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Review: Cardiovascular Disease and Osteoporosis Strategies

Abstract

Cardiovascular disease and osteoporosis: balancing risk management.

In this narrative review of the current literature, we examine the traditional risk factors and patient profiles leading to cardiovascular disease and osteoporosis. We discuss the interrelationships between risk factors and common pathophysiological mechanisms for cardiovascular disease and osteoporosis. We evaluate the increasing evidence that supports an association between these disabling conditions. We reveal that vascular health appears to have a strong effect on skeletal health, and vice versa. We highlight the importance of addressing the risk benefit of preventative interventions in both conditions. We discuss how both sexes are affected by these chronic conditions and the importance of considering the unique risk of the individual. We show that habitual physical activity is an effective primary and secondary preventative strategy for both cardiovascular disease and osteoporosis. We highlight how a holistic approach to the prevention and treatment of these chronic conditions is likely warranted.

Warburton DE, Nicol CW, Gatto SN, Bredin SS
Vasc Health Risk Manag 2007
PMID: 18078019 | Free Full Text

Review: Genetics of Cardiovascular Diseases and Osteoporosis

Abstract

Genetic determinants of osteoporosis: common bases to cardiovascular diseases?

Osteoporosis is the most common and serious age-related skeletal disorder, characterized by a low bone mass and bone microarchitectural deterioration, with a consequent increase in bone fragility and susceptibility to spontaneous fractures, and it represents a major worldwide health care problem with important implications for health care costs, morbidity and mortality. Today is well accepted that osteoporosis is a multifactorial disorder caused by the interaction between environment and genes that singularly exert modest effects on bone mass and other aspects of bone strength and fracture risk. The individuation of genetic factors responsible for osteoporosis predisposition and development is fundamental for the disease prevention and for the setting of novel therapies, before fracture occurrence. In the last decades the interest of the Scientific Community has been concentrated in the understanding the genetic bases of this disease but with controversial and/or inconclusive results. This review tries to summarize data on the most representative osteoporosis candidate genes. Moreover, since recently osteoporosis and cardiovascular diseases have shown to share common physiopathological mechanisms, this review also provides information on the current understanding of osteoporosis and cardiovascular diseases common genetic bases.

Marini F, Brandi ML
Int J Hypertens 2010
PMID: 20948561 | Free Full Text

Vitamin D in Atherosclerosis and Osteoporosis

Abstract

Association between atherosclerosis and osteoporosis, the role of vitamin D.

The latest data support the correlation of atherosclerosis and osteoporosis, indicating the parallel progression of two tissue destruction processes with increased fatal and non-fatal coronary events, as well as higher fracture risk. Vitamin D inadequacy associated with low bone mineral density increases fall and fracture risk, leads to secondary hyperparathyroidism, calcifies coronary arteries and significantly increases cardiovascular disease. Randomized clinical trial evidence related to extraskeletal vitamin D outcomes was limited and generally uninformative. A recent recommendation on vitamin D dietary requirements for bone health is 600 IU/d for ages 1-70 years and 800 IU/d for 71 years and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/l). Further large randomized controlled trials are needed to reassess laboratory ranges for 25-hydroxyvitamin D in both diseases, in order to avoid under- and over-treatment problems, and completely clarify the relationship between atherosclerosis and osteoporosis.

Stojanovic OI, Lazovic M, Lazovic M, Vuceljic M
Arch Med Sci Apr 2011
PMID: 22291755 | Free Full Text

Oxidized Phospholipids May Interfere With Bone Growth

Abstract

Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and parathyroid hormone in osteoblasts.

