Review: Hearts and Bones

Abstract

Hearts and bones.

Cardiovascular disease (CVD) and osteoporosis (OP) are two common degenerative processes that contribute in great measure to the decline in performance and quality of life of the elderly population. Traditionally, these disorders have been considered as distinct and unrelated entities. However, over the last few years, there has been increasing evidence supporting an important link between CVD and OP. Several genetic association and linkage studies have shown the existence of common genetic determinants for cardiovascular and skeletal diseases. These genes code for several key players on the metabolism of nutrients, such as lipids, calcium and folate, as well as other factors (e.g. sex hormone receptors) that are known to be subject to dietary modulation, suggesting the links at the level of dietary response. Some dietary factors have shown similarities in influencing the risks of both conditions. However, some others act differently in relation with their effects on the development of cardiovascular disease and osteoporosis. We therefore suggest that, any dietary and behavioral recommendations targeting to the ‘global health’ of the ageing population would take a comprehensive consideration of their potentially diverse effects (beneficial or deleterious) on the risks of various ageing related disorders, and would be tailored to the individual genetic background.

Qi L, Shen H, Ordovas JM
Nutr Metab Cardiovasc Dis Jun 2003
PMID: 12955798

Review: Lipids and Bone

Abstract

Cardiovascular disease and osteoporosis: is there a link between lipids and bone?

Atherosclerotic heart disease and osteoporosis are both diseases of old age. Evidence is accumulating for a link between vascular and bone disease. Calcification is a common feature of atherosclerotic plaques, and osteoporosis is associated with both atherosclerosis and vascular calcification. However, the relationship of vascular calcification to the pathogenesis of atherosclerosis remains incompletely understood. Hormone replacement therapy has beneficial effects in the prevention of both atherosclerosis and osteoporosis. Bisphosphonates inhibit bone resorption and are used in the treatment of osteoporosis, whereas the statins inhibit cholesterol biosynthesis and are used for the treatment of atherosclerosis. We have reviewed recent advances in the knowledge of the actions of bisphosphonates and statins at the cellular, molecular and end-organ levels in order to examine the relationship between cardiovascular disease and osteoporosis and to explore the link between lipids and bones. These studies suggest that the mechanism of actions of these two classes of drugs at the cellular level may not be mutually exclusive. There are some early clinical data to complement these findings, suggesting that statins increase bone density and bisphosphonates may have a beneficial effect in vivo on plasma lipid levels and on the atherosclerotic process. Properly designed prospective studies that examine the effect of statins on bone density and fractures, as well as the effects of bisphosphonates on lipid profiles, atherosclerotic progression and cardiovascular morbidity and mortality are needed to define clearly the clinical effects and potential new roles for these agents.

Burnett JR, Vasikaran SD
Ann. Clin. Biochem. May 2002
PMID: 12038594

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.

Review: Cholesterol Effects on Osteoblasts

Abstract

Role of the cholesterol biosynthetic pathway in osteoblastic differentiation.

Cholesterol (C27H46O) is the principal structural lipid of the biological membrane, but it also plays an important role in many other biological functions. Even though the majority of body cholesterol is synthesized by the liver and secreted as circulating lipoproteins, many cell types can synthesize cholesterol ex novo. The biosynthetic pathway of cholesterol proceeds through several intermediates and involves different enzymes. The rate-limiting step of cholesterol synthesis is the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that synthesizes mevalonate starting from HMG-CoA. Since natural inhibitors of HMG-CoA reductase, named statin, have been isolated, many others have been developed, which differ in their lipophilicity/ hydrophilicity. By using statins, many studies have been performed in order to shed light on the role of cholesterol on different cell types and, among these, on bone cells. In vivo studies have demonstrated that treatment of pluripotent mouse marrow stromal cells (M2-10B4) with statins inhibited the differentiation of these cells into osteoblastic cells, confirming the crucial role of cholesterol biosynthetic pathway for osteoblast differentiation. Conversely, other studies, using other cellular systems, have reported that statins may exert an anabolic effect on bone. Moreover, human and animal studies have shown that hypercholesterolemia may play an adverse effect in osteoporotic bone loss. In conclusion, it appears that cholesterol is important for different cellular activities, such as osteoblastic differentiation, if present in “normal” physiological concentration and particular experimental conditions, but it may exert adverse effects if present in excess.

