Vascular calcification and osteoporosis—from clinical observation ...

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252 Osteoporos Int (2007) 18:251–259 Fig. 1 The osteoporosis/arterial calcification syndrome. Computed tomography demonstrating severe aortic calcification (arrow) in a 71- year-old man with an osteoporotic hip fracture (T score by DEXA: −3.1 at the spine and −2.6 at the proximal femur). His risk profile includes type 2 diabetes mellitus, arterial hypertension and a 60-packyear history of cigarette smoking California revealed that aortic calcifications represent a strong predictor for low bone density and fragility fractures [2]. A longitudinal subgroup analysis showed a graded association between atherosclerotic vascular calcification and vertebral bone loss [2]. Another prospective study on 2,662 postmenopausal women from Denmark demonstrated that advanced aortic calcification, a surrogate marker for atherosclerosis, was significantly associated with lower BMD and rapid bone loss of the proximal femur [3]. Of note, a study on 963 Danish women aged 60–85 years revealed that BMD at the proximal femur, but not at the distal radius or the lumbar spine, was inversely correlated with the severity of aortic calcification [4]. This phenomenon could also indicate that the proximal femur, which is supplied by end-arteries, is more vulnerable to atherosclerosis than the lumbar spine with its redundant arterial supply [3, 4]. A small study in 36 patients also demonstrated a high occurrence of osteoporosis in patients with advanced atherosclerotic involvement of the carotid and/or femoral artery [5]. However, common mechanisms in the pathogenesis of osteoporosis and vascular diseases, especially arterial calcification, have been suggested [6–9], which include: – age-related mechanisms – chronic inflammation (e.g., in rheumatoid arthritis) – cigarette smoking – diabetes mellitus – estrogen deficiency – hypovitaminosis C, D and K – oxidized lipids and free radicals – renal failure During the last decade, various research tools have become available that allow clinicians and scientists to take a closer look at the molecular and cellular mechanisms underlying these two disorders. This has led to the characterization of osteoblastic and osteoclastic lineage cell differentiation from pluripotent stem cells and the discovery of essential factors and transcriptional regulators, including receptor activator of NF-κB ligand (RANKL) and corebinding factor a-1 (cbfa-1). In addition, signaling pathways such as c-jun N-terminal kinase, nuclear factor-κB and Wnt signaling have been identified and their role in animal models of human disease dissected. This has led to major advancements in the understanding of bone metabolism. Moreover, major similarities between vascular biology and the evolution of vascular calcification and the process of bone formation were subsequently described [10–12]. In addition, some knockout mouse models with targeted deletion of bone-related genes yielded a combined skeletal and vascular phenotype [13, 14]. In recent years, sophisticated imaging techniques that combine non-invasive evaluation with high resolution [electron-beam computed tomography (EBCT), multi-detector computed tomography (CT) and ultrafast spiral CT] now allow better and more detailed assessment of coronary artery disease and arterial calcification in vivo. The advantage of EBCT scanning of coronary calcifications include a shorter acquisition time and lower radiation exposure, whereas multislice CT scanners yield better reproducibility [15]. With technical improvements in CT imaging techniques such as rapid gantry rotation, multidetector arrays and electrocardiographic gating, these techniques are virtually equivalent to EBCT (if calcification is present) and are becoming more accessible [16, 17]. Another technical innovation is the use of dual-energy X-ray absorptiometry (DXA) commonly used to detect prevalent vertebral fractures on lateral spine imaging, but which can also be simultaneously employed to assess aortic arterial calcification [18]. In this review, we will discuss common molecular and cellular mechanisms of bone metabolism and vascular biology as they relate to the osteoporosis/arterial calcification syndrome, based on the phenotypes of knockout mice that are lacking matrix Gla protein (MGP), osteopontin, fetuin-A (α 2 -Heremans-Schmid glycoprotein), Smad-6, Klotho and osteoprotegerin (OPG) and present a unifying hypothesis. Single nucleotide polymorphisms in patients with osteoporosis and/or vascular disease Genetic studies in monozygotic twins have indicated that approximately 70% of the variability of human bone mineral density is genetically determined [19]. Candidate
