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Publication
Journal: Journal of Bone and Mineral Research
March/29/2011
Abstract
Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation.
Publication
Journal: Journal of Bone and Mineral Research
July/19/2007
Abstract
After acute estrogen withdrawal in postmenopausal women, administration of anakinra or etanercept, specific blockers of IL-1 and TNF-alpha, respectively, reduced the rise in bone resorption markers to about one half of that in controls. This is consistent with an important role for these immune cytokines in mediating the effect of estrogen deficiency on bone.
BACKGROUND
Studies in rodents have implicated increased production of interleukin (IL)-1 beta and TNF-alpha as mediators of bone loss after ovariectomy, but their roles are unclear in humans whose immune system differs markedly from that of rodents.
METHODS
We administered transdermal estradiol, 0.1 mg/d, for 60 days to 42 early postmenopausal women. Estrogen treatment was discontinued, and subjects were randomly assigned to intervention groups receiving 3 wk of injections with 0.9% saline, anakinra 100 mg/d, or etanercept 25 mg/twice weekly. Bone turnover was assessed by measuring serum carboxyl-terminal telopeptide of type 1 collagen (CTX) and amino-terminal telopeptide of type 1 collagen (NTX), markers for bone resorption, and serum amino-terminal propeptide of type 1 collagen (P1NP), a marker for bone formation. Results were expressed as percent change in markers from baseline (last 2 days of estrogen treatment and days 20 and 21 of intervention).
RESULTS
The percent changes from baseline during intervention for serum CTX, urine NTX, and serum PINP, respectively, were 43.3 +/- 8.0%, 12.0 +/- 7.1%, and -41.0 +/- 2.5% for the control group; 25.9 +/- 6.3%, 9.5 +/- 4.0%, and -37.8 +/- 3.0% for the anakinra group; and 21.7 +/- 5.0%, 0.32 +/- 3.82%, and -34.5 +/- 3.9% for the etanercept group. Compared with the control group, the blunting of the increase in serum CTX fell just below the level of significance (p=0.10) after anakinra treatment, whereas the blunting of the increase in serum CTX (p=0.034) and in urine NTX (p=0.048) were significant after etanercept treatment. Other changes were not significant.
CONCLUSIONS
The data are consistent with a role for TNF-alpha, and possibly for IL-1 beta, in mediating increased bone resorption during estrogen deficiency in women. Although either cytokine blocker reduced serum CTX by about one half, the effect of combined blockade could not be tested because of concerns about toxicity. The data do not exclude direct or indirect contributory roles for RANKL or for other cytokines.
Publication
Journal: Osteoporosis International
August/16/2012
Abstract
CONCLUSIONS
We compared skeletal parameters in type 2 diabetic (T2DM) and non-diabetic postmenopausal women. Bone structure by dual energy x-ray absorptiometry (DXA) and HR-pQCT was not different, although procollagen type 1 amino-terminal propeptide (P1NP) and osteocalcin levels were lower in T2DM.
BACKGROUND
T2DM is associated with increased fracture risk, but, paradoxically, with higher cross-sectional bone density (BMD) as measured by DXA. We sought explanations to this puzzle by investigating detailed structural and biochemical skeletal parameters in T2DM.
METHODS
Cross-sectional comparison of 25 postmenopausal T2DM women and 25 matched controls using DXA, high-resolution peripheral quantitative computed tomography (HR-pQCT) and biochemical bone turnover markers.
RESULTS
BMD by DXA did not differ between T2DM and controls. HR-pQCT assessment also did not differ, with the exception of cortical area at the tibia, which tended to be lower in the diabetics (difference of 12 ± 6 [mean ± SD] mm, p = 0.06). P1NP and osteocalcin levels were lower in T2DM as compared to controls (P1NP, 34.3 ± 16 vs. 57.3 ± 28 ng/ml; p = 0.005; osteocalcin, 4.5 ± 2 vs. 6.2 ± 2 nmol/L; p = 0.001).
CONCLUSIONS
Postmenopausal women with T2DM had lower levels of bone formation markers as compared to controls. Aside from a possible decrease in cortical bone area at a weight-bearing site, bone structure was not altered in T2DM. Lower bone turnover may be a skeletal parameter that is present in T2DM.
