Background: Zoledronate 5 mg intravenous (IV) annually is approved for treatment of post-menopausal osteoporosis. Zoledronate 4 mg which is approved for the treatment of cancer related hypercalcemia can be an alternative for Asian women who have smaller stature.

Objectives: To examine the efficacy and safety of Zoledronate 4 mg IV annually for the treatment of post-menopausal osteoporosis.

Method: A prospective open-labeled study was performed on 33 post-menopausal osteoporosis patients. All patients received a dose of IV Zoledronate 4 mg. Bone mineral density (DXA) was examined at baseline and 12 months after treatment. Beta-C-terminal telopeptide (β-CTX) and procollagen type-1-amino-terminal propeptide (P1NP) were obtained at baseline, 6, and 12 months after treatment. Adverse events were recorded.

Results: The mean age (SD) was 69 (11.1) years old. The lumbar spine BMD increased significantly from the mean (SD) lumbar spine BMD at baseline of 0.833 (0.132) g/cm² to 0.862 (0.132) after treatment (p = 0.001). There was no significant differences in total hip and femoral neck BMDs between baseline and 12 months after treatment. The β-CTX and P1NP decreased significantly from the mean (SD) of 0.44 (0.24) and 55.57 (38.6) ng/ml at baseline to 0.21 (0.11) and 27.26 (10.95) ng/ml after treatment (p < 0.001), respectively. Infusion reaction was observed in five patients. There were two fractures observed.

Conclusion: Zoledronate 4 mg improved lumbar BMD and decreased β-CTX and P1NP significantly after 12 months of treatment. Zoledronate 4 mg could be an alternative to Zoledronate 5 mg for the treatment of post-menopausal osteoporosis.

Keywords: Bone mineral density; Osteoporosis; Postmenopausal women; Zoledronic acid.

The present study compared the first (EC1) and second (EC2) bouts of whole-body eccentric exercises to examine the effects of the magnitude of muscle damage on changes in blood bone markers. Fifteen sedentary young men performed nine eccentric exercises of arm, leg and trunk muscles, and repeated them two weeks later. Blood samples were taken before and two hours and one to five days following each bout to analyze plasma creatine kinase (CK) activity and myoglobin concentration, serum tartrate resistant acid phosphatase (TRAP), type 1 C-terminal telopeptide (CTX-1), procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BAP), undercarboxylated-osteocalcin (ucOCN), carboxylated-osteocalcin (cOCN), and leptin concentrations. All except ucOCN changed significantly (P<0.05) after both bouts. When comparing bouts for peak changes, P1NP (bone formation marker) and CTX-1 (bone resorption marker) increased less after EC2 (peak: 137±96% and 7±6%, respectively) than after EC1 (146±80% and 30±21%, respectively), whereas BAP (bone formation marker) increased more after EC2 (18±16%) than after EC1 (4±15%) (P<0.05). Leptin (49±58%) and cOCN (14±10%) increased more (P<0.05) after EC2 than after EC1 (-30±15%, 9±26%). Significant (P<0.05) correlations were evident between peak CK activity and peak CTX-1 (r=0.847), P1NP (r=0.815), BAP (r=-0.707), ucOCN (r=0.627), cCON (r=-0.759) and leptin (r=-0.740) changes after EC1, but many of these correlations disappeared after EC2. This was also found for the relationships between other muscle damage markers (myoglobin, muscle soreness and muscle strength) and the bone markers. It was concluded that bone turnover was affected by eccentric exercise, but muscle damage was unfavorable for bone formation.

Keywords: C-terminal telopeptide of type I collagen; bone-specific alkaline phosphatase; creatine kinase activity; lengthening muscle action; muscle damage; procollagen type I c-terminal peptide; repeated bout effect; tartrate-resistant acid phosphatase.

Objective: We examined the role of vitamin D on volumetric bone mineral density (vBMD) and architecture during the first week's post-fracture in postmenopausal women (PMW) with distal radial fractures (DRF) treated conservatively using peripheral Quantitative Computed Tomography (pQCT).

Methods: Patients were classified into 2 groups according to initial median 25(OH)D level; Group A (25(OH)D ≥15 ng/ml) and group B (25(OH)D <15 ng/ml). All patients were followed for 12 weeks at three visits: baseline, 6 weeks and 12 weeks post fracture. pQCT was performed at baseline in fractured and contralateral non-fractured radius and at 6^th and 12^th week on the fractured side.

Results: 39 patients completed the protocol. Mean 25(OH)D levels were 15.60±7.35 ng/ml (3.5-41.7). Trabecular (trab) bone mineral content (BMC) and trabvBMD increased at 6 wk. vs. baseline (p<0.001). Cortical BMC, cortvBMD and cross- sectional area (CSA) progressively decreased (p<0.001) during the 12 weeks. There was no interaction between baseline 25(OH)D levels and changes in trabecular and cortical BMC, vBMD and CSA. Advanced age and higher CTX and P1NP were associated with higher cortical bone loss.

Conclusion: Vitamin D deficiency does not affect the early architectural changes after a DRF. Advanced age and higher bone remodeling were associated with higher cortical bone loss, probably related to immobilization and independent of vitamin D levels.

Keywords: Osteoporosis; Peripheral Quantitative Computed Tomography; Radial Fractures; Vitamin D.

Background: Biochemical markers of bone turnover are lower in patients with type 2 diabetes, which may be explained by genetic variants being associated with type 2 diabetes and bone turnover as well as environmental factors. We hypothesized that bone turnover markers associate with and predict changes in glucose homeostasis after control for genetics and shared environment.

Methods: 1071 healthy, non-diabetic (at baseline, 1997-2000) adult mono- and dizygotic twins participating in the prospective study GEMINAKAR were reassessed between 2010 and 2012 with clinical evaluation, biochemical tests and oral glucose tolerance test. Fasting bone turnover markers (CTX, P1NP and osteocalcin) were measured. The association between bone turnover, glucose homeostasis and the ability of bone turnover markers to predict changes in glucose homeostasis were assessed in cross-sectional and longitudinal analyses. Analyses were performed both at an individual level and adjusted for shared environmental and genetic factors.

