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NEW EVIDENCE CONNECTING CARDIOVASCULAR DISEASE AND OSTEOPOROSIS

NIAMS-NHLBI Working Group
September 14-15, 1999
Bethesda, Maryland

Background

Several lines of evidence suggest that there are connections between cardiovascular disease and osteoporosis. Epidemiological studies suggest an association between low bone mass and mortality from coronary artery disease and stroke. Insights into the molecular mechanisms of vascular calcification suggest parallels with bone formation. New information about the actions of statins, a class of cholesterol-lowering drugs, suggest that they may have effects in both bone and vascular tissue. A Working Group was convened by the National Heart, Lung, and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases to bring together researchers from the bone and cardiovascular fields to review recent observations bearing on possible links between cardiovascular disease and osteoporosis and identify future research directions.

Discussion


Epidemiology

Several studies have reported an association between low bone mass and cardiovascular disease. More recently, an association was found between low bone mass and the risk of mortality from cardiovascular disease later in life. These results would suggest that strategies to prevent osteoporosis might prevent the development of cardiovascular disease as well. However, an association is not consistently observed between low bone mass and physiological markers of cardiovascular disease risk and progression. Further, it is unclear how the calcification of atherosclerotic lesions, which appears to parallel bone formation in some respects, is related to cardiovascular mortality. A number of technical problems confound both the assessment of bone mineral density and its correlation with vascular calcification.

Mechanisms
Work with animal models suggests several biological interactions and functional parallels between bone and vascular tissue. Both types of tissue are responsive to hormones such as sex steroids, and both cardiovascular disease and osteoporosis appear to develop in part through the effects of inflammatory mediators. Cells with both osteoblastic and osteoclastic potential may reside in vascular tissue. The induction of obesity and diabetes in low density lipoprotein receptor-deficient mice by a high-fat diet results in aortic calcification, characterized by adventitial expression of genes typical of osteoblastic differentiation. Oxidized lipids, long recognized as a factor in atherogenesis, may have opposite effects on cells in the vascular and bone environments, accounting for the paradoxical coincidence of vascular mineralization with bone loss. However, it is clear that a variety of conditions can produce vascular calcification, and that some types of calcification are distinct from that observed in atherosclerotic lesions. For example, mice lacking osteoprotegerin frequently exhibit aortic calcification in addition to osteopenia. Mice lacking matrix Gla protein exhibit marked arterial calcification, suggesting that matrix Gla protein acts as an inhibitor of arterial mineralization. The ectopic calcification of aortic valves is enhanced in mice deficient in osteoprotegerin, suggesting that osteoclast-like cells may resorb calcium mineral in the artery wall.

Pharmacology
Recently, several statins have been shown to induce new bone formation in cell cultures and animal models. The mechanism(s) responsible for this effect on bone are unknown. The statins are recognized as very effective agents in lowering cholesterol levels and reducing cardiovascular risk. Their primary effect is inhibition of a key enzyme in cholesterol synthesis, but this inhibition may have complex down-stream effects. For example, a neuroprotective effect of statins in stroke appears to reflect the inhibition of lipid modification of the GTPase Rho, which in turn leads to up-regulation of endothelial nitric oxide synthase. Disruption of sterol metabolism may also affect protein trafficking, membrane invagination, exocytosis, and fluidity.

Attempts to detect the skeletal effects of statins in existing clinical cohorts have yielded only suggestive trends, falling short of statistical significance. However, since the statins are targeted to the liver for maximal effects on cholesterol synthesis, they may not reach bone in effective concentrations. Interestingly, amino-bisphosphonates, which are widely used to block bone resorption, also may act in part by inhibiting lipid modification of signaling proteins such as Rho. There is a clear distinction, however, between the anti-resorptive effect of bisphosphonates and the anabolic effect of statins. The anti-resorptive action of bisphosphonates, along with the observation of apparently resorptive cells in some instances of vascular calcification, raises the possibility that bisphosphonates could actually exacerbate cardiovascular disease.

Future Directions

Much of the evidence available at this time is suggestive, rather than definitive. Further efforts across a broad range of scientific and medical disciplines will be necessary to refine these indications into clear conclusions. The goals stated below are illustrative of those identified in the course of the meeting, but are not intended to be comprehensive or exclusive of other relevant research areas.

Epidemiology
Define the relationship between cardiovascular disease, osteoporosis, and related pathologies. It would be valuable to know whether osteoporosis and atherosclerosis progress in parallel, and whether they share genetic or environmental risk factors. Studies are needed to determine whether the association between bone mass and cardiovascular disease indicated in women is also observed in men, and in specific racial and ethnic groups which are known to differ either in bone density and vitamin D metabolism or cardiovascular risk. Also, studies to determine the mechanisms of bioprosthetic mineralization (e.g valve implants) and vascular mineralization in dialysis patients are needed. In many instances, analyses may be most efficiently performed by utilizing existing clinical cohorts in which bone or vascular parameters already have been or will be determined. Reproducible, non-destructive serial imaging methods, such as quantitative CT scanning, need to be validated.

Characterize the relationship between lipid metabolism and skeletal health. Clinical studies are needed to determine whether lipid accumulation contributes to osteoporosis. Studies on the relationship between marrow fat and body fat, marrow fat and osteogenesis, and marrow fat and cardiovascular events may be valuable.