Publication
Journal: International Journal of Cancer
August/30/2004
Abstract
Our aim was to assess the diagnostic accuracy of bone markers in serum of patients with prostate cancer (PCa) for early detection of bone metastases and their usefulness as predictors of PCa-caused mortality. In sera of 117 PCa patients (pN0M0, n = 39; pN1M0, n = 34; M1, n = 44), 35 healthy men and 35 patients with benign prostatic hyperplasia, bone formation markers [total and bone-specific alkaline phosphatase (tALP, bALP), amino-terminal procollagen propeptides of type I collagen (P1NP), osteocalcin (OC)], bone resorption markers [bone sialoprotein (BSP), cross-linked C-terminal (CTX) and cross-linked N-terminal (NTX) telopeptides of type I collagen, tartrate-resistant acid phosphatase isoenzyme 5b (TRAP)] and osteoclastogenesis markers [osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL)] were measured. tALP, bALP, BSP, P1NP, TRAP, NTX and OPG were significantly increased in PCa patients with bone metastases compared to patients without metastases. OPG showed the best discriminatory power to differentiate between these patients. Logistic regression analysis resulted in a model with OPG and TRAP as variables that predicted bone metastasis with an overall correct classification of 93%. Patients with concentrations of OPG, P1NP, tALP, bALP, BSP, NTX, TRAP and CTX above cut-off levels showed significantly shorter survival than patients with low marker concentrations. Multivariate Cox proportional hazards regression revealed that only OPG and BSP were independent prognostic factors for PCa-related death. Thus, the importance of serum OPG in detecting bone metastatic spread, alone or in combination with other bone markers, and predicting survival in PCa patients has been clearly demonstrated.
Publication
Journal: Bone
July/27/2011
Abstract
Despite being a risk factor for cardiovascular disease and diabetes mellitus, obesity has been thought to protect against osteoporosis. However, recent studies have demonstrated a differential impact of specific fat compartments on bone mineral density (BMD) with visceral adipose tissue (VAT) having potential detrimental effects on BMD. Visceral obesity is also associated with dysregulation of the GH/IGF-1 axis, an important regulator of bone homeostasis. The purpose of our study was to evaluate the differential effects of abdominal fat depots and muscle, vitamin D, and hormonal determinants, including insulin-like growth factor-1 (IGF-1), testosterone, and estradiol, on trabecular BMD of the lumbar spine. We studied 68 healthy obese premenopausal women (mean BMI, 36.7±4.2 kg/m(2)). Quantitative computed tomography (QCT) was used to assess body composition and lumbar trabecular BMD. There was an inverse association between BMD and VAT, independent of age and BMI (p=0.003). IGF-1 correlated positively with BMD and negatively with VAT and, in stepwise multivariate regression modeling, was the strongest predictor of BMD and procollagen type 1 amino-terminal propeptide (P1NP). Thigh muscle cross sectional area (CSA) and thigh muscle density were also associated with BMD (p<0.05), but 25-hydroxyvitamin D [25(OH)D], testosterone, free testosterone, and estradiol levels were not. 25(OH)D was associated inversely with BMI, total, and subcutaneous abdominal adipose tissue (p<0.05). These findings support the hypothesis that VAT exerts detrimental effects, whereas muscle mass exerts positive effects on BMD in premenopausal obese women. Moreover, our findings suggest that IGF-1 may be a mediator of the deleterious effects of VAT on bone health through effects on bone formation.
Publication
Journal: Nature
June/29/1999
Abstract
The molecular controls governing organ shape are poorly understood. In the nematode Caenorhabditis elegans, the gonad acquires a U-shape by the directed migration of a specialized 'leader' cell, which is located at the tip of the growing gonadal 'arm'. The gon-1 gene is essential for gonadal morphogenesis: in gon-1 mutants, no arm elongation occurs and somatic gonadal structures are severely malformed. Here we report that gon-1 encodes a secreted protein with a metalloprotease domain and multiple thrombospondin type-1-like repeats. This motif architecture is typical of a small family of genes that include bovine procollagen I N-protease (P1NP), which cleaves collagen, and murine ADAMTS-1, the expression of which correlates with tumour cell progression. We find that gon-1 is expressed in two sites, leader cells and muscle, and that expression in each site has a unique role in forming the gonad. We speculate that GON-1 controls morphogenesis by remodelling basement membranes and that regulation of its activity is crucial for achieving organ shape.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
January/31/2010
Abstract
BACKGROUND
An increase in bone fractures has been observed in women taking thiazolidinediones.
OBJECTIVE
The objective of the study was to examine whether changes in circulating bone biomarkers provide insight into the underlying mechanisms responsible for the increase in bone fractures in female participants randomized to rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT).
METHODS
Paired stored baseline and 12-month serum samples were available from 1605 participants (689 women, 916 men) in ADOPT, a long-term clinical trial comparing the effects of rosiglitazone, glyburide, and metformin on glycemic control in patients with type 2 diabetes.
