Introduction
Vascular calcification (VC), a common complication in haemodialysis (HD) patients, is associated with stiffening of the arterial wall and disruption of blood flow and significantly increases the risk of cardiovascular-related morbidity and mortality [
1‐
3]. Thus, improving or reversing vascular calcification is of great significance and extremely urgent. To date, numerous studies have been conducted to explore the mechanisms of vascular calcification in an attempt to identify effective therapeutic approaches. However, there is still a lack of an unequivocal intervention to consistently attenuate vascular calcification progression [
4].
Recent studies have proven that VC is a complicated active pathological process involving mineral metabolism disturbance, a reduction in mineralization inhibition factors, and secondary hyperparathyroidism (SHPT) [
5‐
7]. Sodium thiosulfate, bisphosphonates, and cinacalcet, which target the above mechanisms, are currently being used to mitigate vascular calcification in clinical practice. Studies have shown that sodium thiosulfate (STS) plays a role in maintaining the balance of bone mineral metabolism and might retard the progression of vascular calcification by chelating precipitated calcium to form soluble calcium thiosulfate [
8,
9]. Adirekkiat et al. evaluated the effect of STS on vascular calcification in 87 dialysis patients and observed a delay in VC progression [
10]. Coincidentally, bisphosphonates, a type of mineralized inhibitor, have also been indicated to prevent hydroxyapatite formation by inhibiting calcium-phosphate crystal construction and soft tissue growth [
11]. In patients undergoing dialysis, bisphosphonate administration for 12 months reduced coronary artery calcification progression but was associated with an increased risk of osteomalacia [
12,
13]. Additionally, cinacalcet, a new drug recently incorporated into clinical practice for vascular calcification treatment, is used to treat secondary hyperparathyroidism by decreasing serum parathyroid hormone levels, thereby delaying the progression of vascular calcification [
14]. The ADVANCE study, a multicentre trial conducted in dialysis patients, observed the effect of cinacalcet and reported a reduction in coronary artery calcification volume scores [
15]. However, the above studies were limited by their small sample sizes and short follow-up times, making the conclusions restricted and reducing the generalizability. Moreover, there are few studies comparing the above three drugs with each other; thus, it cannot be determined which intervention is the most promising for treating vascular calcification.
Therefore, the aim of this study was to identify an appropriate intervention for vascular calcification among these different treatments. Conventional pairwise meta-analysis fails to analyse the associated merits of different treatments if they have not been examined in head-to-head trials. Network meta-analysis (NMA) allows comparisons to be inferred and then estimates the best approach. Thus, we conducted a network meta-analysis to compare the efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet in terms of vascular calcification and provide a prospective strategy for the future.
Discussion
To the best of our knowledge, this network meta-analysis is the first to synthesize evidence for evaluating the impact of sodium thiosulfate, bisphosphonates and cinacalcet on vascular calcification. Notably, the results of network meta-analysis indicated that compared with conventional therapy, cinacalcet could significantly reduce vascular calcification in haemodialysis patients. In addition, the most striking result indicated that cinacalcet was superior to sodium thiosulfate and bisphosphonates in delaying the process of vascular calcification. Mechanistically, our findings illustrated that the maintenance of stable calcium and iPTH levels might be the main reason for the effect of cinacalcet on reducing vascular calcification. Overall, our outcomes demonstrated that cinacalcet is a promising choice of treatment for vascular calcification in patients with haemodialysis.
Cinacalcet is a calcimimetic compound that acts on the calcium sensing receptor (CaSR) and subsequently inhibits parathyroid hormone secretion [
35,
36]. Currently, cinacalcet is widely used to treat moderate and severe secondary hyperparathyroidism in dialysis patients. A prospective cohort study conducted in Japan with 47 patients demonstrated a reduction in abdominal aortic calcification over a 12-month period of cinacalcet treatment in the real world [
37]. Moreover, in in vitro experiments, Wu et al. illustrated significant aortic calcification attenuation in uraemic rats that were orally administered cinacalcet for 12 weeks [
38]. Consistently, our systematic review of large and comprehensive RCTs also revealed that cinacalcet delayed the process of vascular calcification relative to conventional therapy.
