Spinal cord injury (SCI) is associated with marked bone loss and an increased risk of fracture. We randomized 61 individuals with chronic SCI and low bone mass to receive either teriparatide 20 μg/d plus sham vibration 10 min/d (n = 20), placebo plus vibration 10 min/d (n = 20), or teriparatide 20 μg/d plus vibration 10 min/d (n = 21). Patients were evaluated for 12 months; those who completed were given the opportunity to participate in an open-label extension where all participants (n = 25) received teriparatide 20 μg/d for an additional 12 months and had the optional use of vibration (10 min/d). At the end of the initial 12 months, both groups treated with teriparatide demonstrated a significant increase in areal bone mineral density (aBMD) at the spine (4.8% to 5.5%). The increase in spine aBMD was consistent with a marked response in serum markers of bone metabolism (ie, CTX, P1NP, BSAP), but no treatment effect was observed at the hip. A small but significant increase (2.2% to 4.2%) in computed tomography measurements of cortical bone at the knee was observed in all groups after 12 months; however, the magnitude of response was not different amongst treatment groups and improvements to finite element-predicted bone strength were not observed. Teriparatide treatment after the 12-month extension resulted in further increases to spine aBMD (total increase from baseline 7.1% to 14.4%), which was greater in patients initially randomized to teriparatide. Those initially randomized to teriparatide also demonstrated 4.4% to 6.7% improvements in hip aBMD after the 12-month extension, while all groups displayed increases in cortical bone measurements at the knee. To summarize, teriparatide exhibited skeletal activity in individuals with chronic SCI that was not augmented by vibration stimulation. Without additional confirmatory data, the location-specific responses to teriparatide would not be expected to provide clinical benefit in this population. © 2018 American Society for Bone and Mineral Research.

The plasma cell malignancy multiple myeloma (MM) is unique amongst haematological malignancies in its capacity to cause osteoclast-mediated skeletal destruction. The PI3K/Akt pathway mediates proliferation, survival and drug resistance in MM plasma cells and is also involved in regulating the formation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts. NVP-BKM120 (Buparlisib, Novartis) is a PI3K inhibitor that is currently undergoing clinical evaluation in several tumour settings. In this study, we have examined the anti-tumorigenic effects of BKM120 in an immunocompetent mouse model of MM and its effects on osteoblast and osteoclast formation and function. BKM120 treatment (40 mg/kg) resulted in a significant decrease in serum paraprotein and tumour burden, and μCT analysis of the proximal tibia revealed a significant reduction in the number of osteolytic bone lesions in BKM120-treated animals. BKM120 also mediated a significant increase in serum levels of the osteoblast marker P1NP, and a significant decrease in serum levels of the osteoclast marker TRAcP5. In vitro, BKM120 decreased MM plasma cell proliferation, osteoclast formation and function, and promoted osteoblast formation and function. These findings suggest that, in addition to its anti-tumour properties, BKM120 could be used to treat osteolytic bone disease in MM patients.

OBJECTIVE

We aimed to compare the effect of risedronate (RIS) and teriparatide (TPTD) (recombinant human parathyroid hormone 1-34) on bone turnover markers in women with postmenopausal osteoporosis.

METHODS

Forty-four Caucasian women (age 65.1 +/- 1.6 years) with postmenopausal osteoporosis were randomly assigned to receive either RIS 35 mg once weekly (n = 22) or TPTD 20 microg once daily (n = 22) for 12 months. Serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx), total alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) were obtained from all women before, 3 and 6 months after treatment initiation. Lumbar spine bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry before and 12 months after treatment initiation.

RESULTS

P1NP, CTx and total ALP levels decreased in RIS group (p < 0.001) and increased in TPTD group (p < 0.001) throughout the treatment. iPTH increased significantly in RIS group (p < 0.05) and decreased in TPTD group (p < 0.001). Finally, lumbar spine BMD increased significantly in both RIS (p = 0.003) and TPTD groups (p < 0.001) without significant differences between them.

CONCLUSIONS

Our data suggest that both serum P1NP and CTx are reliable markers of RIS and TPTD action in women with postmenopausal osteoporosis. In a similar way, serum total ALP can be used as an alternative marker for monitoring both RIS and TPTD action, while iPTH can be used only for TPTD-treated women. The increase in P1NP and CTx after 3 months of treatment with RIS or TPTD can predict the increase in BMD after 12 months of treatment.

