Effect of vitamin D supplementation or fortification on bone turnover markers in women: a systematic review and meta-analysis.

Vitamin D is a vital indicator of musculoskeletal health, as it plays an important role through the regulation of bone and mineral metabolism. This meta-analysis was performed to investigate the effects of vitamin D supplementation/fortification on bone turnover markers in women. All human randomised clinical trials reported changes in bone resorption markers (serum C-terminal telopeptide of type-I collagen (sCTX) and urinary type I collagen cross-linked N-telopeptide (uNTX)) or bone formation factors (osteocalcin (OC), bone alkaline phosphatase (BALP) and procollagen type-1 intact N-terminal propeptide (P1NP)) following vitamin D administration in women (aged ≥ 18 years) were considered. Mean differences (MD) and their respective 95 % CI were calculated based on fixed or random effects models according to the heterogeneity status. Subgroup analyses, meta-regression models, sensitivity analysis, risk of bias, publication bias and the quality of the included studies were also evaluated. We found that vitamin D supplementation had considerable effect on sCTX (MD: -0·038, n 22) and OC (MD: -0·610, n 24) with high heterogeneity and uNTX (MD: -8·188, n 6) without heterogeneity. Our results showed that age, sample size, dose, duration, baseline vitamin D level, study region and quality of studies might be sources of heterogeneity in this meta-analysis. Subgroup analysis also revealed significant reductions in P1NP level in dose less than 600 µg/d and larger study sample size (>100 participants). Moreover, no significant change was found in BALP level. Vitamin D supplementation/fortification significantly reduced bone resorption markers in women. However, results were inconsistent for bone formation markers.

Relationship Between Serum 25-Hydroxyvitamin D and Bone Mineral Density, Fracture Risk, and Bone Metabolism in Adults With Osteoporosis/Fractures.

OBJECTIVE: To evaluate the association of serum 25-hydroxyvitamin D (25(OH) D) levels with bone mineral density (BMD), fracture risk, and bone metabolism. METHODS: This multicenter cross-sectional study recruited menopausal females and males greater than or equal to 50 year old with osteoporosis/fractures between September 2016 and September 2021. Assessment included clinical data, 25(OH)D, intact parathyroid hormone (iPTH), procollagen type 1 amino-terminal propeptide (P1NP), carboxy-terminal collagen crosslinks (CTX), lateral thoracolumbar spine x-rays, and BMD. RESULTS: A total of 3003 individuals were stratified by 25(OH) D levels: 720 individuals (24%) <20 ng/mL, 1338 individuals (44.5%) 20 to 29 ng/mL, and 945 individuals (31.5%) ≥30 ng/mL. In unadjusted and multivariable models, BMD T-score, except spine, was significantly and positively associated with 25(OH)D levels. 25(OH) D levels were inversely associated with Fracture Risk Assessment Tool scores. Patients with 25(OH)D <20 ng/mL had significantly higher iPTH and bone turnover markers (P1NP and CTX) than patients with 25(OH)D â‰§20 ng/mL in all models. When analyzing bone-related markers and BMD, total hip and femoral neck BMD T-scores were positively correlated with 25(OH)D concentrations and BMI but negatively correlated with iPTH, P1NP, CTX, and age. In multivariate models with all bone-related markers, only 25(OH)D levels were significantly associated with total hip and femoral neck BMD. CONCLUSION: Vitamin D deficiency is significantly associated with decreased total hip and femoral neck BMD and increased fracture risk as assessed by Fracture Risk Assessment Tool. In those with osteoporosis/fractures, vitamin D is implicated in the causal relationship between bone remodeling and BMD. Assessing vitamin D status is imperative for those at risk for osteoporosis/fractures.

Maternal vitamin D levels correlate with fetal weight and bone metabolism during pregnancy: a materno-neonatal analysis of bone metabolism parameters.

