Accumulation of Bisphosphonates in Human Artery and their Effects on Human and Rat Arterial Function in vitro

Abstract

Ah.wocf: Clodronate. etidronate and pamidronate are bisphosphonates introduced in the treatment of hypercalcaemia and osteoporosis. Interestingly, they also inhibit development of experimental atherosclerosis and affect smooth muscle tone of isolated rat tail artery. We have studied in vitro whether these hydrophilic compounds 1) accumulate in the wall of the human artery, 2) influence human arterial tone, and 3) interfere with the vascular action of L-type Ca2+ antagonists. Human internal mammary artery rings were incubated with ''C-labelled bisphosphonates. After a 2-hr incubation, the ratios of artery-to-incubate concentrations with 4 and 40 pmolil of clodronate were, respectively, 3.020.5 (mean?S.E.M.) and 1.320.2, with 4 and 40 pmol/l of etidronate 7.4+-0.9 and 3.2?0.4, and with 0.4 and 4 pmol/l of pamidronate 4.7+0.7 and 3.920.8. Both tested bisphosphonates, clodronate and pamidronate, reduced the arterial contractile force induced by a-adrenergic stimulation with noradrenaline and membrane depolarization with high concentration of KCI. Clodronate also decreased the arterial contraction induced by cumulative addition of Ca2+ with KCI as the agonist, and had an additive inhibitory effect on this response with the L-type Ca2+-channel blocker nifedipine. The results demostrate that I ) bisphosphonates accumulate markedly in human artery, 2) clodronate and pamidronate reduce human arterial contactile force to a-adrenergic and depolarizing stimuli, and 3) as shown with clodronate, bisphosphonates may exert an additive inhibitory effect on human arterial contractions with an L-type Ca2+-channel blocker.

Beneficial effect of risedronate on arterial thickening and stiffening with a reciprocal relationship to its effect on bone mass in female osteoporosis patients: A longitudinal study

“…Antiatherogenic effects of bisphosphonates have also been observed in animal models (Ylitalo et al, 1994), although the effects in humans are limited (Koshiyama et al, 2000). Bisphosphonates accumulate in arterial walls, sensitize macrophages to undergo apoptosis, and prevent formation of foam cells by inhibiting uptake of low-density lipoprotein (Ylitalo et al, 1998). These drugs also inhibit the cholesterol biosynthetic pathway in the vasculature.…”

Efficacy and safety of 2-year etidronate treatment in a child with generalized arterial calcification of infancy

“…The mechanisms by which bisphosphonates influence GACI are uncertain. In vitro studies have shown that bisphosphonates accumulate within vessel walls suggesting that these drugs may have a direct effect on calcification [31]. Bisphosphonates might also influence arterial smooth muscle differentiation and phenotype plasticity [9].…”

The effects of zoledronic acid on neointimal hyperplasia: a rabbit carotid anastomosis model

“…Accordingly, zoledronic acid, the most potent one in biphosphonates family was shown to inhibit tumor burden and prevent tumor cell metastasis (30). Furthermore, increasing studies have indicated that bisphosphonates could inhibit the development of experimental atherosclerosis (31,32) and neointimal hyperplasia (33,34). Although in most of the studies, biphosphonates have been shown to have inhibitory effects on MMPs in tumor growth and invasion (16,19), their possible inhibitory effects on intimal hyperplasia and MMPs remains unclear.…”