BACKGROUND

Bone turnover markers (BTMs) may identify changes in bone remodeling within a relatively short time interval before changes in bone mineral density can be detected. New markers such as osteoprotegerin, receptor activator of nuclear factor-κB ligand, and sclerostin have emerged, but there is little information about their potential use in clinical practice.

OBJECTIVE

The aim of this study was to analyze the ability of several BTMs to predict bone loss in pre- and postmenopausal women and to monitor the efficacy of treatment in osteoporotic women.

METHODS

We performed an observational prospective study in pre- and postmenopausal ambulatory women (n = 72 and n = 152, respectively).

METHODS

Postmenopausal women with osteoporosis (n = 18) were treated with risedronate and calcium. Women filled out a questionnaire and underwent bone mineral density measurement using dual-energy x-ray absorptiometry at the time of enrollment and after 1 year of follow-up. BTMs were measured at baseline, at 6 months, and after 1 year.

RESULTS

Increased levels of N-terminal propeptide of type 1 procollagen (P1NP) and β-type I collagen telopeptides (CTXs) were associated with low bone mineral density in the premenopausal (P = .02 and P = .04, respectively) and postmenopausal (P = .03 and P = .02) groups. The best analytical performance to diagnose osteoporosis was for β-CTX, osteocalcin, and P1NP, with areas under the curve of 0.70 (P = .005), 0.64 (P = .048), and 0.71 (P = .003). A significant decrease was found in P1NP, osteocalcin, tartrate-resistant acid phosphatase-5b, β-CTX, and bone alkaline phosphatase after 1 year of treatment (all P < .05).

CONCLUSIONS

Our data suggest that measurement of β-CTX and P1NP shows adequate analytical performance and could potentially be included in algorithms for the screening of osteoporosis. Furthermore, these two markers, along with osteocalcin and tartrate-resistant acid phosphatase-5b, are useful to monitor the response to risedronate.

Vitamin D "insufficiency" and "deficiency" are defined as serum 25-hydroxyvitamin D [25(OH)D] levels <75 and <30 nmol/L, respectively. We aimed to determine whether these values signal hypocalcemia and hypophosphatemia, secondary hyperparathyroidism, high bone remodeling, low areal bone mineral density (aBMD), microstructural deterioration, or reduced matrix mineralization density (MMD) and so suggest whether bone fragility is present.

Concentrations of 25(OH)D, calcium, phosphate, creatinine, and parathyroid hormone (PTH) were measured in 11,855 participants. Serum C-terminal telopeptide of type 1 collagen, procollagen type 1 N-terminal propeptide (P1NP), aBMD, and distal radius microstructure and MMD were measured in a second subset of 150 participants.

A breakpoint for calcium, PTH, and alkaline phosphatase was identified at a threshold 25(OH)D level <30 nmol/L. There was no plateau beyond 75 nmol/L. In the subgroup with measurements of bone morphology, no associations were detectable between serum 25(OH)D concentration, aBMD, trabecular density, cortical porosity, or MMD. Among 1439 participants with serum 25(OH)D <30 nmol/L, 6.1% had low serum calcium, 3.4% had low serum phosphate, 6.1% had high alkaline phosphatase, and 34.2% had elevated PTH. Most participants did not have any abnormalities.

At a 25(OH)D threshold of ≤30 nmol/L, abnormalities in biochemical features support the notion of a "deficiency" state predisposing to bone disease. However, no deleterious effects were found in participants within an insufficiency threshold of a 25(OH)D level of 30 to 75 nmol/L, which challenges the rationale justifying vitamin D supplementation in these individuals.

Misbalances in extracellular matrix turnover are key factors in the development of stricturing (Montreal B2) and penetrating (Montreal B3) Crohn's disease.

To determine whether serological markers for collagen formation and degradation could serve as biomarkers for complications of Crohn's disease.

Serum biomarkers for type I, III, V and VI collagen formation (P1NP, Pro-C3, Pro-C5, Pro-C6) and matrix metalloproteinase mediated degradation (C1M, C3M, C5M and C6M) were measured in a retrospective, single centre cohort of 112 patients with Crohn's disease in the terminal ileum (nonstricturing/nonpenetrating: n=40, stricturing: n=55, penetrating: n=17) and 24 healthy controls. Active inflammation was defined as CRP >5 mg/L.