OBJECTIVES: Vitamin D plays an essential role in neonatal skeletal development and maternal weight gain during pregnancy. We aim to study the association between vitamin D status, maternal weight, and materno-neonatal bone metabolism parameters. METHODS: From January to June 2017, we conducted this cross-sectional study among 103 pregnant women (21-42 years old) and their singletons. The levels of serum 25-(OH)D, PTH, P1NP, OC, and CTX were measured for mothers and neonates (cord blood). Serum vitamin D and OC were measured using chemiluminescence and two-site immunoradiometric assay, respectively. Meanwhile, P1NP, CTX, and PTH were measured by ELISA. RESULTS: The average serum vitamin D levels from mothers were 15.1 ng/mL during pregnancy and 16.2 ng/mL in the umbilical cord. At baseline, vitamin D deficient mothers were more likely to have higher PTH (36.4 vs. 18 pg/mL; p=0.029) and lower P1NP levels (90 vs. 92.5 ng/mL; p=0.026). Also, vitamin D deficient status was associated with lower fetal weight (3,293 vs. 3,358 g; p=0.019). Maternal weight was significantly correlated with P1NP (65.86 vs. 109.35; p=0.001) and OC (14.52 vs. 18.24; p=0.038), as well as cord vitamin D level (13.31 vs. 18.46; p=0.039) among normal vs. overweight women. No significant differences were found for the correlation between maternal weight and fetal parameters except for fetal weight which significantly increased with the increase in maternal weight (overweight vs. obese women=3,280 vs. 3,560; p=0.06). CONCLUSIONS: Maternal vitamin D status is associated with maternal and neonatal bone metabolism parameters as well as maternal and neonatal weight.

Exercise-induced hypercalcemia and vasopressin-mediated bone resorption.

Our human observational study showed that elevated arginine vasopressin levels by heavy exercise, not catecholamines, were associated with elevated serum tartrate-resistant acid phosphatase 5b (TRACP-5b). The increase in serum calcium was positively associated with percent changes of TRACP-5b, implying the involvement of bone resorption in the pathogenesis of exercise-induced hypercalcemia. INTRODUCTION: It remains unclear whether enhanced bone resorption explains exercise-induced hypercalcemia. An experimental study demonstrated that arginine vasopressin (AVP) stimulated osteoclast activity. METHODS: We conducted a prospective observational study, enrolling 65 trained healthy male officers of the Japan Self-Defense Forces (34 and 31 in waves 1 and 2, respectively). Before and after a 5-h heavy exercise, we collected laboratory data including bone markers, symptoms, and ionized calcium (iCa; wave 2 only). As blood calcium levels change after exercise, we estimated calcium (corrected calcium) levels immediately after the exercise using the correlation between blood calcium and time from the end of exercise in another cohort. RESULTS: Body weight decreased by 6.9% after the exercise. Corrected post-exercise serum total calcium (tCa) and iCa levels were significantly higher than pre-exercise levels, and 18% of participants showed hypercalcemia defined as corrected tCa >10.4 mg/dL or iCa >1.30 mmol/L. Serum tartrate-resistant acid phosphatase 5b (TRACP-5b), plasma three fractions of catecholamines, and AVP elevated significantly (median 14.3 pg/mL), while procollagen type 1 N-terminal propeptide and whole parathyroid hormone showed significant decreases. Corrected tCa increase showed a non-linear positive association with percent changes of TRACP-5b (%ΔTRACP-5b) even after adjustment for confounders. In addition, %ΔTRACP-5b was not associated with catecholamines, but with post-exercise AVP levels after adjustment for pre-exercise TRACP-5b. Symptoms of nausea or vomiting (observed in 20%) were positively associated with corrected post-exercise iCa after adjustment for post-exercise blood pH. CONCLUSION: AVP elevation may explain bone resorption and the following hypercalcemia in the setting of heavy exercise.

Early changes in bone turnover and inflammatory biomarkers and clinically significant bone mineral density loss over 48 weeks among HIV-infected patients with virological failure of a standard first-line antiretroviral therapy regimen in the SECOND-LINE study.

