The Time-Dependent Role of Bisphosphonates on Atherosclerotic Plaque Calcification

Abstract

Atherosclerotic plaque calcification directly contributes to the leading cause of morbidity and mortality by affecting plaque vulnerability and rupture risk. Small microcalcifications can increase plaque stress and promote rupture, whereas large calcifications can stabilize plaques. Drugs that target bone mineralization may lead to unintended consequences on ectopic plaque calcification and cardiovascular outcomes. Bisphosphonates, common anti-osteoporotic agents, have elicited unexpected cardiovascular events in clinical trials. Here, we investigated the role of bisphosphonate treatment and timing on the disruption or promotion of vascular calcification and bone minerals in a mouse model of atherosclerosis. We started the bisphosphonate treatment either before plaque formation, at early plaque formation times associated with the onset of calcification, or at late stages of plaque development. Our data indicated that long-term bisphosphonate treatment (beginning prior to plaque development) leads to higher levels of plaque calcification, with a narrower mineral size distribution. When given later in plaque development, we measured a wider distribution of mineral size. These morphological alterations might be associated with a higher risk of plaque rupture by creating stress foci. Yet, bone mineral density positively correlated with the duration of the bisphosphonate treatment.

Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease

“…159 Our recent studies investigated the effects of bisphosphonate treatment on vascular calcification in vitro and in a hyperlipidemic mouse model of atherosclerosis. 160,161 Using a collagen hydrogel-based model of calcification formation that mimics aspects of the atherosclerotic fibrous cap, we showed that bisphosphonate treatment given after mineralization begins alters the shape and size of microcalcifications that form as the mineral grows. 161 In atherogenic mice, bisphosphonate treatment given before mature plaque formation resulted in larger, more uniform calcifications.…”

“…Bisphosphonates given to the mice after early signs of mineralization are observed in the plaques, leading to less uniform calcification distribution with a broader range of sizes. 160 These data may, in part, explain some of the contradictory clinical outcomes observed with bisphosphonates, where the treatment may result in stable plaque morphologies in some individuals but promote destabilizing microcalcifications in others. Further studies are needed to clarify the therapeutic effects of bisphosphonates in valvular and vascular calcification, especially in the context of CKD.…”

Vascular calcification: Molecular mechanisms and therapeutic interventions

“…Bisphosphonates and denosumab were reported to affect the progress of VC via the suppression of atherosclerotic lesions and mineralization. 250 , 251 , 252 However, the functions of bisphosphonates are disputable. Some experiments found that bisphosphonates can prevent from VC in several animal models through their affinity to hydroxyapatite.…”

“…Bisphosphonates and denosumab were reported to affect the progress of VC via the suppression of atherosclerotic lesions and mineralization 250–252 . However, the functions of bisphosphonates are disputable.…”