Procollagen Type 1 N Propeptide Research Articles

Are bone turnover markers associated with volumetric bone density, size, and strength in older men and women? The AGES-Reykjavik study.

Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). A total of 1745 older individuals (773 men and 972 women, aged 66-92years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10%). Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

Clonidine increases bone resorption in humans.

SummaryInhibition of sympathetic signaling to bone reduces bone resorption in rodents. In contrast, we show that pharmacological reduction of the sympathetic tone increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct pharmacological effect on the osteoclast.IntroductionInhibition of sympathetic signaling to bone reduces bone resorption in rodents. It is uncertain whether a similar role for the sympathetic nervous system exists in humans. The sympathetic tone can be reduced by clonidine, which acts via alpha-2-adrenergic receptors in the brainstem. Our objective was to determine the effect of clonidine on bone turnover in humans.MethodsThe acute effect of a single oral dose of 0.3 mg clonidine on serum bone turnover markers (C-terminal cross-linking telopeptides of collagen type I (CTx), a marker for bone resorption, and procollagen type 1 N propeptide (P1NP), a marker for bone formation) was determined in a randomized crossover design in 12 healthy volunteers, aged 18–70 years. In addition, we assessed the effect of clonidine on the number of tartrate-resistant acid phosphatase–positive multinucleated cells (TRAcP+ MNCs) and bone resorption.ResultsCTx concentrations increased after clonidine treatment compared to the control condition (p = 0.035). P1NP concentrations were not affected by clonidine (p = 0.520).In vitro, clonidine had no effect on the number of TRAcP+ MNCs (p = 0.513) or on bone resorption (p = 0.996).ConclusionsWe demonstrated that clonidine increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct effect on the osteoclast.

Switching from tenofovir to abacavir in HIV-1-infected patients with low bone mineral density: changes in bone turnover markers and circulating sclerostin levels.

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

Bone Turnover Biomarkers Are Useful In Monitoring Myeloma Bone Disease and As Early Predictor Biomarkers For Relapse Disease In Multiple Myeloma

BackgroundMultiple myeloma is a plasma cell disorder characterised by bone marrow infiltration with clonal plasma cells that secrete monoclonal immunoglobulin which is detected in serum or urine samples. Bone disease is a well-known devastating complication. It has a significant impact to the quality of life and morbidity in multiple myeloma. The uncoupling effect of osteoblast and osteoclast activity is the major element in development of myeloma bone disease (MBD). Imaging techniques are used as the current standard method for detection of bony lesions. They have limitations as they cannot provide a real-time assessment of bone turnover. Early detection of relapse disease is crucial to allow preventative therapeutic intervention as it could significantly impact on quality of life. AimsBone biomarkers such as C-terminal telopeptide of type 1 collagen (CTX-1) and procollagen type 1 N-propeptide (P1NP) can be used as an early predictor marker for MBD relapses and a monitor for MBD at different stages of the disease. MethodsCTX-1 and P1NP were measured by chemiluminescent immunoassay on fasting plasma samples from 111 patients including newly diagnosed multiple myeloma (n=28), remission (n=34), relapses (n=22) and control (n=27). These were measured at regular intervals over a 30 month study period. Relapse disease was identified by conventional biomarkers like paraprotein and serum free light chains, and confirmed by imaging and bone marrow biopsy. In a subset of patients with disease relapse, the Mann-Whitney test was used to compare bone markers pre-relapse and at relapse. ResultsCTX-1 levels were significantly higher in newly diagnosed multiple myeloma compared to remission and control groups (p < 0.0001). In relapse group, CTX-1 rose significantly at the time of pre-relapse to relapse state (p=0.0001). A rise of ≥ 2.0 fold rise in the level of CTX-1 from remission to relapse disease was noted. The median time between the pre-relapse sample and relapse disease was 3 months (range 1-14 months). Most of them had new bone lesions at relapse. This proves that it has potential as an early predictor of relapse or progressive bone disease. A case showed CTX-1 level was the only biochemical parameter to rise significantly prior to relapse as compared to the other conventional biomarkers (ie. paraprotein and serum free light chain). As for P1NP, the rise in P1NP from pre-relapse to relapse was not significant (p=0.0810). ConclusionOsteoclast biomarker serum CTX-1 correlates accurately with the disease burden in newly diagnosed multiple myeloma patients as compared to the rest of the groups. It is a more sensitive early predictor of relapse/progressive disease than established biomarkers. It is a more robust marker than P1NP. The rise in P1NP goes against the theory that there is an uncoupling of bone turnover in MBD and requires further study. CTX-1 is more cost effective and accessible than imaging and should be used routinely when monitoring bone disease activity in multiple myeloma patients, facilitating early intervention when relapse occurs. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Vitamin D and Its Relationship with Markers of Bone Metabolism in Healthy Asian Women