OBJECTIVES: We assessed whether changes at week 12 in markers of bone turnover, inflammation, and immune activation were associated with clinically important (≥ 5%) bone mineral density (BMD) loss from baseline to week 48 at the proximal femur (hip) and lumbar spine in the SECOND-LINE study. METHODS: We measured concentrations of procollagen type 1 pro-peptide (P1NP), carboxyl-terminal collagen crosslinks (CTX), high-sensitivity C-reactive protein (hs-CRP), D-dimer, interleukin (IL)-6, tumor necrosis factor (TNF), neopterin, and soluble CD14 and 163 at weeks 0, 12, and 48 in 123 SECOND-LINE dual-energy X-ray absorptiometry (DXA) substudy participants. Linear regression was used to compare changes in biomarkers. Predictors of ≥ 5% BMD loss were examined using multivariable regression. RESULTS: The mean age was 38 years, the mean CD4 T-cell count was 252 cells/µL and the mean viral load was 4.2 log HIV-1 RNA copies/mL; 56% of participants were female and 47% were randomized to receive a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI]-based regimen [91% (53/58) were randomized to receive a tenofovir disoproxil fumarate (TDF)-containing regimen]. Over 48 weeks, 71% in the N(t)RTI arm experienced ≥ 5% hip BMD loss vs. 29% in the raltegravir arm (P = 0.001). Week 12 changes in P1NP and CTX were significantly greater among patients experiencing ≥ 5% hip BMD loss, patients randomized to N(t)RTI, and male patients. Predictors of ≥ 5% hip BMD loss at week 48 were P1NP increase [odds ratio (OR) 5.0; 95% confidence interval (CI) 1.1-27; P < 0.043]; N(t)RTI randomization (OR 6.7; 95% CI 2.0-27.1; P < 0.003), being African, higher baseline CD4 T cell count , and smoking. CONCLUSIONS: In a diverse cohort of viraemic HIV-infected patients, switching to second-line antiretroviral therapy (ART) was associated with clinically significant BMD loss, which was correlated with an early increase in P1NP. Measurement of P1NP may facilitate timely interventions to reduce rapid BMD loss among at-risk patients.

Device-Induced Neocollagenesis: Profibrotic Response or True Neocollagenesis?

BACKGROUND AND OBJECTIVES: Many light and radiofrequency-based rejuvenation devices have claimed to increase collagen production in the skin dermal tissue. However, there has not been enough scientific evidence to prove whether the result is just a profibrotic response or not. We aimed to find the optimal skin rejuvenation device that shows true neocollagenesis. STUDY DESIGN/MATERIALS AND METHODS: We evaluated dermal collagen thickness and gene expression of procollagen type 1, 3, matrix metalloproteinase-3 (MMP-3), and transforming growth factor-ß (TGF-ß) resulting from different energy-based devices in a rat model in vivo. The wound-healing response was evaluated histologically and by real-time polymerase chain reaction (RT-PCR) at immediate, 1st, 2nd, 4th, 8th, and 12th week after the initial procedure. RESULTS: At the 12th week, the most relevant changes of the dermal thickness were found in specimens after treatment with electrosurgical unit, fractional CO2 and 1064 nm Q-switched Nd:YAG. Procollagen 1 and 3 were also found to be the highest in electrosurgical unit, fractional CO2 , and microneedle radiofrequency. Dramatic changes of MMP-3 and TGF-ß were remarkable at the early observation but went back to normal level at 12th week. The ratio of procollagen 1 and 3 was found to be the lowest with Q-Switched Nd:YAG 1064 nm and fractional CO2 . CONCLUSION: Electrosurgical unit resulted in most significant changes, but due to irreversible thermal damage and extremely high procollagen results it is considered as a profibrotic response. Fractional CO2 and Q-Switched Nd:YAG 1064 nm are applicable to face skin rejuvenation treatment considering thickening of dermal tissue and lower procollagen 1:3 ratio similar to the neocollagenesis purpose. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Therapeutic Effect of Calcimimetics on Osteoclast-Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease.

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast-osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast-osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = -0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/ß-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid-bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast-osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Chemical Constituents from Leaves of Hydrangea serrata and Their Anti-photoaging Effects on UVB-Irradiated Human Fibroblasts.

