scholarly journals Recombinant Human Chorionic Gonadotropin But Not Dihydrotestosterone Alone Stimulates Osteoblastic Collagen Synthesis in Older Men with Partial Age-Related Androgen Deficiency

2004 ◽  
Vol 89 (6) ◽  
pp. 3033-3041 ◽  
Author(s):  
Christian Meier ◽  
Peter Y. Liu ◽  
Lam P. Ly ◽  
James de Winter-Modzelewski ◽  
Mark Jimenez ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Turnover ◽  
Type I Collagen ◽  
Older Men ◽  
Type I ◽  
Androgen Deficiency ◽  
Age Related ◽  
Aging Men ◽  
To Receive ◽  
Androgen Supplementation

Abstract Several randomized trials of androgen supplementation in older men have been undertaken. However, the relative contributions of testosterone (T) and estrogens on bone metabolism in aging men are controversial. Within the setting of two double-blind, placebo-controlled studies, we evaluated the effect of dihydrotestosterone (DHT) and recombinant human chorionic gonadotropin (rhCG) on bone turnover in healthy, community-dwelling older men with partial androgen deficiency (total T ≤ 15 nmol/liter). In the first study, 35 men (age 68.3 ± 6.8 yr; baseline T, 13.9 ± 3.3 nmol/liter) were randomized to receive either daily transdermal DHT (n = 17) or placebo for 3 months. In the second study, 40 men (age 67.4 ± 5.4 yr; baseline T, 11.4 ± 2.2 nmol/liter) were randomized to receive either rhCG sc (n = 20), two injections weekly, or placebo for 3 months. The following parameters were measured before, monthly during, and 1 month after treatment: serum T, estradiol (E2), and LH; markers of bone formation, serum amino-terminal propeptide of type I procollagen (S-PINP) and osteocalcin; markers of bone resorption, serum carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline. Compared with placebo, treatment with DHT significantly increased serum DHT and suppressed LH and T levels, whereas E2 concentrations and markers of bone turnover did not change. In contrast, rhCG therapy significantly increased both T and E2, with the increases in E2 being supraphysiological. At the same time, rhCG significantly increased S-PINP concentrations with peak levels after 1 month (Δ40%; P = 0.02 compared with placebo). In contrast, serum osteocalcin and carboxyterminal cross-linked telopeptide of type I collagen and urinary deoxypyridinoline levels did not change. The change in S-PINP levels correlated with the change in E2 levels (r = 0.59; P = 0.02) but not with a change in T. We conclude that in older men with partial age-related androgen deficiency, rhCG treatment stimulates osteoblastic collagen formation proportionally to increased E2 concentrations but does not alter markers of mature osteoblastic function or bone resorption. In contrast, treatment with a pure, nonaromatizable androgen (DHT) has no effect on bone turnover despite a 20-fold increase in serum levels. Bone resorption was not accelerated during unchanged (DHT) or increased (rhCG) E2 levels, suggesting that minimal E2 levels are needed to maintain stable resorption, although direct androgen receptor-mediated effects cannot be excluded. If androgen supplementation is required for aging men, aromatizable androgens with sufficient endogenous estrogenic activity may have the most beneficial effects on bone.

scholarly journals High-dose glucocorticoids increase serum levels of soluble IL-6 receptor α and its ratio to soluble gp130: an additional mechanism for early increased bone resorption

2006 ◽  
Vol 154 (5) ◽  
pp. 745-751 ◽  
Author(s):  
Andrea Dovio ◽  
Laura Perazzolo ◽  
Laura Saba ◽  
Angela Termine ◽  
Marco Capobianco ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Bone Resorption ◽  
Bone Turnover ◽  
Peripheral Blood ◽  
Bone Turnover Markers ◽  
Type I Collagen ◽  
Serum Levels ◽  
High Dose ◽  
Type I ◽  
Turnover Markers

