In this ethnically diverse cohort of women, we demonstrated robust and consistent relationships between the prevalence of cardiovascular calcification and NCBP use. We found a clear interaction of NCBP use with age such that there was reduced prevalence of vascular and valvular calcification in women ≥65 years of age and increased prevalence of cardiovascular calcification in younger women on treatment. Finer age stratification supported a gradual transition of risk with increasing age.
Independent data from MESA and other observational studies have associated osteoporosis with cardiovascular calcification.(28
) However, the mechanisms responsible for the inverse relationship between cardiovascular calcification and bone mineral density (BMD) are not known. In cell culture models, valve and bone cell types respond in opposite ways to statins, with reduced calcification in aortic valve myofibroblasts and augmented calcification in a pre-osteoblast cell line.(31
) Similar effects have been demonstrated in response to inflammatory cytokines and oxidized LDL in other models of vascular and bone calcification.(30
) Among the proposed explanations for this paradox is that chronic inflammation in response to oxidized LDL modulates calcification differently in vascular tissue and in bone, resulting in tandem calcification of soft tissue and softening of calcified tissues.(30
) These observations suggest that NCBPs, which lead to increases in BMD, may be inversely associated with cardiovascular calcification.
NCBPs have the potential to influence calcium homeostasis in cardiovascular tissue by several mechanisms. NCBPs exert pleiotropic, statin-like effects that include inhibition of protein prenylation,(14
) various inflammatory processes,(14
) and vitamin K metabolism,(11
) each of which has been associated with atherosclerotic disease.(3
) Inhibition of isoprenoid synthesis, which is required for vitamin K metabolism, affects several vitamin K-dependent bone regulatory proteins, such as osteocalcin and matrix Gla protein.(11
) NCBPs inhibit secretion of interleukin (IL)-1β, IL-6, TNF-α, and several matrix metalloproteinases in a variety of cell types and reduce numbers of circulating monocytes and tissue macrophages at the time of vascular injury.(17
) NCBPs may also reduce serum lipids, which accumulate in vessel walls and valve leaflets triggering calcification.(15
) Alternatively, cardiovascular effects of NCBPs may be related to selective inhibition of bone resorption by which calcium-phosphate mineral complexes released into the bloodstream are deposited in vascular and valvular tissues.(11
) Hence, though the effects of NCBPs may be similar to statins in some respects, the two drug classes may have disparate actions mediated by effects on bone metabolism.
In a recent retrospective analysis of echocardiographic data, Skolnick and colleagues demonstrated in patients with a mean baseline aortic valve area of 1.33 cm2
, that the use of bisphosphonates, calcitonin, or estrogen receptor modulators for osteoporosis was associated with a mean annual change in aortic valve area of -0.10±0.18 cm2
compared to -0.22±0.22cm2
in those not receiving these medications (p<0.03).(19
) Our findings in subjects ≥ 65 years of age lend support to this previous report and suggest that the observed effects on progression of aortic stenosis may be due to modulation of calcification within the cardiovascular system, broaden the potential impact of bisphosphonate drugs to include direct or indirect effects on aortic, coronary artery, and mitral valve calcification.
We found a surprising association of NCBP use with increased prevalence of cardiovascular calcification in those subjects younger than 65 years of age. While the reasons for this relationship are elusive, there are several possible explanations. First, low BMD has been associated with increased risk of cardiovascular calcification.(28
) Given that NCBP therapy is prescribed predominantly for patients with osteoporosis, treatment may identify a group of patients in whom an increased risk of cardiovascular calcification is associated with low BMD (). With age, and presumably longer duration of NCBP use the putative protective effect of these agents may overcome BMD-associated cardiovascular risk thereby reversing the association. Previous data from MESA demonstrated that compared to those women in the highest quartile of bone density, those in the lowest quartile displayed a modestly increased risk of prevalent CAC (adjusted PR 1.16 [95%CI 0.96, 1.41]) but no difference in risk of prevalent aortic calcification (adjusted PR 1.02 [95%CI 0.93, 1.12]).(28
) These effects were smaller in magnitude than those that we observed with NCBP use, suggesting that NCBPs may exert a direct cardiovascular effect beyond modulating BMD. Alternatively, bisphosphonate use in younger women may be a marker for another disease. The U.S. Preventive Services Task Force recommends screening postmenopausal women beginning at age 60 years for osteoporosis if they are at increased risk and routinely for those over 65 years.(38
) As such, women who warrant therapy at a young age possess a more aggressive form of osteoporosis, secondary osteoporosis, or other diseases that places them at higher risk of cardiovascular calcification. Lastly, a true age-dependent mechanism of NCBP action or of the relationship between osteoporosis and atherosclerosis remains. Further clarification of the observed age-dependent associations between NCBP use and cardiovascular calcification requires knowledge of indication for NCBP use and duration of use, neither of which were available for this analysis. Future evaluations of NCBP effects on cardiovascular calcification are warranted with particular attention to age, indication for NCBP, and duration of use.
Our findings suggest that NCBPs may modulate cardiovascular calcification, a surrogate marker for atherosclerosis and cardiovascular outcomes. Whether attenuation of cardiovascular calcification alone, without interruption of the underlying atherosclerotic process, improves cardiovascular morbidity and mortality remains controversial.(39
) NCBPs may attenuate elements of the atherosclerotic process through several pleiotropic effects,(11
) but further study is needed to elucidate the clinical impact of these effects. Unfortunately, randomized trials evaluating NCBPs, until recently, have not reported cardiovascular events. The HORIZON Recurrent Fracture Trial, a randomized, trial evaluating the benefits and safety of zoledronate therapy after low-trauma hip fracture, provides the most substantial supportive evidence.(40
) Annual intravenous administration of zoledronate was associated with a trend towards reduced cardiovascular mortality compared to placebo (3.4 vs 4.9%; p=0.10). No such effect was suggested among patients enrolled in the HORIZON Pivotal Fracture Trial who had not experienced prior hip fracture.(41
) Additional studies are needed to specifically address the effects of NCBP use on cardiovascular morbidity and mortality.
Given our cross-sectional study design, lack of serological data on levels of calcium, phosphate, parathyroid hormone, vitamin D, and various inflammatory markers, and unavailability of data on duration of NCBP use, the effects of NCBP use on cardiovascular calcification cannot be defined mechanistically. Moreover, the relatively good health of the MESA cohort limits our ability to evaluate the development or progression of cardiovascular calcification over time. Despite these limitations, the robust and consistent associations between NCBPs and vascular and valvular calcification within a cohort of relatively healthy women highlight the need for further study of the effect of NCBPs on cardiovascular calcification and to explore their therapeutic potential. Additional studies are needed to elucidate the mechanisms involved and to evaluate whether NCBP's may exert harmful effects in younger women.
In summary, this study suggests an association between nitrogen-containing bisphosphonate drug therapy and valvular, aortic, and coronary arterial calcification in women with subclinical cardiovascular disease. Given similarities between the effects of NCBP and statin agents on lipid metabolism and protein prenylation and the beneficial effects of NCBPs on bone metabolism, these drugs warrant further investigation as potential therapeutic agents in elderly women prone to calcific cardiovascular disease. It is also important to determine whether an apparently detrimental increase in the prevalence of cardiovascular calcification in younger women reflects heightened cardiovascular risk associated with osteoporosis, a toxic effect of this type of medication, or another age-dependent processes.