In addition, our analysis suggested that cinacalcet was better than sodium thiosulfate and bisphosphonates in retarding vascular calcification, which was confirmed by its high SUCRA values. Regarding sodium thiosulfate, Mathews et al. treated 22 HD patients with intravenous sodium thiosulfate for 5 months and reported no significant differences in the mean annualized changeable rates of the calcium volume in aorta, coronary, or vertebral bone density [
39]. Although it has been proposed that sodium thiosulfate can chelate calcium to form highly soluble calcium thiosulfate salt [
40], this process seems to be unreasonable because sodium thiosulfate cannot lower circulating calcium levels [
14]. To date, bisphosphonates have also been used to alleviate vascular calcification. Nevertheless, in the CKD stage 3–4 population, 18 months of bisphosphonate usage failed to lead to a difference in the progression of aortic vascular calcification [
41]. Furthermore, the safety of bisphosphonates regarding long-term use is unclear, and researchers are still concerned about the possible risk of exacerbated adynamic bone disease and osteomalacia [
42]. However, the bisphosphonate included in the present study is etidronate only, and these results may not be generalizable to other bisphosphonates. In summary, neither drug led to a reduction in vascular calcification. Consistent with the above studies, our findings demonstrated that neither sodium thiosulfate nor bisphosphonates significantly mitigated vascular calcification, while cinacalcet exhibited such an effect. Therefore, cinacalcet might be the best recommendation for dialysis patients with potentially progressive vascular calcification.
Cinacalcet mimics the action of calcium by allosterically activating CaSR on the chief cell of the parathyroid gland to directly suppress PTH secretion and indirectly reduce serum calcium levels [
43]. Joki et al. evaluated the role of calcimimetics in uraemic mice and emphasized that the activation of CaSR might contribute to slowing the progression of vascular calcification [
44]. In addition, Kawata et al. found that cinacalcet markedly lessened calcification-related changes by reducing serum parathyroid hormone and calcium levels in rats with a remnant kidney model of uraemia [
45]. Similarly, clinical treatment with cinacalcet lowered serum calcium and phosphate levels, thereby slowing the progression of cardiovascular calcification [
46]. In summary, cinacalcet is now successfully used in conjunction with phosphate binders and active vitamin D in the treatment of SHPT and vascular calcification in dialysis patients. However, the side effects associated with cinacalcet should also be brought up as high importance. The results of a meta-analysis suggested that cinacalcet significantly increased the risk of hypocalcaemia, nausea, and vomiting [
47], and Xu et al. found out that gastrointestinal events were noted at greater doses [
48]. These side effects may be correlated with the pharmacological action and therefore need to be closely monitored during the use of cinacalcet.
Recent studies have indicated that the cardiovascular benefits of cinacalcet are also worth noting. Cunningham et al. analysed the clinical data of four RCTs and demonstrated that cinacalcet decreased the risk of cardiovascular hospitalization [
49]. In addition, the post hoc analysis of the EVOLVE trial, which was conducted in 3883 dialysis patients with a 2-year follow-up, showed a lower incidence of calcific uraemic arteriolopathy [
50], a tendency towards a reduced fracture rate [
51], and a decreased risk of cardiovascular events in patients over the age of 65 years [
52]. Overall, the cardiovascular benefit demonstrated by cinacalcet might be associated with a reduction in vascular calcification.
The follow-up time in the studies included in the present meta-analysis is relatively short (ranging from 3 to 12 months). However, the hemodialysis patients we included already had vascular calcification at the baseline of the studies. In our analysis, our focus is on whether vascular calcification has progressed before and after these drugs treatment. And the follow-up time in all studies included in the present meta-analysis is similar. Hence, its influence on the results is limited. Another question worth considering is that the drug dosages and durations were not entirely consistent among the studies we included. However, the pairwise meta-analysis revealed no significant heterogeneity in the combination of the same drugs. And the sensitivity analyses showed that the results of network meta-analyses were stable. Therefore, we thought our network meta-analyses had certain clinical value to roughly compare the efficacy of these three drugs. Certainly, different doses of intervention and durations of treatment made some limitations for the results, and further direct RCT research is needed in the future to prove our results of NMA.
There are several potential limitations in this network meta-analysis. First, due to the lack of direct RCTs of treatment comparisons, consistency was unable to assess. However, after excluding studies may potentially lead to heterogeneity, the results of NMA did not materially change for the primary outcome, which hinted at the stability of our findings. For sure, further direct comparative trials for sodium thiosulfate, bisphosphonates, and cinacalcet are needed to verify our conclusion. Second, in the hemodialysis population, the disturbances of calcium and phosphorus metabolism induces systemic vascular calcification, and the progression of vascular calcification may vary among different sites. This variation may affect the evaluation of drug efficacy, leading to a certain bias in our analysis and further homogeneity research is needed to confirm our results. Third, our study was conducted with haemodialysis patients but did not assess the underlying ability of these drugs in the chronic kidney disease population with renal transplantation or peritoneal dialysis. Certainly, further large-scale and head-to-head studies should be conducted to confirm the generalizability of the present results.
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