Results: Glucose levels increased with age, and 33 (3%) participants had developed type 2 diabetes at follow-up. In women, bone turnover markers increased with age, whereas for men only osteocalcin increased with age. Bone turnover markers were not associated with fasting glucose, insulin, or HOMA-IR at baseline or follow-up before or after adjustment for age, sex, BMI, smoking, and use of medication at baseline. Variation in bone turnover markers was mainly explained by unique environmental factors, 70%, 70% and 55% for CTX, P1NP and osteocalcin, respectively, whereas additive genetic factors explained 7%, 13% and 45% of the variation in CTX, P1NP and osteocalcin.

Conclusions: Bone turnover markers were not associated with baseline plasma glucose levels and did not predict changes in glucose homeostasis. Variation in bone turnover markers is mainly explained by environmental factors, however, compared to CTX and P1NP, genetic factors have a larger impact on osteocalcin levels.

Keywords: Bone turnover markers; Glucose homeostasis; Heritability; Twins.

Suppression of insulin-like growth factor 1 (IGF-1) and leptin secondary to low energy availability (LEA) may contribute to adverse effects on bone health. Whether a high-protein diet attenuates these effects has not been tested. Seven men completed three five-day conditions operationally defined as LEA (15 kcal kg fat-free mass (FFM)^-1 day^-1) with low protein (LEA-LP; 0.8 g protein·kg body weight (BW)^-1), LEA with high protein (LEA-HP; 1.7 g protein·kg BW^-1) and control (CON; 40 kcal·kg FFM^-1·day^-1, 1.7 g protein·kg BW^-1). In all conditions, participants expended 15 kcal·kg FFM^-1·day^-1 during supervised cycling sessions. Serum samples were analyzed for markers of bone turnover, IGF-1 and leptin. The decrease in leptin during LEA-LP (-65.6 ± 4.3%) and LEA-HP (-54.3 ± 16.7%) was greater than during CON (-25.4 ± 11.4%; p = 0.02). Decreases in P1NP (p = 0.04) and increases in CTX-I (p = 0.04) were greater in LEA than in CON, suggesting that LEA shifted bone turnover in favour of bone resorption. No differences were found between LEA-LP and LEA-HP. Thus, five days of LEA disrupted bone turnover, but these changes were not attenuated by a high-protein diet.

Keywords: aerobic exercise; caloric restriction; energy deficit.

Objectives: SLE is a chronic autoimmune disease, which can affect the level of bone metabolism and increase the risk of osteoporosis and fracture. The purpose of this research is to study the effect of SLE on bone turnover markers without the influence of glucocorticoids.

Methods: A total of 865 female subjects were recruited from Zhejiang Provincial People's Hospital and the First Hospital of Jiaxing, including 391 SLE patients without the influence of glucocorticoids and 474 non-SLE people. We detected Bone turnover markers including amino-terminal propeptide of type 1 procollagen (P1NP), C-terminal turnover of β - I collagen (β-CTX), N-terminal midfragment of osteocalcin (NMID) and 25(OH)D, and analyzed the difference in Bone turnover markers between the SLE group and the control group, as well as the influence of age and season on bone metabolism in female SLE patients.

Results: In the SLE group, the average age was 43.93±13.95 years old. In the control group, the average age was 44.84±11.42 years old. There was no difference between the two groups (t = 1.03, P = 0.30). P1NP, NMID and 25(OH)D in the SLE group were significantly lower than those in the control group (Z = 8.44, p < 0.001; Z = 14.41, p < 0.001; Z = 2.19, p = 0.029), and β-CTX in the SLE group was significantly higher than that in the control group (Z = 2.61, p = 0.009). In addition, the levers of β-CTX, NMID, P1NP and 25(OH)D in older SLE female patients were statistically significantly higher than those in younger (ρ = 0.104, p = 0.041; ρ = 0.223, p < 0.001; ρ = 0.105, p = 0.038; ρ = 0.289, p < 0.001). Moreover, β-CTX reached a high value in summer and PINP reached a low value in winter.

Conclusion: The bone formation markers of female SLE patients without glucocorticoid were lower than those of normal people and the bone resorption marker was higher than that of normal people. The 25 (OH) D of female SLE patients without glucocorticoid was lower than that of normal people. The risk of osteoporosis and fracture may be higher in elderly women with SLE. The bone resorption level of female SLE patients is high in summer and the bone formation level is low in winter.

Keywords: P1NP; Systemic lupus erythematosus; β-CTX.

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

Keywords: Wnt/β-catenin signaling; bone deterioration; osteocytes; pulsed electromagnetic fields; type 2 diabetes mellitus.

In pregnancy, changes in maternal calcium (Ca) economy occur to satisfy fetal Ca demand. It is unclear whether maternal mineral reserves facilitate these requirements and no data exist from sub-Saharan Africa. The aim was to determine skeletal changes with pQCT and bone biochemistry between early second and third trimesters. Pregnant rural Gambians aged 18-45 years (n = 467) participating in a trial of antenatal nutritional supplements (ISRCTN49285450) had pQCT scans and blood collections at mean(SD) 14 (3) and 31 (1) weeks gestation. Outcomes were pQCT: radius/tibia 4% total vBMD, trabecular vBMD, total CSA, 33%/38% radius/tibia cortical vBMD, BMC, total CSA; biochemistry: collagen type 1 cross-linked β-C-telopeptide (β-CTX), type 1 procollagen N-terminal (P1NP), parathyroid hormone (PTH) and 1,25(OH)₂ D. Independent t-tests tested whether pooled or within-group changes differed from 0. Multiple regression were performed adjusting for age. Data for change are expressed as mean[CI 2.5, 97.5]%. Radius trabecular vBMD, cortical vBMD and BMC increased by 1.15 [0.55, 1.75]%, 0.41 [0.24, 0.58]%, and 0.47 [0.25, 0.69]%. Tibia total and trabecular vBMD increased by 0.34 [0.15, 0.54]% and 0.46 [0.17, 0.74]%, while tibia cortical vBMD, BMC, and cortical CSA increased by 0.35 [0.26, 0.44]%, 0.55 [0.41, 0.68]% and 0.20 [0.09, 0.31]% respectively. CTX, PTH and 1,25(OH)₂ D increased by 23.0 [15.09, 29.29]%, 13.2 [8.44, 19.34]%, and 21.0 [17.67, 24.29]%, while P1NP decreased by 32.4 [-37.19, -28.17]%. No evidence of mobilization was observed in the peripheral skeleton. Resorption, while higher in late- versus early-gestation, was lower throughout pregnancy compared to non-pregnant non-lactating (NPNL) in the same community. Formation was lower in late pregnancy than in early, and below NPNL levels. This suggests a shift in the ratio of resorption to formation. Despite some evidence of change in bone metabolism, in this population, with habitually low Ca intakes, the peripheral skeleton was not mobilized as a Ca source for the fetus.

