Osteopathy represents a prominent cause of morbidity in patients with beta-thalassemia major (TM) and manifests as osteopenia/osteoporosis. Biochemical turnover markers (BTMs) are considered a useful, non-invasive tool for the clinical follow-up of osteoporotic patients; they can provide a dynamic view of the remodeling process and give information on the metabolic activity of bone tissue as well as on the pathogenesis of bone loss. The amino-terminal pro-peptide of type I procollagen (P1NP) is a recently introduced marker that is considered the most sensitive index of bone formation. Although demonstrated in several categories of patients with bone disease, there is little information on the clinical usefulness of this bone formation index in thalassemic patients. We evaluated the P1NP levels of 53 adult patients with b-thalassemia major (21 males and 32 females, mean age 34.5 ± 5.7, range 22-46 years) and associated osteopathy. We investigated the correlation between P1NP and bone condition as examined by dual X-ray photon absorptiometry and with BTMs expressing bone resorption and bone mineralization (carboxyterminal collagen cross-linked (CTX) terminal regions of type I collagen and osteocalcin, respectively). P1NP serum levels were correlated with CTX levels (r=0.545, p<0.001); the results were unchanged when males and females, as well as osteoporotic and osteopenic subgroups, were considered separately. No correlation was demonstrated neither between OC and CTX (r=0.17, p=ns), nor between P1NP and OC levels (r=0.11, p=ns). No correlation was demonstrated among the P1NP/CTX ratio and age, OC or densitometric values and no difference was found in the same ratio between osteopenic (0.19 ± 0.16) and osteoporotic (0.15 ± 0.14) patients. Similar results were obtained for the OC/CTX ratio, as it was not correlated with age, P1NP or densitometric values. This is the first report of circulating P1NP in patients with TM-associated osteoporosis. P1NP and CTX assays show good precision and low analytical CV, and, compared to other markers, they can acceptably reflect bone metabolic processes and promptly respond to antiosteoporotic treatments. We trust that this sensitive marker can be useful in the assessment of treatment efficacy and can overcome the pitfalls due to wide variability in the normal values of most BTMs that create difficulty in pinpointing the individual patient's response.

Objective: Type 2 diabetic patients have a higher incidence of nonalcoholic steatohepatitis (NASH) and advanced stages of fibrosis, and nonalcoholic fatty liver disease (NAFLD) is associated with impaired bone health. We aimed to investigate whether bone turnover is associated with the probable presence of NASH and fibrosis. Methods: In total, 4,937 diabetic participants from Shanghai, China were enrolled in 2018. Subjects with NAFLD were categorized into simple NAFLD and probable NASH groups based on the presence of a metabolic syndrome. The NAFLD fibrosis score was used to identify patients with a higher likelihood of advanced fibrosis. Results: In postmenopausal women, large N-mid fragment of osteocalcin (N-MID osteocalcin) was negatively associated with probable NASH (P for trend < 0.001). β-C-terminal cross-linked telopeptides of type I collagen (β-CTX) and procollagen type I N-terminal propeptide (P1NP) were positively associated with the probable presence of significant fibrosis in postmenopausal women (P for trend 0.015 and <0.001). However, in men, N-MID osteocalcin and β-CTX were negatively associated with the probable presence of significant fibrosis (P for trend 0.029 and 0.027). Conclusions: Significant associations among N-MID osteocalcin, β-CTX and P1NP, and probable advanced NAFLD were observed. Further prospective and animal studies are warranted to understand the causal relationship and underlying mechanism.

Introduction: There have been no reports of the effects of baseline lumbar spine bone mineral density (LS-BMD) and bone turnover marker levels on the therapeutic effect of a 28.2-μg teriparatide formulation for twice-weekly use (2/W-TPTD).

Materials and methods: An analysis was performed using data from a double-blind, randomized, non-inferiority trial (TWICE study) conducted with patients who received 2/W-TPTD or a 56.5-μg teriparatide formulation for once-weekly use (1/W-TPTD) for 48 weeks. The patients were divided into tertile groups based on baseline LS-BMD, urinary type I collagen cross-linked N-telopeptide (u-NTX), and serum type I procollagen-N-propeptide (P1NP) levels, respectively. Time profiles of these measurements were analyzed. Furthermore, whether a change in P1NP is a predictor for percentage change in BMD was assessed.

