Elsevier

Bone

Volume 142, January 2021, 115751
Bone

Full Length Article
Is there a role for bisphosphonates in vascular calcification in chronic kidney disease?

https://doi.org/10.1016/j.bone.2020.115751Get rights and content

Highlights

  • The decreased bone buffering capacity of the kidney in advanced renal disease may lead to medial vascular calcification

  • Bisphosphonates reduce bone turnover, and with this, reduce calcium flux

  • The reduction in vascular calcification shown by etidronate has not been replicated by later generation bisphosphonates

Abstract

Theoretically bisphosphonates could accelerate or retard vascular calcification. In subjects with low GFR, the position is further confounded by a combination of uncertain pharmacokinetics (GI absorption is poor and inconsistent at all levels of renal function and the effect of low GFR generally is to increase bioavailability) and a highly variable skeletal substrate with extremes of turnover that increase unpredictably further. Although bisphosphonates reduce bone formation by 70–90% in subjects with normal GFR and reduce the ability of bone to buffer exogenous calcium fluxes, in bisphosphonate treated postmenopausal women accelerated vascular calcification has not been documented. The kidneys assist with this buffering, but the capacity to modulate calcium excretion declines as GFR falls, increasing the risk of hypercalcaemia in the event of high calcium influx. In the ESRD patient, decreased buffering capacity substantially increases the risk of transient hypercalcaemia, especially in the setting of dialysis, and as such may promote vascular calcification which is highly prevalent in the CKD population. Low bone turnover may thus be less of a vascular problem in patients with preserved renal function and a bigger problem when the GFR is low. In patients with stage 4 and 5 CKD, adynamic bone disease associates with the severity and progression of arterial calcification, including coronary artery calcification, and further suppression of bone turnover by a bisphosphonate might exacerbate an already high predisposition to vascular calcification. No convincing signal of harm has emerged from clinical studies thus far. For example 51 individuals with CKD stage 3–4 treated with either alendronate 70 mg per week or placebo for 18 months showed no difference in the rate of vascular calcifications. Conversely an observational study of women with stage 3–4 CKD with pre-existing cardiovascular disease found an increased risk of mortality with a hazard ratio of 1.22 (1.04–1.42) in those given bisphosphonates. Direct suppression of vascular calcification by bisphosphonates is probably confined to etidronatetreatment of soft tissue calcification was a recognized indication for this drug and etidronate markedly reduced progression of vascular calcification in CKD patients. Bisphosphonates are analogues of pyrophosphate, a potent calcification inhibitor in bone and soft tissue. Thus the efficacy of etidronate as treatment for soft tissue calcification brought with it a problematic tendency to cause osteomalacia. In contrast, conventional doses of nitrogen-containing bisphosphonates fail to yield circulating concentrations sufficient to exert direct anti-calcifying effects, at least in patients with good renal function and studies using alendronate and ibandronate have yielded inconsistent vascular outcomes.

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.

References (83)

  • H. Yang et al.

    Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro

    Kidney Int.

    (2004)
  • S. Yamada

    PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet

    Kidney Int.

    (2018)
  • J.J. Westendorf et al.

    Wnt signaling in osteoblasts and bone diseases

    Gene

    (2004)
  • K.A. Hruska et al.

    The chronic kidney disease - mineral bone disorder (CKD-MBD): advances in pathophysiology

    Bone

    (2017)
  • A.R. Qureshi

    Increased circulating sclerostin levels in end-stage renal disease predict biopsy-verified vascular medial calcification and coronary artery calcification

    Kidney Int.

    (2015)
  • B. Jobke et al.

    Bisphosphonate-osteoclasts: changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients

    Bone

    (2014)
  • M.T. Drake et al.

    Bisphosphonates: mechanism of action and role in clinical practice

    Mayo Clin. Proc.

    (2008)
  • T. Bellido et al.

    Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability

    Bone

    (2011)
  • R.G. Russell

    Bisphosphonates: the first 40 years

    Bone

    (2011)
  • P.D. Miller

    The kidney and bisphosphonates

    Bone

    (2011)
  • R. Ylitalo

    Bisphosphonates and atherosclerosis

    Gen. Pharmacol.

    (2000)
  • S. Gonnelli

    Effects of intravenous zoledronate and ibandronate on carotid intima-media thickness, lipids and FGF-23 in postmenopausal osteoporotic women

    Bone

    (2014)
  • K. Tamura

    Effect of etidronate on aortic calcification and bone metabolism in calcitriol-treated rats with subtotal nephrectomy

    J. Pharmacol. Sci.

    (2005)
  • K. Tamura

    Prevention of aortic calcification by etidronate in the renal failure rat model

    Eur. J. Pharmacol.

    (2007)
  • K. Nitta

    Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis

    Am. J. Kidney Dis.

    (2004)
  • N.D. Toussaint et al.

    Effect of alendronate on vascular calcification in CKD stages 3 and 4: a pilot randomized controlled trial

    Am. J. Kidney Dis.

    (2010)
  • J.E. Hartle

    Bisphosphonate therapy, death, and cardiovascular events among female patients with CKD: a retrospective cohort study

    Am. J. Kidney Dis.

    (2012)
  • C.A. Bassett

    Diphosphonates in the treatment of myositis ossificans

    Lancet

    (1969)
  • G.H. Nancollas

    Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite

    Bone

    (2006)
  • A.S. Go et al.

    Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization

    N. Engl. J. Med.

    (2004)
  • S.M. Moe et al.

    Pathophysiology of vascular calcification in chronic kidney disease

    Circ. Res.

    (2004)
  • M. Cozzolino et al., Cardiovascular disease in dialysis patients. Nephrol Dial Transplant 33, iii28-iii34...
  • W.G. Goodman

    Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis

    N. Engl. J. Med.

    (2000)
  • M. Cano-Megias

    Coronary calcification as a predictor of cardiovascular mortality in advanced chronic kidney disease: a prospective long-term follow-up study

    BMC Nephrol.

    (2019)
  • N.D. Toussaint et al.

    Vascular calcification and arterial stiffness in chronic kidney disease: implications and management

    Nephrology (Carlton)

    (2007)
  • M. Rattazzi

    Aortic valve calcification in chronic kidney disease

    Nephrol. Dial. Transplant.

    (2013)
  • M.C. Lamarche et al.

    Relationship of coronary artery calcification with renal function decline and mortality in predialysis chronic kidney disease patients

    Nephrol. Dial. Transplant.

    (2019)
  • K. Vipattawat

    Vascular calcification in long-term kidney transplantation

    Nephrology (Carlton)

    (2014)
  • G. Cianciolo

    Importance of vascular calcification in kidney transplant recipients

    Am. J. Nephrol.

    (2014)
  • N.D. Toussaint et al.

    Associations between vascular calcification, arterial stiffness and bone mineral density in chronic kidney disease

    Nephrol. Dial. Transplant.

    (2008)
  • I. Pavik

    Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study

    Nephrol. Dial. Transplant.

    (2013)
  • Cited by (9)

    View all citing articles on Scopus
    View full text