C3M and Pro-C5 levels were higher in penetrating vs nonpenetrating/nonstricturing and stricturing disease (33.6±5 vs 25.8±2.2 [P=.004] and 27.2±2.3 [P=.018] nmol/L C3M, 1262.7±259.4 vs 902.9±109.9 [P=.005] and 953.0±106.4 [P=.015] nmol/L Pro-C5). C1M (71.2±26.1 vs 46.2±6.2 nmol/L [P<.001]), C3M (31.6±3.9 vs 26.1±1.6 nmol/L [P=.002] and Pro-C5 levels (1171.7±171.5 vs 909.6±80.4 nmol/L [P=.002]) were higher in patients with active inflammation vs without active inflammation. Pro-C3/C3M-ratios were best to differentiate between penetrating vs nonstricturing/nonpenetrating and stricturing disease with area under the curves of 0.815±0.109 (P<.001) and 0.746±0.114 (P=.002) respectively.

Serological biomarkers show that penetrating Crohn's disease is characterised by increased matrix metalloproteinase-9 degraded type III collagen and formation of type V collagen. Active inflammation in Crohn's disease is characterised by increased formation of type V collagen and increased matrix metalloproteinase mediated breakdown of type I, III collagen. Pro-C3/C3M ratios are superior in differentiating between penetrating Crohn's disease vs inflammatory and stricturing Crohn's disease.

UNASSIGNED

Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis.

UNASSIGNED

Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided.

UNASSIGNED

When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid.

UNASSIGNED

Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study.

Type 1 diabetes (T1D) is associated with impaired bone health and both osteocalcin (OCN) and procollagen type 1 amino terminal propetide (P1NP) (markers of bone formation) and C-terminal cross-linked telopeptide (CTX) (marker of bone resorption) are decreased in adult patients with T1D. We review the existing literature characterizing these bone turnover markers in children and adolescents with T1D and by meta-analysis examine whether alterations in OCN, P1NP, and CTX are evident and if potential changes correlate to the metabolic control (hemoglobin A1c, HbA1c). Systematic searches at MEDLINE and EMBASE were conducted in January 2018 identifying all studies describing OCN, P1NP, or CTX in children and adolescents with T1D. A total of 26 studies were included, representing data from more than 1000 patients with T1D. Pooled analyses of standard mean difference and summary effects analysis were performed when sufficient data were available. Pooled analysis revealed mean OCN to be significantly lower in children and adolescents with T1D compared to healthy controls (standard mean difference: -1.87, 95% confidence interval, CI: -2.83; -0.91) whereas both P1NP and CTX did not differ from the controls. Only data on OCN was sufficient to make pooled correlation analysis revealing a negative correlation between OCN and HbA1c (-0.31 95% CI: -0.45; -0.16). In conclusion, OCN is decreased in children and adolescents with T1D, whether CTX and P1NP are affected as well is unclear, due to very limited data available. New and large studies including OCN, P1NP, and CTX (preferably as z-scores adjusting for age variability) is needed to further elucidate the status of bone turnover in children and adolescents with T1D.

The coupling of bone formation to bone resorption during treatment of postmenopausal osteoporosis with antiresorbers might be related to changes in Wnt/b-catenin signaling. We compared the effects of two bisphosphonate treatments on two Wnt-inhibitors Sclerostin (SOST) and Dickkopf-related protein 1 (DKK1). The study population included 74 women with postmenopausal osteoporosis participating simultaneously in two multicenter, placebo controlled trials. The patients were randomized to: intramuscular clodronate 100mg/week (CLO) (N=36), and yearly intravenous therapy with 5mg zoledronate (ZOL) (N=18) and placebo (N=20). Bone turnover markers (intact N-propeptide of type I collagen [P1NP], C-terminal telopeptide of type I collagen [CTX]) remained unchanged in the placebo group while they significantly decreased during treatment with the two bisphosphonates, versus both placebo and baseline. In CLO treated patients serum DKK1 remained stable over the entire period of observation while serum SOST levels increased significantly after 12months of treatment both versus placebo group (p<0,005), baseline (p<0,001) and ZOL treated group. In the ZOL group, DKK1 levels increased significantly within one month and for the following 6months and it fell back to baseline values at 12months. The second ZOL infusion was again associated with an increase in DKK1 a month later, although to a lesser extent. In conclusion, in this study we have found that the treatment of postmenopausal osteoporosis with intermittent yearly ZOL is associated with transient and declining increases in DKK1 while continuous treatment with CLO, results in a late increase in serum SOST. These preliminary results and further ad hoc studies might contribute to shed light on our understanding of the bone coupling effects taking place during treatment of osteoporosis with different anti-resorbers or with different treatment regimens.