Hydrangea serrata (THUNB.) SER. (Hydrangeaceae) leaves have been used as herbal teas in Korea and Japan. The objective of this study was to identify anti-photoaging compounds in aqueous EtOH extract prepared from leaves of H. serrata and their effects on UVB-irradiated Hs68 human foreskin fibroblasts. Phytochemical study on H. serrata leaves led to the isolation and characterization of ten compounds: hydrangenol, thunberginol A, thunberginol C, hydrangenoside A, hydrangenoside C, cudrabibenzyl A, 2,3,4'-trihydroxystilbene, thunberginol F, quercetin 3-O-ß-D-xylopyranosyl (1-2)-ß-D-galactopyranoside, quercetin 3-O-ß-D-xylopyranosyl (1-2)-ß-D-glucopyranoside. Cudrabibenzyl A, 2,3,4'-trihydroxystilbene, quercetin 3-O-ß-D-xylopyranosyl (1-2)-ß-D-galactopyranoside, quercetin 3-O-ß-D-xylopyranosyl (1-2)-ß-D-glucopyranoside were firstly isolated from H. serrata. We estimated the effects of 10 compounds on cell viability and production of pro-collagen Type I, matrix metalloproteinase (MMP)-1, and hyaluronic acid (HA) after UVB irradiation. Of these compounds, hydrangenol showed potent preventive activities against reduced cell viability and degradation of pro-collagen Type I in UVB-irradiated Hs68 fibroblasts. Hydrangenol had outstanding inductive activities on HA production. It suppressed mRNA expression levels of MMP-1, MMP-3, hyaluronidase (HYAL)-1, HYAL-2, cyclooxygenase-2 (COX-2), interleukin (IL)-6, IL-8, and IL-1ß in UVB-irradiated Hs68 fibroblasts. When Hs68 fibroblasts were exposed to hydrangenol after UVB irradiation, UVB-induced reactive oxygen species (ROS) production was suppressed. Hydrangenol also inhibited the activation of activator protein-1 (AP-1) and signal transduction and activation of transcription 1 (STAT-1) by downregulating phosphorylation of p38 and extracellular signal-regulated kinase (ERK). Our data indicate that hydrangenol isolated from H. serrata leaves has potential protective effects on UVB-induced skin photoaging.

A Double-blind, Randomized Controlled Trial of Ciplukan (Physalis angulata Linn) Extract on Skin Fibrosis, Inflammatory, Immunology, and Fibrosis Biomarkers in Scleroderma Patients.

BACKGROUND: scleroderma is an autoimmune disease characterized by organ fibrosis, resistant to standard treatment. It is suspected the addition of Physalis angulata Linn. (Ciplukan) extract as adjuvant therapy can improve the scleroderma skin fibrosis. The aim at this study is to evaluate the effect of ciplukan extract as adjuvant on scleroderma skin fibrosis in standard therapy, based on modified Rodnan skin scale (MRSS), inflammatory biomarkers, immunology and serum fibrosis. METHODS: double-blind, randomized clinical trial was performed in scleroderma patients with stable disease at Cipto Mangunkusumo hospital and Hasan Sadikin hospital during November 2015-March 2017 who met the selection criteria and continued to receive standard therapy. The subjects were randomly allocated into two groups: the study group received the ciplukan  extract 3 x 250 mg / day for 12 weeks and the placebo group. Examination of MRSS, ESR, P1NP, BAFF and sCD40L was performed every 4 weeks until the end of the study. RESULTS: fifty-nine subjects completed the study. They consisted of 29 subjects of the treatment group and 30 of the placebo group, with an average age of 41 (SD 9) years, the proportion of women: male = 9 : 1. There was a significant improvement of skin fibrosis in the study group with a highly significant decrease in MRSS (35.9% VS 6.3%, p <0.001) and a relative decrease in P1NP levels (17.8% VS 0.7%, p = 0.002). No decrease in ESR, BAFF and sCD40L levels in both groups. There was a weak but significant positive correlation between MRSS with P1NP levels (r = 0.236, p = 0.036). CONCLUSION: Ciplukan extract with dose 3 x 250 mg for 12 weeks as adjuvant on scleroderma standard therapy alleviates skin fibrosis significantly based on MRSS and P1NP levels.

Eucalyptus globulus extract protects against UVB-induced photoaging by enhancing collagen synthesis via regulation of TGF-ß/Smad signals and attenuation of AP-1.

UV irradiation triggers the overproduction of matrix metalloproteinases and collagen degradation, which in turn causes increased pigmentation, dryness, and deep wrinkling of the skin. These chronic symptoms are collectively referred to as photoaging. Eucalyptus globulus is an evergreen tree that is widely used in cosmetics because of its antimicrobial activity. In this study, we investigated the protective effect of 50% ethanol extracts of Eucalyptus globulus on UV-induced photoaging in vitro and in vivo. Normal human dermal fibroblasts were treated with Eucalyptus globulus at concentrations ranging from 1 to 100 µg/mL after UVB or non-UVB irradiation. We found that Eucalyptus globulus suppressed the expression of MMPs and IL-6, but increased the expression of TGF-ß1 and procollagen type 1. In addition, Eucalyptus globulus inhibited activation of the AP-1 transcription factor, an inducer of MMPs. Eucalyptus globulus was also found to regulate TGF-ß/Smad signaling by reversing the activity of negative Smad regulators. Lastly, in vivo studies showed that topical application of Eucalyptus globulus on UVB-irradiated hairless mice reduced wrinkle formation and dryness by down-regulating MMP-1 and up-regulating expression of elastin, TGF-ß1, and procollagen type 1. Taken together, these data suggest that Eucalyptus globulus may be a useful agent in cosmetic products.