Cardiovascular disease, such as atherosclerosis, has been associated with reduced bone mineral density and fracture risk. A major etiologic factor in atherogenesis is believed to be oxidized phospholipids. We previously found that these phospholipids inhibit spontaneous osteogenic differentiation of marrow stromal cells, suggesting that they may account for the clinical link between atherosclerosis and osteoporosis. Currently, anabolic agents that promote bone formation are increasingly used as a new treatment for osteoporosis. It is not known, however, whether atherogenic phospholipids alter the effects of bone anabolic agents, such as bone morphogenetic protein (BMP)-2 and parathyroid hormone (PTH). Therefore we investigated the effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) on osteogenic signaling induced by BMP-2 and PTH in MC3T3-E1 cells. Results showed that ox-PAPC attenuated BMP-2 induction of osteogenic markers alkaline phosphatase and osteocalcin. Ox-PAPC also inhibited both spontaneous and BMP-induced expression of PTH receptor. Consistently, pretreatment of cells with ox-PAPC inhibited PTH-induced cAMP production and expression of immediate early genes Nurr1 and IL-6. Results from immunofluorescence and Western blot analyses showed that inhibitory effects of ox-PAPC on BMP-2 signaling were associated with inhibition of SMAD 1/5/8 but not p38-MAPK activation. These effects appear to be due to ox-PAPC activation of the ERK pathway, as the ERK inhibitor PD98059 reversed ox-PAPC inhibitory effects on BMP-2-induced alkaline phosphatase activity, osteocalcin expression, and SMAD activation. These results suggest that atherogenic lipids inhibit osteogenic signaling induced by BMP-2 and PTH, raising the possibility that hyperlipidemia and atherogenic phospholipids may interfere with anabolic therapy.

Huang MS, Morony S, Lu J, Zhang Z…
J. Biol. Chem. Jul 2007
PMID: 17522049 | Free Full Text

High Cholesterol Promotes Osteoclasts in Mice

Abstract

Hypercholesterolemia promotes an osteoporotic phenotype.

A role for hypercholesterolemia in the development of osteoporosis has been suggested in published reports. However, few studies contain direct evidence of a role for maintenance of cholesterol homeostasis in bone health. Using isocaloric high-fat/high-cholesterol and low-fat/no-cholesterol diets in a 4-month feeding study combined with micro computed tomography analysis, we demonstrated in two different mouse strains that mice with hypercholesterolemia lose cortical and trabecular bone in the femurs and vertebrae (bone mineral density was decreased on average by ≈90 mg/mL in the cortical vertebrae in one strain) and cortical bone in the calvariae (bone mineral density was decreased on average by ≈60 mg/mL in one strain). Mechanical testing of the femurs demonstrated that loss of bone in the mice with hypercholesterolemia caused changes in the mechanical properties of the bone including loss of failure load (failure load was decreased by ≈10 N in one strain) and energy to failure. Serologic and histomorphologic analyses suggested that hypercholesterolemia promotes osteoclastogenesis. These studies support a role for hypercholesterolemia in the development of osteoporosis and provide a model with which to test intervention strategies to reduce the effects of hypercholesterolemia on bone health.

Pelton K, Krieder J, Joiner D, Freeman MR…
Am. J. Pathol. Sep 2012
PMID: 22770664 | Free Full Text

Lipids not Associated with Bone Density in Korean Women

Abstract

Association between Serum Cholesterol Level and Bone Mineral Density at Lumbar Spine and Femur Neck in Postmenopausal Korean Women.

Blood lipid profiles have been suggested to be a risk factor for osteoporosis. However, the association between lipid profiles and bone mineral density (BMD) is still unclear. This study aimed to evaluate an association between blood lipid profiles and BMD through both a cross-sectional and a longitudinal study.
Study subjects were 958 postmenopausal Korean women who have repeatedly undertaken laboratory tests and BMD measurements at lumbar spine and femur neck with an interval of 7.1 years. The associations between lipid profiles and BMD were examined using Spearman correlation analysis with an adjustment for age, smoking, alcohol drinking, physical activity, body mass index, and follow-up duration.
Lumbar spine BMD was not associated with total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HLD-C) regardless of when the measurement was performed. In an analysis using data measured at the beginning of the study, femur neck BMD was not associated with TC and LDL-C. However, femur neck BMD showed weak but significantly positive correlation with HDL-C (correlation coefficient, 0.077; 95% confidence interval, 0.005 to 0.149). When the analysis was repeated with data measured at the end of the follow-up, there was no significant correlation between femur neck BMD and any lipid profile. In addition, change in femur neck BMD during follow-up was not associated with the change in lipid profiles.
Although further study with a consideration of calcium intake and osteoporosis medication seems necessary, this study found no association between serum lipid profiles and BMD in postmenopausal Korean women.