RESULTS
This subset was well matched to the total ADOPT study population. In women a marker of osteoclast activity, C-terminal telopeptide (for type 1 collagen), increased by 6.1% with rosiglitazone compared with reductions of 1.3% (P = 0.03 vs. rosiglitazone) and 3.3% (P = 0.002 vs. rosiglitazone) with metformin and glyburide, respectively. In men, C-terminal telopeptide was unchanged on rosiglitazone (-1.0%) and fell on metformin (-12.7%; P < 0.001) and glyburide (-4.3%, P = NS). Markers of osteoblast activity, procollagen type 1 N-propeptide (P1NP) and bone alkaline phosphatase, were reduced for women and men in almost all treatment groups, with the greatest changes in the metformin group (P1NP in females, -14.4%; P1NP in males, -19.3%), intermediate for rosiglitazone (P1NP in females, -4.4%; P1NP in males, -14.4%), and smallest for glyburide (P1NP in males, +0.2%; bone alkaline phosphatase in females, -11.6%).
CONCLUSIONS
Commonly measured bone biomarkers suggest that changes in bone resorption may be partly responsible for the increased risk of fracture in women taking thiazolidinediones.
Publication
Journal: Bone
September/22/2011
Abstract
OBJECTIVE
To establish a drill-hole defect model in osteoporotic mouse femur by comparing temporal cortical bone healing pattern between OVX-induced osteoporotic bone and sham-operated bone.
METHODS
3-month-old female C57BL/6 mice were randomly divided into an ovariectomy group (OVX) and a sham-operated group (Sham). At 6 weeks post-surgery, 7 mice from each group were sacrificed to examine the distal femur and femoral shaft by both micro-CT and mechanical testing for confirming established osteoporosis induced by OVX. In the remaining mice, a cortical bone defect 0.8mm in diameter was created on the mid-diaphysis of the right femur. The local repair process at days 0, 3, 7, 10, 14 and 21 after creation of the drill-hole was in vivo monitored by high-resolution micro-CT scanning. At each time point, each animal was scanned four times and was removed from the scanner between scans to determine reproducibility. Mice were sacrificed at each time point (n=12 at days 0, 3, 7, 10 and 14; n=20 at day 21). Before sacrifice, sera were collected to examine expression of bone formation marker P1NP (procollagen type I N-terminal propeptide) and bone resorption marker CTX (C-terminal telopeptide of type I collagen). After sacrifice, callus samples were collected and subjected to the following analyses: micro-CT-based angiography; histological examination; immunohistochemical staining to determine estrogen receptor expression; quantitative real-time PCR analysis of collagen type I, collagen type II, collagen type X, osteocalcin, tartrate-resistant acid phosphatase, estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) gene expression; and three-point mechanical testing.
RESULTS
At 6 weeks post-surgery, OVX mice had significantly lower bone mass, impaired bone micro architecture and compromised mechanical properties compared to the Sham mice. In vivo micro-CT analysis revealed that the bone volume fraction in the defect region was significantly lower in the OVX group from day 10 to day 21 post-injury as compared to the Sham group, and was significantly lower in the intra-medulla region in the OVX group from day 7 to day 14 as compared to the Sham group, consistent with the histological data. Analysis of bone biochemical markers indicated that circulating P1NP levels normalized by baseline in the OVX mice were significantly lower than in the Sham mice from day 7 to day 10, and that temporal expression of circulating CTX levels normalized by baseline was also lower in the OVX mice as compared to the Sham mice. These results were consistent with quantitative real-time PCR analysis. ER alpha mRNA expression was significantly lower in the OVX mice, whereas ER beta mRNA expression was significantly higher in the OVX mice as compared to the Sham mice at all time points examined, consistent with immunohistochemical staining. The restoration of femoral mechanical property, determined based on ultimate load and energy-to-failure, was significantly lower in the OVX mice than in the Sham mice. In addition, in vivo micro-CT scanning for quantifying new bone formation in the defect site was highly reproducible in this model.
CONCLUSIONS
The bone healing of the drill-hole defect was impaired in mice with OVX-induced osteoporosis. The present study provides a model to investigate the functional role of specific gene in osteoporotic bone healing and may facilitate development of novel therapeutic strategies for promoting osteoporotic bone healing.
Publication
Journal: American Journal of Kidney Diseases
July/31/2016
Abstract
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.
METHODS
Cross-sectional retrospective diagnostic test study.
METHODS
492 dialysis patients from Brazil, Portugal, Turkey, and Venezuela with prior bone biopsy and stored (-20 °C) serum.