Results: Across all tertile groups divided based on baseline LS-BMD and levels of bone turnover markers, the LS-BMD increased significantly. The u-NTX level decreased throughout the study period in the high- and middle-u-NTX-level groups. The P1NP level increased after 4 weeks, but subsequently decreased after 12 weeks and thereafter in the high-P1NP-level group; it increased after 4 weeks and subsequently fluctuated near the baseline level in the middle-P1NP-level group. A cut-off value of 12.0 µg/L for change in P1NP after 4 weeks of 2/W-TPTD as a predictor for percentage change in LS-BMD of 3% or more after 48 weeks gave a positive predictive value of 89.6%.

Conclusion: 2/W-TPTD, just like 1/W-TPTD, improved LS-BMD significantly, regardless of baseline LS-BMD and bone turnover marker levels.

Keywords: Bone mineral density; Bone turnover markers; Osteoporosis; Teriparatide; twice weekly.

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.

Keywords: Bone mineral density; Bone turnover markers; Denosumab; Postmenopausal osteoporosis; Zoledronate.

Gaucher disease (GD) is the most prevalent lysosomal storage disease, and bone involvement is the most disabling condition. The aim of the present study was to evaluate bone involvement in adult patients with GD, using an observational cross-sectional study. Patients were evaluated using X-rays, bone densitometry (BMD), trabecular bone score (TBS), magnetic resonance imaging (MRI), and biochemical bone markers. Thirty-two type 1GD patients were included (mean age: 40 ± 16 years). Patients had received velaglucerase for 2.7 ± 1.4 years; 19/32 had been treated previously with imiglucerase. Ninety-four percent of subjects met therapeutic goals for hematological parameters, and eight were splenectomized (SPX). Nineteen patients had irreversible bone lesions (IL), i.e., avascular necrosis, bone infarction, and/or vertebral fractures. MRI showed marrow infiltration in 71% of patients. Patients with IL had higher bone marrow burden than those without (p = 0.001). All SPX patients had IL, a higher prevalence of bone marrow edema (p = 0.02), and lower TBS (p = 0.03) than non-SPX patients. Only 18.7% of patients had abnormal BMD, with no correlation with fractures (FX). TBS values were < 1350 in 53% of patients and tended to be lower in those with FX (p = 0.06). Patients with P1NP in the lower quartile had lower TBS (p = 0.03) than those with P1NP in the higher quartiles. TBS correlated moderately but not significantly with P1NP (r = 0.32) and BMB (r = - 0.44). A high prevalence of IL was documented. Bone quality was more affected than BMD in fracture patients. Low bone formation, active bone marrow infiltration, and splenectomy might be implicated in IL.

Objective: To study the curative effect of bionic tiger-bone powder on osteoporosis in ovariectomized rats and investigate its mechanism.

Methods: Overall, a 120 female Wistar rats were randomly divided into Sham (sham-operated group), ovariectomy (OVX, ovariectomized group), TB (bionic tiger-bone powder treatment group after ovariectomy) and TB + VD groups (bionic tiger-bone powder + vitamin D treatment group after ovariectomy). The osteoporotic rat model was established 3 months after ovariectomy, and rats were intragastrically administrated with the corresponding drugs. Serum and bone tissue samples were collected from 10 rats in each group at weeks 4, 12 and 24 after intragastric administration. The bone microstructure of L₆ vertebrae was analyzed by MicroCT, the biomechanical strength of left femurs was measured by the three-point bending test, and serum bone metabolism markers (P1NP and CTX) were detected by ELISA. Changes in bone collagen were analyzed by Masson's trichrome staining and hydroxyproline detection, and members of the BMP2/SMAD/RUNX2 and OPG/RANKL/RANK signal pathways were detected by immunoblotting.

