Bone Metabolism and the Cardiometabolic Syndrome: Pathophysiologic Insights

Authors

  • Samy I. McFarlane MD, MPH

    1. From the Division of Endocrinology, Diabetes and Hypertension, SUNY-Downstate and Kings County Hospital Center, Brooklyn, NY
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Samy I. McFarlane, MD, MPH, Associate Professor of Medicine, Chief, Division of Endocrinology, Diabetes and Hypertension, SUNY-Downstate and Kings County Hospital Center, 450 Clarkson Avenue, Box 50, Brooklyn, NY 11203
E-mail: smcfarlane@downstate.edu

Abstract

Accumulating evidence indicates that the several components of the cardiometabolic syndrome such as hypertension, increased triglycerides, and reduced high-density lipoprotein cholesterol are also risk factors for low bone mineral density. Furthermore, some of the underlying risk factors for atherosclerosis in the cardiometabolic syndrome, such as inflammation, also play a major role in the pathogenesis of osteoporosis, the most common metabolic bone disease. In this article for the premiere issue of the Journal of the CardioMetabolic Syndrome, the author presents the current evidence of the interaction of bone metabolism and the cardiometabolic syndrome, highlighting the major research in this area and discussing the potential of therapeutic agents that will be useful in the treatment of osteoporosis as well as atherosclerosis.

Regardless of the criteria used by various organizations to define the cardiometabolic syndrome (CMS),1–4 these different groups agree on the core components of the syndrome, including central obesity, hypertension, insulin resistance/hypertriglyceridemia, and decreased high-density lipoprotein cholesterol (HDL-C). These components are linked to bone metabolism in several ways (Figure).5 For example, triglycerides predicted the presence of vertebral fractures in postmenopausal women, while HDL-C was positively correlated with bone mineral density (BMD) at the lumbar spine and forearm.6 In both men and women, lipid abnormalities appear to be intricately related to decreased bone density.7 Hypertension, a major component of the CMS and a strong predictor of cardiovascular disease (CVD), appears to increase the risk of low BMD in both men and women.8,9 This decrease in BMD is likely related to increased urinary calcium excretion, as demonstrated in humans10 and in animal studies.11

Figure Figure.

Figure Figure.

Common cellular mechanisms highlighting the interactions between bone metabolism and the vasculature. TNF=tumor necrosis factor; Est=estrogen; ox-LDL=oxidized low-density lipoprotein; IL=interleukin; OPG=osteoprotegerin; eNOS=endothelial NO synthase; iNOS=inducible NO synthase; Cbf=core binding factor; HDL=high-density lipoprotein; RANKL=receptor-activated nuclear factor-kappa B (RANK) ligand; BMP=bone morphogenetic protein; MGP=matrix gamma-carboxyglutamic acid protein; OC=osteocalcin; M-CSF=macrophage colony stimulating factor; PGE2=prostaglandin E2; CVC=calcifying vascular cell; OPN=osteopontin; OLC=osteoclast-like cell; TGF=transforming growth factor; TRAIL=TNF-related ligand. Adapted with permission from Endocrine. 2004;23:1–10.5

Pathophysiologic interactions of bone metabolism and obesity are also evident (albeit more complex) and appear to be race related.12 Increased body mass index (BMI)—generally viewed as protective from osteoporosis because it is associated with increased BMD—appears to offer less protection and may, perhaps, increase the risk for osteoporosis in African-American women.12 Furthermore, changes in cytokine profile are similar between osteoporosis and atherosclerosis,13 and factors that are atheroprotective, such as NO (Figure),14 also prevent bone loss.15 Clinically, the protective effects of NO on bone were demonstrated in a randomized, controlled trial where nitroglycerine (an NO donor) was as effective as estrogen replacement therapy in maintaining bone density and preventing bone loss in women with surgical menopause.16 Finally, therapeutic agents known and used to prevent atherogenesis, such as statins,17 also stimulate bone formation,18 and agents that inhibit bone resorption and used to treat osteoporosis, such as bisphosphonate19 also have antiatherogenic effects.20