Dietary calcium intake and rate of bone loss in men.

A high Ca intake has been recommended for osteoporosis prevention; however, little research has examined the relationship between dietary Ca and bone health in men. We examined associations between dietary Ca intake, bone mineral density (BMD) and change in BMD at the total body, hip and spine over 2 years in a cohort of men (mean age 57 years, BMI 26 kg/m2) from a trial. Data from the total cohort (n 323) were used in the analysis of Ca intake and BMD at baseline, and data from the placebo group (n 99) were used in the longitudinal analysis of Ca intake and change in BMD. Parathyroid hormone (PTH) and the markers of bone turnover serum total alkaline phosphatase activity, serum C-telopeptide and serum procollagen type-1 N-terminal propeptide were measured in a subset of participants at baseline (n 150), and associations with dietary Ca at baseline were examined. Mean Ca intake was 870 mg/d. Baseline BMD was not related to dietary Ca intake at any site, before or after adjustment for covariables. Similarly, bone loss over 2 years was not related to Ca intake at any site, before or after adjustment. Dietary Ca intake was inversely correlated with PTH at baseline (r -0·19, P=0·02), but was not associated with the markers of bone turnover. BMD and rates of bone loss were unrelated to Ca intake in these men. This suggests that strategies to increase Ca intake are unlikely to impact on the prevalence of and morbidity from male osteoporosis.

Diagnostic Accuracy of Bone Turnover Markers and Bone Histology in Patients With CKD Treated by Dialysis.

BACKGROUND: The management of chronic kidney disease-mineral and bone disorder requires the assessment of bone turnover, which most often is based on parathyroid hormone (PTH) concentration, the utility of which remains controversial. STUDY DESIGN: Cross-sectional retrospective diagnostic test study. SETTING & PARTICIPANTS: 492 dialysis patients from Brazil, Portugal, Turkey, and Venezuela with prior bone biopsy and stored (-20 °C) serum. INDEX TESTS: Samples were analyzed for PTH (intact [iPTH] and whole PTH), bone-specific alkaline phosphatase (bALP), and amino-terminal propeptide of type 1 procollagen (P1NP). REFERENCE TEST: Bone histomorphometric assessment of turnover (bone formation rate/bone surface [BFR/BS]) and receiver operating characteristic curves for discriminating diagnostic ability. RESULTS: The biomarkers iPTH and bALP or combinations thereof allowed discrimination of low from nonlow and high from nonhigh BFR/BS, with an area under the receiver operating characteristic curve > 0.70 but < 0.80. Using iPTH level, the best cutoff to discriminate low from nonlow BFR/BS was <103.8 pg/mL, and to discriminate high from nonhigh BFR/BS was >323.0 pg/mL. The best cutoff for bALP to discriminate low from nonlow BFR/BS was <33.1 U/L, and for high from nonhigh BFR/BS, 42.1U/L. Using the KDIGO practice guideline PTH values of greater than 2 but less than 9 times the upper limit of normal, sensitivity and specificity of iPTH level to discriminate low from nonlow turnover bone disease were 65.7% and 65.3%, and to discriminate high from nonhigh were 37.0% and 85.8%, respectively. LIMITATIONS: Cross-sectional design without consideration of therapy. Potential limited generalizability with samples from 4 countries. CONCLUSIONS: The serum biomarkers iPTH, whole PTH, and bALP were able to discriminate low from nonlow BFR/BS, whereas iPTH and bALP were able to discriminate high from nonhigh BFR/BS. Prospective studies are required to determine whether evaluating trends in biomarker concentrations could guide therapeutic decisions.

Lower bone turnover markers in metabolic syndrome and diabetes: the population-based Study of Health in Pomerania.