Low serum 25-hydroxyvitamin D (25OHD) is associated with osteoporosis and osteoporotic fracture, but it remains uncertain whether these associations are causal. We conducted a Mendelian randomization (MR) study of 1,824 postmenopausal Chinese women to examine whether the detected associations between serum 25OHD and bone mineral density (BMD) and bone metabolism markers were causal. In observational analyses, total serum 25OHD was positively associated with BMD at lumbar spine (P = 0.003), femoral neck (P = 0.006) and total hip (P = 0.005), and was inversely associated with intact parathyroid hormone (PTH) (P = 8.18E-09) and procollagen type 1 N-terminal propeptide (P1NP) (P = 0.020). By contract, the associations of bioavailable and free 25OHD with all tested outcomes were negligible (all P>> 0.05). The use of four single nucleotide polymorphisms, GC-rs2282679, NADSYN1-rs12785878, CYP2R1-rs10741657 and CYP24A1-rs6013897, as candidate instrumental variables in MR analyses showed that none of the two stage least squares models provided evidence for associations between serum 25OHD and either BMD or bone metabolism markers (all P>> 0.05). We suggest that after controlling for unidentified confounding factors in MR analyses, the associations between genetically low serum 25OHD and BMD and bone metabolism markers are unlikely to be causal.

OBJECTIVE

Amenorrhoea and low bone density are common in excessive exercisers, yet endocrine factors that differentiate adolescent amenorrhoeic exercisers (AE) from eumenorrhoeic exercisers (EE) are unclear. We have previously reported that high ghrelin and low leptin predict lower LH secretion in AE. Leptin and ghrelin impact cortisol secretion, and hypercortisolaemia can inhibit LH pulsatility. We hypothesized that higher cortisol secretion in young endurance weight-bearing AE compared with EE and nonexercisers predicts lower LH secretion, lower levels of a bone formation marker and higher levels of a bone resorption marker.

METHODS

Cross-sectional.

METHODS

We studied 21 AE, 18 EE and 20 nonexercisers aged 14-21 years (BMI 10th-90th%iles).

METHODS

Subjects underwent frequent sampling (11 p.m. to 7 a.m.) to assess cortisol, ghrelin, leptin and LH secretory dynamics. Fasting levels of a bone formation (P1NP) and bone resorption (CTX) marker were measured.

RESULTS

BMI did not differ among groups. Cortisol pulse amplitude, mass, half-life and area under the curve (AUC) were highest in AE (P = 0.04, 0.007, 0.04 and 0.003) and were associated inversely with fat mass (r = -0.29, -0.28 and -0.35, P = 0.03, 0.04 and 0.007). We observed inverse associations between cortisol and LH AUC (r = -0.36, P = 0.008), which persisted after controlling for fat mass, leptin and ghrelin AUC. Cortisol correlated positively with CTX in EE and inversely with P1NP in nonexercisers.

CONCLUSIONS

Higher cortisol secretion in AE compared with EE and nonexercisers is associated with lower LH secretion. Effects of leptin and ghrelin on LH secretion may be mediated by increased cortisol.

The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, β-catenin. Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of β-catenin turnover, and heterozygous germ-line mutations in the APC gene cause familial adenomatous polyposis (FAP). Whether APC mutations affect bone mass has not been previously investigated. We conducted a cross-sectional study evaluating skeletal status in FAP patients with a documented APC mutation. Twenty-two FAP patients with a mean age of 42 years (54.5% women) were included in this study. Mean bone mineral density (BMD) Z-scores were significantly increased above normal at all measured sites: lumbar spine (p < .01), total hip (p < .01), femoral neck (p < .05), and trochanter (p < .01). Z-scores were +1 or greater in 14 patients (63.6%) and +2 or greater in 5 (22.7%). Mean values of bone turnover markers were within normal ranges. There was a significant positive correlation between procollagen type I N-terminal propeptide (P1NP) and β-crosslaps (β-CTX) (r = 0.70, p < .001) and between these markers and sclerostin and BMD measurements. We demonstrate that FAP patients display a significantly higher than normal mean BMD compared with age- and sex-matched healthy controls in the presence of a balanced bone turnover. Our data suggest a state of "controlled" activation of the Wnt signaling pathway in heterozygous carriers of APC mutations, most likely owing to upregulation of cytoplasmic β-catenin levels.

