Tag Archives: review

Review: Cardiovascular Disease and Osteoporosis

Abstract

Cardiovascular disease and osteoporosis.

Cardiovascular disease (CVD) and osteoporosis (OP) are public health problems with numerous epidemiological links and important economic consequences. Recent studies have demonstrated that CVD and cardiovascular mortality are associated with reduced bone mineral density (BMD) and bone fractures. These two conditions may be sustained by similar or common pathophysiological mechanisms and risk factors. There are several matrix proteins, such as type 1 collagen, proteoglycan, osteopontin, and osteonectin, which are found in bone and vascular matrix components. Matrix proteins play an important role both in bone formation and in the development of atherosclerosis. Estrogens also play a role in both CVD and OP through their effects on cytokines, such as IL-1, IL-6 and TNF-alpha and osteoprotegerin (OPG). The lack of estrogens induces an increase in these cytokines and a decrease in OPG, both implicated in the mechanisms of bone loss and atherogenesis. An additional link between CVD and OP seems to be related to the action of some drugs, such as bisphosphonates, statins and raloxifene. Several studies suggest that the mechanism of action of these drugs at cellular level may not be mutually exclusive, acting either in bone or in atherosclerotic plaque. However, further studies are necessary to define the relationship between CVD and OP more specifically and to understand the complex interaction of similar or common risk factors and genetic or molecular determinants.

Baldini V, Mastropasqua M, Francucci CM, D’Erasmo E
J. Endocrinol. Invest. 2005
PMID: 16550727

Review: Arteries an Brittle Bones

Abstract

Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link?

Both osteoporosis and cardiovascular disease (CVD) are major public health problems leading to increased morbidity and mortality. Although traditionally viewed as separate disease entities that increase in prevalence with aging, accumulating evidence indicates that there are similar pathophysiological mechanisms underlying both diseases. In addition to menopause and advanced age, other risk factors for CVD such as dyslipidemia, oxidative stress, inflammation, hyperhomocystinemia, hypertension, and diabetes have also been associated with increased risk of low bone mineral density (LBMD). Elevated LDL and low HDL cholesterol are associated with LBMD, altered lipid metabolism is associated with both bone remodeling and the atherosclerotic process, which might explain, in part, the co-existence of osteoporosis and atherosclerosis in patients with dyslipidemia. Similarly, inflammation plays a pivotal role in both atherosclerosis and osteoporosis. Elevated plasma homocysteine levels are associated with both CVD and osteoporosis. Nitric oxide (NO), in addition to its known atheroprotective effects, appears to also play a role in osteoblast function and bone turnover. Supporting this notion, in a small randomized controlled trial, nitroglycerine (an NO donor) was found to be as effective as estrogen in preventing bone loss in women with surgical menopause. Statins, agents that reduce atherogenesis, also stimulate bone formation. Furthermore, bis- phosphonates, used in the treatment of osteoporosis, have been shown to inhibit atherogenesis. Intravenous bisphosphonate therapy significantly decreases serum LDL and increases HDL in postmenopausal women The exciting possibilities of newer pharmacological agents that effectively treat both osteoporosis and CVD hold considerable promise. However, it is important to emphasize that the current evidence linking both of these diseases is far from conclusive. Therefore, additional research is necessary to further characterize the relationship between these two common illnesses.

McFarlane SI, Muniyappa R, Shin JJ, Bahtiyar G…
Endocrine Feb 2004
PMID: 15034190

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

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

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

Review: HDL and Bone Density

Abstract

HDL cholesterol and bone mineral density: is there a genetic link?

Overwhelming evidence has linked cardiovascular disease and osteoporosis, but the shared root cause of these two diseases of the elderly remains unknown. Low levels of high density lipoprotein cholesterol (HDL) and bone mineral density (BMD) are risk factors for cardiovascular disease and osteoporosis respectively. A number of correlation studies have attempted to determine if there is a relationship between serum HDL and BMD but these studies are confounded by a number of variables including age, diet, genetic background, gender and hormonal status. Collectively, these data suggest that there is a relationship between these two phenotypes, but that the nature of this relationship is context specific. Studies in mice plainly demonstrate that genetic loci for BMD and HDL co-map and transgenic mouse models have been used to show that a single gene can affect both serum HDL and BMD. Work completed to date has demonstrated that HDL can interact directly with both osteoblasts and osteoclasts, but no direct evidence links bone back to the regulation of HDL levels. Understanding the genetic relationship between BMD and HDL has huge implications for understanding the clinical relationship between CVD and osteoporosis and for the development of safe treatment options for both diseases.

Ackert-Bicknell CL
Bone Feb 2012
PMID: 21810493

Review: Protein and bones – 2003

Abstract

Dietary protein and bone health.