METHODS
Samples were analyzed for PTH (intact [iPTH] and whole PTH), bone-specific alkaline phosphatase (bALP), and amino-terminal propeptide of type 1 procollagen (P1NP).
METHODS
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.
CONCLUSIONS
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.
Publication
Journal: Osteoporosis International
November/23/2009
Abstract
CONCLUSIONS
Daily dosing with vitamin D often fails to achieve optimal outcomes, and it is uncertain what the target level of 25-hydroxyvitamin D should be. This study found that large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels, and that monthly dosing is similarly effective after 3-5 months. With baseline 25OHD>> 50 nmol/L, vitamin D supplementation does not reduce PTH levels.
BACKGROUND
There is concern that vitamin D supplementation doses are frequently inadequate, and that compliance with daily medication is likely to be suboptimal.
METHODS
This randomized double-blind trial compares responses to three high-dose vitamin D(3) regimens and estimates optimal 25-hydroxyvitamin D (25OHD) levels, from changes in parathyroid hormone (PTH), and procollagen type I amino-terminal propeptide (P1NP) in relation to baseline 25OHD. Sixty-three elderly participants were randomized to three regimens of vitamin D supplementation: a 500,000-IU loading dose; the loading dose plus 50,000 IU/month; or 50,000 IU/month.
RESULTS
The Loading and Loading + Monthly groups showed increases in 25OHD of 58 +/- 28 nmol/L from baseline to 1 month. Thereafter, levels gradually declined to plateaus of 69 +/- 5 nmol/L and 91 +/- 4 nmol/l, respectively. In the Monthly group, 25OHD reached a plateau of ~80 +/- 20 nmol/L at 3-5 months. There were no changes in serum calcium concentrations. PTH and P1NP were only suppressed by vitamin D treatment in those with baseline 25OHD levels <50 and <30 nmol/L, respectively.
CONCLUSIONS
Large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels in the frail elderly. Monthly dosing is similarly effective and safe, but takes 3-5 months for plateau 25OHD levels to be reached.
Publication
Journal: Journal of Bone and Mineral Research
February/9/2011
Abstract
Zoledronic acid (ZOL) has shown beneficial effects on bone turnover and bone mineral density (BMD) in postmenopausal osteoporosis. This study compared the efficacy and safety of a once-yearly i.v. infusion of ZOL with weekly oral alendronate (ALN) in men with osteoporosis. In this multicenter, double-blind, active-controlled, parallel-group study, participants (n = 302) were randomized to receive either once-yearly ZOL 5 mg i.v. or weekly oral ALN 70 mg for 24 months. Changes in BMD and bone marker levels were assessed. ZOL increased BMD at the lumbar spine, total hip, femoral neck, and trochanter and was not inferior to ALN at 24 months [least squares mean estimates of the percentage increases in lumbar spine BMD of 6.1% and 6.2%; difference approximately 0.13; 95% confidence interval (CI) 1.12-0.85 in the ZOL and ALN groups, respectively]. At month 12, the median change from baseline of markers for bone resorption [serum β-C-terminal telopeptide of type I collagen (β-CTx) and urine N-terminal telopeptide of type I collagen (NTx)] and formation [serum N-terminal propeptide of type I collagen (P1NP) and serum bone-specific alkaline phosphatase (BSAP)] were comparable between ZOL and ALN groups. Most men preferred i.v. ZOL over oral ALN. The incidence of adverse events and serious adverse events was similar in the treatment groups. It is concluded that a once-yearly i.v. infusion of ZOL 5 mg increased bone density and decreased bone turnover markers similarly to once-weekly oral ALN 70 mg in men with low bone density.
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Publication
Journal: Diabetes, Obesity and Metabolism
March/21/2013
Abstract
OBJECTIVE
Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycaemia in patients with type 2 diabetes (T2DM) by increasing urinary glucose excretion. Owing to its mechanism of action, dapagliflozin could potentially affect the renal tubular transportation of bone minerals. Therefore, markers of bone formation and resorption and bone mineral density (BMD) were evaluated in patients with T2DM after 50 weeks of dapagliflozin treatment.
METHODS
This international, multi-centre, randomized, parallel-group, double-blind, placebo-controlled study (ClinicalTrials.gov NCT00855166) enrolled patients with T2DM (women 55-75 years and men 30-75 years; HbA1c 6.5-8.5%; BMI ≥ 25 kg/m(2) ; body weight ≤ 120 kg) whose T2DM was inadequately controlled on metformin. One hundred and eighty-two patients were randomly assigned 1:1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 50, serum markers of bone formation (procollagen type 1 N-terminal propeptide; P1NP) and resorption (C-terminal cross-linking telopeptides of type I collagen; CTX), bone mineral density (BMD) as assessed by standardized Dual-Energy X-ray Absorptiometry (DXA) measurements and adverse events of fracture were evaluated as safety objectives.