Objective: Glucocorticoids (GCs) at pharmacological doses stimulate bone resorption. Mechanisms of this action are unclear. The osteoclastogenic cytokine interleukin (IL)-6 acts through an oligomeric receptor consisting of two subunits, gp80 (or IL-6 receptor α, IL-6Rα) and gp130; both exist in membrane and soluble forms. Soluble IL-6Rα (sIL-6Rα) enhances, while sgp130 inhibits IL-6 signalling. In vitro, GCs enhance many effects of IL-6 by up-regulation of IL-6Rα. The aim of the present study was to assess acute changes of IL-6 system in the peripheral blood of patients given high-dose GCs. Subjects and methods: Serum levels of IL-6, sIL-6Rα, sgp130 and bone turnover markers were assessed before and each day during treatment in 24 multiple sclerosis (MS) patients undergoing high-dose (prednisolone, 15 mg/kg per day), short-term (3 to 5 days) intravenous GC therapy for relapse at the Regional Multiple Sclerosis Centre. Results: An immediate and marked fall of osteocalcin and an early increase of C-terminal telopeptide of type I collagen were already noticed at day 2 (P < 0.001 and P < 0.02, respectively); both became more apparent in the subsequent days. IL-6 was always below or near the detection limit of our ELISA. sgp130 showed a slight increase. sIL-6Rα significantly increased, peaking at day 4 (P < 0.01). However, inter-individual variability of response was noticed. Four patients showed a slight decrease, while no change was observed in one patient and an increase was noticed in the remaining nineteen (maximum change ranging from +10% to +67% with respect to baseline). In these patients, a significant increase of sIL-6Rα/sgp130 ratio was apparent. No correlation was found between bone turnover markers and any measured component of the IL-6 system. Conclusions: sIL-6Rα and sIL-6Rα/sgp130 ratio are precociously increased in the peripheral blood of the vast majority of patients given high-dose, intravenous GCs. The increase of systemically available sIL-6Rα conceivably results in the enhancement of IL-6-dependent osteoclastogenesis. The role of such a mechanism in the bone loss observed in inflammatory and immune-mediated diseases (where abundancy of IL-6 in the bone microenvironment is expected) requires further investigation.

scholarly journals Fusion Potential of Human Osteoclasts In Vitro Reflects Age, Menopause, and In Vivo Bone Resorption Levels of Their Donors—A Possible Involvement of DC-STAMP

2020 ◽  
Vol 21 (17) ◽  
pp. 6368
Author(s):  
Anaïs M. J. Møller ◽  
Jean-Marie Delaissé ◽  
Jacob B. Olesen ◽  
Luisa M. Canto ◽  
Silvia R. Rogatto ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Type I Collagen ◽  
Transmembrane Protein ◽  
Type I ◽  
Contributing Factors ◽  
Expression Levels ◽  
Procollagen Type ◽  
Age Related

It is well established that multinucleation is central for osteoclastic bone resorption. However, our knowledge on the mechanisms regulating how many nuclei an osteoclast will have is limited. The objective of this study was to investigate donor-related variations in the fusion potential of in vitro-generated osteoclasts. Therefore, CD14+ monocytes were isolated from 49 healthy female donors. Donor demographics were compared to the in vivo bone biomarker levels and their monocytes’ ability to differentiate into osteoclasts, showing that: (1) C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels increase with age, (2) the number of nuclei per osteoclast in vitro increases with age, and (3) there is a positive correlation between the number of nuclei per osteoclast in vitro and CTX levels in vivo. Furthermore, the expression levels of the gene encoding dendritic cell-specific transmembrane protein (DCSTAMP) of osteoclasts in vitro correlated positively with the number of nuclei per osteoclast, CTX levels in vivo, and donor age. Our results furthermore suggest that these changes in gene expression may be mediated through age-related changes in DNA methylation levels. We conclude that both intrinsic factors and age-induced increase in fusion potential of osteoclasts could be contributing factors for the enhanced bone resorption in vivo, possibly caused by increased expression levels of DCSTAMP.