Keywords: AGING, BONE MODELING AND REMODELING; ANALYSIS/QUANTIFICATION OF BONE, Bone QCT/μCT; Biochemical markers of bone turnover; EPIDEMIOLOGY, General population studies.

Objectives: To compare the efficacy of denosumab and alendronate on raising spine bone mineral density (BMD) in long-term glucocorticoid (GC) users.

Methods: Adult patients receiving long-term prednisolone (≥2.5 mg/day for ≥1 year) were recruited and randomized to either subcutaneous denosumab (60 mg/6 months) or oral alendronate (70 mg/week). BMD (lumbar spine, femoral neck, hip) and bone markers (serum P1NP and CTX) were measured at month 0, 6 and 12. The difference in spine BMD (primary outcome) at month 12 was compared between the two groups.

Results: 139 subjects were recruited (age 50.0 ± 12.7 years; 96% women): 69 assigned denosumab and 70 assigned alendronate. At entry, 73(53%) patients were osteoporotic and 82(59%) patients were naive to the bisphosphonates. Baseline clinical characteristics and BMD values were similar in the two groups. At month 12, a significant gain in mean BMD at the lumbar spine (+3.5 ± 2.5%;p < 0.001), hip (+0.9 ± 2.8%;p = 0.01) and femoral neck (+1.04 ± 4.1%;p = 0.047); was observed in denosumab-treated patients, whereas the corresponding change was +2.5 ± 2.9% (p < 0.001), +1.6 ± 2.7% (p < 0.001) and + 1.5 ± 3.9% (p = 0.002) in the alendronate group. The spine, but not the hip or femoral neck, BMD at month 12 was significantly higher in the denosumab than alendronate group after adjustment for baseline BMD values, age, sex, osteoporosis risk factors and the cumulative prednisolone doses received in one year. The drop in P1NP and CTX was significantly higher in the denosumab than alendronate group. Frequency of adverse events (AEs), including infections, was similar in the two treatment arms. Seven patients withdrew from the study but not related to AEs.

Conclusions: In patients receiving long-term GCs, denosumab is superior to alendronate in raising the spine BMD after 12 months. Both drugs are well-tolerated.

Keywords: Bisphosphonate; Corticosteroids; Denosumab; Fracture; Osteoporosis.

Objectives: Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aim of this study was to examine the associations between subclinical atherosclerosis, assessed by intima-media thickness (IMT), and regulators of bone formation, markers of bone turnover and bone mineral density (BMD) in patients with RA.

Methods: Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were consecutively included in a study of development of atherosclerosis. Ultrasound measurement of IMT of the common carotid artery was undertaken at inclusion (T0) and after 11 years (T11) (n=54). Bone turnover biomarkers were examined in samples collected at T0 and T11. BMD was assessed at T11.

Results: In patients with RA, osteocalcin (OCN) and osteoprotegerin (OPG) measured at T11 were significantly associated with IMT at T11, adjusted for systolic blood pressure (SBP) and age. BMD at T11 and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and carboxy-terminal crosslinked C-terminal telopeptide (CTX) were not associated with IMT. OPG, OCN and sclerostin at T0 were significantly associated with IMT at T11, and OPG and OCN at T0 were associated with change in IMT from T0 to T11. The associations between IMT and bone biomarkers were stronger in patients with joint erosions at onset of RA, than in patients with non-erosive disease.

Conclusions: Atherosclerosis in patients with RA is associated with OPG and OCN, but not with BMD or markers reflecting ongoing bone turnover, indicating that atherosclerosis is not associated with bone turnover per se.

Introduction: To investigate the clinical effectiveness of combination treatment of percutaneous kyphoplasty (PKP) and zoledronic acid (ZOL) in the treatment of osteoporotic vertebral compression fracture (OVCF).

Materials and methods: We searched studies investigating the PKP combined with ZOL in the treatment of OVCF. We used a fixed-effects or random-effects model to analyze the bone mineral density (BMD), visual analogue scale (VAS), Oswestry disability index (ODI), bone markers (N-MID, β-CTX, and P1NP) and adverse events, expressed as weight mean difference (WMD) and risk ratio (RR) with 95% confidence interval (95% CI).

Results: We identified 5 cohort studies with a total of 440 patients. Compared with PKP alone, the combination treatment of PKP and ZOL significantly reduced the VAS score at 6 months (WMD = - 0.78, 95% CI - 1.42, - 0.14; P = 0.018), and 12 months (WMD = - 0.98, 95% CI - 1.46, - 0.51; P < 0.001). Moreover, the combination treatment also improved the BMD at 6 (WMD = 0.06, 95% CI 0.01, 0.11, P = 0.016) and 12 months (WMD = 0.20, 95% CI 0.03, 0.36, P = 0.018) after treatment. The ODI score in the combination group was significantly lower than in PKP group at 6, 12 and 24 months after treatment (at 6 months: WMD = - 9.25, 95% CI - 13.62, - 4.87 P < 0.001; at 12 months: WMD = - 9.21, 95% CI - 11.91, - 6.50, P < 0.001; at 24 months: WMD = - 7.26, 95% CI - 11.39, - 3.14, P = 0.001). The N-MID and P1NP values were found to be significantly lower in the combination group than the PKP group, but the β-CTX value was similar between the two groups. There was no significant difference in incidence of adverse events between the two groups, but more adjacent vertebral fractures and bone cement leakage occurred in PKP alone group.