Go JH, Song YM, Park JH, Park JY…
Korean J Fam Med May 2012
PMID: 22787539 | Free Full Text

Lipids, Obesity, and Bone Density

Abstract

Lipid profile, obesity and bone mineral density: the Hertfordshire Cohort Study.

Body mass index (BMI) and bone mineral density (BMD) are positively correlated in several studies, but few data relate bone density, lipid profile and anthropometric measures.
To investigate these relationships in a large, well-characterized cohort of men and women (The Hertfordshire Cohort Study).Men (n = 465) and women (n = 448) from Hertfordshire, UK were recruited. Information was available on demographic and lifestyle factors, anthropometric measurements, body fat percentage, fasting triglycerides, cholesterol (total, HDL, LDL), apolipoprotein (a) and apolipoprotein (b); bone mineral density (BMD) was recorded at the lumbar spine and total femur.
BMD at the lumbar spine (males r = 0.15, p = 0.001; females r = 0.14, p = 0.003) and total femoral region (males r = 0.18, p = 0.0001; females r = 0.16, p = 0.0008) was related to serum triglyceride level, even after adjustment for waist-hip ratio, age, social class and lifestyle factors, but not if body fat percentage was substituted for waist-hip ratio in the regression model. Fasting HDL cholesterol level was related to lumbar spine BMD in women (r = -0.15, p = 0.001) and total femoral BMD in both sexes (males r = -0.15, p = 0.002; females r = -0.23, p < 0.0001); these relationships were also attenuated by adjustment for body fat percentage but not waist-hip ratio. No relationships were seen between total or LDL cholesterol with BMD.
In this cohort, relationships between lipid profile and BMD were robust to adjustment for one measure of central obesity (waist-hip ratio), but not total body fat. This broadly supports the idea that adiposity may confound the relationship between lipids and bone mass.

Dennison EM, Syddall HE, Aihie Sayer A, Martin HJ…
QJM May 2007
PMID: 17449479 | Free Full Text

A number of studies have suggested a positive relationship between BMD and triglyceride level, in concordance with our own findings [10,13], while the literature concerning relationships between HDL cholesterol levels and BMD is conflicting [12, 13,15,15, 18,19]. While D’Amelio et al [12] found an inverse relationship similar to our own results, Yamaguchi et al [14] described a positive relationship, and Cui et al [13] and Poli et al [15] described no relationship.

LDL May Induce Hormesis Effects in Osteoblasts

Abstract

Characterization of oxidized low-density lipoprotein-induced hormesis-like effects in osteoblastic cells.

Epidemiological studies indicate that patients suffering from atherosclerosis are predisposed to develop osteoporosis. Atherogenic determinants such as oxidized low-density lipoprotein (oxLDL) particles have been shown both to stimulate the proliferation and promote apoptosis of bone-forming osteoblasts. Given such opposite responses, we characterized the oxLDL-induced hormesis-like effects in osteoblasts. Biphasic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reductive activity responses were induced by oxLDL where low concentrations (10-50 microg/ml) increased and high concentrations (from 150 microg/ml) reduced the MTT activity. Cell proliferation stimulation by oxLDL partially accounted for the increased MTT activity. No alteration of mitochondria mass was noticed, whereas low concentrations of oxLDL induced mitochondria hyperpolarization and increased the cellular levels of reactive oxygen species (ROS). The oxLDL-induced MTT activity was not related to intracellular ROS levels. OxLDL increased NAD(P)H-associated cellular fluorescence and flavoenzyme inhibitor diphenyleneiodonium reduced basal and oxLDL-induced MTT activity, suggesting an enhancement of NAD(P)H-dependent cellular reduction potential. Low concentrations of oxLDL reduced cellular thiol content and increased metallothionein expression, suggesting the induction of compensatory mechanisms for the maintenance of cell redox state. These concentrations of oxLDL reduced osteoblast alkaline phosphatase activity and cell migration. Our results indicate that oxLDL particles cause hormesis-like response with the stimulation of both proliferation and cellular NAD(P)H-dependent reduction potential by low concentrations, whereas high concentrations lead to reduction of MTT activity associated with the cell death. Given the effects of low concentrations of oxLDL on osteoblast functions, oxLDL may contribute to the impairment of bone remodeling equilibrium.