The Effect of Aromatase Inhibition on Sex Steroids, Gonadotropins, and Markers of Bone Turnover in Older Men1

2001 ◽  
Vol 86 (6) ◽  
pp. 2869-2874
Author(s):  
Pamela Taxel ◽  
Dayna G. Kennedy ◽  
Pamela M. Fall ◽  
Alice K. Willard ◽  
Jonathan M. Clive ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Turnover ◽  
Older Men ◽  
Sex Hormone Binding Globulin ◽  
Total Testosterone ◽  
Type I ◽  
Aromatase Inhibition ◽  
Bone Specific Alkaline Phosphatase ◽  
Type I Procollagen

There is evidence that estrogen decreases bone turnover in men as well as women. We therefore hypothesized that older men would show increased bone resorption in response to inhibition of the aromatase enzyme, which converts androgens to estrogen. Fifteen eugonadal men over 65 yr were treated for 9 weeks with 2.0 mg/day of anastrozole, an aromatase inhibitor. After 9 weeks of treatment, there were significant decreases in estradiol, estrone, and sex hormone-binding globulin levels by 29%, 73%, and 16%, respectively, and total testosterone increased significantly by 56%. Despite the limited decrease of estrogen and the increase in testosterone, C-telopeptide of type 1 collagen showed a progressive significant increase of 11%, 24%, and 33% (P for trend = 0.033) above baseline at 3, 6, and 9 weeks, respectively. N-telopeptide of type 1 collagen values were highly correlated with C-telopeptide of type 1 collagen, but the change in N-telopeptide of type 1 collagen was not statistically significant. Bone-specific alkaline phosphatase and N-terminal type I procollagen peptides showed significant decreases of 8% and 11% of baseline at 9 weeks. Osteocalcin decreased significantly by 30% at 18 weeks. We conclude that aromatase inhibition can reduce estrogen levels in older men, but this effect is limited, perhaps because of feedback stimulation of testosterone production, and that endogenous estrogen derived from aromatization of testosterone plays a role in bone metabolism of older men by limiting the rate of bone resorption.

scholarly journals Low Dose Estrogen and Calcium Have an Additive Effect on Bone Resorption in Older Women1

1999 ◽  
Vol 84 (1) ◽  
pp. 179-183
Author(s):  
K. M. Prestwood ◽  
D. L. Thompson ◽  
A. M. Kenny ◽  
M. J. Seibel ◽  
C. C. Pilbeam ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Turnover ◽  
Older Women ◽  
Low Dose ◽  
Type I Collagen ◽  
Control Group ◽  
Type I ◽  
Markers Of Bone Formation ◽  
Markers Of Bone Resorption

Previous studies have shown that treatment with estrogen or calcium decreases bone turnover in older women. The mechanisms by which estrogen and calcium exert their effects are probably different. We therefore examined the possibility of an additive or synergistic effect of combined treatment with calcium and low dose estrogen on bone turnover in older women, using biochemical markers. Thirty-one healthy women over 70 yr of age were randomized to 12 weeks of treatment with either micronized 17β-estradiol [0.5 mg/day Estrace (E2)] or 1500 mg/day elemental calcium, given as carbonate plus vitamin D (800 IU/day; Ca+D). At the end of the initial 12-week treatment period, both groups received both Ca+D and E2 for an additional 12 weeks. Eleven older women were followed for 36 weeks without any treatment and served as a control group. Serum and urine were collected at baseline, at 12 and 24 weeks on treatment, and at 12 weeks after treatment was terminated for measurement of biochemical markers of bone turnover. Markers of bone formation were bone alkaline phosphatase, osteocalcin, and type I procollagen peptide; markers of bone resorption were urinary cross-linked C-telopeptides and N-telopeptides of type I collagen, serum cross-linked N-telopeptides of type I collagen, urinary free deoxypyridinoline cross-links, and serum bone sialoprotein. Repeated measures ANOVA was used to determine changes in bone turnover measures over time by group. All markers of bone resorption decreased with initial treatment and decreased further with combination therapy (P &lt; 0.001). Markers of bone formation decreased with Ca+D treatment, but not with E2 alone; there was no additional effect of combination therapy on formation markers compared to Ca+D alone. Neither markers of formation nor resorption changed in the control group. These results suggest that there is an additive effect of low dose estrogen and calcium on bone resorption, but not on bone formation, in older women. Thus, the combination of low dose estrogen plus calcium is likely to be more effective in older women than either treatment alone.

