantly at week 24. P1NP fell by a mean ± SD of -27.6 ± 49.9 pg/mL from weeks 24 to 48 with vitamin D and -2.5 ± 40.2 pg/mL in controls (p = .01). There were no significant between-group differences in the weeks 24-48 change in C-telopeptide, PTH, or 25-OH vitamin D3. Vitamin D3 supplementation with 4,000 IU/day resulted in a significant reduction in the BTM P1NP compared with controls, suggesting that this intervention has potential to improve bone health during PrEP.

Long-Term Bone Scintigraphy Results After Intravenous Zoledronate in Paget's Disease of Bone.

Zoledronate produces long-term normalization of biochemical markers in Paget's disease but whether this implies the absence of active disease is unknown. We have determined whether bone scintigraphy, a more sensitive index of disease activity, is also normalized ≥5 years after treatment with zoledronate. A consecutive case series of 11 individuals with Paget's disease treated with zoledronate 5mg ≥5 years previously is reported. Eight patients received a single zoledronate infusion and were assessed 55-120 months later. Bone scintigraphy showed no evidence of active disease in four of these patients, and there was minimal residual disease activity in the other four. Three other patients required second infusions because of evidence of ongoing disease activity. In two of these, scintigraphy was normal ~90 months after their second infusions. In the third, further follow-up is not available. Procollagen-I N-terminal propeptide and total alkaline phosphatase were normal in all subjects at the time of bone scintigraphy. This case series confirms the high rate of response of Paget's disease to zoledronate, demonstrates the much greater sensitivity of scintigraphy compared with biochemical markers in detecting ongoing disease activity, and indicates that about one-third may be scintigraphically "cured" after one infusion; one-third have scintigraphically trivial disease activity subsequently, and the balance may require a second infusion. Scintigraphic "cure" is achievable after second infusions. Scintigraphy has an important place in the long-term management of Paget's patients following zoledronate, and should guide follow-up decisions in those with normal biochemical markers.

Intravenous Zoledronic Acid 5 mg on Bone Turnover Markers and Bone Mineral Density in East China Subjects with Newly Diagnosed Osteoporosis: A 24-month Clinical Study.

This randomized, double-blind, placebo-controlled study assessed the necessity of early intervention, safety and efficacy of intravenous zoledronic acid 5 mg/year in East China women with newly diagnosed osteoporosis at high risk of fracture during a 24-month treatment period. Subjects (57 [52-62] years old) were randomized 3:2 to zoledronic acid versus placebo (randomized at baseline, zoledronic acid [175 cases], placebo-zoledronic acid [110 cases]). The bone mineral density of the lumbar spine and total hip was measured every 6 months with the use of dual-energy X-ray absorptiometry. Serum procollagen I N-terminal pro-peptide (PINP) and serum C-telopeptide of type I collagen (CTX) levels were measured every 6 months. The primary end point was the rate of change in the bone mineral density at the posteroanterior spine. For subjects with measurements at 24 months, zoledronic acid significantly increased bone mineral density (BMD) at the lumbar spine (mean percent change ± SD, zoledronic acid 5.390% ± 0.854% versus placebo-zoledronic acid -1.038% ± 0.599%), the total hip (zoledronic acid 1.900% ± 0.262% versus placebo-zoledronic acid -1.631% ± 0.649%). Serum procollagen I N-terminal pro-peptide (PINP) and CTX decreased rapidly with zoledronic acid 5 mg treatment (P < 0.001 versus placebo at 6 month and 24 months) and changed from baseline in the zoledronic acid 5 mg and placebo-zoledronic acid 5 mg at 6 months by a mean of -66.348% and -75.375%, respectively (P < 0.001), and at 24 months by -49.950% and -52.325%, respectively (P < 0.001). No cases of serious adverse events were observed in two groups. Headache, pyrexia and myalgia occurred more commonly within the first 3 days after infusion with zoledronic acid 5 mg than with placebo (13.7% versus 2.1%, P = 0.0018; 28.0% versus 3.2%, P < 0.001; 21.7% versus 4.2%, P < 0.001, respectively). These data show that early application of zoledronic acid 5 mg/year was well stimulated and tolerated for bone mass in newly diagnosed east china subjects with osteoporosis in a 24-month treatment.

The Optimal Duration of PTH(1-34) Infusion Is One Hour per Day to Increase Bone Mass in Rats.

Parathyroid hormone (PTH) is a potential medicine for osteoporosis, and subcutaneous (s.c.) PTH treatment enhances bone mass; however, continuous infusion of PTH elicits bone resorption and induces bone loss. To clarify this contradictory phenomenon, we examined bone markers and bone mass in rats to assess the optimal duration of PTH(1-34) infusion. Continuous infusion of PTH at 1 µg/kg/h (Css, steady-state concentration ca. 300 pg/mL) for 1-4 h clearly stimulated the expression both of bone formation-related genes (c-fos, Wnt4, EphrinB2) and of bone resorption-related genes (tnfsf11, tnfsf11b, encoding receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG)), but s.c. treatment stimulated these genes only 1-h after the injection. Rats were treated with 1-, 2-, or 4-h infusions of PTH daily using a totally implanted catheter system, and the femoral bone mineral density (BMD) was measured at 4 weeks. The 1-h infusion of PTH significantly stimulated serum bone formation markers (procollagen I N-terminal propeptide (PINP) and osteocalcin) on day 14 and femoral BMD at 2 and 4 weeks, but the 4-h infusion of PTH did not enhance BMD. Since the 4-h infusion increased the levels of both the bone formation markers and a bone resorption marker (urinary C-terminal telopeptide of type 1 collagen (CTx)), the increased bone resorption may predominate over bone formation. The intermittent elevation of plasma PTH to 300 pg/mL for 1-h each day is optimal for increasing bone mass in rats. In osteoporosis therapy in human, using the optimal duration for the clinical dose of PTH may selectively stimulate bone formation.