Results: Compared with the OVX group, the serum level of P1NP in the TB and TB + VD groups was higher (P < 0.05), while the CTX level was lower (P < 0.05). Bone collagen fiber structures in the TB and TB + VD groups were repaired, and the collagen content was significantly higher than that in the OVX group (P < 0.05). In the TB group, BMP-2, P-SMAD1/5, RUNX2 and OPG levels were increased in bone tissue (P < 0.01), RANKL levels were decreased (P < 0.01), and the bone microstructure and biomechanical strength were improved.

Conclusion: Bionic tiger-bone powder promotes osteogenesis by activating the BMP2/SMAD/RUNX2 signaling pathway, suppresses osteoclasts by downregulating the OPG/RANK/RANKL signaling pathway, increases bone collagen content, and improves bone microstructure and bone biomechanical strength.

Keywords: Bionic tiger-bone powder; Osteoclasts; Osteogenesis; Osteoporosis; Ovariectomized rats.

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.

Keywords: antiretroviral therapy; bone mineral density loss; fracture; low- and middle-income countries; procollagen type 1 pro-peptide (P1NP); tenofovir.

BACKGROUND

Procollagen 1 amino-terminal propeptide (P1NP) is a bone formation marker and has been shown to have a strong association with the extent of bone metastases (BM) in patients with advanced prostate cancer. More recently, its levels were found to be affected by androgen deprivation therapies and bisphosphonates. We investigated the role of P1NP as a surrogate marker of sub-radiological skeletal metastases in prostate cancer patients with biochemical failure (BF).

METHODS

BePrepared is a prospective longitudinal substudy of RADAR trial in which serial P1NPs were collected at regular intervals for 123 patients who had completed RADAR protocol treatment.

RESULTS

There was no trend identified in P1NP levels prior to diagnosis of BM. We found that there was no difference in P1NP concentrations at the time of diagnosis of BM in the group that developed BM compared with P1NP levels in groups with only nodal metastases or BF. In the group of patients who did not experience BF, P1NP was affected by previous luteinizing hormone-releasing hormone-agonist and bisphosphonate therapy. Hence, patients who received an 18-month course of androgen deprivation without bisphosphonates had significantly higher P1NP values than patients with shorter androgen deprivation therapy (ADT) course combined with a course of bisphosphonates.

CONCLUSIONS

P1NP is not a sensitive serum marker of early BM in high-risk prostate cancer patients with BF and low prostate-specific antigen levels as its levels are affected by prior history of bone remodelling therapies such as ADT and bisphosphonates.

Background. The aim of this study was to show the importance of the bone marker procollagen type 1 aminoterminal propeptide (P1NP) in detecting bone metastases in women suffering from breast cancer. We furthermore investigated to what degree P1NP is correlated to the degree of bone metastases, and if P1NP is increased in patients with metastases other than bone. Patients and Methods. We analyzed 80 serum samples of women (17 premenopausal/63 postmenopausal) with breast cancer. Therefore we used a specific immunoassay "ELECSYS 2010" by Roche Diagnostics. We divided our group of patients with regard to menopausal status, sites of metastases and number of bone metastases. Results. As a result we found higher concentrations of P1NP in women with radiologically confirmed bone metastases (median: 125.75 ng/mL) in comparison to the collective without bone involvement (median: 73.61 ng/mL). However, both groups showed values above the applied cutoff values of median 27.8 ng/mL for premenopausal women and median: 37.1 ng/mL for the postmenopausal group due to the fact that all patients had cancer. Furthermore higher P1NP concentrations were found in women with more than 5 sites of bone metastases (median: 183.9 ng/mL) than in patients with only one site of bone metastases (median: 37 ng/mL). Also patients with no bone involvement but other sites of metastases showed quite high P1NP concentrations (median: 73.61 ng/mL). Conclusion. The marker of bone turnover procollagen type 1 aminoterminal propeptide can be considered as a useful tool for estimating the extent of bone involvement and for the detection of bone metastases. P1NP cannot replace conventional methods for detecting bone metastases such as radiological methods but it can help clarify unclear radiological results. This study does not take into account the change of P1NP concentration during the course of therapy.