RESULTS
One hundred and sixty-five patients (90.7%) completed the first 50 weeks. Compared with placebo, no significant changes from baseline in P1NP, CTX or BMD were identified over 50 weeks of dapagliflozin treatment, with no significant treatment-by-gender interactions. No fractures were reported.
CONCLUSIONS
Dapagliflozin had no effect on markers of bone formation and resorption or BMD after 50 weeks of treatment in both male and post-menopausal female patients whose T2DM was inadequately controlled on metformin.
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Publication
Journal: Journal of Translational Medicine
July/6/2014
Abstract
Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3-6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases.
Publication
Journal: Oncotarget
September/21/2017
Abstract
BACKGROUND
We have recently identified interleukin 1B (IL-1B) as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In mouse models, IL-1B and its receptor (IL-1R1) are upregulated in breast cancer cells that metastasise to bone compared with cells that do not. We have now investigated the functional role of IL-1 by blocking IL-1R signalling with the clinically licensed antagonist, anakinra.
METHODS
6-week old female BALB/c mice received a subcutaneous or intra-venous injection of MDA-MB-231-IV or MCF7 cells. Anakinra (1mg/kg/day) or placebo was administered 3 days before (preventative) or 7 days later (treatment). Tumour volume, apoptosis (TUNEL, Caspase 3), proliferation (Ki67) and angiogenesis (CD34, VEGF and endothelin) were analysed. Effects on bone were measured by uCT, and TRAP, P1NP, IL-1B, TNF alpha and IL-6 ELISA.
RESULTS
Anakinra significantly reduced growth of MDA-MB-231-IV tumours in bone from 6.50+/3.00mm2 (placebo) to 2.56+/-1.07mm2 (treatment) and 0.63+/-0.18mm2 (preventative). Anakinra also reduced the number of mice that developed bone metastasis from 90% (placebo) to 40% (treatment) and 10% (preventative). Anti-tumour effects were not confined to bone, subcutaneous tumour volumes reduced from 656.68mm3 (placebo) to 160.47mm3 (treatment) and 31.08mm3 (preventative). Anakinra did not increase tumour cell apoptosis but reduced proliferation and angiogenesis in addition to exerting significant effects on the tumour environment reducing bone turnover markers, IL-1B and TNF alpha.
CONCLUSIONS
Our novel data demonstrate a functional role of IL-1 signalling in breast tumour progression and metastasis, supporting that anakinra could be repurposed for the treatment of breast cancer bone metastasis.
Publication
Journal: Journal of Bone and Mineral Research
March/25/2013
Abstract
Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2-year, phase 2, dose-ranging trial, postmenopausal women with bone mineral density (BMD) T-scores -2.0 to -3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D(3) and calcium. Prespecified trial-extensions continued through 5 years. In year 3, all women were re-randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10-50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus -0.4% (-3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10-50 mg, n = 26-29), year 5 geometric mean percent changes from baseline in bone resorption markers cross-linked N-telopeptide of type I collagen (NTX)/creatinine and cross-linked C-telopeptide (CTX) were approximately -55%, but near baseline for bone formation markers bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10-50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well-tolerated.
Publication
Journal: Journal of Bone and Mineral Research
September/28/2014
Abstract
Several studies, using dual-energy X-ray absorptiometry (DXA), have reported substantial bone loss after bariatric surgery. However, profound weight loss may cause artifactual changes in DXA areal bone mineral density (aBMD) results. Assessment of volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT) may be less susceptible to such artifacts. We assessed changes in BMD of the lumbar spine and proximal femur prospectively for 1 year using DXA and QCT in 30 morbidly obese adults undergoing Roux-en-Y gastric bypass surgery and 20 obese nonsurgical controls. At 1 year, subjects who underwent gastric bypass surgery lost 37 ± 2 kg compared with 3 ± 2 kg lost in the nonsurgical controls (p < 0.0001). Spine BMD declined more in the surgical group than in the nonsurgical group whether assessed by DXA (-3.3 versus -1.1%, p = 0.034) or by QCT (-3.4 versus 0.2%, p = 0.010). Total hip and femoral neck aBMD declined significantly in the surgical group when assessed by DXA (-8.9 versus -1.1%, p < 0.0001 for the total hip and -6.1 versus -2.0%, p = 0.002 for the femoral neck), but no changes in hip vBMD were noted using QCT. Within the surgical group, serum P1NP and CTX levels increased by 82% ± 10% and by 220% ± 22%, respectively, by 6 months and remained elevated over 12 months (p < 0.0001 for all). Serum calcium, vitamin D, and PTH levels remained stable in both groups. We conclude that moderate vertebral bone loss occurs in the first year after gastric bypass surgery. However, striking declines in DXA aBMD at the proximal femur were not confirmed with QCT vBMD measurements. These discordant results suggest that artifacts induced by large changes in body weight after bariatric surgery affect DXA and/or QCT measurements of bone, particularly at the hip.