In this study, we aimed to determine the normal ranges of 25-hydroxy-vitamin D(3) (25-OHD(3)), parathyroid hormone (PTH), and the markers of bone turnover, procollagen type 1 N propeptide (P1NP) and C-terminal cross-linked telopeptide of type 1 collagen (CTX), in normal healthy women in Singapore, and to explore the relationship between vitamin D, PTH, and these markers of bone turnover in the women. One hundred and ninety-seven healthy women, aged 25 to 60, were selected from a hospital staff health screening program; 68% were Chinese, 18% Malay, and 14% Indian. P1NP, CTX, and 25-OHD(3) were measured using the Roche Cobas® electrochemiluminescence immunoassay. Serum PTH was measured using the Siemens ADVIA Centaur® immunoassay. Sixty-five percent had 25-OHD(3) concentrations <50 nmol/l. Vitamin D insufficiency (25-OHD(3) < 50 nmol/l) was more prevalent in Malays (89%) and Indians (82%) compared to Chinese (56%). There was no correlation between vitamin D and age. PTH positively correlated with age, and Malays and Indians had higher PTH concentrations than Chinese. There was an inverse correlation between PTH and 25-OHD(3), but no threshold of 25-OHD(3) concentrations at which PTH plateaued. The bone turnover markers P1NP and CTX inversely correlated with age but were not different between ethnic groups. CTX and P1NP exhibited good correlation, however, there was no significant correlation between 25-OHD(3) or PTH concentrations and the bone turnover markers P1NP and CTX. Healthy women in Singapore have a high prevalence of vitamin D insufficiency. Vitamin D insufficiency was more prevalent in Malays and Indians compared to Chinese.

Bone Resorption Is Increased in Pheochromocytoma Patients and Normalizes following Adrenalectomy

The sympathetic nervous system (SNS) controls bone turnover in rodents, but it is uncertain whether a similar role for the SNS exists in humans. Pheochromocytomas are catecholamine-producing neuroendocrine tumors. Because catecholamines are the neurotransmitters of the SNS, we hypothesized that pheochromocytoma patients have increased bone turnover. Our objective was to compare bone turnover in pheochromocytoma patients and controls. This retrospective case-control study was performed at the Endocrine Department of the Academic Medical Center of the University of Amsterdam in The Netherlands from 2007 until 2011. All patients were screened for pheochromocytoma. Cases (n = 21) were identified by 24-h urinary excretion of fractionated metanephrines above the institutional reference value and confirmed by histology after adrenalectomy. All patients screened and diagnosed as not having pheochromocytoma served as controls (n = 126). The difference in bone turnover markers C-terminal cross-linking telopeptides of collagen type I (CTx) and procollagen type 1 N propeptide (P1NP) between cases and controls was the main outcome measure. CTx concentrations were higher in cases [343 ng/liter; interquartile range (IQR), 295 ng/liter] than in controls (232 ng/liter; IQR, 168 ng/liter; P < 0.001) and decreased after adrenalectomy [before, 365 ng/liter (IQR, 450 ng/liter); after, 290 ng/liter (IQR, 241 ng/liter); P = 0.044]. The effect remained after adjustment for possible confounders. P1NP concentrations did not differ. This study shows that pheochromocytoma patients have increased bone resorption, which normalizes after adrenalectomy. This finding supports the concept of regulation of bone remodeling by the SNS in humans.

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody

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.

Effect of Rosiglitazone, Metformin, and Glyburide on Bone Biomarkers in Patients with Type 2 Diabetes

An increase in bone fractures has been observed in women taking thiazolidinediones. 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). 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. 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%). Commonly measured bone biomarkers suggest that changes in bone resorption may be partly responsible for the increased risk of fracture in women taking thiazolidinediones.