Association of Low Bone Mass and Atherosclerosis: Epidemiologic Insights

Several studies have demonstrated an association between low BMD and atherosclerosis. Among these are the Rotterdam study.21 In this population-based study of 7983 patients, including men and women 55 years or older, designed to assess risk factors for progression of atherosclerosis,21 cross-sectional analyses of BMD and peripheral arterial disease (PAD) were performed on 5268 individuals (3053 women and 2215 men).22 The association between PAD and low BMD at the femoral neck was demonstrated. However, this association was present only in women, suggesting estrogen deficiency as a common denominator between osteoporosis and PAD.22

Early stages of atherosclerosis, as measured by pulse wave velocity, were associated with low BMD.23 In a study that involved 7865 Japanese individuals aged 50 years or older, pulse wave velocity was associated with osteosono-assessment index, a surrogate measure of BMD.23 In both men and women, osteosono-assessment index was negatively correlated with pulse wave velocity, although a strong association was observed in women. This association was independent of age and other CVD risk factors.23 This association suggests a link between bone metabolism and CVD. An inverse relationship between aortic calcification and BMD was demonstrated in a study of 236 premenopausal women, aged 45–57 years, and followed prospectively for 9 years.24 In this prospective study, a cross-sectional analysis was also performed in postmenopausal women, showing a graded inverse relationship between the extent of aortic calcification and metacarpal bone density.24

Increased mortality from CVD has also been associated with low BMD.25,26 For example, in the Study of Osteoporotic Fractures Research Group investigation,25 follow-up of 9704 ambulatory women aged 65 years and older demonstrated that low BMD at the proximal radius was strongly associated with increased mortality from stroke (relative risk, 1.74; 95% confidence interval [CI], 1.12–2.70).25 In this study, adjustments were made for possible confounders for stroke such as age, hypertension, diabetes, smoking, or previous history of stroke.25 In another study involving two populations of healthy women with mean ages of 50 and 70 years,26 each SD decrease in BMD was associated with a 2.3-fold increased risk of CVD mortality. Elderly women (older than 70 years) had a 1.8-fold increase in such risk.26 Collectively, these data suggest that low BMD at menopause is a risk factor for CVD later in life and provide epidemiologic evidence of the association of bone metabolism and CVD.26

Bone Metabolism and Dyslipidemia

Hypertriglyceridemia and decreased HDL-C are components of the metabolic syndrome.1–4 These factors are linked to BMD, as demonstrated in several studies.6,27,28 For example, in a study of 214 postmenopausal Japanese women,6 plasma low-density lipoprotein cholesterol (LDL-C) levels were inversely correlated with BMD at the forearm and the lumber spine, while HDL-C correlated positively with BMD at both the lumbar spine and the forearm. Triglyceride elevations predicted the presence of vertebral fractures in this cohort of postmenopausal women.6 In another study examining the association of BMD and lipid profiles, after adjusting for body weight and BMI, total body and hip BMD were related to serum lipid abnormalities in both women and men.7 The relationship was negative for HDL-C and positive for total cholesterol, triglycerides, and LDL-C. Most of these relationships remained when the BMD values were adjusted for body weight, height, and fat mass. This study demonstrates that the abnormal lipid profiles are related to decreased BMD in men and women.7 These data open new perspectives for understanding the mechanisms controlling bone metabolism.

Mechanisms. Some of the insights into the mechanics of the relationship between lipid and bone metabolism were suggested in a study that examined osteoblast-like calcifying vascular cells in vasculature that undergoes osteoblastic differentiation and calcification in vitro.27 Following HDL treatment, alkaline phosphatase activity, a marker of osteogenic differentiation of osteoblastic cells, was significantly reduced in those cells (Figure). Prolonged treatment with HDL also inhibited calcification of these cells, further supporting the antiosteogenic differentiation effect of HDL when applied to vascular cells.27 Furthermore, HDL inhibited the osteogenic activity that was induced by inflammatory cytokines interleukin-1β and interleukin-6 as well as by minimally oxidized LDL. HDL also partially inhibited the interleukin-6—induced activation of signal transducer and activator of transcription 3 in calcifying vascular cells, suggesting that HDL may inhibit cytokine-induced signal transduction pathways.27 Oxidation of HDL rendered it pro-osteogenic, suggesting that HDL regulates the differentiation of osteoblasts and vascular calcification.27 These results highlight the interactions between HDL and bone metabolism.