Introduction: Investigations in rodents as well as in vitro experiments have suggested an anabolic influence of specific collagen peptides (SCP) on bone formation and bone mineral density (BMD). The goal of the study was to investigate the effect of 12-month daily oral administration of 5 g SCP vs. placebo (CG: control group) on BMD in postmenopausal women with primary, age-related reduction in BMD. Methods: 131 women were enrolled in this randomized, placebo-controlled double-blinded investigation. The primary endpoint was the change in BMD of the femoral neck and the spine after 12 months. In addition, plasma levels of bone markers-amino-terminal propeptide of type I collagen (P1NP) and C-telopeptide of type I collagen (CTX 1)-were analysed. Results: A total of 102 women completed the study, but all subjects were included in the intention-to-treat (ITT) analysis (age 64.3 ± 7.2 years; Body Mass Index, BMI 23.6 ± 3.6 kg/m²; T-score spine -2.4 ± 0.6; T-score femoral neck -1.4 ± 0.5). In the SCP group (n = 66), BMD of the spine and of the femoral neck increased significantly compared to the control group (n = 65) (T-score spine: SCP +0.1 ± 0.26; CG -0.03 ± 0.18; ANCOVA p = 0.030; T-score femoral neck: SCP +0.09 ± 0.24; CG -0.01 ± 0.19; ANCOVA p = 0.003). P1NP increased significantly in the SCP group (p = 0.007), whereas CTX 1 increased significantly in the control group (p = 0.011). Conclusions: These data demonstrate that the intake of SCP increased BMD in postmenopausal women with primary, age-related reduction of BMD. In addition, SCP supplementation was associated with a favorable shift in bone markers, indicating increased bone formation and reduced bone degradation.

X-linked hypophosphatemia (XLH) is a rare, inheritable disorder manifesting as rickets in children and osteomalacia in adults. While conventional medical treatment with oral phosphate and alfacalcidol is recommended in childhood, it is undecided whether adults should continue therapy. The aim of this 6-year prospective study was to determine the impact of conventional medical treatment on areal bone mineral density (aBMD), bone turnover markers (BTMs) and measures of calcium homeostasis in 27 adult patients with XLH, 11 of whom received medical treatment. Lumbar spine and total hip aBMD, as assessed by DXA, and biochemical measures of calcium, phosphate, PTH, 1,25 dihydroxyvitamin D2+3 (1,25(OH)2D), fibroblast growth factor 23 (FGF23), P1NP and CTX were measured at baseline and at follow-up. The renal tubular reabsorption of PO4 (TmPO4/GFR) was calculated at both time points. Multilevel mixed-effects linear regression models were used for analyses. During the study period, spine and hip aBMD did not change significantly between treated and non-treated XLH patients. There was a trend towards a decrease in calcium, phosphate and TmPO4/GFR in the treatment group (p = 0.057, p = 0.080 and p = 0.063, respectively), whereas PTH, FGF23, 1,25(OH)2D and P1NP did not change significantly in either groups. However, CTX increased significantly in the treated compared to non-treated group (p = 0.044). Continuing conventional medical therapy in adulthood, although associated with increased bone resorption, does not promote or prevent loss of bone mass as evidenced from the stable aBMD of the hip and spine in XLH patients.

BACKGROUND

The aim of the study was to investigate whether the bone turnover marker procollagen type 1 amino-terminal propeptide (P1NP) could be useful for the early detection of bone metastases in patients with renal cell carcinoma (RCC) and if chemotherapy influences P1NP concentrations in patients with bone metastases.

METHODS

Serum samples of 36 patients were analyzed using a specific immunoassay. The patients were divided into three groups: 24 patients without metastatic spread, 6 patients with untreated bone metastases and 6 patients who had received sorafenib.

RESULTS

The P1NP concentration was significantly higher (p< or =0.001) in the patients with bone metastases (median: 396.10 ng/ml) than in those without bone involvement (median: 35.53 ng/ml). The patients treated with sorafenib showed levels within the normal range (median: 28.96 ng/ml).

CONCLUSIONS

P1NP is a significant diagnostic marker for the development of bone metastases in patients with RCC and could help to evaluate the progress of chemotherapy.