Hamel P, Abed E, Brissette L, Moreau R
Am. J. Physiol., Cell Physiol. Apr 2008
PMID: 18287334 | Free Full Text

Review: Cardiovascular Disease and Osteoporosis Links

Abstract

The link between osteoporosis and cardiovascular disease.

Cardiovascular disease (CVD) and osteoporosis are common age-related conditions associated with significant morbidity, mortality, and disability.Traditionally, these two conditions were considered unrelated and their coexistence was attributed to independent age-related processes. However, an increasing body of biological and epidemiological evidence has provided support for a link between the two conditions that cannot be explained by age alone. Several hypotheses have been proposed to explain the link between osteoporosis and CVD including: 1) shared risk factors, 2) common pathophysiological mechanisms, 3) common genetic factors, or 4) a causal association. This review highlights the epidemiologic literature on the association of bone density with cardiovascular mortality, cardiovascular morbidity, and subclinical measures of atherosclerosis. It also summarizes the different potential mechanisms involved in the link between osteoporosis and CVD.

Farhat GN, Cauley JA
Clin Cases Miner Bone Metab Jan 2008
PMID: 22460842 | Free Full Text

Cholesterol Indirectly Linked to Osteoporosis

Abstract

Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se?

Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa. Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood. We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage.
This was an observational study including 1176 elderly women 60-85 years old. Women were genotyped for epsilon (epsilon) allelic variants of the ApoE gene, and data concerning serum lipids (total cholesterol, triglycerides, HDL-C, LDL-C, apoA1, ApoB, Lp(a)), hip and spine BMD, aorta calcification (AC), radiographic vertebral fracture and self-reported wrist and hip fractures, cardiovascular events together with a wide array of demographic and lifestyle characteristics were collected.
Presence of the ApoE epsilon 4 allele had a significant impact on serum lipid profile, yet no association with spine/hip BMD or AC could be established. In multiple regression models, apoA1 was a significant independent contributor to the variation in AC. However, none of the lipid components were independent contributors to the variation in spine or hip BMD. When comparing the women with or without vertebral fractures, serum triglycerides showed significant differences. This finding was however not applicable to hip or wrist fractures. After adjustment for age, severe AC score (>or=6) and/or manifest cardiovascular disease increased the risk of hip but not vertebral or wrist fractures.
The contribution of serum lipids to the modulators of BMD does not seem to be direct but rather indirect via promotion of atherosclerosis, which in turn can affect bone metabolism locally, especially when skeletal sites supplied by end-arteries are concerned. Further studies are needed to explore the genetic or environmental risk factors underlying the association of low triglyceride levels to vertebral fractures.

Bagger YZ, Rasmussen HB, Alexandersen P, Werge T…
Osteoporos Int Apr 2007
PMID: 17109061 | Free Full Text

In summary, the results of the present observational study provide further evidence for the independent association of peripheral vascular disease with osteoporosis in the proximal femur. Since the association of lipids and lipoproteins to BMD and non-vertebral fractures is not independent of the severity of AC, it seems unlikely that these metabolites exert direct and clinically significant effects on bone turnover in postmenopausal women. Their contribution is via promotion of atherogenesis, in which regard ApoA1 levels seem to take a leading role. The remaining issue to be clarified is which genetic or environmental factors underlie the association of low triglycerides levels to vertebral fractures.