The Association Between Cysteine, Bone Turnover, and Low Bone Mass

With the identification of hyperhomocysteinemia as a risk factor for developing osteoporosis, the contribution of thiols metabolically linked with homocysteine (tHcy) may be of importance. Cysteine (Cys) is formed from tHcy and is involved in bone metabolism via incorporation into collagen and cysteine protease enzymes. We investigated the association of plasma Cys and related thiols, the bone turnover markers C-telopeptide (CTX) and procollagen type 1 N propeptide (P1NP) and folate and vitamin B(6) with calcaneal bone mineral density (BMD) in 328 postmenopausal British women grouped according to their BMD measurement. Subjects with low BMD had a significantly lower plasma Cys concentration (146.3 vs. 177.7 micromol/l, p < 0.0001), a significantly higher recent fracture rate (30.9% vs. 16.4%, p = 0.017), and a significantly higher percentage of current smokers (26.4% vs. 7.3%. p = 0.003) than those with normal BMD. Additionally, they had a significantly lower plasma Cys, and higher plasma tHcy and CTX, than those with osteopenia. In the whole population, Cys was significantly associated with BMD, weight, height, smoking habit, log creatinine, Cys-Gly, log tHcy, and log folate, but the significant positive association of Cys with BMD was maintained after correction for all other variables (r = 0.197, p = 0.003). After weight, Cys was the next most significant predictor of BMD in a stepwise multiple linear regression model. Our study suggests a significant association between plasma Cys and BMD. A reduced Cys concentration, possibly modulated by smoking, or reduced flux from tHcy, may lead to reduced availability for collagen formation. Increased osteoclast activation, possibly as a result of relative hyperhomocysteinemia, may lead to increased Cys utilization in cysteine proteases.

Effect of an Aromatase Inhibitor on BMD and Bone Turnover Markers: 2-Year Results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) Trial (18233230)

Aromatase inhibitors reduce estrogen levels in postmenopausal women with breast cancer. Residual estrogen is an important determinant of bone turnover. Adjuvant anastrozole was associated with significant BMD loss and increased bone remodeling, whereas tamoxifen reduced bone marker levels. In the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial after a median follow-up of 68 months, a significant improvement in disease-free survival was observed with anastrozole treatment (hazard ratio [HR], 0.87; 95% CI, 0.78-0.97; p = 0.01). Anastrozole was also associated with tolerability benefits compared with tamoxifen, but with higher fracture rates. The HR of anastrozole compared with tamoxifen after 60 months of treatment was 1.49 (95% CI, 1.25-1.77). This prospectively designed subprotocol (n = 308) of ATAC assessed changes in BMD and bone turnover markers in postmenopausal women with invasive primary breast cancer receiving anastrozole 1 mg/day, tamoxifen 20 mg/day, or combination treatment with both agents for 5 years. Patients with osteoporosis were excluded (osteopenia permitted at the investigators discretion). Lumbar spine and total hip BMD was assessed at baseline and after 1 and 2 years; bone turnover markers (serum C-telopeptide, urinary N-telopeptide [NTX], free deoxypyridinoline, serum procollagen type-1 N-propeptide, bone alkaline phosphatase [ALP]) were assessed at baseline and after 3, 6, and 12 months. Results were expressed as median percentage change. After 2 years of anastrozole treatment, BMD was lost at lumbar spine (median 4.1% loss) and total hip (median 3.9% loss) sites; increases of 2.2% and 1.2%, respectively, were observed with tamoxifen. After 1 year of anastrozole treatment, increased bone remodeling was observed (NTX, +15%; 95% CI, 3-25%; bone ALP, +20%; 95% CI, 14-25%); decreased bone remodeling was observed with tamoxifen (NTX, -52%; 95% CI, -62% to -33%; bone ALP, -16%; 95% CI, -24% to -11%). Anastrozole is associated with significant BMD loss and a small increase in bone turnover, whereas tamoxifen (and the combination) is associated with increased BMD and decreased remodeling. These data may explain the increased fracture risk observed with anastrozole treatment in the ATAC trial. The impact of anastrozole on bone should be weighed against its overall superior efficacy and tolerability as observed in the main ATAC trial.