Full Length ArticleIs there a role for bisphosphonates in vascular calcification in chronic kidney disease?
Introduction
The widespread use of bisphosphonates in populations with osteoporosis includes many patients with impaired renal function. Cardiovascular disease presents a huge burden of morbidity and mortality within the chronic kidney disease (CKD) population [1] and it is therefore important to understand any “off target” effects of these agents on the vasculature and whether, if present, these effects are beneficial or harmful. Such effects are plausible in that bisphosphonates are analogues of pyrophosphate, a potent calcification inhibitor in bone and soft tissue. The pathophysiology of this cardiovascular disease is distinct from that seen in those with normal renal function in whom intimal atherosclerotic plaques are deposited in intimal lining leading to stenotic lesions. In contrast, CKD is associated with arteriosclerosis and excessive calcium deposition in the media driven by differentiation of vascular smooth muscle cells into osteoblasts [2]. This review discusses the pathophysiological basis by which this occurs, the impact of renal mineral bone disease (CKD-MBD) on this process and whether there is a role for bisphosphonates in modification of this process.
Section snippets
The impact of vascular calcification in renal disease
Cardiovascular disease is the major cause of death in the dialysis population, with rates up to twenty times higher than in the general population. Coronary artery disease (CAD) is present in between 40 and 70% of dialysis patients [3] with a disproportionate number of younger individuals and females affected compared to the profile of CAD within the general population [4].
A major contributor to the cardiovascular disease burden is the underlying arterial calcification (CAC) seen in affected
Chronic kidney disease-mineral bone disease
The link between CKD-MBD and arterial calcification has been reported in a number of studies [14,15]. The nature of the bone disease in these affected individuals underlies its influence on vascular calcification. CKD-MBD was defined by the Kidney Disease: Improving Global Outcomes (KDIGO) as a “systemic disorder of mineral and bone disease due to CKD manifested by one of the following: abnormalities of calcium, phosphorus, PTH or vitamin D metabolism; abnormalities in bone turnover,
Pathophysiology of CKD-MBD
The bone-kidney endocrine axis is a complex interplay of mineral and hormonal factors including serum calcium, phosphate, fibroblast growth factor-23 (FGF-23), klotho, sclerostin, parathyroid hormone (PTH) and vitamin D.
One of the earliest adaptive changes seen as renal function declines is linear reduction of klotho.1 [17]. The failure to activate klotho contributes to profound increases of FGF-23 and to a lesser extent PTH, which in turn serve to delay the onset of overt hyperphosphataemia [
Links between bone disease and vascular calcification
A sizeable literature supports a link between CKD-MBD and vascular calcification in advanced renal disease [[27], [28], [29]]. London et al. examined vascular calcification, as measured ultrasonographically and graded between zero and four was correlated with bone biopsy findings. Samples were assessed for trabecular bone volume, osteoid surface and volume, osteoblast surface, osteoclast resorption surface and osteoclast number amongst other measurements. Histologically, there was a lower rate
Calcification of the vasculature in renal disease
The striking histological finding in the vasculature of those with CKD-MBD is vascular smooth muscular cells (VSMC) located within the media of the artery undergoing osteochrondogenic differentiation [33]. This process resembles physiological bone formation which occurs under the influence of the osteogenic transcription factors CBFA1, MSX2, SOX9 and osterix leads the resultant osteo-/chrondrogenic cell to promote calcification. Parallel reduction of MGP and pyrophosphate, apoptosis with
The impact of CKD-MBD on arterial calcification
The direct impact of renal disease with CKD-MBD on development of arterial calcification is mediated through a number of interplaying factors. The changes in hormone and mineral levels described in Fig. 1 have been shown to influence arterial calcification, the mechanisms of which are discussed below. VSMC have an abundance of type III sodium-phosphate co-transporters, PiT-1 and PiT-2. In the presence of hyperphosphataemia, a key promotor of vascular calcification, PiT-1 promotes
Factors that favour vascular calcification
The discovery of the Wnt-signalling pathway has brought into sharper focus the link between vascular calcification and CKD-MBD. Physiologically Wnt proteins play an important role in bone cell differentiation, proliferation and apoptosis [40] and are an important determinant of trabecular and cortical bone mass [41]. Wnt activates receptors on the cell surface composed of Lrp 5/6 and Frizzled proteins. This activates a number of intracellular pathways. The pathway of focus with regards to bone
Is this process of vascular calcification modifiable?
