| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
BRIEF REPORT |
B Ligand Mediate the Association between Bone and Coronary Artery Calcification?Division of Pharmacy Practice College of Pharmacy and Department of Family and Community Medicine, (L.N.B.), University of New Mexico, Albuquerque, New Mexico 87131; and Department Family and Preventive Medicine (G.A.L., R.B., E.B.-C.), University of California, San Diego, La Jolla, California 92093
Address all correspondence and requests for reprints to: Gail A. Laughlin, Ph.D., Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, 0631C, La Jolla, California 92093. E-mail: glaughlin{at}ucsd.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Objective: Our objective was to investigate whether an observed inverse association between bone mineral density (BMD) and coronary artery calcification (CAC) in postmenopausal women currently taking estrogen therapy is mediated by osteoprotegerin (OPG) or receptor activator of nuclear factor-
B ligand (RANKL).
Design: Participants were 92 postmenopausal women (aged 58–81 yr) taking estrogen therapy who had hip and spine BMD assessed by dual-energy x-ray absorptiometry and CAC measured by electron-beam computed tomography in 1998–2002 and serum RANKL and OPG levels measured in samples collected in 1997–1999. Total CAC score was dichotomized as none/minimal (
10) vs. some (>10).
Results: OPG serum levels were higher in women who had some CAC compared with those who had none/minimal (126.8 ± 1.08 vs. 102.9 ± 1.07 pg/ml, respectively, P = 0.03); these differences became nonsignificant after adjustment for age and other risk factors (P = 0.51). A 1 SD increase in hip BMD was associated with significantly lower odds of having CAC > 10 (odds ratio = 0.52; 95% confidence interval = 0.29–0.93) independent of age, fat-free mass, high-density lipoprotein cholesterol, current smoking, and use of cholesterol-lowering medications. Other skeletal sites demonstrated a similar pattern. Addition of RANKL and/or OPG to the model had minimal effect on the magnitude or statistical significance of the BMD-CAC association. Additionally, a test of interaction indicated that RANKL and OPG are not significant effect modifiers.
Conclusions: Serum OPG and RANKL do not account for the observed association between bone and coronary artery calcification among postmenopausal women using hormone therapy.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In an earlier Rancho Bernardo Study report, we found an inverse association between coronary calcification and bone mass at the hip in elderly women using estrogen therapy (ET), whereas no association was observed in women not on ET (9). We hypothesized that this selective association between coronary and bone calcification might be mediated by estrogen, because estrogen is known to regulate both bone metabolism and the development of atherosclerosis.
New members of the TNF-signaling superfamily, osteoprotegerin (OPG) and receptor activator of nuclear factor-B (RANK) ligand (RANKL), are thought to play an important role in vascular calcification and bone remodeling and have been proposed to represent the molecular link between arterial calcification and bone resorption (reviewed by Schoppet et al. in Ref. 10). Maturation of pre-fusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANKL binds to the RANK receptor. Up-regulation of osteoclasts by RANKL leads to bone resorption and bone loss. OPG acts as a decoy receptor by binding with RANKL, thereby inhibiting osteoclastogenesis and decreasing survival of preexisting osteoclasts (reviewed by Boyle et al. in Ref. 11). The inhibitory effect of estrogen on bone resorption and vascular calcification might occur through the OPG/RANK/RANKL system (12). The purpose of this study was to determine whether OPG and/or RANKL mediate the observed association between coronary and bone calcification among current ET users in the Rancho Bernardo Study cohort.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Detailed inclusion and exclusion criteria and data collection methods have been published elsewhere(9). Briefly, hip and spine BMD was assessed by dual-energy x-ray absorptiometry and CAC by electron-beam computed tomography. Only women who were postmenopausal and had no known coronary heart disease were offered an assessment of CAC; 85% of eligible women participated. During the osteoporosis visit, lifestyle, medical history, and medication use were assessed using structured questionnaires, and fasting blood was obtained to measure plasma cholesterol, triglyceride, high-density lipoprotein (HDL) and low-density lipoprotein cholesterol, and C-reactive protein. Serum samples obtained on the day of the bone scan and stored frozen at –70 C were used to measure OPG and RANKL in 2004 at Amgen, Inc. (Thousand Oaks, CA) using commercial ELISA kits (Biomedica Gruppe, Vienna, Austria). The manufacturer's insert indicates that the RANKL assay can reliably detect values less than 1.6 pg/ml using extrapolation. As in our previous study (13), values more than 0.20 pg/ml were included in the analyses as measured; values less than 0.20 pg/ml (n = 17) were set at 0.20 pg/ml for analyses.
The distribution of RANKL and OPG was skewed; therefore, values were log-transformed for analysis, and geometric means are presented in tables. Total CAC score (CACS) was dichotomized as none/minimal (<10) vs. some (
10). CACS was also categorized into four categories using Rumberger criteria: none/minimal (10), mild (11–100), moderate (101–399), and severe (400). Mean values of RANKL and OPG were compared by CAC category using ANOVA and analysis of covariance adjusting for age, fat-free mass, HDL cholesterol, smoking, and use of cholesterol-lowering medications.