scholarly journals Effects of the Circadian Variation in Serum Cortisol on Markers of Bone Turnover and Calcium Homeostasis in Normal Postmenopausal Women1

1998 ◽  
Vol 83 (3) ◽  
pp. 751-756 ◽  
Author(s):  
Hassan M. Heshmati ◽  
B. Lawrence Riggs ◽  
Mary F. Burritt ◽  
Carol A. McAlister ◽  
Peter C. Wollan ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Turnover ◽  
Type I Collagen ◽  
Serum Cortisol ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Type I ◽  
Serum Osteocalcin ◽  
Circadian Pattern

Bone turnover has a circadian pattern, with bone resorption and, to a lesser extent, bone formation increasing at night. Serum cortisol also has a circadian pattern and is a potential candidate for mediating the circadian changes in bone turnover. Thus, we measured bone formation and resorption markers before (study A) and after (study B) elimination of the morning peak of cortisol. We also assessed effects of the circadian cortisol pattern on serum calcium, PTH, and urinary calcium excretion. Ten normal postmenopausal women, aged 63–75 yr (mean, 69 yr), were studied. Metyrapone was administered to block endogenous cortisol synthesis and either a variable (study A) or a constant (study B) infusion of cortisol was given to reproduce and then abolish the morning cortisol peak. Blood was sampled every 2 h for serum cortisol, ionized calcium, PTH, and bone formation markers[ osteocalcin and carboxyl-terminal propeptide of type I collagen (PICP)], and timed 4-h urine samples were collected for measurement of calcium, phosphorus, sodium, potassium, and bone resorption markers (N-telopeptide of type I collagen and free deoxypyridinoline). During study A, serum osteocalcin had a circadian pattern, with a peak at 0400 h and a nadir at 1400 h. During study B, however, the afternoon nadir of serum osteocalcin was eliminated (P &lt; 0.001 and P &lt; 0.005 for the difference in the patterns of peak and nadir, respectively, on the 2 study days). In contrast, the circadian patterns of serum PICP and urinary N-telopeptide of type I collagen and free deoxypyridinoline were virtually identical during the two studies. Urinary calcium excretion declined after the cortisol peak, without differences between the 2 study days in phosphorus or sodium excretion or in serum PTH. We conclude that the circadian variation in serum cortisol is responsible for the circadian pattern of serum osteocalcin, but not that of PICP or bone resorption markers. The physiological variation in serum cortisol may also reduce urinary calcium excretion.

scholarly journals Serum Osteoprotegerin as a Determinant of Bone Metabolism in a Longitudinal Study of Human Pregnancy and Lactation

2003 ◽  
Vol 88 (11) ◽  
pp. 5361-5365 ◽  
Author(s):  
K. E. Naylor ◽  
A. Rogers ◽  
R. B. Fraser ◽  
V. Hall ◽  
R. Eastell ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Bone Resorption ◽  
Bone Turnover ◽  
Type I Collagen ◽  
Human Breast Milk ◽  
Type I ◽  
Mineral Density ◽  
Human Pregnancy ◽  
Pregnancy And Lactation ◽  
In Pregnancy

Abstract Osteoprotegerin (OPG) is a soluble decoy receptor that inhibits bone resorption by binding to receptor activator of nuclear factor κB ligand. Murine studies suggest that OPG is elevated in pregnancy, but its role in human pregnancy is unknown. We evaluated the relationship among OPG, bone turnover, and bone density in a longitudinal study of planned human pregnancy and lactation (n = 17; age, 20–36 yr). Samples were collected before conception; at 16, 26, and 36 wk gestation; and at 2 and 12 wk postpartum. Indexes of bone resorption included serum β C-terminal and urinary N-terminal (uNTX) telopeptides of type I collagen. OPG increased by 110 ± 16% (mean ± sem) at 36 wk (P &lt; 0.001), followed by a rapid postpartum decline in both lactating and nonlactating women. Bone resorption was elevated at 36 wk (serum β C-terminal telopeptides by 76 ± 17%; urinary N-terminal telopeptides by 219 ± 41%; P &lt; 0.001). The tissue source of OPG in pregnancy is unknown. Human breast milk contains large amounts of OPG (162 ± 58 ng/ml in milk vs. 0.42 ± 0.03 ng/ml in nonpregnant serum). However, the rapid postpartum decline in serum OPG and the low serum OPG in neonates suggest a placental source. There was no correlation between change in OPG and bone turnover or bone mineral density (P &gt; 0.05), and the physiological importance of elevated OPG in human pregnancy remains uncertain.

