Bisphosphonates prevent experimental vascular calcification: Treat the bone to cure the vessels?

Persy, Veerle P.; Broe, Marc De; Ketteler, Markus

doi:10.1038/sj.ki.5001899

Cited by 42 publications

(32 citation statements)

References 16 publications

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“…[1][2][3][4] Because the presence of vascular calcification is strongly associated with increased cardiovascular morbidity and mortality, several studies in both animals and humans have sought ways to reduce the extent of vascular calcification. [5][6][7][8][9][10] However, satisfactory therapies have not yet been established. 11 Adenine-induced renal failure is one of the commonly used animal models for studying the development of vascular calcification, but the prevalence of vascular calcification in this model is not very high.…”

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confidence: 99%

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Shimomura¹,

Matsui²,

Hamano

et al. 2014

Journal of the American Society of Nephrology

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Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary L-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+L-lysinezHCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. L-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary L-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of L-lysine. Dietary L-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/ phosphate solution. In conclusion, dietary supplementation of L-lysine ameliorated VC by modifying key pathways that exacerbate VC.

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confidence: 99%

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Shimomura¹,

Matsui²,

Hamano

et al. 2014

Journal of the American Society of Nephrology

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“…Cbfa-1 and OPN have previously been described as markers of VSMC transition to osteoblast-like cells. BPs have been widely used in the treatment of excessive bone resorption, hypercalcemia and osteoporosis (12,13). Etidronate has been reported to decrease the intima-media thickening of carotid arteries (20).…”

Section: Discussionmentioning

confidence: 99%

“…The classical pharmacological effects of BPs appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs, and this may influence their differential distribution within bone, their biological potency and their duration of action (12,13). It is reported that ibandronate prevents experimentally induced arterial calcification in uremic rats (14).…”

Section: Introductionmentioning

confidence: 99%

Zoledronate inhibits phosphate and bone morphogenetic protein 2-induced extracellular calcification of vascular smooth muscle cells in vitro

Huang

Zheng

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. The aim of this study was to explore the effects of the bisphosphonate zoledronate on calcification induced by inorganic phosphate (Pi) and/or bone morphogenetic protein 2 (BMP-2) and the underlying mechanisms. Primary vascular smooth muscle cells (VSMCs) from rats were treated with 3 mM Pi or 3 mM Pi/BMP-2, with and without addition of zoledronate; 1.4 mM Pi served as a control. Calcium deposits, expression of core binding factor α-1 (Cbfa-1), osteopontin (OPN), parathyroid pituitary-specific transcription factor (Pit)-1 and Pit-2, and Pi uptake of VSMCs was determined. The calcification of VSMCs induced by elevated Pi or Pi/ BMP-2 was significantly inhibited by zoledronate. The expression of Cbfa-1, OPN and Pit-1 was increased significantly after treatment with an elevated level of Pi or Pi/BMP-2, and this expression was significantly suppressed by addition of zoledronate. Pi uptake of VSMCs increased following treatment with elevated Pi and significantly decreased by addition of zoledronate. These results indicated that zoledronate effectively inhibited calcification induced by Pi/BMP-2, and this may have been achieved by means of the downregulation of expression of calcification-related proteins and uptake of Pi. IntroductionVascular calcification is highly prevalent and is a major contributor to cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Susceptibility to vascular calcification is in part genetically determined and actively regulated by diverse inducers and inhibitors. One of these inducers, hyperphosphatemia, promotes vascular calcification, and the control of arterial calcification is now recognized as a means to prevent CVD events in patients with CKD (1,2).Vascular calcification is an active, cell-mediated process that results from an imbalance between the promoters and inhibitors of mineralization (3,4). Several molecules that normally regulate osteoblast differentiation and bone formation have been found in calcifying vessels, such as osteonectin, osteocalcin, matrix Gla protein and bone morphogenetic protein 2 (BMP-2) (5-7). Elevated phosphate (Pi) levels also induce smooth muscle cell (SMC) calcification and osteogenic phenotypic modulation (8,9).Bisphosphonates (BPs) are widely used in the treatment of diseases associated with excessive osteoclast-mediated bone resorption, such as osteoporosis (10,11). The classical pharmacological effects of BPs appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs, and this may influence their differential distribution within bone, their biological potency and their duration of action (12,13). It is reported that ibandronate prevents experimentally induced arterial calcification in uremic rats (14). These findings extend the link between bone remodeling and vascular calcification of CKD, opening perspectives toward novel therapeutic strategies. However, whether zoledronate, a new third generati...

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“…Previous experimental animal studies have demonstrated that bisphosphonates, especially when given in higher doses, can induce osteomalacia (124) or result in accumulated microdamage (125,126). In the later stages of CKD a potential problem of bisphosphonate therapy is diminished bone remodeling that could lead to reduced repair of microcracks and impairment of bone strength (108). The frequency of microcracks in clinical studies of patients on long-term bisphosphonates varies from low (127) to high, with an increased accumulation of microdamage (128), although there is as yet no clinical evidence demonstrating that bisphosphonates actually result in impairment of bone strength.…”

Section: Accumulation Of Bisphosphonates and Low Bone Turnover In Ckdmentioning

confidence: 99%

“…It may be by inhibition of bone resorption, with reduced efflux of calcium and phosphate limiting their availability for deposition in the vasculature (108) or their ability to influence the activity of the VSMC NaPi co-transporter. Alternatively, bisphosphonates may have direct effects on the vessel wall and, like pyrophosphate, on crystal formation.…”

Section: Bisphosphonates and Vascular Calcificationmentioning

confidence: 99%

Bisphosphonates in Chronic Kidney Disease; Balancing Potential Benefits and Adverse Effects on Bone and Soft Tissue

Toussaint

Elder

Kerr

2009

Clinical Journal of the American Society of Nephrology

126

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Cardiovascular disease is highly prevalent in chronic kidney disease (CKD) and is often associated with increased vascular stiffness and calcification. Recent studies have suggested a complex interaction between vascular calcification and abnormalities of bone and mineral metabolism, with an inverse relationship between arterial calcification and bone mineral density (BMD). Although osteoporosis is recognized and treated in CKD 1 to 3, the interpretation of BMD levels in the osteoporotic range is controversial in CKD 4, 5, and 5D when renal osteodystrophy is generally present. In addition, there is a paucity of data for patients with CKD mineral and bone disorder (MBD), because studies using bisphosphonates in postmenopausal and glucocorticoid-induced osteoporosis have generally excluded patients with significant CKD. For these patients, treatment of low BMD using standard therapies for osteoporosis is not without potential for harm due to the possibility of worsening low bone turnover, osteomalacia, mixed uraemic osteodystrophy, and of exacerbated hyperparathyroidism; and bisphosphonates should only be used selectively and with caution. Some experimental and clinical studies have also suggested that bisphosphonates may reduce progression of extra-osseous calcification and inhibit the development of atherosclerosis. The authors review the potential benefits and risks associated with bisphosphonate use for bone protection in CKD, and assess their effect on vascular calcification and atherosclerosis.

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Bisphosphonates prevent experimental vascular calcification: Treat the bone to cure the vessels?

Cited by 42 publications

References 16 publications

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

Zoledronate inhibits phosphate and bone morphogenetic protein 2-induced extracellular calcification of vascular smooth muscle cells in vitro

Bisphosphonates in Chronic Kidney Disease; Balancing Potential Benefits and Adverse Effects on Bone and Soft Tissue

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