The effects of dietary protein on bone health are paradoxical and need to be considered in context of the age, health status and usual diet of the population. Over the last 80 years numerous studies have demonstrated that a high protein intake increases urinary Ca excretion and that on average 1 mg Ca is lost in urine for every 1 g rise in dietary protein. This relationship is primarily attributable to metabolism of S amino acids present in animal and some vegetable proteins, resulting in a greater acid load and buffering response by the skeleton. However, many of these early studies that demonstrated the calciuric effects of protein were limited by low subject numbers, methodological errors and the use of high doses of purified forms of protein. Furthermore, the cross-cultural and population studies that showed a positive association between animal-protein intake and hip fracture risk did not consider other lifestyle or dietary factors that may protect or increase the risk of fracture. The effects of protein on bone appear to be biphasic and may also depend on intake of Ca- and alkali-rich foods, such as fruit and vegetables. At low protein intakes insulin-like growth factor production is reduced, which in turn has a negative effect on Ca and phosphate metabolism, bone formation and muscle cell synthesis. Although growth and skeletal development is impaired at very low protein intakes, it is not known whether variations in protein quality affect the achievement of optimal peak bone mass in adolescents and young adults. Prospective studies in the elderly in the USA have shown that the greatest bone losses occur in elderly men and women with an average protein intake of 16-50 g/d. Although a low protein intake may be indicative of a generally poorer diet and state of health, there is a need to evaluate whether there is a lower threshold for protein intake in the elderly in Europe that may result in increased bone loss and risk of osteoporotic fracture.

Ginty F
Proc Nutr Soc Nov 2003
PMID: 15018487

Review: Melatonin Effects on Bone – 2003

Abstract

Melatonin effects on bone: experimental facts and clinical perspectives.

Bone formation proceeds through a remodeling process that runs continuously, involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic hormones, like parathyroid hormone, estradiol or growth hormone (GH). One candidate for hormonal modulation of osteoblast and osteoclast formation is melatonin. Because circulating melatonin declines with age, its possible involvement in post-menopausal and senescence osteoporosis is considered. This review article discusses early studies on melatonin-bone relationships and recent data that suggest a direct effect of melatonin on bone. Melatonin could act as an autacoid in bone cells as it is present in high quantities in bone marrow, where precursors of bone cells are located. Melatonin dose-dependently augmented proteins that are incorporated into the bone matrix, like procollagen type I c-peptide. Osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts is also augmented by melatonin in vitro. Another possible target cell for melatonin is the osteoclast, which degrades bone partly by generating free radicals. Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Therefore, the documented bone-protecting effect of melatonin in ovariectomized rats can depend in part on the free radical scavenging properties of melatonin. Additionally, melatonin may impair development of osteopenia associated with senescence by improving non-rapid eye movement sleep and restoring GH secretion. Whether melatonin can be used as a novel mode of therapy for augmenting bone mass in diseases deserves to be studied.

Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA…
J. Pineal Res. Mar 2003
PMID: 12562498

Review: Melatonin Effects on Bones and Teeth

Abstract

Melatonin effects on hard tissues: bone and tooth.

Melatonin is an endogenous hormone rhythmically produced in the pineal gland under the control of the suprachiasmatic nucleus (SCN) and the light/dark cycle. This indole plays an important role in many physiological processes including circadian entrainment, blood pressure regulation, seasonal reproduction, ovarian physiology, immune function, etc. Recently, the investigation and applications of melatonin in the hard tissues bone and tooth have received great attention. Melatonin has been investigated relative to bone remolding, osteoporosis, osseointegration of dental implants and dentine formation. In the present review, we discuss the large body of published evidence and review data of melatonin effects on hard tissues, specifically, bone and tooth.

Liu J, Huang F, He HW
Int J Mol Sci 2013
PMID: 23665905 | Free Full Text

From the full text:

Bone remolding processes are mediated by hormones, cytokines, growth factors and other molecules [22]. One of the hormones modulating bone formation and resorption is melatonin. It is hypothesized that melatonin, perhaps through three principle actions, modulates bone metabolism. Firstly, melatonin directly affects the actions of osteoblast and osteoclast. Numerous studies documented that melatonin increases pre-osteoblast/osteoblast/osteoblast-like cell proliferation, promotes the expression of type I collagen and bone marker proteins (e.g., alkaline phosphatase, osteopontin, bone sialoprotein and osteocalcin), and stimulates the formation of a mineralized matrix in these cells [23–27]. Besides, melatonin inhibits the differentiation of osteoclasts via decreases in the expression of RANK mRNA and increases in both the mRNA and protein levels of osteo-protegerin [28,29]. Secondly, melatonin indirectly regulates bone metabolism through the interaction with systemic hormones (e.g., PTH, calcitonin, and estrogen) or other moleculars. Ladizesky et al. [15] revealed that estradiol treatment could prolong the effect of melatonin to augment bone remodeling in ovariectomized rats; it indicates that appropriate circulating estradiol levels might be needed for melatonin effects on bone. Thirdly, osteoclasts generate high levels of superoxide anions during bone resorption that contribute to the degradative process. Melatonin is a significant free-radical scavenger and antioxidant. It can clear up the free radicals generated by osteoclast during the bone resorption process and protect bone cells from oxidative attacks [18,30,31].

And:

Some studies revealed the possible etiologic role of melatonin in osteoporosis. Nocturnal plasma melatonin levels decline with age. It has also been reported that melatonin secretion decreases sharply during menopause, which is associated with post-menopausal osteoporosis [46,47]. A correlation between decreased plasma melatonin levels and an increased incidence of bone deterioration as seen in post-menopausal women has been examined [48]. Furthermore, Ostrowska et al. [49] found that a pinealectomy in rats promotes the induction of bone metabolism biomarkers. In addition, Feskanich et al. [50] reported that twenty or more years of nightshift work significantly increased the risk of wrist and hip fractures in post-menopausal women. Nightshift work leads to disturbances of melatonin secretion as well as severe circadian rhythm disruption. These observations taken together suggest that melatonin may be involved in the pathogenesis of osteoporosis.