Publication
Journal: Journal of Bone and Mineral Research
January/22/2012
Abstract
In hypoparathyroidism, plasma parathyroid hormone (PTH) levels are inadequate to maintain plasma calcium concentration within the reference range. On conventional treatment with calcium supplements and active vitamin D analogues, bone turnover is abnormally low, and BMD is markedly increased. We aimed to study the effects of PTH-replacement therapy (PTH-RT) on calcium-phosphate homeostasis and BMD. In a double-blind design, we randomized 62 patients with hypoparathyroidism to daily treatment with PTH(1-84) 100 µg or similar placebo for 24 weeks as add-on therapy to conventional treatment. Compared with placebo, patients on PTH(1-84) reduced their daily dose of calcium and active vitamin D significantly by 75% and 73%, respectively, without developing hypocalcemia. However, hypercalcemia occurred frequently during the downtitration of calcium and active vitamin D. Plasma phosphate and renal calcium and phosphate excretion did not change. Compared with placebo, PTH(1-84) treatment significantly increased plasma levels of bone-specific alkaline phosphatase (+226% ± 36%), osteocalcin (+807% ± 186%), N-terminal propeptide of procollagen 1 (P1NP; +1315% ± 330%), cross-linked C-telopeptide of type 1 collagen (CTX; +1209% ± 459%), and urinary cross-linked N-telopeptide of type 1 collagen (NTX; (+830% ± 165%), whereas BMD decreased at the hip (-1.59% ± 0.57%), lumbar spine (-1.76% ± 1.03%), and whole body (-1.26% ± 0.49%) but not at the forearm. In conclusion, the need for calcium and active vitamin D is reduced significantly during PTH-RT, whereas plasma calcium and phosphate levels are maintained within the physiologic range. In contrast to the effect of PTH(1-84) treatment in patients with osteoporosis, PTH-RT in hypoparathyroidism causes a decrease in BMD. This is most likely due to the marked increased bone turnover. Accordingly, PTH-RT counteracts the state of overmineralized bone and, during long-term treatment, may cause a more physiologic bone metabolism.
Publication
Journal: Clinical Chemistry
February/11/2008
Abstract
BACKGROUND
Biochemical markers of bone turnover can provide prognostic information about the risk of fracture and may be useful for monitoring efficacy of antiresorptive and anabolic therapy in osteoporosis. We evaluated the performance of a fully automated assay for serum total N-terminal propeptide of type I collagen (P1NP), a marker of bone formation.
METHODS
Serum P1NP was measured on the Elecsys 2010 automated analyzer (Roche) in 230 healthy premenopausal women, age 30-49 years, 179 postmenopausal women with osteoporosis participating in the previously published 1 year randomized Parathyroid Hormone and Alendronate for Osteoporosis study of full-length parathyroid hormone (PTH 1-84, >100 microg/day subcutaneously; n = 119) or oral alendronate 10 mg/day (n = 60), and 64 healthy men, age 40 to 65 years.
RESULTS
The within-run and between-run (total) imprecision (CVs) were < or =1.7% (n = 20) and 4.4% (n = 15), respectively. The median within-person variability of results (3 measurements over 3 months in 15 postmenopausal women) was 7.2%, resulting in a least significant change (LSC) value of 20%. Serum P1NP concentrations were 74% (P <0.0001) higher in postmenopausal women than in premenopausal controls. After 3 months of treatment, 83% and 88% of patients treated with PTH 1-84 and alendronate, respectively, demonstrated changes of serum P1NP that exceeded the LSC.
CONCLUSIONS
The automated assay for serum total P1NP is precise and sensitive enough to detect changes that exceed the LSC in a majority of postmenopausal women after 3 months of treatment with PTH 1-84 or alendronate. Because of its convenience and high throughput, this bone formation marker may be useful for the monitoring of patients with osteoporosis.