BACKGROUND AND AIMS: Accumulating evidence demonstrates an important interaction between bone and energy metabolism. We aimed to study the associations of three bone turnover markers (BTM: osteocalcin, beta-crosslaps, procollagen type 1 N-terminal propeptide) as well as of 25-hydroxyvitamin D and parathyroid hormone with metabolic syndrome (MetS) or type 2 diabetes mellitus (T2DM) in a large population-based cohort. METHODS AND RESULTS: This cross-sectional study comprised 2671 adult men and women participating in the first follow-up of the population-based Study of Health in Pomerania (SHIP-1). Multivariable logistic regression analyses were performed to assess sex-specific associations between the BTMs, 25-hydroxyvitamin D or parathyroid hormone and metabolic disease. All models were adjusted for age, body mass index, smoking status, physical activity, estimated glomerular filtration rate and month of blood sampling. The models for women were further adjusted for menopausal status. Higher BTM or 25-hydroxyvitamin D concentrations were associated with significantly lower odds for metabolic disease, while there was no association between parathyroid hormone and MetS or T2DM. CONCLUSION: Our results contribute to the accumulating evidence of a cross-sectional association between high BTM or 25-hydroxyvitamin D concentrations and a lower prevalence of MetS or T2DM. Further research is necessary to evaluate the mechanisms underlying these results.

Predictive value of bone turnover markers and thyroid indicators for bone metabolism in GD patients after treatment.

Purpose: To investigate the relationship between bone turnover markers (BTMs) and thyroid indicators in Graves' disease (GD) and to further assess predictive value of changes in early stage retrospectively. Methods: We studied 435 patients with GD and 113 healthy physical examiners retrospectively and followed up these two groups of patients after 6 months. We investigated the correlations between BTMs and other 15 observed factors, and analyzed the predictive value of FT3 and FT4 before and after treatment (FT3-P/FT3-A, FT4-P/FT4-A) on whether BTMs recovered. Results: The levels of thyroid hormones and BTMs in GD group were significantly higher than those in control group (P < 0.05) and decreased after 6 months of treatment. FT3, W, Ca and ALP were independent factors in predicting the elevation of OST. Duration of disease, FT3, TSH and ALP were independent factors in predicting the elevation of P1NP. Age, duration of disease, TRAb and ALP were independent factors in predicting the elevation of CTX-1. The AUC of FT3-P/FT3-A and FT4-P/FT4-A for predicting OST recovery were 0.748 and 0.705 (P < 0.05), respectively, and the cut-off values were 0.51 and 0.595. There was no predictive value for P1NP and CTX-1 recovery (P > 0.05). Conclusion: BTMs were abnormally elevated in GD and were significantly correlated with serum levels of FT3, FT4, TRAb, Ca, and ALP. FT3 decreased more than 51% and FT4 dropped more than 59.5% after 6 months of treatment were independent predictors for the recovery of BTMs in GD.

Procollagen type 1 N-terminal propeptide, neurofilament light chain, proinflammatory cytokines, and cognitive function in bipolar and major depressive disorders: An exploratory study of brain- bone axis and systemic inflammation.

BACKGROUND: Higher levels of neurofilament light chain (NfL) and proinflammatory cytokines (i.e., tumor necrosis factor [TNF]-α) were observed in patients with bipolar disorder (BD) and major depressive disorder (MDD). Procollagen type 1 N-terminal propeptide (P1NP), a bone turnover biomarker, is related to MDD. The association among the brain-bone axis, systemic inflammation, and cognitive function remains unclear in severe affective disorders. METHODS: Overall, 25 patients with BD, 24 with MDD, and 29 matched controls were enrolled in the current study and underwent the measurements of the NfL, P1NP, and proinflammatory cytokine levels and 1-back and 2-back working memory tasks. Generalized linear models (GLMs) were used to examine the aforementioned biomarkers between the groups and clarify the association with each other. RESULTS: GLMs showed increased levels of NfL (p = 0.001, p = 0.020) and P1NP (p = 0.050, p = 0.032) in the patients with BD and MDD than in the controls and suggested significant correlations between the NfL level and the mean time of the 2-back working memory task (p = 0.038) and between P1NL and TNF-α levels (p < 0.001). DISCUSSION: Our study revealed the dysregulated brain-bone axis, indicated by elevated NfL and P1NP levels, and related cognitive impairment and systemic inflammation in the patients with BD and MDD. Additional studies are necessary to elucidate definite pathomechanisms underlying those conditions.

Impact of Intravenous Iron Substitution on Serum Phosphate Levels and Bone Turnover Markers-An Open-Label Pilot Study.

