(Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis

Abstract

Introduction: Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms.

Methods: A systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized.

Results: Seventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation.

Conclusions: The current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk.

Figure 1

Flow-chart of the systematic review.

Figure 2

Vascular calcification. Vascular calcification is an active process regulated by factors known to be involved in the process of osteogenesis. Vascular smooth muscle cells are able to differentiate towards osteoblast-like cells, promoted by a variety of stimuli, including BMP, RANKL, oxidative stress, inflammation and estrogen deficiency. These osteoblastic cells produce osteocalcin and ALP, important factors in mineralisation. ^# Excessive vitamin D promotes mineralisation. * It is not clear whether OPN promotes or inhibits calcification in the arterial wall, in bone mineralisation it is a known mineralisation inhibitor. Abbreviations: ALP, alkaline phosphatase; BMP, bone morphogenetic protein; Cbfa1, core binding factor-α1; MGP, matrix GLA protein; Msx2, msh homeobox 2; OPG, osteoprotegerin; OPN, osteopontin; ox-LDL, oxidized low density lipoprotein; RANKL, receptor activator of nuclear factor-B ligand; VSMC, vascular smooth muscle cell; Wnt, combination of wingless and Int.