Background: Low bone mineral density (BMD) represents a major risk factor for bone fractures in patients with chronic kidney disease (CKD) as well as after kidney transplantation. However, modalities to solidly predict patients at fracture risk are yet to be defined. Better understanding of bone turnover biomarkers (BTMs) may close this diagnostic gap. This study strives to correlate BTMs to BMD in kidney transplant recipients.

Methods: Changes in BTMs - procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSAP), β-isomer of the C-terminal telopeptide of type I collagen, and urine deoxypyridinoline/Cr - at the time of transplant and 3 months were correlated to changes in BMD measured by dual-energy X-ray absorptiometry at the time of transplant, 6, and 12 months, respectively. Half of the collective was treated with denosumab twice yearly in addition to the standard treatment with calcium and vitamin D.

Results: Changes in bone formation markers BSAP and P1NP within 3 months showed a significant negative correlation to changes in BMD at the hip within 6 months in denosumab-naïve patients. This correlation was abrogated by denosumab treatment.

Conclusions: Changes in BSAP and P1NP showed promise in short-term prediction of BMD. We suggest further trials expanding on the knowledge of these BTMs with assessment of fracture risk, sequential measurements of BTMs within the first 6 months, and the additional use of computed tomography to assess BMD.

Keywords: Biomarkers of bone turnover; Bone mineral metabolism; Denosumab; Kidney transplantation.

OBJECTIVE

There is intense interest in soy isoflavone as a hormone replacement therapy for the prevention of postmenopausal osteoporosis. A new kind of isoflavone-enriched whole soy milk powder (I-WSM) containing more isoflavones than conventional whole soy milk powder was recently developed. The aim of this study was to investigate the effects of I-WSM on bone metabolism in ovariectomized mice.

METHODS

Sixty female ICR mice individually underwent ovariectomy (OVX) or a sham operation, and were randomized into six groups of 10 animals each as follows: Sham, OVX, OVX with 2% I-WSM diet, OVX with 10% I-WSM diet, OVX with 20% I-WSM diet, and OVX with 20% WSM diet. After an 8-week treatment period, bone mineral density (BMD), calcium, alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) 5b, osteocalcin (OC), procollagen 1 N-terminal propeptide (P1NP), and osteoprotegenin (OPG) were analyzed.

RESULTS

BMD was significantly lower in the OVX group compared to the Sham group but was significantly higher in OVX + 10% I-WSM and OVX + 20% I-WSM groups compared to the OVX group (P < 0.05). Serum calcium concentration significantly increased in the OVX + 10% and 20% I-WSM groups. Serum ALP levels were significantly lower in the OVX + 10% and 20% I-WSM groups compared to the other experimental groups (P < 0.05). OC was significantly reduced in the OVX group compared to the Sham group (P < 0.05), but a dose-dependent increase was observed in the OVX groups supplemented with I-WSM. P1NP and OPG levels were significantly reduced, while TRAP 5b level was significantly elevated in the OVX group compared with the Sham group, which was not affected by I-WSM (P < 0.05).

CONCLUSIONS

This study suggests that I-WSM supplementation in OVX mice has the effect of preventing BMD reduction and promoting bone formation. Therefore, I-WSM can be used as an effective alternative to postmenopausal osteoporosis prevention.

OBJECTIVE

To determine bone mineral content (BMC), bone mineral density (BMD), Z scores, and markers of bone turnover in African American children with juvenile rheumatoid arthritis (JRA).

METHODS

Eight children with JRA with no prior exposure to corticosteroids were evaluated. Lumbar spine (L1-L4) and total body and total hip BMC and BMD were determined using dual x-ray absorptiometry (DXA), and Z scores (BMD) were calculated. Serum samples of markers of bone turnover including pyridinoline (PYR), N-terminal propeptide of type I procollagen (P1NP), osteocalcin (OC), and bone-specific alkaline phosphatase (BSAP) were measured.

RESULTS

The mean Z score (BMD) at the lumbar spine (L1-L4) in patients with JRA was -1.2+/-0.8. Z scores for total body and total hip were within 1 standard deviation of normal compared with healthy historical controls matched for age, sex, and race.