The association between intravenous iron substitution therapy and hypophosphatemia was previously reported in patients with iron deficiency anemia. However, the extent of hypophosphatemia is thought to depend on the type of iron supplementation. We hypothesized that the intravenous application of ferric carboxymaltose and iron sucrose leads to a different longitudinal adaptation in serum phosphate levels. In this open-label pilot study, a total of 20 patients with inflammatory bowel diseases or iron deficiency anemia were randomly assigned to one of two study groups (group 1: ferric carboxymaltose, n = 10; group 2: iron sucrose, n = 10). Serum values were controlled before iron substitution therapy, as well as 2, 4, and 12 weeks after the last drug administration. The primary objective of the study was the longitudinal evaluation of serum phosphate levels after iron substitution therapy with ferric carboxymaltose and iron sucrose. The secondary objective was the longitudinal investigation of calcium, 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone, procollagen type 1 amino-terminal propeptide (P1NP), beta-CrossLaps (CTX), hemoglobin (Hb), iron, ferritin, and transferrin saturation levels. Two weeks after drug administration, phosphate levels were significantly lower (p < 0.001) in group 1 and ferritin levels were significantly higher (p < 0.001) in group 1. Phosphate levels (0.8-1.45 mmol/L) were below the therapeutic threshold and ferritin levels (10-200 ng/mL for women and 30-300 ng/mL for men) were above the therapeutic threshold in group 1. P1NP (15-59 µg/L) and CTX (<0.57 ng/mL) levels were above the therapeutic threshold in group 2. Four weeks after drug administration, significant differences were still observed between both study groups for phosphate (p = 0.043) and ferritin (p = 0.0009). All serum values except for Hb were within the therapeutic thresholds. Twelve weeks after drug administration, no differences were observed in all serum values between both study groups. Hb values were within the therapeutic threshold in both study groups. Serum 25(OH)D levels did not differ between both study groups throughout the whole study period and remained within the therapeutic threshold.

Acarbose diminishes postprandial suppression of bone resorption in patients with type 2 diabetes.

AIMS: The alpha-glucosidase inhibitor acarbose is an antidiabetic drug delaying assimilation of carbohydrates and, thus, increasing the amount of carbohydrates in the distal parts of the intestines, which in turn increases circulating levels of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1). As GLP-1 may suppress bone resorption, acarbose has been proposed to potentiate meal-induced suppression of bone resorption. We investigated the effect of acarbose treatment on postprandial bone resorption in patients with type 2 diabetes and used the GLP-1 receptor antagonist exendin(9-39)NH2 to disclose contributory effect of acarbose-induced GLP-1 secretion. METHODS: In a randomised, placebo-controlled, double-blind, crossover study, 15 participants with metformin-treated type 2 diabetes (2 women/13 men, age 71 (57-85 years), BMI 29.7 (23.6-34.6 kg/m2), HbA1c 48 (40-74 mmol/mol)/6.5 (5.8-11.6 %) (median and range)) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a six-week wash-out period. At the end of each period, circulating bone formation and resorption markers were assessed during two randomised 4-h liquid mixed meal tests (MMT) with infusions of exendin(9-39)NH2 and saline, respectively. Glucagon-like peptide 2 (GLP-2) was also assessed. RESULTS: Compared to placebo, acarbose impaired the MMT-induced suppression of CTX as assessed by baseline-subtracted area under curve (P = 0.0037) and nadir of CTX (P = 0.0128). During acarbose treatment, exendin(9-39)NH2 infusion lowered nadir of CTX compared to saline (P = 0.0344). Neither parathyroid hormone or the bone formation marker procollagen 1 intact N-terminal propeptide were affected by acarbose or GLP-1 receptor antagonism. Acarbose treatment induced a greater postprandial GLP-2 response than placebo treatment (P = 0.0479) and exendin(9-39)NH2 infusion exacerbated this (P = 0.0002). CONCLUSIONS: In patients with type 2 diabetes, treatment with acarbose reduced postprandial suppression of bone resorption. Acarbose-induced GLP-1 secretion may contribute to this phenomenon as the impairment was partially reversed by GLP-1 receptor antagonism. Also, acarbose-induced reductions in other factors reducing bone resorption, e.g. glucose-dependent insulinotropic polypeptide, may contribute.

Intra-Individual Changes in Total Procollagen-Type 1 N-terminal Propeptide in a Korean Adult Population.