The BMD-CACS association was evaluated using logistic regression analyses and dichotomized CACS similar to our previous study (9). Among numerous risk factors for CVD and osteoporosis collected in this study, only those associated with both total hip BMD and CAC score at P < 0.2 and those that changed the crude BMD-CACS association by more than 5% were included in multivariate analyses. The potential mediating effect of RANKL and OPG was tested by examining the change in the magnitude of the BMD-CACS association after adding RANKL and OPG levels (separately and together) to univariate and multivariate logistic regression models. Potential effect modification was tested by introducing interaction terms (RANKL x BMD and OPG x BMD) in the logistic regression models.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
OPG levels were higher in women with some CAC (geometric mean 126.8 ± 1.1 pg/ml) compared with those with no/minimal calcification (102.9 ± 1.1 pg/ml; P = 0.033) (Table 1
). This difference was no longer significant after adjustment for age and other risk factors (P = 0.51). Crude and multiply adjusted levels of RANKL did not differ by dichotomized CACS category (both P > 0.10). Similar results were observed when OPG and RANKL levels were compared among subjects with no/minimal (10), mild (11–100), moderate (101–399), or severe (400) CAC (data not shown).
|
. Consistent with our previous report (9), among current ET users, 1 SD increase in BMD was associated with lower odds of CACS of more than 10, independent of age and other risk factors (9). Addition of RANKL and/or OPG to the multivariate model had minimal effect on the effect size or statistical significance of the association between BMD and CACS (Table 2). Similar results were observed when analyses were repeated with four categories of CACS and with CACS as a continuous variable (data not shown). No significant interaction was detected between RANKL or OPG and BMD in predicting CACS (all P values > 0.3; data not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This study showed that the association between bone and coronary artery calcification in women using ET did not materially change after addition of RANKL or OPG in the model. Even though this pilot study included only 92 women, limited power is unlikely to explain our results because neither the effect size nor SE of the BMD-CAC association changed appreciably in the presence of RANKL and/or OPG. Nonetheless, it is possible that a statistically significant effect of RANKL and OPG might have been evident in a larger sample. Generalizability of results might be limited because the women were from a middle- to upper-middle-class Caucasian community. The exclusion of women with known CVD might have truncated the range of CAC, reducing the ability to assess the role of the OPG/RANK/RANKL system among symptomatic subjects, even though one in five of these asymptomatic women had moderate or severe calcification (CACS > 100).
Although our findings need to be confirmed in larger studies and different populations, this report suggests that circulating OPG and RANKL may be markers rather than mediators of vascular and bone mineralization or that the association between these two common conditions is mediated by other mechanisms. In addition to the OPG/RANK/RANKL system, there are a number of alternative pathophysiological mechanisms and factors that might modulate both osteoporosis and atherosclerosis. These include 
-carboxyglutamic acid-containing proteins such as matrix -carboxyglutamic acid protein (MGP) and osteocalcin, bone morphogenetic protein (BMP) and osteopontin, nitric oxide, dyslipidemia and oxidative stress, metabolic disorders, cytokines and inflammation, homocysteinemia, and even some pharmacological agents such as 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and bisphosphonates (reviewed by McFarlane et al. in Ref. 1).
Since the discovery of the RANK/RANKL/OPG system, its role in bone remodeling has been widely studied and is now quite well understood. Conversely, knowledge about the role of RANK/RANKL/OPG in vascular mineralization is just being accumulated. Paradoxically, although OPG has a positive effect on calcification of bone tissue, it may prevent vascular calcification. OPG knockout mice display osteoporosis and arterial calcification of the aorta and renal arteries (15). Low-density lipoprotein receptor knockout mice on an atherogenic diet developed vascular calcification that was inhibited by treatment with OPG, whereas no OPG-related changes in noncalcified lesions were noted. In these mice, serum OPG levels increased upon introduction of the atherogenic diet, consistent with the possibility that OPG is a reaction to, or marker of, vascular disease (16). However, evidence of a more direct role exists. Deletion of the OPG gene in apolipoprotein E knockout mice results in the acceleration of atherosclerotic lesion progression and calcification (17). In clinical studies, elevated serum OPG levels correlate with the presence and severity of coronary artery disease, vascular dysfunction, and increased CVD mortality (reviewed by Collin-Osdoby in Ref. 18).
It is unclear why serum OPG levels are elevated in the presence of vascular calcification and whether OPG is simply a marker of vascular calcification or even other coexisting conditions or a cause of such processes. Although these uncertainties remain to be answered by future studies, in the present population-based epidemiological study, we found no evidence that serum OPG or RANKL mediates the association between vascular and bone calcification observed in older women taking ET.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Conflict of Interest: Amgen, Inc. paid for and ran the OPG and RANKL assays. E.B.-C. is the principal investigator of an Amgen-sponsored registry designed to study patient compliance with bone-specific medications or hormone therapy. Neither of these activities influenced this manuscript, and there is no conflict of interest. All other authors have no conflicts of interest.
First Published Online March 4, 2008
Abbreviations: BMD, Bone mineral density; CAC, coronary artery calcification; CACS, CAC score; CVD, cardiovascular disease; ET, estrogen therapy; HDL, high-density lipoprotein; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor-B; RANKL, RANK ligand.
Received November 28, 2007.
Accepted February 22, 2008.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
B legend with bone mineral density in older adults: the Rancho Bernardo study. Eur J Endocrinol 156:555–562This article has been cited by other articles:
 |
|
 |
|
  H. F Escobar-Morreale, J. I Botella-Carretero, M. A. Martinez-Garcia, M. Luque-Ramirez, F. Alvarez-Blasco, and J. L S. Millan Serum osteoprotegerin concentrations are decreased in women with the polycystic ovary syndrome Eur. J. Endocrinol., September 1, 2008; 159(3): 225 - 232. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