CONCLUSIONS

BMD was normal for chronological age (defined as Z score>>or= 2.0) in African American children with JRA who had not previously been treated with corticosteroids. Further studies are needed on the effects of JRA on skeletal health in African American children.

This study examined the associations of 25-hydroxycholecalciferol [25(OH)D3] and intact parathyroid hormone (iPTH) concentrations with bone status parameters in elderly subjects.

Cross-sectional data based on the follow-up 2008 of the longitudinal study on nutrition and health status of senior citizens in Giessen, Germany.

One hundred eighty-eight independently living subjects aged 66-96 years.

Serum concentrations of 25(OH)D3, iPTH, N-terminal propeptide of type 1 collagen (P1NP) and activity of alkaline phosphatase (ALP) were assessed. Broadband ultrasound attenuation, speed of sound and stiffness index were determined by calcaneal quantitative ultrasound (QUS). Multiple linear regression analyses were performed to analyse associations of 25(OH)D3 and iPTH with bone status parameters.

Median (range) 25(OH)D3 and iPTH concentrations were 62.8 (29.9-106.7) nmol/L and 4.6 (1.3-21.0) pmol/L, respectively. Neither 25(OH)D3 nor iPTH was associated with calcaneal bone characteristics measured by QUS, whereas negative associations between 25(OH)D3 and bone formation markers (P1NP and ALP) were found. In a sub analysis, 25(OH)D3 was negatively associated with ALP only in subjects with iPTH concentrations>> 4.59 pmol/L.

The present study provides no evidence for independent associations of 25(OH)D3 and iPTH with calcaneal bone characteristics in community-dwelling elderly subjects with 25(OH)D3 concentrations between 30 and 107 nmol/L. However, 25(OH)D3 interacts with bone formation markers, particularly in subjects with high iPTH concentrations.

Silicon is one of the essential trace elements in the human body; the deficiency of which may lead to bone diseases. Numerous animal experiments have shown that an appropriate increase in the intake of silicon is beneficial to enhancing bone density and toughness to prevent osteoporosis. However, the molecular mechanisms of the silicon-mediated osteogenesis process have not been sufficiently clarified. In this study, we determined the possible osteogenesis-related mechanisms of orthosilicic acid at a molecular level. We detected the relevant pathway and osteogenic indicators by immunofluorescence (IF), Western blot, alkaline phosphatase (ALP) staining (using 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium [BCIP/NBT]), ALP enzyme labeling method, osteocalcin (OCN), and N-terminal propeptide of type 1 procollagen (P1NP) enzyme-linked immunosorbent assay (ELISA). We found that orthosilicic acid is capable of enhancing the expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phospho-protein kinase B (P-Akt), phospho-mammalian target of rapamycin (P-mTOR), and related osteogenic markers (runt-related transcription factor 2 [RUNX2], type I collagen [COL1], ALP, OCN, and P1NP). However, with the addition of PI3K-Akt-mTOR pathway-specific inhibitor LY294002, the expression of PI3K, P-Akt, P-mTOR, RUNX2, COL1, ALP, OCN, and P1NP decreased. The results indicated that the PI3K-Akt-mTOR pathway played a positive regulatory role in the process of orthosilicic acid-mediated osteogenesis in vitro.

OBJECTIVE

Bone changes are increasingly described after burn. How bone markers could help to detect early bone changes or to screen burn patients at higher risk of demineralization is still not made clear. We performed an observational study assessing the changes in serum bone markers after moderate burn.

METHODS

Adults admitted in the first 24h following burn extended on >10% body surface area were included. Serum levels of collagen type 1 cross-linked C-telopeptide (CTX), tartrate-resistant acid phosphatase 5b (TRAP), type 1 procollagen N-terminal (P1NP) and bone alkaline phosphatase (b-ALP) were measured at admission and every week during the first month. Data are expressed as median [min-max].