We aimed to investigate intra-individual changes in total procollagen-type 1 N-terminal pro-peptide (P1NP), a biochemical marker of bone turnover, to understand patient populations and test utilization in a Korean adult population while considering different definitions of least significant changes by sex, age, and medical institution type. Overall, 31,501 P1NP tests were performed on 24,644 Korean adults (3389 men and 21,255 women) with a median age of 68.9 years (interquartile range, IQR, 61.2-77.2) for osteoporosis evaluation. Among these, 1331 (5.4%) patients (127 men and 1204 women) underwent ≥3 follow-up P1NP measurements. The median follow-up period was 12.5 months (IQR, 11.7-15.9). Among 1331 patients, 64.4% experienced a decrease in P1NP and 35.6% experienced an increase in P1NP during follow-up. Among these, the proportion of patients who experienced serum P1NP changes ≥14.4% from baseline was 92.3%, and the proportion of patients who achieved ≤40 ng/mL (a median level of premenopausal Korean women) during follow-up was 31.8%. The overall proportion of patients that experienced a serum P1NP change exceeding the least significant change during follow-up was not significantly different by the type of medical institution.

Association between P1NP and bone strength in postmenopausal women treated with teriparatide.

OBJECTIVE: To evaluate the association between P1NP and bone strength in postmenopausal women treated with teriparatide. MATERIALS AND METHODS: This prospective study enrolled 248 postmenopausal women with severe osteoporosis treated with teriparatide. Procollagen type 1 N-terminal propeptide (P1NP) were assessed at baseline, 3, 6, and 12 months. Lumbar spine (LS), femoral neck (FN), and total hip (TH) bone mineral density (BMD) and LS trabecular bone score (TBS) were measured by Dual-energy x-ray absorptiometry at baseline and 12 months. RESULTS: With teriparatide use, P1NP levels increase and peaked at 6 months. Significant increase in LS and hip BMD and LS TBS were also noted. The percentage change or absolute change >10 µg/L in PINP at 3 months was only related to changes in LS BMD at 12 months. With a median baseline P1NP level was 65.5 ng/mL, we found no correlation between P1NP and LS and hip BMD nor LS TBS. There was no association between LS TBS and axial BMD. After treatment, there was also no significance between the changes in TBS and axial BMD. Over the study period, 83.9% of the 248 participants were persistent with teriparatide at 3 months, 77.8% at 6 months, and 67.3% women at 12 months. CONCLUSION: P1NP levels may provide a signal of osteoporosis risk but is not related to bone strength. Early changes in P1NP may offer information regarding subsequent BMD response so standardized monitoring of P1NP levels at baseline and at 3 months should be considered during osteoporosis therapy. As an additional benefit, serum level monitoring during treatment may also improve medication persistence.

Impact of romosozumab on serum calcium concentration and factors predicting the fluctuations in calcium concentration upon romosozumab administration: A multicenter retrospective study.

Objectives: As romosozumab has both bone anabolic and antiresorptive effects, it is not clear which patient groups are more likely to have decreased calcium concentrations when treated with romosozumab. The aim of this study was to investigate the impact of romosozumab treatment on serum calcium concentration in patients with osteoporosis with a high risk of fractures and identify factors that might be associated with, or even predict, a fluctuation in calcium concentration upon romosozumab administration. Materials and methods: In total, 47 patients were included in this retrospective study. We performed a Wilcoxon signed-rank test to identify differences in the calcium concentration before and 1 month after romosozumab initiation. Associations between baseline variables and changes in serum calcium concentration were investigated with a multiple-linear regression model using a forward-backward stepwise procedure. Results: Romosozumab administration reduced the serum calcium concentration by an average of 3.1 % after 1 month. No patient complained of symptoms of hypocalcemia during the first month after treatment. Univariate regression analysis showed that age and calcium concentration were significantly associated with the decrease in serum calcium concentrations by romosozumab administration. In addition, stepwise regression analysis identified age and calcium concentrations as independent factors associated with the decrease in calcium concentration by romosozumab. Conclusion: Romosozumab administration caused a modest but significant decrease in serum calcium concentration. Older age and higher baseline calcium concentrations were associated with a greater decrease in calcium concentrations by romosozumab administration. Although the likelihood of severe hypocalcemia from romosozumab administration may be low, physicians prescribing romosozumab to patients with osteoporosis should be aware of the symptoms of hypocalcemia and promptly evaluate calcium levels if patients complain of these symptoms.