A comprehensive search for RCTs was performed to evaluate the efficacy and safety profile of lanthanum in maintenance-dialysis patients. A total of 16 trials involving 3789 patients met our criteria and were enrolled in our meta-analysis. Our results show no lanthanum-induced decrease in all-cause mortality or cardiovascular events. Only one RCT  reported on vascular calcification and showed that lanthanum delayed the progression of aortic calcification compared with CC. Lanthanum efficiently lowered the serum phosphorus, Ca × P, and iPTH levels compared with placebos. Moreover, lanthanum showed equal efficiency in lowering serum phosphorus, Ca × P, and iPTH levels as calcium bicarbonate but with a lower serum calcium level. No statistical differences in 1,25-(OH)D3, 25-(OH)2D3 and TAP were observed between lanthanum and CC. However, lanthanum caused a statistically significant increase in the BAP level compared to previous phosphate binder. No differences were observed between SH and LC in controlling serum phosphorus, serum calcium, TAP, and BAP levels. However, SH reduced the total cholesterol and the LDL cholesterol levels. The efficacy of lanthanum on bone disorder was reported in only a few studies, and different parameters were used. Thus, our meta-analysis cannot draw reliable conclusions.
The two trials that observed all-cause mortality reported no difference in the risks of all-cause mortality between lanthanum and calcium bicarbonate  or standard therapy (without lanthanum) . Wilson et al.  performed a trial involving 1354 patients and conducted follow-up examinations for 40 months. The study contributed 98.9% of the weight in our all-cause mortality analysis because of its large sample size. The study found no significant difference between the overall mortality rates of the LC treatment [19.9% (135/680)] and standard therapy [23.3% (157/674)]. Subgroup analysis showed that the mortality for patients aged > 65 years was significantly lower in the LC treatment than in the standard therapy. This trend is highly similar to that of the Dialysis Clinical Outcomes Revisited (DCOR) study , which is the largest randomized comparator-controlled trial that assessed the mortality risks of non-calcium-based binders (sevelamer) and CC.
Vascular calcification is a common and severe problem associated with mortality in adult ESRD patients . LC was demonstrated to attenuate the progression of vascular calcification in several animal models [43, 44]. In the present analysis, only one trial  observed this outcome and reported that compared with CC, lanthanum carbonate was associated with the reduced progression of aortic calcification in 30 HD patients for over 18 months. Additional clinical studies involving large sample sizes and long-term follow-up must be conducted to determine whether lanthanum confers the advantage of inhibiting vascular calcification to dialysis patients. A prospective, large-scale observational study [Study of Hyperphosphatemia in CKD5D Patients Undergoing Hemodialysis (STOP-HD trial): UMIN-ID 000002002] is currently underway to confirm the inhibitory effect of LC on vascular calcification. The results of this study are being anticipated.
A small number of trials performed bone biopsy; however, the efficiency on bone disorder was difficult to evaluate. Two trials [20, 21] found improvements in renal osteodystrophy in lanthanum-treated patients compared with those treated with CC or with their previous phosphate binders (without lanthanum). However, another trial  showed no difference between the two binders. D’Haese et al.  found that the number of patients with renal osteodystrophy decreased in the lanthanum group, whereas that in the CC group increased. Malluche et al.  found an improvement in bone turnover during the first year as well as a significant improvement in bone volume during the second year. By contrast, Spasovski et al.  found no significant differences in the osteoblast number, bone formation rate, osteoid volume, or mineral apposition rate in the lanthanum and CC groups after a one-year treatment. None of these trials found association with aluminium-like bone toxicity after treatment of lanthanum. A standard and uniform evaluation system for bone disorder in CKD-MBD must be established to improve the assessment of the effects of LC on ROD.
Sevelamer is another calcium- and aluminum-free phosphate binder. A small number of studies directly compared this binder with LC. Only two cross-over studies were identified, and our meta-analysis showed that the two treatments were similarly effective in controlling serum calcium and phosphorus levels. However, compared with LC, SH can improve the lipid profile by reducing the total cholesterol and LDL levels. SH differs from other phosphate binders because of its unique ability to reduce the levels of serum cholesterol and proinflammatory factors. However, it also increases the risks of hyperchloremic metabolic acidosis and hyperkalemia. Sevelamer binds to bile acids probably because of its physiochemical similarities to common bile sequestrants. This characteristic allows sevelamer to interfere with fat absorption and reduce LDL cholesterol levels . In addition, sevelamer can physicochemically bind to the negatively charged lipid A portion of endotoxin (ET). In vitro experiments showed that SH can bind to ET in a dose-dependent manner . Moreover, an in vivo experiment demonstrated that sevelamer can reduce ET which was triggered by renal failure . Previous trials [48–50] showed that compared with calcium-containing phosphate binders, sevelamer reduces the levels ET and proinflammatory markers such as CRP, interlekin-6, endothelin-1, and plasminogen activator inhibitor-1 in dialysis patients. In patients with early diabetic CKD, sevelamer carbonate significantly reduces HbA1c, fibroblast growth factor 23, lipids, tumor necrosis factor-α, and oxidative stress compared with CC . However, the studies included in our systematic review did not compare the anti-inflammatory effects of LC and SH. Compelling preliminary data demonstrate that the ET-binding effect and anti-inflammatory activity of SH are associated with the improvement of mortality in ESRD compared with those of calcium-containing phosphate binders . Long-term clinical trials must be conducted to confirm the relationship between the amelioration of lipid metabolism and the improvement of patient survival. In particular, we recommend that additional studies be performed to determine if the lipid-lowering effect or anti-inflammatory activity of SH can improve the clinical outcome for CKD–MBD patients compared with LC.