Bone Metabolism and Hypertension

Hypertension, a component of the CMS, is a well established risk factor for atherosclerosis and CVD.1–4 High blood pressure (BP) is also associated with abnormalities in calcium homeostasis leading to hypercalciuria.8,10,11,29,30 For example, the bone of adult spontaneously hypertensive rats was compared with normotensive Wistar-Kyoto rats.30 The mean femoral cortical thickness and the mean ash weight per unit of bone volume were significantly lower in spontaneously hypertensive rats than in Wistar-Kyoto rats.30 These findings demonstrate the relationship between high BP and low BMD in rats, which is related, in part, to increased urinary calcium excretion.11 This negative calcium balance was also demonstrated in a prospective study involving 3676 white women.8 After adjusting for age, body weight, smoking, and baseline BMD, higher BP in these elderly white women was associated with decreased BMD at the femoral neck.8 Association of low BMD and high BP in postmenopausal women is also believed to be related to increased urinary excretion of calcium.29

In a cross-sectional analysis, we reviewed the charts of 887 men referred for BMD measurements at two institutions,9 including a Veterans Administration hospital. Risk factors were assessed via a questionnaire. Low BMD was defined as a T-score <1 at the lumbar spine. Of these 887 elderly men, 52.8% were white, 38.5% were black, and 7.9% were Hispanic. In a logistic regression model, hypertension predicted the presence of low BMD after adjusting for osteoporosis risk factors (odds ratio [OR], 1.7; 95% CI, 1.16–4.8; p<0.02). These data indicate that hypertension, which is found to be associated with low BMD in women, is also a risk factor for low BMD in men.

Diabetes Mellitus and Bone Metabolism

Diabetes mellitus is an established risk for atherosclerosis and is often present in conjunction with the CMS.1–4 Epidemiologic data indicate that diabetes itself is associated with increased risk of fracture of the hip, proximal humerus, and bones of the feet.31 Analysis of data from 9654 women aged 65 years or older in the Study of Osteoporotic Fractures31 indicated that diabetes was also associated with a higher risk of specific fractures. Observational studies and animal models suggest that decreased bone strength in diabetes may contribute to fracture risk, but this remains a controversial issue.32 While type 1 diabetes is associated with modest reductions in BMD, type 2 diabetes may be characterized by elevated BMD.32,33 This paradox of higher BMD but increased fracture risk in type 2 diabetes may be explained by a combination of more frequent falls and poorer bone quality. Diabetes can impact bone through multiple pathways, some with contradictory effects— including obesity, changes in insulin levels, higher collagen concentrations of advanced glycation end-products, hypercalciuria associated with glycosuria, reduced renal function, lower insulin-like growth factor-I, microangiopathy, and inflammation.32 A better understanding of the interaction of diabetes and bone metabolism will require further studies in this area.

Obesity and Bone Metabolism

Evidence from the National Osteoporosis Risk Assessment (NORA) study34,35 demonstrated decreased risk of osteoporosis with increasing obesity as measured by BMI and reported BMI as a BMD-protective factor.34,35 Among postmenopausal women of Caucasian descent, sufficient moderate obesity is protective from osteoporosis,34,35 and obesity positively correlates with BMD.34–38 These beneficial effects appear to be mediated, in part, by mechanical loading on weight-bearing bones and increased estrogen synthesis in adipose tissue.37,39 Furthermore, studies evaluating the effect of low BMI on BMD have shown unfavorable results. In the Early Postmenopausal Intervention Cohort (EPIC) study,40 early postmenopausal women in the lowest tertiles of BMI had baseline BMDs that were nearly 12% lower and experienced over two-fold increases in bone loss at 2 years when compared with the highest tertiles of percentage of body fat or BMI.40 Tus, low BMI is a risk factor for osteoporosis, predisposing to lower peak bone mass and accelerated bone loss. These studies, however, were mainly done in Caucasian women.34,35 Recent evidence suggests that obesity might not be protective against low BMD in other ethnic groups. For example, in a study by our group12 that included 3206 post-menopausal women of different ethnic backgrounds, we examined the interaction between race and BMD. For white women, as the BMI increases by unity, the odds of low BMD decreased—while African-American women had higher odds of low BMD compared with white women for every unit increase in BMI (OR, 1.015; 95% CI, 1.007–1.14; p <0.01). This effect was not observed when Hispanic women were compared with white women.