scholarly journals Low calcium intake is associated with increased bone resorption in postmenopausal Japanese women: Yokogoshi Study

2009 ◽  
Vol 12 (12) ◽  
pp. 2366-2370 ◽  
Author(s):  
Kazutoshi Nakamura ◽  
Toshiko Saito ◽  
Akihiro Yoshihara ◽  
Miki Ishikawa ◽  
Yasuo Tsuchiya ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Turnover ◽  
Bone Metabolism ◽  
Type I Collagen ◽  
Community Setting ◽  
Serum Markers ◽  
Japanese Women ◽  
Type I ◽  
Cross Sectional ◽  
Markers Of Bone Turnover

AbstractObjectiveLow Ca intake is common among Japanese women, but its effect on bone metabolism has not been fully elucidated. The aim of the present study was to determine the relationship between Ca intake and serum markers of bone turnover in postmenopausal Japanese women.DesignA cross-sectional study.SettingA community setting.SubjectsSubjects were 595 home-dwelling postmenopausal Japanese women. Ca intake was assessed by a validated FFQ. Serum type I collagen cross-linked N-telopeptides (NTX) and osteocalcin were measured as markers of bone turnover. The relationships between demographic characteristics, lifestyles, serum Ca, vitamin D and intact serum parathyroid hormone and bone turnover were also assessed.ResultsThe average age of the subjects was 64·5 (sd 5·8) years and the mean Ca intake was 527 (sd 160) mg/d. Ca intake was significantly associated with serum NTX (P = 0·0104), but not with serum osteocalcin. Mean serum NTX concentration in the lowest quartile of Ca intake (<417 mg/d) was significantly higher than in the fourth, referent quartile. Among these Japanese postmenopausal women, very low Ca intake (less than ∼400 mg/d) was associated with increased bone resorption but not bone formation.ConclusionsIncreased bone resorption may be one mechanism by which this Ca-depleted population normalizes bone metabolism and prevents osteoporosis.

scholarly journals Serum Sclerostin and Bone Turnover in Latent Autoimmune Diabetes in Adults

2018 ◽  
Vol 103 (5) ◽  
pp. 1921-1928 ◽  
Author(s):  
Nicola Napoli ◽  
Rocky Strollo ◽  
Giuseppe Defeudis ◽  
Gaetano Leto ◽  
Chiara Moretti ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Turnover ◽  
Type I Collagen ◽  
Autoimmune Diabetes ◽  
Positive Trend ◽  
Type I ◽  
Cross Sectional ◽  
Latent Autoimmune Diabetes

Abstract Purpose Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA. Methods This cross-sectional study included 98 patients with T2D and 89 with LADA from the Action LADA and Non Insulin Requiring Autoimmune Diabetes cohorts. Patients were further divided according to MetS status. Nondiabetic participants (n = 53) were used as controls. Serum sclerostin, bone formation (pro-collagen type 1 N-terminal propeptide [P1NP]), and bone resorption (C-terminal telopeptide of type I collagen [CTX]) were analyzed. Results Patients with T2D had higher sclerostin than did those with LADA [P = 0.0008, adjusted for sex and body mass index (BMI)], even when analysis was restricted to patients with MetS (adjusted P = 0.03). Analysis of T2D and LADA groups separately showed that sclerostin was similar between those with and those without MetS. However, a positive trend between sclerostin and number of MetS features was seen with T2D (P for trend = 0.001) but not with LADA. Patients with T2D or LADA had lower CTX than did controls (P = 0.0003) and did not have significantly reduced P1NP. Sclerostin was unrelated to age or hemoglobin A1c but was correlated with BMI (ρ = 0.29; P = 0.0001), high-density lipoprotein (ρ = −0.23; P = 0.003), triglycerides (ρ = 0.19; P = 0.002), and time since diagnosis (ρ = 0.32; P &lt; 0.0001). Conclusions Patients with LADA presented lower bone resorption than did controls, similar to patients with T2D. Sclerostin is increased in T2D but not in LADA, suggesting possible roles on bone metabolism in T2D only.