The effects of a calcium-rich pre-exercise meal on biomarkers of calcium homeostasis in competitive female cyclists: a randomised crossover trial.

Cycling is recognised as a sport in which there is a high incidence of poor bone health. Sweat calcium losses may contribute to this.PurposeTo examine whether a calcium-rich pre-exercise meal attenuates exercise-induced perturbations of bone calcium homeostasis caused by maintenance of sweat calcium losses.MethodsUsing a randomized, counterbalanced crossover design, 32 well-trained female cyclists completed two 90 min cycling trials separated by 1 day. Exercise trials were preceded 2 hours by either a calcium-rich (1352 ± 53 mg calcium) dairy based meal (CAL) or a control meal (CON; 46 ± 7 mg calcium). Blood was sampled pre-trial; pre-exercise; and immediately, 40 min, 100 min and 190 min post-exercise. Blood was analysed for ionized calcium and biomarkers of bone resorption (Cross Linked C-Telopeptide of Type I Collagen (CTX-I), Cross Linked C-Telopeptide of Type II Collagen (CTX-II), Parathyroid Hormone (PTH), and bone formation (Procollagen I N-Terminal Propeptide (PINP)) using the established enzyme-linked immunosorbent assay technique.ResultsPTH and CTX-I increased from pre-exercise to post-exercise in both conditions but was attenuated in CAL (p < 0.001). PTH was 1.55 [1.20, 2.01] times lower in CAL immediately post-exercise and 1.45 [1.12, 1.88] times lower at 40 min post-exercise. CTX-I was 1.40 [1.15, 1.70] times lower in CAL at immediately post-exercise, 1.30 [1.07, 1.57] times lower at 40 min post-exercise and 1.22 [1.00, 1.48] times lower at 190 min post-exercise (p < 0.05). There was no significant interaction between pre-exercise meal condition and time point for CTX-II (p = 0.732) or PINP (p = 0.819).ConclusionThis study showed that a calcium-rich pre-exercise breakfast meal containing ~1350 mg of calcium consumed ~90 min before a prolonged and high intensity bout of stationary cycling attenuates the exercise induced rise in markers of bone resorption – PTH and CTX-I.Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12614000675628

SAT0341 Pathways linking adiposity and bone properties in early adolescence: A population-based study on the roles of leptin and adiponectin

BackgroundThe paradoxical role of the adipose tissue on bone homeostasis is increasingly recognized, resulting partly from the mechanical osteogenic stimulus imposed by fat mass, but also from the possible deleterious...

Low Molecular Weight Iron Dextran Increases Fibroblast Growth Factor‐23 Concentration, Together With Parathyroid Hormone Decrease in Hemodialyzed Patients

Fibroblast growth factor (FGF)-23 inhibits PTH production. Elevated FGF-23 and parathyroid hormone (PTH) levels are characteristic of hemodialyzed patients. Iron polymaltose was shown to increase FGF-23 concentration. The effect of intravenous low molecular weight iron dextran (LMID) on these hormones and bone metabolism has not been studied in hemodialysis (HD). Twelve HD patients were prospectively followed up for 3 weeks after a single infusion of LMID. Calcium, phosphate, FGF-23, PTH, degradation products of C-terminal telopeptides of type I collagen (CTX) and procollagen I N-terminal propeptide (PINP) were measured prior to, and at week 1 and week 3 after the LMID administration. FGF-23 increased significantly from 453.4 (68.6-3971.5) pg/mL at baseline to 971.8 (779.5-3361.4) pg/mL (P = 0.001) at week 1 and started to decrease toward the initial value at week 3. The changes were accompanied by a significant decline in PTH from 367.6 (21.4-1487.4) pg/mL at baseline to 315.7 (16.4-1339.8) pg/mL (P = 0.018) at week 1 and subsequently began to increase toward the initial values. Phosphate, calcium, CTX and PINP did not change over the study course. LMID causes an increase in FGF-23 concentration together with a decrease in PTH. Our study highlights a pathophysiological element, which may connect suppression of parathyroid glands with intravenous iron supplementation.

Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-Month, randomized, placebo-controlled, double-blind and 12-month open-label phases

This multicenter study assessed the safety and efficacy of teriparatide 20 µg/day in Japanese men and women with osteoporosis at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled treatment period followed by second and third treatment periods (to 18 and 24 months, respectively,) in which all subjects received open-label teriparatide. Subjects (93% female; median age 70 years) were randomized 2:1 to teriparatide versus placebo (randomized at baseline, teriparatide n = 137, placebo–teriparatide n = 70; entering the second period, teriparatide n = 119, placebo–teriparatide n = 59; entering the third period, teriparatide n = 102, placebo–teriparatide n = 50). For subjects with measurements at 12 months, teriparatide significantly increased bone mineral density (BMD) at the lumbar spine L2–L4 (mean percent change ± SD, teriparatide 10.04 ± 5.23% versus placebo–teriparatide 0.19 ± 4.33%), the femoral neck (teriparatide 2.01 ± 4.63% versus placebo–teriparatide 0.44 ± 3.97%), and the total hip (teriparatide 2.72 ± 4.04% versus placebo–teriparatide − 0.26 ± 3.42%). In the placebo–teriparatide group at 24 months (12-month teriparatide dosing) BMD increased by 9.11 ± 5.14% at the lumbar spine, 2.19 ± 4.81% at the femoral neck and 2.46 ± 3.54% at the total hip. In the teriparatide group at 18 and 24 months, BMD increased from baseline at the lumbar spine by 11.93 ± 5.79% and 13.42 ± 6.12%, respectively; at the femoral neck by 2.68 ± 4.45% and 3.26 ± 4.25%, respectively; and at the total hip by 3.02 ± 3.79% and 3.67 ± 3.98%, respectively. Serum procollagen I N-terminal pro-peptide (PINP) increased rapidly with teriparatide treatment ( P < 0.001 versus placebo at 1 month) and changed from baseline in the teriparatide and placebo–teriparatide groups at 12 months by a median of 78.95% and − 17.23%, respectively, ( P < 0.001) and at 24 months by 49.24% and 76.12%, respectively. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs were comparable in the teriparatide and placebo–teriparatide groups. These data show that teriparatide 20 µg/day was well tolerated and stimulated bone formation in Japanese subjects with osteoporosis at high risk of fracture during 18 and 24 months of treatment.

Short-Term Changes in Serum PINP Predict Long-Term Changes in Trabecular Bone in the Rat Ovariectomy Model

Serum procollagen I N-terminal propeptide (PINP) is a sensitive bone formation marker in humans. We have developed a nonradioactive immunoassay for rat PINP and studied PINP as a bone formation marker in the rat ovariectomy (OVX) model. Two OVX studies were performed with 3-month-old rats, both including measurement of PINP, C-terminal cross-linked telopeptide of type I collagen (CTX), and N-terminal mid-fragment of osteocalcin. A pilot 14-day study contained a sham-operated control group and an OVX group, and an extensive 8-week study contained a sham-operated control group and OVX groups receiving vehicle and 17 beta-estradiol (E2, 10 microg/kg/day s.c.). The bone markers were measured before the operation and at days 2, 4, 7, 10, and 14 in the pilot study and before the operations and at 2 and 8 weeks in the extensive study. Trabecular bone parameters were determined by peripheral quantitative computed tomography and histomorphometry from tibial metaphysis in the extensive study. The rat PINP immunoassay had the following characteristics: intra-assay coefficient of variation (CV) 2.8%, interassay CV 7.5%, dilution linearity 95%, and recovery 107%. PINP increased significantly during the first 2 weeks after OVX and returned to sham level at 8 weeks. E2 prevented the increase caused by OVX. Changes in PINP at 2 weeks correlated strongly with changes in CTX and osteocalcin at 2 weeks and with trabecular bone parameters at 8 weeks. As a conclusion, short-term changes in PINP predict long-term changes in trabecular bone parameters, suggesting that PINP is a reliable marker of bone formation in the rat OVX model.

Pravastatin therapy increases procollagen I N-terminal propeptide (PINP), a marker of bone formation in post-menopausal women

Background: The aim of our study was to evaluate whether pravastatin treatment affected biochemical markers of bone turnover. Methods: Thirty-six hypercholesterolemic post-menopausal women, not on hormonal replacement therapy, were selected from a population study evaluating factors affecting cholesterol response to pravastatin. After a 6-week period on a 30% fat diet, participants received treatment with 20 mg/day of pravastatin during a 16-week follow-up period. Pre- and post-treatment samples were analyzed for procollagen I aminoterminal peptide (PINP) and bone alkaline phosphatase (bAP) as markers of bone formation, carboxyterminal telopeptide of collagen I (CTX) as a marker of bone resorption, and procollagen III aminoterminal propeptide (PIIINP) as a marker of fibrogenesis. Results: Total cholesterol decreased from 7.26±0.83 to 6.1±0.77 mmol/l with pravastatin treatment. PINP levels significantly increased (from 33.6±13 to 37.4±16, p=0.03) without changes in bAP or CTX. Individual changes in PINP correlated with individual reduction in cholesterol levels ( r=0.337, p=0.04). There was no significant change in PIIINP concentration. Conclusions: Pravastatin treatment increased PINP levels, a marker of bone formation, in hypercholesterolemic, post-menopausal women, without affecting bone resorption. PIIINP concentration, a marker of liver fibrogenesis, was not affected by the treatment.