Conclusion: In patients with OVCF, combination treatment of PKP and ZOL showed more effective than PKP alone in improving BMD and bone marker levels, relieving pain, as well as reducing the risk of new fractures. More large-scale RCTs are needed to verify our findings.

Keywords: Meta-analysis; Osteoporotic vertebral compression fracture; Percutaneous kyphoplasty; Zoledronic acid.

The process of bone loss occurs silently and progressively with age, often appearing as osteopenia or osteoporosis or related fractures. Given the rapid raise in disease burden and socio-economic costs of these conditions worldwide, drug therapy combined with physical activity can be a useful strategy and bone biomarkers, can represent a useful evaluation tool to assess their effects. The objective of this systematic review, conducted according to PRISMA statement, was to investigate the effects of physical activity interventions combined with drug treatments on bone biomarkers in people with osteopenia and osteoporosis. Through PubMed, Cochrane, Cinahl, Embase, Trip, a comprehensive literature search was performed. Each study's quality was assessed according to the Cochrane risk-of-bias tool. Out of 582 identified articles, 50 full texts were screened. Only one matched the eligibility criteria. The study, scored as high quality, showed, in both experimental and control groups, an increase of CTX and P1NP bone biomarkers, without statistically significant differences. Based on available evidence, no exhaustive conclusion can be drawn. However, this systematic review critically analyses the literature, highlighting the knowledge gap on combined treatments efficacy assessed by bone biomarkers. Moreover, an outlook is provided for the planning of future studies.

Keywords: bone biomarkers; exercise; osteopenia; osteoporosis; pharmacological treatment; physical activity; training.

Introduction: Romosozumab reportedly increases bone mineral density (BMD) potently but might adversely affect cardiovascular disease (CVD). We evaluated the efficacy of romosozumab in osteoporotic HD patients with a high risk of fracture.

Materials and methods: This was a single-center 1-year study in Japanese HD patients. Among 96 HD romosozumab-treated HD patients with high risk of fracture, 76 HD patients completed 1 year of subcutaneous administration of romosozumab (210 mg/4 weeks) for 1 year. Romosozumab-untreated HD patients (n = 55) were also included. Changes in BMD and serum markers, together with fracture occurrence, and CVD events, were monitored.

Results: During romosozumab treatment of 76 HD patients, BMD time-dependently increased significantly by 15.3% ± 12.9% at the lumbar spine (L1-4), and 7.2% ± 8.3% at the femoral neck at 1 year. Serum BAP and total P1NP increased significantly and serum TRACP-5b decreased at 4 weeks. Fragility fractures occurred in three (3.8%) patients. Hypocalcemia occurred at 4-48 weeks despite the increased dosing of active vitamin-D derivatives, but without any symptom. New CVD events occurred in 5.2% of romosozumab-treated HD patients and10.9% in romosozumab-untreated HD patients.

Conclusions: BMD was increased significantly during romosozumab treatment at the lumbar spine, and the femoral neck, respectively, at 1 year in HD patients. Hypocalcemia occurred but without any intolerable event. There was no apparent increase in CVD events during 1 year of study, suggesting romosozumab as a promising agent for HD patients with severe osteoporosis.

Keywords: Bone mineral density; Hemodialysis; Osteoporosis; Romosozumab; TRACP-5b.

Objective: Children with obesity are known to have reduced bone density and are at a higher risk for fractures. This may be caused by decreased physical activity or a metabolic phenomenon. In this study, we evaluated associations of physical activity with bone metabolism in children and adolescents with and without obesity.

Methods: Results from 574 visits of 397 subjects, 191 girls and 206 boys aged five to 18 years (mean: 11.7±2.8) representing 180 children with (mean BMI SDS 2.5 ± 0.4) and 217 without obesity (mean BMI SDS 0.2 ± 1.0) from the LIFE Child study, a population-based cohort of children/adolescents with normal weight and with obesity were analyzed for the impact of their daily physical activity (MET/day, SenseWear Accelerometer) on serum SDS levels for bone formation (alkaline phosphatase, osteocalcin, procollagen type I N propeptide [P1NP]), bone resorption (beta-crosslaps), and calcium homeostasis (parathormone, OH-25-vitamin D) by a linear regression model adjusted for sex- and age-based differences.

Results: For male subjects, BMI SDS significantly influenced the association of physical activity to PTH, vitamin D, and beta-crosslaps SDS levels. A higher physical activity was accompanied by increased PTH but decreased vitamin D SDS levels in children with normal weight. In males with obesity, all levels remained unaltered. In females, BMI SDS significantly impacted the association of physical activity to PTH, vitamin D, P1NP, beta-crosslaps, and osteocalcin SDS levels. In females with obesity, higher physical activity was related to higher SDS levels of vitamin D, P1NP, and beta-crosslaps. In contrast, in normal weight females, only PTH SDS was higher.

Conclusions: The effect of daily physical activity on bone metabolic markers and calciotropic hormones depends significantly on gender and BMI SDS. However, higher levels of physical activity were associated with increased bone turnover for female subjects with obesity onlyThus, motivating especially girls with obesity to be physically active may help improve their bone health.

Keywords: SDS; bone marker; children; metabolic equivalents; metabolism; obesity; physical activity.

Objectives: This study investigated the impact of the MR antagonist (MRA) eplerenone on LVM in type 2 diabetes patients at high risk for cardiovascular disease (CVD).

Background: MRA activation is associated with cardiac fibrosis and increased left ventricular mass (LVM), which is an independent predictor of adverse CVD, including heart failure in patients with type 2 diabetes.