To further examine the linear relationship between BMI and BMD for each race, regression parameters were estimated for each race, with specific contrasts between each pair. Significant differences were found between whites and African-American women and between Hispanic and African-American women but not between whites and Hispanics. These data suggest a race-dependent effect of BMI on BMD. With each unit increase in BMI, BMD increases for white women, while a slight but significant decrease in BMD occurs in African-American women.12 These findings also indicate that further studies are needed to clarify the relationship between low BMD and body fat composition, which is known to be different among various ethnic groups.41

Therapeutic Agents

Evidence suggesting a “common soil” hypothesis for low BMD and atherosclerosis is also suggested by the common pathway and the overlapping effects of bisphosphonates and statins.5 These agents have beneficial effects on both the bone and the vascular wall.5 This is not surprising given the common pathway and site of actions for each of these agents.17 Statins (3-hydroxy-3-methylglutaryl coenzyme-A [HMG-CoA] reductase inhibitors) are commonly used for treatment of dyslipidemia. These agents lower cholesterol production and enhance LDL clearance. In addition, statins also reduce cellular isoprenoid intermediates, leading to decreased isoprenylation and decreased activity of small guanosine triphosphate-binding proteins from the Ras/Rho family.17 Bisphosphonates act one step downstream from the site of action of statins on the mevalonate pathway, which is involved in the regulation of Ras/Rho proteins.17 Inhibition of protein prenylation is thought to be responsible for the antiresorptive actions of bisphosphonates.19 Accumulating evidence indicates that these two classes of medications, which affect the mevalonate pathway, may modulate both osteoporosis and atherosclerosis.17 In addition to their pleiotropic effects on the cardiovascular system, statins also stimulate bone formation in vitro and in rodents, an effect that is associated with increase in bone morphogenetic protein-2 gene expression in bone cells.18 Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and, when given orally, these agents increased cancellous bone volume.18 The effect of statins on fracture risk, however, is unclear, and although observational studies showed reduced risk of fracture, randomized trials have not been done.42

Bisphosphonates have long been shown to decrease atherosclerosis.20 These agents prevent the development of atheromatous lesions when used in animal models fed with a high-cholesterol diet.20 Furthermore, bisphosphonates have been shown to reduce the extent of established atherosclerotic lesions and, in high doses, a bisphosphonate derivative has also been shown to reduce serum cholesterol by 33% and to exert multiple antiatherosclerotic effects, including suppression of HMG-CoA reductase activity and prevention of lipid oxidation.43 Oral etidronate has been shown to decrease carotid arterial intima—media thickness in type 2 diabetes without changing cardiovascular parameters, suggesting a direct effect of bisphosphonates on the vascular wall.44 In elderly patients with diabetes, the use of alendronate for the treatment of osteoporosis was associated with a 36% reduction in daily insulin dosage.45 This suggests improvement in insulin sensitivity associated with bisphosphonate use.

Conclusions

Components of the CMS such as hypertension, obesity, high triglycerides, and low HDL appear to have pathophysiologic interactions with bone metabolism. Evidence presented suggests a “common soil” hypothesis between osteoporosis, the most common metabolic bone disease, and CVD, resulting from the risk conferred by the various components of the CMS. Further studies are needed to explore this relationship, with the prospect of developing therapeutic agents that will be useful in both osteoporosis and CMS, two of the most common disorders leading to increased morbidity and mortality in our population.

Disclosure: This work is supported by grants to the author from the National Institutes of Health (K12HD043428, BIRCWH) and from the American Diabetes Association (7—05-RA-89).

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