RESULTS

Bone markers were measured in 20 patients: 18 men, 2 women (including one post-menopausal). Age was 46 [19-86] years old, burn surface area reached 15 [7-85] %. Twelve patients completed the study. All biomarkers mainly remained into normal ranges during evolution. A huge variability was observed regarding biomarkers evolution. Patient's evolution was not linear and could fluctuate from a decrease to an increase of blood concentrations. There was not necessarily a consistency between the two formation or the two resorption markers. Variations observed between two consecutive measurements were lesser than the accepted critical difference in almost one third of the cases.

CONCLUSIONS

Considering available data, role and interest of bone markers in management of burn related bone disease remain unclear.

Paget's disease of bone (PDB) is a common chronic bone disorder. In the French-Canadian population, the p.Pro392Leu mutation within the SQSTM1 gene is involved in 46% of familial forms. In New Zealand, the emergence of PDB in offspring inheriting SQSTM1 mutations was reported to be delayed by a decade compared to their parents. We aimed at assessing the clinical phenotype of offspring carriers of this mutation in our French-Canadian cohort. We reviewed research records from adult offspring carriers of this mutation aged <90 years and their affected parents. In parents, we collected data on sex, age at diagnosis, number of affected bones, total serum alkaline phosphatase levels (tALPs) at diagnosis. In offspring, PDB extended phenotype assessment relying on tALPs, bone specific alkaline phosphatase levels (bALPs), procollagen type 1 amino-terminal propeptide (P1NP), whole body bone scan and skull and pelvis radiographs, was performed at inclusion from 1996 to 2009 and updated in 2016 to 2018, if not done during the past 8 years. The results showed that among the 36 offspring with an updated phenotype, four of them developed a clinical phenotype of PDB characterized by monostotic or polyostotic increased bone uptake associated with typical radiographic lesions in the affected sites, representing an incidence of 1.83 per 1000 person-years. Moreover, the age at PDB diagnosis was delayed by at least 10 years in the adult offspring carriers of the p.Pro392Leu mutation versus their affected parents. Our findings support the utility of a regular monitoring of the adult offspring without PDB but carriers of this mutation.

Keywords: Bone scan; Clinical phenotype; Paget's disease of bone; SQSTM1 gene; p.Pro392Leu mutation.

<AbstractText>We investigated the impact of long-term levothyroxine (LT4) treatment on bone mineral density (BMD) and bone turnover markers (BTMs) in premenopausal women with differentiated thyroid cancer (DTC) after thyroidectomy.</AbstractText><AbstractText>65 premenopausal women who received LT4 therapy at least 1 year after thyroidectomy for DTC and 50 premenopausal women without thyroid diseases were enrolled in this study. We measured the T-scores of lumbar and hip BMD, Serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), intact parathyroid hormone (iPTH), N-terminal propeptide of type 1 N procollagen (<em>P1NP</em>), C-terminal telopeptide of type 1 collagen (CTX-1), calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) in all participants.</AbstractText><AbstractText>In DTC subjects, serum TSH levels was lower, serum FT4, <em>P1NP</em>, CTX-1 and ALP levels were higher compared with controls. The prevalence of osteopenia was higher in DTC subjects than in controls. Multivariate logistic regression analysis showed that serum TSH levels were negatively associated with CTX-1 and ALP.</AbstractText><AbstractText>We found high prevalence of osteopenia among premenopausal women who received long-term LT4 therapy for DTC after thyroidectomy. Long-term TSH suppression therapy was an significant risk factor for decreased bone strength mainly by increasing bone turnover.</AbstractText>