Methods: A prespecified analysis of secondary endpoints in a randomized, double-blinded clinical trial of 140 patients with type 2 diabetes at high risk of or established CVD. Patients were randomized to receive high-dose eplerenone therapy (100 mg-200 mg) or placebo as an add-on to standard care for 26 weeks. Indexed LVM (LVMi) and T1 time were measured using cardiac magnetic resonance (CMR) imaging. Biomarkers included N-terminal pro-B-type natriuretic peptide (NT-proBNP), pro-collagen type I N-terminal propeptide (P1NP), and type III N-terminal propeptide (P3NP).

Results: Of 140 patients in the MIRAD trial, 104 patients were subject to CMR imaging (eplerenone: 54 patients; placebo: 50 patients). Mean LVMi at baseline was 74.2 ± 16 g/m². The treatment effect (ie, between-group differences) was a decrease of 3.7 g/m² following the eplerenone treatment (95% CI: -6.7 to -0.7; P = 0.017), with a corresponding decrease in absolute LVM. Plasma NT-proBNP concentrations decreased by 22% (P = 0.017) using eplerenone compared with placebo, and P1NP decreased 3.3 ng/mL (P = 0.019). No differences in T1 times or P3NP concentrations were observed between groups.

Conclusions: The addition of high-dose eplerenone in high-risk type 2 diabetes was associated with a clear reduction in LVMi and in NT-proBNP and P1NP levels, which may suggest a clinical benefit in heart failure prevention. (EU Clinical trials: Mineralocorticoid Receptor Antagonists in Type 2 Diabetes [MIRAD]; 2015-002519-14).

Keywords: cardiovascular risk; fibrosis; left ventricular mass regression; mineralocorticoid receptor antagonist; preserved ejection fraction; type 2 diabetes.

Background: Bone disease in primary hyperparathyroidism is a clear indication for surgical treatment. However, it is not known whether surgery benefits hypercalcemic primary hyperparathyroidism and normocalcemic primary hyperparathyroidism equally. The aim of our study was to evaluate the bone changes in patients undergoing parathyroidectomy based on the biochemical profile 1 and 2 years after surgery.

Methods: This prospective study included 87 consecutive patients diagnosed with primary hyperparathyroidism who underwent surgery between 2016 and 2018. Bone densitometry (1/3 distal radius, lumbar, and femur) and bone remodeling markers (osteocalcin, type 1 procollagen [P1NP], β-cross-linked telopeptide of type I collagen [BCTX]) were performed preoperatively and postoperatively. Postoperative changes in bone mineral density and bone markers were compared and evaluated according to the clinical characteristics and the individual biochemical profile.

Results: One year after surgery, all patients showed an increase in bone mineral density at the lumbar site (mean, 0.029 g/cm²; range, 0.017-0.04; P < .001) and femur neck (mean, 0.025 g/cm²; range, 0.002-0.05; P < .001); however, there were no changes in the distal third of the radius (mean, -0.003 g/cm²; range, -0.008 to 0.002; P = NS). There were no significant differences when comparing normocalcemic primary hyperparathyroidism and hypercalcemic primary hyperparathyroidism. Serum osteocalcin (37 ± 17.41), P1NP (67.53 ± 31.81) and BCTX (0.64 ± 0.37) levels were elevated before surgery. One year after the surgery, we observed a significant decrease in P1NP (33.05 ± 13.16, P = .001), osteocalcin (15.80 ± 6.19, P = .001), and BCTX (0.26 ± 0.32, P < .001) levels.

Conclusion: Our findings indicate that parathyroidectomy has similar benefits for normocalcemic primary hyperparathyroidism and hypercalcemic primary hyperparathyroidism in terms of bone improvement. Although the most substantial improvement occurred during the first postoperative year in both groups, we consider that studies with longer follow-up are warranted.

Objective: The primary purpose of this cross-sectional study was to investigate the characteristics of age-related changes in bone microstructure on high-resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) on dual-energy X-ray absorptiometry (DXA), and bone-related biochemical markers in men. The secondary purpose of this study was to examine how bone microstructure is related to aBMD and biochemical markers.

Methods: The subjects were 128 healthy Japanese men (20-97 years old). Bone microstructure was measured in the distal radius and tibia using second-generation HR-pQCT; aBMD in the proximal femur and lumbar spine was measured with DXA; and tartrate-resistant acid phosphatase-5b (TRACP-5b), type I procollagen-N-propeptide (P1NP), 25(OH) vitamin D, and pentosidine concentrations were measured by blood tests.

Results: In trabecular bone, the trabecular volumetric BMD (Tb.vBMD) and trabecular number (Tb.N) were lower with age (r = -0.23, -0.35) (r = -0.36,-0.33), and trabecular separation (Tb.Sp) and the star volume of marrow space (V*ms) were higher with age (r = 0.29, 0.41) (r = 0.34, 0.38) in both the radius and tibia. In cortical bone, cortical volumetric BMD (Ct.vBMD) was lower with age (r = -0.25, -0.52), and cortical porosity (Ct.Po) was higher with age (r = 0.67, 0.62) in both the radius and tibia. In the tibia, cortical thickness (Ct.Th) and cortical area (Ct.Ar) were lower with age (r = -0.40) (r = -0.43), whereas, in the radius, they were maintained, and periosteal perimeter (Ct.Pm) was higher with age (r = 0.35). aBMD in the proximal femur and P1NP were lower, and pentosidine was higher with increased age, whereas aBMD in the lumbar spine, TRACP-5b, and 25(OH) vitamin D had no relationships with age. DXA and HR-pQCT showed strong correlations particularly with femoral aBMD and tibial Tb.vBMD and Ct.Ar (r = 0.61) (r = 0.61), whereas no DXA parameters were related with Ct.Po. In correlations between biochemical markers and HR-pQCT, TRACP-5b and total P1NP were negatively correlated with Ct.vBMD (r = -0.31) (r = -0.35), but almost no other correlations were seen.

Conclusions: Age-related changes of the bone microstructure in men were characterized by decreases in trabecular and cortical vBMD associated with decreased trabecular number, cavitation of the trabecular structure, and increased cortical porosity. Femoral aBMD was strongly related to bone microstructure in the tibia, whereas both lumbar aBMD and femoral aBMD were not related to Ct.Po, and biochemical markers showed almost no relationships with bone microstructure.