scholarly journals The Antioxidant EnzymeGPX1Gene Polymorphisms Are Associated with Low BMD and Increased Bone Turnover Markers

2010 ◽  
Vol 29 (2) ◽  
pp. 71-80 ◽  
Author(s):  
Simona Jurkovic Mlakar ◽  
Josko Osredkar ◽  
Janez Prezelj ◽  
Janja Marc
Keyword(s):  
Oxidative Stress ◽  
Bone Turnover ◽  
Bone Turnover Markers ◽  
Type I Collagen ◽  
Elderly Women ◽  
Type I ◽  
Mineral Density ◽  
General Linear Model Analysis ◽  
Age Related ◽  
Turnover Markers

Recently, oxidative stress has been suggested as participating in the development of osteoporosis. Glutathione peroxidase 1 (GPX1) is one of antioxidant enzymes responsible for the defence of cells against oxidative damage and thus for protection against age related diseases such as osteoporosis.The aim of present study was to associate genetic variances of GPX1 enzyme with bone mineral density (BMD) and biochemical bone turnover markers and to show the influence of antioxidative defence system in genetics of osteoporosis.We evaluated 682 Slovenian subjects: 571 elderly women and 111 elderly men. All subjects were genotyped for the presence ofGPX1gene polymorphisms Pro198Leu and polyAla region. BMD and biochemical markers were also measured. General linear model analysis, adjusted to height, and (one-way) analysis of variance were used to assess differences between the genotype.and haplotype subgroups, respectively.The significant or borderline significant associations were found between the polyAla or the Pro198Leu polymorphisms and total hip BMD (0.018; 0.023, respectively), femoral neck BMD (0.117; 0.026, respectively) and lumbar spine BMD (0.032; 0.086, respectively), and with biochemical bone turnover markers such as plasma osteocalcin (0.027; 0.025, respectively) and serum C-terminal telopeptide of type I collagen concentrations (0.114; 0.012, respectively) in whole group. Haplotype analysis revealed that the 6-T haplotype is associated significantly with low BMD values (p> 0.025) at all measured locations of the skeleton, and with high plasma osteocalcin concentrations (p= 0.008).This study shows for the first time that the polymorphisms polyAla and Pro198Leu of theGPX1gene, individually and in combination, are associated with BMD and therefore may be useful as genetic markers for bone disease. Moreover, it implies the important contribution of the oxidative stress to pathogenesis of osteoporosis.

Bone formation is increased to a greater extent than bone resorption during a cycling stage race

2010 ◽  
Vol 35 (3) ◽  
pp. 344-349 ◽  
Author(s):  
Pamela S. Hinton ◽  
Anna Rolleston ◽  
Nancy J. Rehrer ◽  
Ien J. Hellemans ◽  
Benjamin F. Miller
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Turnover ◽  
Energy Intake ◽  
Type I Collagen ◽  
Serum Markers ◽  
Type I ◽  
Markers Of Bone Turnover

This study examined the effects of participation in the Tour of Southland, a 6-day bicycle race, on serum markers of bone turnover in 5 elite male cyclists. During the race, energy intake matched expenditure. Osteocalcin was increased ~300% on days 1–5; and C-terminal telopeptide of type I collagen was elevated (43%) on day 3. Participation in a cycling stage race does not appear to have deleterious effects on bone turnover.

Sign in / Sign up

Export Citation Format

Share Document