Abaloparatide (ABL) is a novel synthetic peptide analog of parathyroid hormone-related protein. In previous reports, intermittent ABL administration showed robust bone mineral density (BMD) increase and reduced the incidence of fractures in patients with osteoporosis, while its calcemic effect was reduced, as compared with teriparatide (TPTD), a parathyroid hormone N-terminal fragment. The present study aimed to elucidate the effects of ABL on bone anabolism and bone turnover as compared with TPTD. In ovariectomized (OVX) rats, ABL increased the bone strength and BMD of lumbar spine by intermittent administration similar to TPTD. Both ABL and TPTD increased the bone formation marker serum P1NP with little effect on the bone resorption maker urine DPD/Cr, suggesting anabolic effects on bone. In human osteoblastic cells, both peptides increased the expression of bone resorption-related factors such as RANKL/OPG and M-CSF, and the effects of ABL were significantly attenuated as compared with those of TPTD under transient 6-h treatment, although no significant differences were found under continuous treatment. In contrast, ABL and TPTD similarly promoted the expression of bone formation-related factors, IGF-1 and osteocalcin. In addition, there were no significant differences in the effects on WNT signaling inhibitors such as sclerostin and dickkopf-related protein 1 (DKK1) between the two peptides. These results demonstrate that ABL exerts bone anabolic effects in OVX rats. It is also indicated that ABL stimulates the expression of RANKL/OPG and M-CSF less than TPTD, while showing similar effects on bone formation-related factors and WNT signaling inhibitors in vitro. The profile of ABL indicates that it would be a suitable bone anabolic agent for osteoporosis.

OBJECTIVE

To determine if GC (group-specific component globulin) and CYP2R1 genetic variants have an association with serum 25-OHD3 levels, BMD or bone turnover markers in a population of Chinese postmenopausal women.

METHODS

We randomly selected 1494 postmenopausal women of the Han ethnic group from seven communities in Beijing. BMD was determined by dual energy X-ray absorptiometry; serum bone turnover markers and 25-OHD3 were measured by the automated Roche electrochemiluminescence system; genotypes of GC and CYP2R1 were detected by the TaqMan allelic discrimination assay. Multiple statistic methods were used to test the associations of SNP genotypes and vitamin D levels.

RESULTS

In our sample, 89.6% women had vitamin D deficiency and another 9.8% had vitamin D insufficiency. The variants of rs2298849 (β=0.105, P<0.001) in GC were significantly associated with serum 25-OHD3 levels. Allele G of rs2298849 might be protective for serum 25-OHD3 level. Among the haplotypes of rs222020-rs2298849, CG (β=0.104, P=0.001) corresponded to increasing serum 25-OHD3 concentrations. CYP2R1 polymorphisms showed some significant association with serum β-CTX and P1NP levels.

CONCLUSIONS

We found that GC variants had a significant association with serum 25-OHD3 levels among postmenopausal women of the Han ethnic group in Beijing, while CYP2R1 variants were not found to be significant.

OBJECTIVE

To investigate the activity profile of football training and its short-term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT).

METHODS

This was a randomised 12-week study in which men with PCa undergoing ADT were assigned to a football intervention group [FTG, n = 29, 67 ± 7 (±SD) years] training 2‒3 times per week for 45‒60 min or to a control group (n = 28, 66 ± 5 years). The activity profile was measured using a 5-Hz GPS. The outcomes were total body and leg bone mineral content (BMC) and density, BTMs and postural balance.

RESULTS

In the last part of the 12 weeks, FTG performed 194 ± 41 accelerations and 296 ± 65 decelerations at >0.6 m/s/s and covered a distance of 905 ± 297 m at speeds >6 km/h and 2646 ± 705 m per training session. Analysis of baseline-to-12-week change scores showed between-group differences in favour of FTG in total body BMC [26.4 g, 95 % confidence interval (CI): 5.8-46.9 g, p = 0.013], leg BMC (13.8 g, 95 % CI: 7.0‒20.5 g, p < 0.001) and markers of bone formation: P1NP (36.6 µg/L, 95 % CI: 10.4‒62.8 µg/L, p = 0.008) and osteocalcin (8.6 µg/L, 95 % CI: 3.3‒13.8 µg/L, p < 0.01). The number of decelerations correlated to the increase in leg BMC (r = 0.65, p = 0.012). No between-group differences were observed for the remaining outcomes.

CONCLUSIONS

Football training involves numerous runs, accelerations and decelerations, which may be linked to marked increases in bone formation markers and preserved bone mass in middle-aged and elderly men with PCa undergoing ADT.

BACKGROUND

ClinicalTrials.gov: NCT01711892.

The aim of this study was to develop and validate a model for pulmonary fibrosis, using ex vivo tissue cultures of lungs from bleomycin treated animals, enabling the investigation of fibrosis remodeling using novel biomarkers for the detection of ECM protein fragments. The combination of in vivo and ex vivo models together with ECM remodeling markers may provide a translational tool for screening of potential treatments for IPF.