Keywords: Bone microstructure; Bone turnover marker; Dual-energy X-ray absorptiometry; High-resolution peripheral quantitative computed tomography (HR-pQCT); Male osteoporosis.

Context: Foods containing vitamin D reduce the deficiency of this vitamin and improve bone turnover.

Objective: To discuss effects of the intake of vitamin D-fortified foods in isolated form or associated with calcium on bone remodeling in postmenopausal women.

Data sources: PubMed, Lilacs, Scopus, and Bireme databases. OpenThesis and Google Scholar were searched as "grey literature". Medical subject headings or similar terms related to food fortified with vitamin D and bone in postmenopausal women were used.

Data extraction: Information was collected on study methodology and characteristics of studied populations; dosage; the food matrix used as the fortification vehicle; duration of intervention; dietary intake; 25-hydroxyvitamin D [25(OH)D] levels; serum parathyroid hormone (PTH) concentrations; bone resorption and/or formation markers (ie, carboxy terminal cross-linked telopeptide of type I collagen [CTX], tartrate-resistant acid phosphatase isoform 5b [TRAP5b], and procollagen type 1 N-terminal propeptide [P1NP]); main results; and study limitations.

Data analysis: Five randomized controlled trials involving postmenopausal women were included. The mean ages of participants ranged from 56.1 to 86.9 years. Daily consumption of soft plain cheese fortified with 2.5 µg of vitamin D3 and 302 mg of calcium for 4 weeks resulted in a mean increase of 0.8 ng/mL in 25(OH)D and 15.9 ng/mL in P1NP levels compared with baseline, and decreased CTX, TRAP5b, and PTH values. A similar intervention for 6 weeks, using fortified cheese, showed a reduction only in TRAP5b values (-0.64 U/L). Yogurt fortified with 10 µg of vitamin D3 and 800 mg of calcium did not change P1NP values after 8 weeks of intervention, but was associated with decreases of 0.0286 ng/mL and 1.06 U/L in PTH and TRAP5b, respectively. After 12 weeks of eating the fortified yogurt, 25(OH)D levels increased by a mean of 8.8 ng/mL and PTH levels decreased in by a mean of 0.0167 ng/mL.

Conclusions: The interventions contributed toward the improvement of the bone resorption process but not to the bone formation process in postmenopausal women.

Prospero registration number: CRD42019131976.

Keywords: bone turnover; cholecalciferol; ergocalciferol; fortified foods; nutritional status.

Objective: To explore the predictive effect of the femoral neck strength composite indexes on femoral head collapse in non-traumatic osteonecrosis of the femoral head (ONFH) compared with bone turnover marker.

Methods: The non-traumatic ONFH patients who were admitted and received non-surgical treatment between January 2010 and December 2016 as the research object. And 96 cases (139 hips) met the selection criteria and were included in the study. There were 54 males (79 hips) and 42 females (60 hips), with an average age of 40.2 years (range, 22-60 years). According to whether the femoral head collapsed during follow-up, the patients were divided into collapsed group and non-collapsed group. The femoral neck width, hip axis length, height, body weight, and bone mineral density of femoral neck were measured. The femoral neck strength composite indexes, including the compressive strength index (CSI), bending strength index (BSI), and impact strength index (ISI), were calculated. The bone turnover marker, including the total typeⅠcollagen amino terminal elongation peptide (t-P1NP), β-crosslaps (β-CTx), alkaline phosphatase (ALP), 25 hydroxyvitamin D [25(OH)D], and N-terminal osteocalcin (N-MID), were measured. The age, gender, height, body weight, body mass index (BMI), bone mineral density of femoral neck, etiology, Japanese Osteonecrosis Investigation Committee (JIC) classification, femoral neck strength composite indexes, and bone turnover marker were compared between the two groups, and the influencing factors of the occurrence of femoral head collapse were initially screened. Then the significant variables in the femoral neck strength composite indexes and bone turnover marker were used for logistic regression analysis to screen risk factors; and the receiver operating characteristic (ROC) curve was used to determine the significant variables' impact on non-traumatic ONFH.

Results: All patients were followed up 3.2 years on average (range, 2-4 years). During follow-up, 46 cases (64 hips) had femoral head collapse (collapsed group), and the remaining 50 cases (75 hips) did not experience femoral head collapse (non-collapsed group). Univariate analysis showed that the difference in JIC classification between the two groups was significant ( Z=-7.090, P=0.000); however, the differences in age, gender, height, body weight, BMI, bone mineral density of femoral neck, and etiology were not significant ( P>0.05). In the femoral neck strength composite indexes, the CSI, BSI, and ISI of the collapsed group were significantly lower than those of the non-collapsed group ( P<0.05); in the bone turnover marker, the t-P1NP and β-CTx of the collapsed group were significantly lower than those of the non-collapsed group ( P<0.05); there was no significant difference in N-MID, 25(OH)D or ALP between groups ( P>0.05). Multivariate analysis showed that the CSI, ISI, and t-P1NP were risk factors for femoral collapse in patients with non-traumatic ONFH ( P<0.05). ROC curve analysis showed that the cut-off points of CSI, BSI, ISI, t-P1NP, and β-CTx were 6.172, 2.435, 0.465, 57.193, and 0.503, respectively, and the area under the ROC curve (AUC) were 0.753, 0.642, 0.903, 0.626, and 0.599, respectively.

Conclusion: The femoral neck strength composite indexes can predict the femoral head collapse in non-traumatic ONFH better than the bone turnover marker. ISI of 0.465 is a potential cut-off point below which future collapse of early non-traumatic ONFH can be predicted.

目的: 与骨转换标志物比较，探讨股骨颈骨强度综合指数对非创伤性股骨头坏死（osteonecrosis of the femoral head，ONFH）患者股骨头塌陷发生的预测作用。.