Publication
Journal: Steroids
January/11/2005
Abstract
In vitro models of bone cells are important for the study of bone biology, including the regulation of bone formation and resorption. In this study, we have validated an in vitro model of human osteoblastic cells obtained from bone marrow biopsies from healthy, young volunteers, aged 20-31 years. Osteoblast phenotypes were induced by either dexamethasone (Dex) or bone morphogenetic protein-2 (BMP-2). Bone marrow was obtained from biopsies at the posterior iliac spine. Cells were isolated by gradient centrifugation and grown to confluence. Cells were treated with 1 nM 1,25-dihydroxyvitamin D (vitamin D), 100 nM Dex, and/or 100 ng/ml BMP-2. The osteoblast phenotype was assessed as alkaline phosphatase (AP) activity/staining, production of osteocalcin and procollagen type 1 (P1NP), parathyroid hormone (PTH)-induced cyclic adenosine mono-phosphate (cAMP) production, and in vitro mineralization. AP activity was increased by Dex, but not by BMP-2 treatment. P1NP production was decreased after Dex treatment, while BMP-2 had no effect on P1NP levels. Osteocalcin production was low in cultures not stimulated with vitamin D. Dex or BMP-2 treatment alone did not affect the basic osteocalcin levels, but in combination with vitamin D, BMP-2 increased the osteocalcin production, while Dex treatment completely suppressed osteocalcin production. Further, PTH-induced cAMP production was greatly enhanced by Dex treatment, whereas BMP-2 did not affect cAMP production. Finally, in vitro mineralization was greatly enhanced in cultures enriched with either BMP-2 or Dex. Cell proliferation was only increased significantly by Dex treatment. In conclusion, the model described produces cells with an osteoblastic phenotype, and both Dex and BMP-2 can be used as osteoblast inducers. However, the two treatments produce osteoblastic cells with different phenotypic characteristics, and a selective activation of some of the most important genes and functions of the mature osteoblast can thus be performed in vitro.
Publication
Journal: Bone
April/16/2014
Abstract
Connexin 43 (Cx43) is a gap junction protein that plays an integral role in the skeletal response to mechanical loading and unloading. In a previous study, we demonstrated preservation of trabecular bone mass and cortical bone formation rate in mice with an osteoblast/osteocyte-selective deficiency of Cx43 (cKO) following mechanical unloading via hindlimb suspension (HLS). In the present study, we sought to define the potential mechanisms underlying this response. Following three weeks of HLS, mRNA levels of Sost were significantly greater in wild-type (WT)-Suspended mice vs. WT-Control, while there was no difference between cKO control and cKO-Suspended. Unloading-induced decreases in P1NP, a serum marker of bone formation, were also attenuated in cKO-Suspended. The proportion of sclerostin-positive osteocytes was significantly lower in cKO-Control vs. WT-Control (-72%, p<0.05), a difference accounted for by the presence of numerous empty lacunae in the cortical bone of cKO vs. WT. Abundant TUNEL staining was present throughout the cortical bone of the tibia and femur, suggesting an apoptotic process. There was no difference in empty lacunae in the trabecular bone of the tibia or femur. Trabecular and cortical osteoclast indices were lower in cKO-Suspended vs. WT-Suspended; however, mRNA levels of the gene encoding RANKL increased similarly in both genotypes. Connexin 43 deficient mice experience attenuated sclerostin-mediated suppression of cortical bone formation and lower cortical osteoclast activity during unloading. Preservation of trabecular bone mass and attenuated osteoclast activity during unloading, despite an apparent lack of effect on osteocyte viability at this site, suggests that an additional mechanism independent of osteocyte apoptosis may also be important. These findings indicate that Cx43 is able to modulate both arms of bone remodeling during unloading.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
June/29/2017
Abstract
Established bone turnover markers do not reflect fracture risk in idiopathic male and premenopausal osteoporosis and the role of microRNAs (miRNAs) in these patients is currently unclear. miRNAs are a class of small non-coding RNAs that regulate gene expression and bone tissue homeostasis. They are considered a new class of endocrine regulators with promising potential as biomarkers.
Evaluation of circulating miRNA signatures in male and female subjects with idiopathic and postmenopausal osteoporotic low-traumatic fractures.
This was a case-control study of cross-sectional design of 36 patients with prevalent low-traumatic fractures and 39 control subjects Main Outcome Measures: One hundred eighty-seven miRNAs were quantified in serum by qPCR, compared between groups and correlated with established bone turnover markers.