Twenty female Sprague-Dawley rats, twelve weeks of age, were administrated either two doses of bleomycin (BLM) (n = 14) or saline (n = 6) I.T., two days apart. Ten rats were euthanized at day seven and the remaining ten rats at day fourteen, after the last dose. Precision-cut lung slices (PCLS) were made and cultured for 48 h. Ten female Sprague-Dawley rats, twelve weeks of age, were administrated either two doses of BLM (n = 7) or saline (n = 3) I.T., two days apart. The rats were euthanized fourteen days after the last dose. PCLS were made and cultured for 48 h in: medium, medium + 100 μM IBMX (PDE inhibitor), or medium + 10 μM GM6001 (MMP inhibitor). Turnover of type I collagen (P1NP, C1M), type III collagen (iP3NP, C3M) and elastin degradation (ELM7) was measured in the supernatant of the cultured PCLS.

P1NP, C1M, iP3NP, C3M and ELM7 were significantly increased in supernatants from BLM animals (P ≤ 0.05 - P ≤ 0.0001) when compared to controls. P1NP, C1M, iP3NP, C3M and ELM7 were significantly increased in supernatants from day seven BLM animals compared to day fourteen BLM animals (P ≤ 0.05 - P ≤ 0.0001). P1NP, C1M, iP3NP, C3M and ELM7 were significantly decreased when adding IBMX to the culture medium of fibrotic lung tissue (P ≤ 0.05 - P ≤ 0.0001). C1M, C3M and ELM7 were significantly decreased when adding GM6001 to the culture medium (P ≤ 0.05 - P ≤ 0.0001). Sirius Red and Orcein staining confirmed the presence of collagen and elastin deposition in the lungs of the animals receiving BLM.

The protein fingerprint technology allows the assessment of ECM remodeling markers in the BLM PCLS model. By combining in vivo, ex vivo models and the protein fingerprint technology in the fibrotic phase of the model, we believe the chance of translation from animal model to human is markedly increased.

BACKGROUND

Tenofovir is involved in accelerated bone mineral density (BMD) loss.

METHODS

We recently published a hip BMD improvement at week 48 [+2.1% (95% CI: -0.6, 4.7) (P = 0.043)] in HIV-infected patients with osteopenia/osteoporosis randomized to switch from tenofovir to abacavir (n = 26), although without reaching statistical significance compared with those who maintained tenofovir (n = 28). Here, we present changes at week 48 in bone markers [C-terminal telopeptide of collagen type 1 (CTX), osteocalcin and procollagen type 1 N propeptide (P1NP)] as well as in circulating levels of three proteins involved in bone regulation [osteoprotegerin, receptor activator for NF-κB ligand (RANKL) and sclerostin, a selective regulator of bone formation through the Wnt pathway] in 44 of these patients. χ(2) or Fisher and Student t-tests were performed according to the distribution of the variables.

RESULTS

Bone markers decreased only in the abacavir group [mean (SD) CTX changed from 0.543 (0.495) to 0.301 (0.306) ng/mL; mean (SD) osteocalcin changed from 23.72 (22.20) to 13.95 (12.40) ng/mL; and mean (SD) P1NP changed from 54.68 (54.52) to 28.65 (27.48) ng/mL (P < 0.001 in all cases)], reaching statistical significance between the groups at week 48. Osteoprotegerin did not vary, but sclerostin significantly increased in the abacavir group [from 29.53 (27.91) to 35.56 (34.59) pmol/L, P = 0.002]. No significant differences in osteoprotegerin and sclerostin were detected between the groups at week 48. RANKL values were below the limit of detection in all samples.

CONCLUSIONS

The switch from tenofovir to abacavir seems to induce a positive effect on bone tissue, since bone turnover markers decreased. In addition, circulating sclerostin levels increased, a change associated with improved bone properties.

BACKGROUND

Puberty is characterized by increases in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) and the pubertal growth spurt. Bone formation and resorption also increase, consistent with increased bone metabolism.

OBJECTIVE

To determine the relationship between pubertal bone metabolism, GH and IGF-1. We hypothesized that bone turnover peaks at the time of greatest pubertal GH secretion.

METHODS

Subjects included 86 girls and boys, 9-17 years-old (BMI 10th-90th percentiles). Because higher endogenous GH secretion is associated with a higher nadir following oral glucose, we used the GH nadir following a 2-h OGTT as indicative of GH status. Fasting serum IGF-1, aminoterminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal collagen crosslinks (CTX) were obtained. Subjects were grouped per expected timing of peak growth. Group 1: Tanner 1 girls and Tanner 1-2 boys (period preceding peak growth), Group 2: Tanner 2-3 girls and Tanner 3-4 boys (period of peak growth) and Group 3: Tanner 4-5 girls and Tanner 5 boys (period following peak growth).