Viccica G, Vignali E, Marcocci C
J. Endocrinol. Invest. 2007
PMID: 17721067

LDL Effects on Osteoblasts

Abstract

Influence of oxidized low-density lipoproteins (LDL) on the viability of osteoblastic cells.

Cardiovascular diseases have recently been noted as potential risk factors for osteoporosis development. Although it is poorly understood how these two pathologies are related, it is a known fact that oxidized low-density lipoproteins (OxLDL) constitute potential determinants for both of them. The current study investigated the metabolism of OxLDL by osteoblasts and its effect on osteoblastic viability. The results obtained show that OxLDL are internalized but not degraded by osteoblasts while they can selectively transfer their CE to these cells. It is also demonstrated that OxLDL induce proliferation at low concentrations but cell death at high concentrations. This reduction of osteoblast viability was associated with lysosomal membrane damage caused by OxLDL as demonstrated by acridine orange relocalization. Accordingly, chloroquine, an inhibitor of lysosomal activity, accentuated cell death induced by OxLDL. Finally, we demonstrate that osteoblasts have the capacity to oxidize LDL and thereby potentially increase the local concentration of OxLDL. Overall, the current study confirms the potential role of OxLDL in the development of osteoporosis given its influence on osteoblastic viability.

Brodeur MR, Brissette L, Falstrault L, Ouellet P…
Free Radic. Biol. Med. Feb 2008
PMID: 18241787

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

High Cholesterol Diet Decreases Bone Density in Rats

Abstract

High cholesterol diet increases osteoporosis risk via inhibiting bone formation in rats.

To investigate the effects of high cholesterol diet on the development of osteoporosis and the underlying mechanisms in rats.
Female Sprague-Dawley rats were randomly separated into 3 groups: (1) the high cholesterol fed rats were fed a high cholesterol diet containing 77% normal diet food, 3% cholesterol and 20% lard for 3 months; (2) ovariectomised (OVX) rats were bilaterally ovariectomised and fed a standard diet; and (3) the control rats were fed the standard diet.

Bone mineral density (BMD) of the rats was measured using dual-energy X-ray absorptiometry. Serum levels of oestradiol (E2), osteocalcin (BGP) and carboxy-terminal collagen crosslinks (CTX) were measured using ELISA. Gene expression profile was determined with microarray. Mouse osteoblast cells (MC3T3-E1) were used for in vitro study. Proliferation, differentiation and oxidative stress of the osteoblasts were investigated using MTT, qRT-PCR and biochemical methods.
In high cholesterol fed rats, the femur BMD and serum BGP level were significantly reduced, while the CTX level was significantly increased. DNA microarray analysis showed that 2290 genes were down-regulated and 992 genes were up-regulated in this group of rats. Of these genes, 1626 were also down-regulated and 1466 were up-regulated in OVX rats. In total, 370 genes were up-regulated in both groups, and 976 genes were down-regulated. Some of the down-regulated genes were found to code for proteins involved in the transforming growth factor beta (TGF-β)/bone morphogenic protein (BMP) and Wnt signaling pathways. The up-regulated genes were found to code for IL-6 and Ager with bone-resorption functions. Treatment of MC3T3-E1 cells with cholesterol (12.5-50 μg/mL) inhibited the cell proliferation and differentiation in vitro in a concentration-dependent manner. The treatment also concentration-dependently reduced the expression of BMP2 and Cbfa1, and increased the oxidative injury in MC3T3-E1 cells.
The results suggest a close correlation between hypercholesterolaemia and osteoporosis. High cholesterol diet increases the risk of osteoporosis, possible via inhibiting the differentiation and proliferation of osteoblasts.

You L, Sheng ZY, Tang CL, Chen L…
Acta Pharmacol. Sin. Dec 2011
PMID: 22036861

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