Significant differences in serum levels of circulating miRNAs were identified in all three subgroups (46 in premenopausal, 52 in postmenopausal, 55 in male). A set of 19 miRNAs was consistently regulated in all three subgroups. Eight miRNAs [miR-152-3p, miR-30e-5p, miR-140-5p, miR-324-3p, miR-19b-3p, miR-335-5p, miR-19a-3p, miR-550a-3p] were excellent discriminators of patients with low-traumatic fractures, regardless of age and sex, with area under the curve values>> 0.9. The 11 remaining miRNAs showed area under the curve values between 0.81 and 0.89. Correlation analysis identified significant correlations between miR-29b-3p and P1NP, and miR-365-5p and iPTH, TRAP5b, P1NP and Osteocalcin, as well as BMDL1-L4 and miR-19b-3p, miR-324-3p, miR-532-5p, and miR-93-5p.
Specific serum miRNA profiles are strongly related to bone pathologies. Therefore miRNAs might be directly linked to bone tissue homeostasis. In particular, miR-29b-3p has previously been reported as regulator of osteogenic differentiation and could serve as a novel marker of bone turnover in osteoporotic patients as a member of a miRNA signature.
Publication
Journal: European Journal of Endocrinology
October/25/2010
Abstract
OBJECTIVE
In vitro and in vivo studies in animal models have shown that parathyroid hormone (PTH) inhibits the expression of the SOST gene, which encodes sclerostin, an osteocyte-derived negative regulator of bone formation. We tested the hypothesis that chronic PTH excess decreases circulating sclerostin in humans.
METHODS
We studied 25 patients with elevated serum PTH concentrations due to primary hyperparathyroidism (PHPT) and 49 patients cured from PHPT after successful parathyroidectomy (PTx; euparathyroid controls (EuPTH)).
METHODS
We measured plasma PTH and serum sclerostin levels and the serum markers of bone turnover alkaline phosphatase, P1NP, and β-CTX.
RESULTS
As expected by the design of the study, mean plasma PTH was significantly higher (P<0.001) in PHPT patients (15.3 pmol/l; 95% confidence interval (CI): 11.1-19.5) compared with that of EuPTH controls (4.1 pmol/l; 95% CI: 3.6-4.5). PHPT patients had significantly lower serum sclerostin values compared with those in EuPTH subjects (30.5 pg/ml; 95% CI: 26.0-35.1 vs 45.4 pg/ml; 95% CI: 40.5-50.2; P<0.001) and healthy controls (40.0 pg/ml; 95% CI: 37.1-42.9; P=0.01). Plasma PTH concentrations were negatively correlated with serum sclerostin values (r=-0.44; P<0.001). Bone turnover markers were significantly correlated with PTH, but not with sclerostin.
CONCLUSIONS
Patients with PHPT have significantly lower serum sclerostin values compared with PTx controls with normal PTH concentrations. The negative correlation between PTH and sclerostin suggests that SOST is downregulated by PTH in humans.
Publication
Journal: Bone
April/16/2014
Abstract
The aim of this study was to analyse the effect of glucocorticoid therapy (GCCT) on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. 25 patients (8 M/17 F, aged 48±19yrs) recently initiating GCCT (≥7.5mg/day, ≤6months) were prospectively included. Bone turnover markers (bone formation: P1NP, osteocalcin [OC], bone ALP; bone resorption: sCTx) and Wnt antagonists (serum sclerostin and Dkk-1) were assessed in all patients (short-term and 12months after initiating GCCT). Bone mineral density (BMD) was performed to assess osteoporosis. The results were compared with 60 healthy controls. At short-term patients on GCCT showed a significant decrease in bone formation markers versus controls (P1NP: 19±9 vs. 43±16ng/mL, p<0.001; OC: 7.4±2.4 vs. 18.4±5.2ng/mL, p=0.001) and in Dkk-1 levels (24.5±20.1 vs. 36.8±13.7pmol/L, p=0.008) with similar sclerostin values (41.8±21.8 vs. 42.1±13.9pmol/L, p=0.950). Sclerostin correlated positively with GCCT doses (r=0.449, p=0.024) and lumbar BMD (r=0.424, p=0.035), and negatively with bone ALP (r=-0.398, p=0.049). A progressive decrease in Dkk-1 levels was observed at 12months, (19.1±14.9, p=0.001), whereas sclerostin increased compared to controls (48.9±11.6, p=0.045). In conclusion, the effect of GCCT on the serum levels of the Wnt signalling parameters differs depending on the antagonist evaluated. Whereas sclerostin values increased and showed a relationship with the dose and bone AP, Dkk-1 levels decreased throughout the study suggesting a counter-regulatory mechanism of this factor thereby reducing the deleterious effect of GCCT in the bone.
Publication
Journal: Journal of Bone and Mineral Research
March/12/2012
Abstract
Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked C-telopeptide (CTX) in serum of 19 patients with sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption.
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