RESULTS

GH peaked at mid-puberty (Group 2) and IGF-1 in late puberty (Group 3). P1NP and CTX were highest in mid-puberty compared with early and late puberty (P = 0·0009 and 0·006 in girls and P = 0·005 and 0·04 in boys). GH, but not IGF-1, correlated with P1NP (r = 0·46 in both genders, P ≤ 0·008) and CTX (r = 0·37 and 0·38, P = 0·04 and 0·02 in girls and boys, respectively). Similarly, on regression modelling, GH (but not IGF-1) predicted both bone turnover markers in both genders.

CONCLUSIONS

GH is strongly associated with pubertal bone metabolism, independent of systemic IGF-1 in girls and boys.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare, severe, early form of osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. In studies of idiopathic osteoporosis (IOP) in premenopausal women, we enrolled 78 women with low-trauma fractures and 40 healthy controls, all with normal menses and no secondary cause of bone loss. In 15 of the affected women, the PLO subgroup, fractures had occurred during late pregnancy or lactation. We hypothesized that clinical, bone structural, and metabolic characteristics would differ between women with PLO and those with (non-PLO) IOP and controls. All were evaluated > 12 months postpartum, when structural and remodeling characteristics would be expected to reflect baseline premenopausal status rather than transient postpartum changes. As previously reported, affected subjects (PLO and IOP) had BMD and microarchitectural deficiencies compared to controls. Women with PLO did not differ from those with IOP in terms of age, BMI, body fat, menarcheal age, parity, or age at first pregnancy. However, women with PLO had a more severe clinical presentation than those with IOP: more fractures (5.5 ± 3.3 versus 2.6 ± 2.1; p = 0.005); more vertebral fractures (80% versus 17%; p < 0.001); and higher prevalence of multiple fractures. BMD deficits were more profound and cortical width tended to be lower in PLO. PLO subjects also had significantly lower tissue-level mineral apposition rate and bone formation rates (0.005 ± 0.005 versus 0.011 ± 0.010 mm² /mm/year; p = 0.006), as well as lower serum P1NP (33 ± 12 versus 44 ± 18 µg/L; p = 0.02) and CTX (257 ± 102 versus 355 ± 193 pg/mL; p = 0.01) than IOP. The finding that women with PLO have a low bone remodeling state assessed more than a year postpartum increases our understanding of the pathogenic mechanism of PLO. We conclude that women with PLO may have underlying osteoblast functional deficits which could affect their therapeutic response to osteoanabolic medications. © 2019 American Society for Bone and Mineral Research.

BACKGROUND

Roux-en-Y gastric bypass (RYGB) is associated with high bone turnover. In healthy subjects, feeding causes acute reduction of bone resorption, which is regulated by several intestinal and pancreatic peptides.

OBJECTIVE

Our objective was to assess bone turnover after feeding in patients with RYGB.

METHODS

This was a cross-sectional case-control study at a university hospital.

METHODS

Fifteen postmenopausal women who underwent RYGB 7.4 ± 4.1 years previously were matched by age and body mass index with 15 nonoperated women (controls).

RESULTS

Serum PTH, calcium, phosphorus, insulin, carboxy telopeptide (CTX), procollagen type I N-terminal propeptide (P1NP), and glucagon-like peptide 2 (GLP-2) were measured while fasting and after a standard meal (SM).

RESULTS

The fasting calcium, phosphorus, and PTH were similar in both groups and exhibited similar decreases after an SM. The fasting CTX level was higher in the RYGB than in the control group (0.589 ± 0.18 vs 0.382 ± 0.11 ng/mL; P < .05) and fell to a nadir of 42.2% of the basal value in the RYGB and 53.9% in controls (P < .05). The fasting and postprandial P1NP levels were similar in both groups and fell to a nadir of 85.8% in the RYGB and 89.3% in controls. Insulin and GLP-2 levels were similar during fasting in both groups. RYGB patients had exaggerated postprandial insulin and GLP-2 response compared with the controls with the insulin and GLP-2 area under the curve being significantly higher in the RYGB group. There was a significant negative correlation between the peak of insulin levels and the CTX changes.

CONCLUSIONS

The acute reduction in bone resorption after feeding is preserved in RYGB and is even higher than in nonoperated subjects. This phenomenon is related to the increase of postprandial levels of insulin. These findings suggest a bone-protecting mechanism in RYGB that may counteract the elevated bone resorption that occurs during fasting.