方法: 以 2010 年 1 月—2016 年 12 月收治并接受非手术治疗的非创伤性 ONFH 患者作为研究对象，其中 96 例（139 髋）符合选择标准纳入研究。男 54 例（79 髋），女 42 例（60 髋）；年龄 22～60 岁，平均 40.2 岁。根据随访期间是否出现股骨头塌陷，将患者分为塌陷组和未塌陷组。测量患者股骨颈宽度、髋轴长度、身高、体质量及股骨颈骨密度，计算股骨颈骨强度综合指数，包括抗压强度指数（compressive strength index，CSI）、抗折强度指数（bending strength index，BSI）、抗冲击强度指数（impact strength index，ISI）；测量骨转换标志物血清总Ⅰ型胶原氨基端延长肽（total typeⅠcollagen amino terminal elongation peptide，t-P1NP）、β-胶原特殊序列（β-crosslaps，β-CTx）、ALP、25 羟基维生素 D ［25 hydroxyvitamin D，25（OH）D］、N 端骨钙素（N-terminal osteocalcin，N-MID）水平。比较两组患者年龄、性别、身高、体质量、体质量指数（body mass index，BMI）、股骨颈骨密度、ONFH 病因、日本骨坏死调查委员会（JIC）分型以及股骨颈骨强度综合指数、骨转换标志物，初步筛选股骨头塌陷发生的影响因素。取股骨颈骨强度综合指数及骨转换标志物中差异有统计学意义的变量，行 logistic 回归分析，筛选危险因素；并采用受试者操作特征（receiver operating characteristic，ROC）曲线判断其对非创伤性 ONFH 患者股骨头塌陷发生的预测价值。.

结果: 所有患者均获随访，随访时间 2～4 年，平均 3.2 年。随访期间，46 例（64 髋）发生股骨头塌陷（塌陷组），其余 50 例（75 髋）未发生股骨头塌陷（非塌陷组）。单因素分析显示，两组患者 JIC 分型差异有统计学意义（ Z=–7.090， P=0.000）；但年龄、性别、身高、体质量、BMI、股骨颈骨密度及 ONFH 病因比较，差异均无统计学意义（ P>0.05）。股骨颈骨强度综合指数中，塌陷组 CSI、BSI、ISI 均低于非塌陷组（ P<0.05）；骨转换标志物中，塌陷组 t-P1NP 及 β-CTx 低于非塌陷组（ P<0.05），N-MID、25（OH）D 及 ALP 组间比较差异均无统计学意义（ P>0.05）。多因素分析显示，CSI、ISI 和 t-P1NP 是非创伤性 ONFH 患者股骨头塌陷的危险因素（ P<0.05）。ROC 曲线分析显示 CSI、BSI、ISI、t-P1NP、β-CTx 的截断值分别为 6.172、2.435、0.465、57.193、0.503，ROC 曲线下面积（area under the ROC curve，AUC）分别为 0.753、0.642、0.903、0.626、0.599。.

结论: 股骨颈骨强度综合指数比骨转换标志物更能预测非创伤性 ONFH 股骨头塌陷的发生。其中，ISI 0.465 是一个潜在临界值，低于该值可以预测早期非创伤性 ONFH 股骨头塌陷的发生。.

Keywords: Osteonecrosis of the femoral head; bone turnover marker; femoral head collapse; femoral neck strength composite indexes; prediction.

Purpose: In this multicenter retrospective observational study, we examined the early effects of romosozumab in patients with severe osteoporosis in terms of time-course changes in bone metabolism marker, improvement in bone density, and adverse effects.

Materials and methods: Patients with severe osteoporosis were included. We investigated the progress of TRACP 5b and P1NP before and 1-2 months after the administration of romosozumab. We also investigated the bone density of lumbar spine, femoral neck, and the entire femur, measured by the DXA method, before and 5-7 months after the administration of romosozumab.

Results: A total of 70 patients (7 males and 63 females, age 75.0±3.6 years) participated in this study. Significant improvements in TRACP 5b and P1NP levels were observed before and 1-2 months after romosozumab administration. The average bone density of lumbar spine, femoral neck, and the entire femur were measured before and 5-7 months after romosozumab administration; and a significant increase only observed in the lumbar spine.

Conclusion: Consistent with the findings of previous clinical studies, romosozumab has both bone formation-enhancing and bone resorption effects (dual effect). In addition, romosozumab also demonstrated improvement in bone density from the early phase after the administration, though the result was only seen in the lumbar spine.

Keywords: Bone and bones; bone density; bone resorption; metabolism; osteogenesis; osteoporosis.

Basic combat training (BCT) is a period of novel physical training including load carriage resulting in higher risk of stress fracture compared to any other time during military service. Prior trials reported a 20% reduction in stress fracture incidence with Ca and vitamin D (Ca + D) supplementation (2000 mg Ca, 800 IU vitamin D), and greater increases in tibia vBMD during BCT compared to placebo. The primary objective of this randomized, double-blind, placebo-controlled trial was to determine the efficacy of a lower dose of Ca (1000 mg/d Ca, 1000 IU vit D) on PTH, bone biomarkers and tibial microarchitecture during BCT. One hundred volunteers (50 males, 50 females; mean age 21.8 ± 3.5 y) were block randomized by race and sex to receive a daily Ca + D fortified food bar or placebo. Anthropometrics, dietary intake, fasted blood draws and high resolution pQCT scans of the distal and mid-shaft tibia were obtained at the start of BCT and 8 wks later at the conclusion of training. As compliance was 98% in both treatment groups, an intent-to-treat analysis was used. At the distal tibia, total vBMD, Tb.vBMD, Tb.N, Th.Th and Tb.BV/TV increased (+1.07 to 2.12% for all, p < 0.05) and Tb.Sp decreased (0.96 to 1.09%, p < 0.05) in both treatment groups. At the mid-shaft, Ct.Pm increased (+0.18 to 0.21%, p = 0.01) and Ct.vBMD decreased (-0.48 to -0.77%, p < 0.001) in both groups. Ca + D prevented increases in CTX and TRAP, which were observed in the placebo group (group-by-time, p < 0.05). Mean circulating 25OHD, BAP, P1NP and iCa increased and PTH decreased in both treatment groups (p < 0.05). These results, in agreement with other studies, suggest that bone microarchitectural changes indicative of bone formation occur during BCT. While Ca + D supplementation at lower doses than those tested in previous studies prevented increases in biochemical markers of bone resorption in this study, there were no significant changes in bone tissue after 8 wks of Army BCT.