We now consider whether the use of medication that powerfully affects bone turnover would also influence the progression of vascular calcification and thereby modify cardiovascular risk. Theoretically at least, bisphosphonates could accelerate or retard vascular calcification.
Bisphosphonates, bone and vasculature
Bisphosphonates impair osteoclasts' ability to resorb bone [49]. Osteoclastic activity is further reduced by the bisphosphonate decreasing production of the osteoclast progenitor, although this is partially offset with a reduction of osteoclast apoptosis [50]. In vitro, there is also an anti-apoptotic effect on osteoblasts by bisphosphonates mediated by connexin-43 (Cx-43), supporting ongoing bone mineralisation [51]. Bisphosphonates open the Cx43 hemichannel leading to the activation of the
Pharmacokinetics of bisphosphonates
Bisphosphonates are poorly and variably absorbed orally (between 2 and 3%) and disappear rapidly from the circulation, with most bound to hydroxyapatite in the bone or excreted by the kidneys within a few hours. The bisphosphonates preferentially bind trabecular bone, which has a higher vascular supply [58] and once incorporated, remain there for up to 10 years [59]. Renal excretion is initially brisk through a combination of glomerular filtration and proximal tubular secretion and subsequently
Bisphosphonate use in renal disease
Vascular calcification in CKD is a highly regulated active process. The complex interaction of calcification inducers and inhibitors are similar to those involved in osteogenesis, but distinct from those involved in passive mineral deposition. The potential impact of bisphosphonates on this process is summarised in Fig. 3.
Fig. 3 Bisphosphonates and the vasculature in the CKD setting.
As the GFR falls the AUC after an administered bisphosphonate dose increases and with that its effective
Bone turnover in renal disease and implications for vascular calcification
The aforementioned prolonged duration of bisphosphonates within the circulation in renal disease increases exposure of soft tissue to the effects of bisphosphonates. This includes the vasculature where there is the potential for direct action, as well as indirect via effects on bone turnover.
Modification of extraskeletal calcium deposition
The understanding that the pathophysiology of vascular calcification had much in common with bone formation in the skeleton raises the possibility that medications that targeted one of these processes, osteogenesis, could also impact upon the other, vascular calcification [66]. Bisphosphonates, with their ability to suppress osteoclast activity, and therefore bone turnover, would be a prime candidate for this. Experimentally, bisphosphonates have been shown to accumulate within the vasculature,
Clinical studies of the effect of bisphosphonates on vasculature
In 2004, Nitta conducted the first study on the use of etidronate in haemodialysis patients and its effects of cardiovascular calcification. It reported on 35 individuals who had CAC scoring prior to a 6 month run in period and upon initiation of treatment. Individuals were treated with etidronate, on a cyclical protocol of 200 mg per day for 2 weeks, repeated at 90 day intervals on three separate occasions. Changes in CAC were compared with a retrospective temporal control group derived from
Differences between first and subsequent generation bisphosphonates
As bisphosphonates have developed, their potency as antiresorptive agents has increased. The high dosages of etidronate required to achieve the desired antiresorptive effect impairs mineralisation significantly with a high risk of osteomalacia if dosing and/or duration thresholds are exceeded. Thus there is a narrow therapeutic window between achieving this and impairment of normal bone mineralisation, and the development of osteomalacia [78]. The early generation bisphosphonates undergo
Conclusions
Non-invasive determination of bone turnover in those with advanced renal disease is difficult. Both extremes of bone turnover have been associated with an increased cardiovascular risk. The similarity between osteogenesis and the vascular calcium deposition of renal disease has led to interest in medication that can affect both processes. Bisphosphonates, which modify rate of osteogenesis, have potential to reduce the ectopic calcification of renal disease, as well as physiological
CRediT authorship contribution statement
SH-writing of the original draft; JC-conceptualisation, review of draft.
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