Determine significance of vascular calcification in progression and outcome of cardiovascular disease. It is important to determine whether vascular calcification is harmful or beneficial both in terms of plaque instability and congestive heart failure. Research on the types, distribution and anatomy of vascular calcification is needed. The identification of serum markers for the incidence and progression of vascular calcification, corresponding to those widely used to assess bone turnover, would be a valuable adjunct to radiological methods. It is important to determine whether vascular calcification alters serum markers currently attributed to bone turnover.

Mechanisms
Determine similarities and differences in the mechanisms of vascular calcification and bone mineralization.
It is important to determine the cellular and molecular biology of atherosclerotic calcification, including the roles of oxidized lipids, cell populations, and gene products that parallel aspects of osteogenesis. It is important to determine the effects of normal and oxidized lipids on bone turnover. The role, if any, of cellular (e.g., osteoclastic) resorptive mechanisms in vascular calcification should be determined. It is important to determine the contribution of inflammatory mediators and cytokines to cardiovascular disease and bone remodeling.

Determine the mechanisms underlying the phenotypes of animal models in which pathological vascular calcification or osteoporosis/osteogenesis is observed. One resource-efficient approach is to test for cardiovascular phenotypes in animals with known bone phenotypes and vice versa. Continued use of mouse genetics and genetically-modified mice such as the osteoprotegerin and matrix Gla protein deficient mice could potentially yield important new information. The observations on arterial calcification raise the possibility of examining naturally occurring mutations of these genes with these apparent phenotypes to determine the relationship between these gene products in physiologic and pathologic calcification. New resources such as other animal models, particularly larger species (e.g., swine and rabbit) suitable for physiologic studies and those with features closely resembling human disease would be helpful. Also, an organ culture model for vascular calcification should be developed.

Determine the effects of statins and bisphosphonates on the skeleton and the cardiovascular system. Side-by-side comparisons of vascular and bone cell responses to these commonly used therapeutic agents are needed. In vivo models are needed to explore indirect and down-stream effects, such as the alteration of signaling molecule maturation. It is important to determine whether bisphosphonates exacerbate or reduce vascular calcification.

Pharmacology
Determine whether commonly used therapeutic and preventive treatments for osteoporosis have an impact on cardiovascular disease progression and conversely, whether treatments for atherosclerosis have an impact on skeletal health. Since many therapeutic agents, such as estrogen, calcium supplements, 1,25-dihydroxyvitamin D, warfarin, and antioxidants potentially affect both bone and cardiovascular function, it is essential to exclude damaging effects, and identify the beneficial side effects. Determine whether other lipid-lowering agents have effects on the skeleton. Small scale clinical studies should be utilized to make these determinations.

Explore refinements of statin administration to optimize effects on bone. Alternative approaches to clinical use of statins should be considered, including transdermal application, utilization of statins that are not extracted so efficiently by the liver, and possibly the use of high doses of those statins with better biodistribution beyond the liver. Parallel determination of the effects of these alternative approaches to statin use on cholesterol synthesis and cardiovascular disease should be included.


PARTICIPANTS:

John S. Adams, M.D.
Professor, Department of Medicine
Cedars-Sinai Medical Center
Los Angeles, CA

Warren S Browner, M.D., M.P.H.
Professor of Medicine, Epidemiology & Biostatistics & Anesthesia
Veterans Affairs Medical Center 18 201
San Francisco, CA

Steven R. Cummings, M.D.
Professor of Medicine and Epidemiology
Univ. of California-San Francisco
San Francisco, CA

Linda Demer, M.D., Ph.D.
Associate Professor and Chief, Division of Cardiology
University of California, Los Angeles
Los Angeles, CA

Colin R. Dunstan, Ph.D.
Research Scientist
Amgen, Inc.
Thousand Oaks, CA

Cecilia M. Giachelli, Ph.D.
Associate Professor, Department of Bioengineering
Univ. of Washington School of Medicine
Seattle, WA

Judith A. Hsia, M.D.
Professor, Division of Cardiology
George Washington University Medical Center
Washington DC

Gerard Karsenty, M.D., Ph.D.
Associate Professor, Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, TX

Lewis H. Kuller, M.D., Dr.P.H.
Professor and Chairperson, Department of Epidemiology
University of Pittsburgh
Pittsburgh, PA

James K. Liao, M.D.
Assistant Professor, Cardiovascular Division
Brigham and Women's Hospital
Boston, MA

Gregory R. Mundy, M.B., B.S.
J.C. and Irene H. Heyser Memorial Professor of Bone and Mineral Metabolism
University of Texas Health Science Center
San Antonio, TX

Susan M. Ott, M.D.
Associate Professor, Division of Metabolism Endocrinology, and Nutrition
University of Washington
Seattle, WA

Clay F. Semenkovich, M.D.
Associate Professor, Division of Atherosclerosis, Nutrition, and Lipid Research
Washington University
St. Louis, MO


NHLBI/NIAMS Staff:

Stephen I. Katz, M.D., Ph.D.
Director, NIAMS

Claude Lenfant, M.D.
Director, NHLBI

Deborah Applebaum-Bowden, Ph.D.
Health Scientist Administrator
NHLBI/NIH

Joan A. McGowan, Ph.D.
Director, Musculoskeletal Diseases Branch
NIAMS/NIH

William Sharrock, Ph.D.
Director, Bone Biology Program
NIAMS/NIH

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