Osteoporos Int (2007) 18:251–259 253 genes that may in part explain this variability can be categorized into receptors, cytokines/growth factors and matrix proteins, and are summarized in Table 1. However, only a few of these single nucleotide polymorphisms have been implicated in both osteoporosis and vascular disease. Gene polymorphisms in the promoter region (G395A) and exon 4 (C1818T) of klotho, which encodes a hormone with anti-aging properties that acts by repressing intracellular signals of insulin and insulin-like growth factor-1 (IGF-1) were associated with bone density in aged Caucasian and Japanese postmenopausal women [20]. Of interest, the klotho promoter polymorphism G395A was also found to be a risk factor for coronary artery disease in Japanese patients [21]. Another gene for which single nucleotide polymorphisms have been implicated in both osteoporosis and vascular disease is OPG, a decoy receptor for the essential osteoclast cytokine RANKL. Single nucleotide polymorphisms within the promoter region (A163G and T245G) were more frequently detected in patients with vertebral fractures [22]. In addition, linkage of polymorphisms T950C (promoter) and G1181C (exon 1) within the OPG gene were associated with an increased risk of coronary artery disease in Caucasian men [23], while the promoter polymorphism T950C was also found to be related to vascular morphology and function [24]. Concurrent analysis of MGP T138C and osteopontin T443C gene polymorphisms revealed no statistical association with coronary artery calcification and bone density [25]. There are no studies on fetuin-A polymorphisms and the risk of osteoporosis and vascular disease. However, one study suggested that fetuin-A polymorphisms are associated with fetuin-A serum levels [26]. Patients with low fetuin-A serum levels were found to have high free phosphate levels, which may affect both bone metabolism and vascular calcification [26]. Table 1 Single nucleotide polymorphisms in patients with osteoporosis and/or vascular disease. IL, interleukin Candidate genes that take part in single nucleotide polymorphisms Receptors Estrogen receptors-α and -β Calcium-sensing receptor Vitamin D receptor Cytokines and cytokine antagonists Interleukin-1β IL-1 receptor antagonist IL-4 IL-6 Osteoprotegerin Transforming growth factor-β Tumor necrosis factor-α Bone-associated proteins Collagen Iα1 Matrix Gla protein Others Apolipoprotein E Klotho Is vascular calcification an active or passive process? Two schools of thought Vascular calcification may arise as a result of two distinct disease entities: atherosclerosis (typically intimal location) and vascular ossification (typically medial location). Atherosclerosis is characterized by a sequence of events, including endothelial dysfunction, intimal edema, foam cell formation and migration of leukocytes and macrophages culminating in the rupture of a plaque with subsequent thrombus formation [27]. Atherosclerotic lesions are predominantly observed in curved arteries and adjacent to bifurcations, i.e., in the beginning of carotid arteries, lumbar aorta and coronary arteries, which may be explained by the hemodynamics of blood flow in these areas. Arterial calcification can occur without (medial calcification) or within (neo-intimal calcification) atherosclerotic lesions. Intimal calcification in late-stage atherosclerotic plaques predominantly occurs in the coronary and carotid arteries as well as the aorta, whereas medial calcification such as in Mönckeberg’s sclerosis is most frequent in the femoral arteries [10]. While clinical practice suggests a high incidence of atherosclerotic lesions in patients with the metabolic syndrome and pronounced arterial calcification in smokers and patients on hemodialysis, there is considerable overlap between atherosclerosis and arterial calcification, since both processes are not mutually exclusive. The coronary calcification score as determined by electron beam and multislice CT scanners has been demonstrated to be a good predictor of coronary heart disease events. Its use and its correlation with other cardiovascular risk scores, e.g., the Framingham risk score, were recently reviewed [15]. The question whether arterial calcification is an active or passive process is still under debate [10, 29]. The active hypothesis is supported by histological findings of bona fide bone tissue with bone marrow, the presence of osteoblast- and osteoclast-like cells and the secretion of various bone-related proteins in lesions affected by arterial calcification [10]. In analogy to bone formation, it is hypothesized that pluripotent mesenchymal stem cells actively differentiate towards osteoblast-like cells capable of forming extracellular matrix that is subsequently mineralized [10]. This process involves activation of osteoblastic transcription factors, including Cbfa-1 [28]. Whether the putative stem cells are smooth muscle cells that transdifferentiate or a phenotypically distinct cell type known as calcifying vascular cells (CVC) [10, 29, 30] is still under discussion. The active process is physiologically inhibited by factors that suppress osteogenic differentiation. Some of the histological features of ectopically formed bone and the presence of bone-like cells and their secretion of bonerelated proteins are arguments in favor of the active process.
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