Introduction: This study investigated the results of 3 years of denosumab treatment for osteoporosis in women with rheumatoid arthritis (RA) and primary osteoporosis (PO).Materials and Methods: This study enrolled 112 women with RA (RA group) and 104 women with PO group who received 60 mg denosumab for 3 years. Bone mineral densitiy (BMD) of the lumbar spine, total hip and femoral neck as well as levels of bone turnover markers [N-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase-5b (TRACP-5b)] were measured at years 1, 2, and 3.Results: The percent changes (Δ) in BMD values at years 1, 2, and 3 were as follows: RA group: 6.7 ± 6.2%, 8.9 ± 6.5%, and 9.8 ± 8.2% and PO group: 6.0 ± 4.8%, 8.9 ± 7.5%, and 12.6 ± 8.7% for the lumbar spine; RA group: 4.5 ± 4.6%, 5.2 ± 5.1%, and 6.8 ± 5.9% and PO group: 3.8 ± 4.5%, 4.6 ± 7.4%, and 6.8 ± 4.6% for the total hip; and RA group: 2.7 ± 5.1%, 4.1 ± 6.8%, and 4.3 ± 6.7% and PO group: 3.6 ± 8.0%, 4.5 ± 10.9%, and 5.7 ± 10.5% for the femoral neck, respectively. The ΔBMD for the lumbar spine, total hip, and femoral neck as well as ΔP1NP and ΔTRACP-5b did not differ significantly between the two groups at any time points.Conclusion: Denosumab treatment for osteoporosis had a similar efficacy over 3 years among women with RA and PO. A better understanding of denosumab treatment for this patient population is important in clinical practice.

Keywords: bone mineral density; denosumab; osteoporosis; rheumatoid arthritis.

Type 1 diabetes (T1D) increases fracture risk across the lifespan. The low bone turnover associated with T1D is thought to be related to glycemic control, but it is unclear whether peripheral hyperinsulinemia due to dependence on exogenous insulin has an independent effect on suppressing bone turnover. The purpose of this study was to test the bone turnover marker (BTM) response to acute hyperinsulinemia. Fifty-eight adults aged 18 to 65 years with T1D over 2 years were enrolled at seven T1D Exchange Clinic Network sites. Participants had T1D diagnosis between age 6 months to 45 years. Participants were stratified based on their residual endogenous insulin secretion measured as peak C-peptide response to a mixed meal tolerance test. BTMs (CTX, P1NP, sclerostin [SCL], osteonectin [ON], alkaline phosphatase [ALP], osteocalcin [OCN], osteoprotegerin [OPG], osteopontin [OPN], and IGF-1) were assessed before and at the end of a 2-hour hyperinsulinemic-euglycemic clamp (HEC). Baseline ON (r = -0.30, p = .022) and OCN (r = -0.41, p = .002) were negatively correlated with age at T1D diagnosis, but baseline BTMs were not associated with HbA1c. During the HEC, P1NP decreased significantly (-14.5 ± 44.3%; p = .020) from baseline. OCN, ON, and IGF-1 all significantly increased (16.0 ± 13.1%, 29.7 ± 31.7%, 34.1 ± 71.2%, respectively; all p < .001) during the clamp. The increase in SCL was not significant (7.3 ± 32.9%, p = .098), but the decrease in CTX (-12.4 ± 48.9, p = .058) neared significance. ALP and OPG were not changed from baseline (p = .23 and p = .77, respectively). Baseline ON and SCL were higher in men, but OPG was higher in women (all p ≤ .029). SCL was the only BTM that changed differently in women than men. There were no differences in baseline BTMs or change in BTMs between C-peptide groups. Exogenous hyperinsulinemia acutely alters bone turnover, suggesting a need to determine whether strategies to promote healthy remodeling may protect bone quality in T1D. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Keywords: BONE METABOLISM; HYPERINSULINEMIC‐EUGLYCEMIC CLAMP; TYPE 1 DIABETES.