The included studies did not compare the serum bicarbonate and potassium levels of the different groups. Moreover, the risks of acidosis and hyperkalemia of SH were unknown. Sevelamer carbonate is an improved, buffered form of SH that has equivalent efficacy in controlling phosphate levels but has a lower incidence of the above adverse effects . Future RCTs that compare LC and sevelamer carbonate is also recommended.
The safety of LC has received considerable concern. All of the studies included in this paper reported that the accumulation of LC in both blood and bone was below toxic levels. After six years of LC treatment, the incidences of fractures and bone-related musculoskeletal adverse events were also significantly low . In addition to that in bone, lanthanum accumulation in the liver should also be a point of concern because LC is excreted through bile. Although increased liver lanthanum deposition after oral lanthanum loading in uremic rats in comparison with normal renal function rats was observed [55, 56], a subsequent investigation showed that lanthanum was present in the lysosomes of hepatocytes and was mostly concentrated in the biliary poles of the hepatocytes and within the bile canaliculi . No lanthanum was detected in the hepatocyte mitochondria, nucleus, or cytoplasm. The six-year, long-term clinical observation also showed that liver enzymes did not increase, and that the few cases of liver- or biliary-related adverse events, none of which were considered to be related to lanthanum, were mainly observed in the first two years of treatment . However, one case study reported that lathanum induced abnormal liver function in one male patient with PD and in one female patient with HD . Our systematic review cannot provide sufficient evidence to show the safety of lanthanum in liver function. Therefore, future studies should also investigate the concentration and possible toxicity of lanthanum in the liver.
The most commonly reported side effects were gastrointestinal adverse events. Our meta-analysis showed no differences in nausea, constipation, and dyspepsia. The prevalence of vomiting was significantly higher in LC compared with that in CC. LC had lower risks of diarrhea and intradialytic hypotension compared with placebos and previous phosphate binders, respectively. Other side effects included dialysis complications, bronchitis, rhinitis, and pruritus while no significant differences were found between the treatments. One study showed that LC-treated patients had lower risks of intradialytic hypotension, diarrhea, cramps or myalgia, and abdominal pain compared with those treated with their previous phosphate binders.
Note that the effects of the dialysis type, dialysis dose, session duration, membrane type, and dialytic modality on phosphate removal were not assessed in the meta-analysis. Only four trials included patients with peritoneal dialysis. Therefore additional RCTs should be conducted to investigate the effects of lanthanum in peritoneal-dialysis patients.
To our knowledge, this study is the first to conduct a comprehensive systematic review of RCTs that assessed the advantages and disadvantages of using lanthanum treatment for CKD-MBD in dialysis patients. A previous  systematic review evaluated the effects of all phosphate binders on CKD-MBD in patients with CKD and also confirmed the efficacy of lanthanum in reducing the phosphorus levels (similar to that of CC) and lowering the incidence of hypercalcemia. However, the study did not evaluate the effects of lanthanum on mortality, vascular calcification, and bone disorder. Moreover, it did not provide the detailed side effects of lanthanum on bone, plasma, and liver contents nor include peritoneal-dialysis patients. Other published meta-analyses focused only on SH  or included both observational studies and RCTs .
Our systematic review has a number of limitations. Except for two trials with large sample sizes of 1359  and 767 , most of the trials enrolled a limited number of patients. The duration of half of these trials ranged from 4 weeks to 8 weeks. The key findings are limited by the lack of long-term studies on mortality, cardiovascular events, cardiovascular calcification, and bone disorder. Most of the included trials only observed the biochemical parameters without considering patient-focused outcomes. Moreover, this review did not evaluate the health economic effectiveness of LC. Although LC can reduce the serum phosphorus level and has a lower risk of vascular calcification and hypercalcemia, it is a rare metal that is more valuable than calcium. A number of studies focused on the cost-effectiveness ratio of phosphate binders [61, 62]. One study  showed that LC is cost-effective as a second-line treatment for patients who are not adequately maintained on CC (serum phosphorus above 5.6 mg/dL). Therefore, a systematic review that evaluates the health economic effectiveness of LC must be conducted to serve as a guideline for clinicians in providing individualized therapies for different patients, particularly for those in developing countries.