Keywords: Bone; Calcium; HRpQCT; Military; Vitamin D.

Background: Fibroblast growth factor-23 (FGF23) is a key regulator of urine phosphate excretion. The aim of the study was to investigate the perioperative (intraoperative and postoperative) changes of plasma intact and C-terminal FGF23 (iFGF23, cFGF23) concentrations in patients with primary hyperparathyroidism (pHPT) submitted to surgery.

Materials and methods: Study involved 38 adult patients with pHPT caused by adenoma. PTH levels were investigated intraoperatively (just before the incision and 10 minutes after adenoma excision). cFGF23, iFGF23, phosphate, eGFR and P1NP were measured intraoperatively and postoperatively (next day after the surgery).

Results: PTH levels decreased intraoperatively (13.10 vs. 4.17 pmol/L, P<0.0001). FGF23 levels measured intraoperatively were at the upper level of reference interval. cFGF23 decreased postoperatively compared with values measured just before the incision (cFGF23: 89.17 vs. 22.23 RU/mL, P<0.0001). iFGF23 decreased as well, but postoperative values were low. Postoperative inorganic phosphate values increased (1.03 mmol/L vs. 0.8 mmol/L, P=0.0025). We proved significant negative correlation of perioperative FGF23 with inorganic phosphate (cFGF23: Spearman r=-0.253,P=0.0065; iFGF23: Spearman r =-0.245, P=0.0085). We also found FGF23 values just before incision correlated with eGFR (cystatin C) (cFGF23: Spearman r=-0.499, P=0.0014; iFGF23: Spearman r=-0.413, P=0.01).

Conclusion: Intraoperative iFGF23 and cFGF23 did not change despite PTH decreased significantly. cFGF23 and iFGF23 significantly decreased one day after parathyroidectomy and are associated with increase of inorganic phosphate in pHPT patients. cFGF23 and iFGF23 just before incision correlated with eGFR (cystatin C). The similar results found in both iFGF23 and cFGF23 suggest each could substitute the other.

Paget's disease of bone (PDB) is a rare metabolic bone disorder, which is extremely rare in Asian population. This study aimed to investigate the phenotypes and the pathogenic mutations of woman with early-onset PDB. The clinical features, bone mineral density, x-ray, radionuclide bone scan, and serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and β-carboxy-terminal cross-linked telopeptide of type 1 collagen (β-CTX) were measured in detail. The pathogenic mutations were identified by whole-exon sequencing and confirmed by Sanger sequencing. We also evaluated the effects of intravenous infusion of zoledronic acid on the bones of the patient and summarized the phenotypic characteristics of reported patients with mutation at position 155 of the valosin-containing protein (VCP). The patient only exhibited bone pain as the initial manifestation with vertebral compression fracture and extremely elevated ALP, P1NP, and β-CTX levels; she had no inclusion body myopathy and frontotemporal dementia. The missense mutation in exon 5 of the VCP gene (p.Arg155His) was identified by whole-exome sequencing and further confirmed by Sanger sequencing. No mutation in candidate genes of PDB, such as SQSTM1, CSF1, TM7SF4, OPTN, PFN1, and TNFRSF11A, were identified in the patient by Sanger sequencing. Rapid relief of bone pain and a marked decline in ALP, P1NP, and β-CTX levels were observed after zoledronic acid treatment. Previously reported patients with VCP missense mutation at position 155 (R155H) always had myopathy, frontotemporal dementia, and PDB, but the patient in this study exhibited only PDB. This was the first report of R155H mutation-induced early-onset in the VCP gene in Asian population. PDB was the only manifestation having a favorable response to zoledronic acid treatment. We broadened the genetic and clinical phenotype spectra of the VCP mutation.

Keywords: Paget’s disease of bone; R155H mutation; VCP; Zoledronic acid.

Background: Bone formation markers c-terminal telopeptide of type I collagen (1CTP) and peptides n-terminal propeptide of type I procollagen (P1NP) were reported to be increased in patients with prostate cancer (PC) and bone metastases. The objective of the presented study was to investigate the utility of serum 1CTP and P1NP values in the diagnosis of bone metastases and in predicting oncological outcome in patients with PC.

Methods: In total, serum samples of 186 patients were included retrospectively including 53 (28.50%) benign prostatic hyperplasia (BPH) patients and 133 (71.50%) PC-patients. The group of patients with PC consisted of 58 patients with non-metastatic PC (cM0) (43.61%) and 70 (52.63%) patients with bone metastases (cM1b). Serum 1CTP and P1NP were measured by radioimmunoassay (RIA). Results were compared to clinical variables including oncologic follow-up data by univariate and multivariate analyses.

Results: Median 1CTP concentrations were significantly higher in patients with PC compared to the BPH group [5.08 (range, 1.73-158.00) vs. 4.00 (range, 2.18-34.19) µg/L, P=0.019]. However, no significant difference of P1NP levels could be shown for these groups. With median values of 6.04 (1.73-158.00) and 3.91 µg/L (2.04-34.51) for 1CTP and 48.60 (9.12-1,074.37) and 33.90 (8.72-149.30) for P1NP both markers were altered in cM1b patients compared to cM0 patients (P=0.001 each). Furthermore, cancer-specific survival (CSS) and overall survival (OS) were significantly shorter in cM1b patients with higher 1CTP concentrations (P=0.037 and P=0.019, respectively), whereas no associations of P1NP and outcomes were observed.

Conclusions: The present study confirms that increased levels of 1CTP and P1NP concentrations are associated with presence of metastatic disease in the bone. Moreover, these markers are able to predict clinical course in PC patients with bone metastases. The potential use of these markers for treatment selection in advanced PC remains to be determined.

Keywords: Bone metastases; bone turnover markers; c-terminal telopeptide of type I collagen (1CTP); peptides n-terminal propeptide of type I procollagen (P1NP); prostate cancer (PC).