This study aimed to evaluate the association of bone metabolism markers with coronary atherosclerosis and coronary artery disease (CAD) in postmenopausal women. Based on the findings of coronary angiography, 111 women with CAD and 116 women without CAD were recruited. Serum calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), osteocalcin, N-terminal propeptide of type I procollagen (P1NP) and C-terminal cross-linked telopeptide of type I collagen (CTX) were measured. The Gensini score was used to assess the severity of coronary atherosclerosis. Compared with women with serum calcium ≤2.29 mmol/L, women with serum calcium >2.29 mmol/L had a 2.63-fold increased risk of CAD after adjusting for multiple cardiovascular risks, PTH and 25OHD [odds ratio (OR) = 2.91, 95% confidence interval (CI) 1.35-6.28]. In the fully adjusted model plus PTH and 25OHD, the risk of CAD increased 1.87-fold with every 1-SD increment of serum calcium (OR = 1.87, 95% CI 1.21-2.88). To further analyze the potential strong confounding effect of albumin, the absolute levels of calcium were replaced by their albumin-corrected values in the regression model. Compared with women with albumin-corrected calcium ≤2.27 mmol/L, women with albumin-corrected calcium >2.27 mmol/L had a 2.36-fold increased risk of CAD in the fully adjusted model plus PTH and 25OHD (OR = 2.36, 95% CI 1.13-4.92). The risk of coronary atherosclerosis as defined by Gensini score >0 increased 1.73-fold with every 1-SD increment of serum calcium in the fully adjusted model plus PTH and 25OHD (OR = 1.73, 95% CI 1.09-2.73). However, albumin-corrected calcium was not associated with coronary atherosclerosis either as a categorical variable or as a continuous variable in all models. No significant association of PTH, 25OHD, osteocalcin, CTX and P1NP with CAD or coronary atherosclerosis was found in this study. Higher serum calcium levels were independently associated with CAD in postmenopausal women.

Context: Acromegaly can impair bone integrity, increasing the risk of vertebral fractures (VF).

Objective: To evaluate the impact of isolated GH/IGF-I hypersecretion on bone turnover markers,Wnt inhibitors, BMD, microarchitecture, bone strength and vertebral fractures in female patients with acromegaly (Acro), compared to healthy control group (HC).

Design, setting, and patients: Cross-sectional study including 83 premenopausal women without any pituitary deficiency:18 acromegaly in remission (AcroR), 12 in group with active acromegaly (AcroA) and 53 HC. Serum P1NP, β-CTX, osteocalcin, sclerostin and DKK1 were measured in blood samples. DXA, HR-pQCT and vertebral fractures evaluation were also assessed simultaneously.

Main outcome and results: AcroA showed significantly lower sclerostin and higher DKK1 as compared to HC. On HR-pQCT of tibia and radius, Acro showed impairment of trabecular (area and trabecular number), increased cortical porosity and increased cortical area and cortical thickness compared to HC. The only significant correlation found with HR-pQCT parameters was a positive correlation between cortical porosity and serum DKK1 (R=0.45, P=0.044). Mild VF were present in approximately thirty percent of patients.

Conclusions: Eugonadal women with acromegaly without any pituitary deficiency showed increased cortical BMD, impairment of trabecular bone microstructure and increased VF. Sclerostin was not correlated with any HR-pQCT parameters, however DKK1 was correlated with cortical porosity in tibia (P=0.027). Additional studies are needed to clarify, the role of Wnt inhibitors on bone microarchitecture impairment in acromegaly.

Keywords: Acromegaly; Wnt signaling pathway; bone microarchitecture; bone mineral density; growth hormone; vertebral fractures.

Training civilians to be soldiers is a challenging task often resulting in musculoskeletal injuries, especially bone stress injuries. This study evaluated bone health biomarkers (P1NP/CTX) and whey protein or carbohydrate supplementations before and after Army initial entry training (IET). Ninety male IET soldiers participated in this placebo-controlled, double-blind study assessing carbohydrate and whey protein supplementations. Age and fat mass predicted bone formation when controlling for ethnicity, explaining 44% (p < 0.01) of bone formation variations. Age was the only significant predictor of bone resorption (p = 0.02) when controlling for run, fat, and ethnicity, and these factors together explained 32% of the variance in bone resorption during week one (p < 0.01). Vitamin D increased across training (p < 0.01). There was no group by time interaction for supplementation and bone formation (p = 0.75), resorption (p = 0.73), Vitamin D (p = 0.36), or calcium (p = 0.64), indicating no influence of a supplementation on bone biomarkers across training. Age, fitness, fat mass, and ethnicity were important predictors of bone metabolism. The bone resorption/formation ratio suggests IET soldiers are at risk of stress injuries. Male IET soldiers are mildly to moderately deficient in vitamin D and slightly deficient in calcium throughout training. Whey protein or carbohydrate supplementations did not affect the markers of bone metabolism.

Keywords: biomarker; bone injury; injury prevention; military training; musculoskeletal injury; stress fracture.