The impact of cinacalcet on the serum phosphorus, calcium and PTH levels in dialysis patients; a systematic review and meta-analysis

: Our meta-analysis was conducted on 1131 people and showed that administration of cinacalcet can lower serum calcium, phosphorus, Ca×P products, and PTH in dialysis patients. Hence, one can infer the effectiveness of cinacalcet in treating hypercalcemia and hyperparathyroidism in these patients. Considering the findings of the present meta-analysis, cinacalcet administration at a daily dose of 30-60 mg for two years seems beneficial for dialysis patients with hypercalcemia. However, further research is required to confirm its efficacy for hemodialysis patients.


Introduction
Cinacalcet is a positive allosteric modulator of the calciumsensing receptor (CaSR), which enhances the CaSR sensitivity in parathyroid glands, thereby diminishing the release of parathyroid hormone (PTH) and calcium serum level (1).This drug is frequently administered in dialysis patients to treat hyperparathyroidism-induced hypercalcemia and is consistently found to lower the risk of persistent hyperparathyroidism in hemodialysis patients (2).Cinacalcet use for 52 weeks is reported elsewhere to control the patients' hypercalcemia (3).
The cinacalcet prescription is approved for primary and secondary hyperparathyroidism (4).In 2014, cinacalcet received approval in Japan to treat hypercalcemia in cases of parathyroid carcinoma and patients with primary hyperparathyroidism (PHPT) who have a contraindication for parathyroidectomy or have experienced postoperative PHPT recurrence (5).The treatment in patients with PHPT is intended to normalize the serum calcium and PTH levels while ameliorating the clinical manifestations (6,7).Secondary hyperparathyroidism occurs due to reduced kidney function in chronic kidney disease and is characterized by elevated serum PTH levels (8).It is present at varying degrees during the dialysis treatment and may manifest as hypercalcemia in the post-kidney transplant period (9).The overproduction of PTH contributes to a systemic disorder characterized by high bone turnover and vascular calcification and elevates the risk of bone fractures and cardiovascular mortality (10,11).Controlling their serum levels of calcium, phosphorus, and PTH is of critical significance concerning the morbidity and risks of hypercalcemia and hyperparathyroidism in patients undergoing dialysis and hemodialysis.Given the inconsistencies in the previous studies regarding the effectiveness of cinacalcet use for dialysis and hemodialysis patients (2,(12)(13)(14).

Objectives
This study aims to evaluate the impact of cinacalcet on calcium, phosphorus, and PTH serum levels in these patients using a systematic review and meta-analysis approach.

Study design
The current study comprised a systematic review and meta-analysis carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.The study protocol was registered on the PROSPERO website (ID: CRD42023428774).
An advanced search was executed by combining the keywords using Boolean operators (OR, AND).Moreover, the reference lists of the identified articles and the Google Scholar search engine were searched to retrieve additional articles.

Inclusion criteria
Cohort studies and clinical trials evaluating the efficacy of cinacalcet on serum levels of calcium, phosphorus, or PTH in dialysis patients entered the study.

Exclusion criteria
The following studies were excluded; duplicate studies, studies whose full texts were unavailable, case reports, descriptive studies, studies lacking the necessary information for data analysis, letters to editors, studies assessing the effect of the combination of cinacalcet with another drug, low-quality articles, studies reporting the results using odds ratio (OR) or relative risk (RR) indices, and studies that only reported the mean serum levels of the outcomes without providing their standard deviations.

Qualitative assessment
Two independent authors assessed the quality of the retrieved articles according to the type of the studies.The quality of cohort studies was evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist (15).This checklist contains 22 items, yielding a total score ranging from 0 to 44.A cut-off score of 16 for the STROBE checklist was considered in this study.Likewise, the Cochrane Institute checklist was utilized for the quality assessment of clinical trials (16).The Cochrane checklist consists of seven items, each assessing a major dimension or type of bias in clinical trials.Each item consists of three choices: "Low risk, " "High risk, " and "Unclear risk." Finally, the interresearcher inconsistencies regarding the quality of a study were resolved by consensus between the two authors on a single choice.

Data extraction
Two researchers extracted the required data to minimize data collection bias and error.The authors designed a checklist for data collection containing the name of the leading author, publication year, country, age of patients, sample size, the number of males and females, study type, disease type, cinacalcet dose, duration of cinacalcet use, and the mean levels of outcomes pre-and postintervention.

Statistical analysis
Given the quantitative nature of the outcomes, the effect size for intervention was measured.The standardized mean difference (SMD) index indicates the strength of the association between the intervention of interest and the studied outcome.The studies examined were pooled using sample sizes, means, and standard deviations.The I 2 index was employed to measure the heterogeneity of the studies.Considering the high heterogeneity among the studies, a random effect model was applied.Data analysis was conducted using STATA 14 software at a significance level of P < 0.05 for all tests.

Results
A total of 1430 articles were retrieved during the search process.After checking the titles, 774 duplicates were eliminated.The abstracts of the remaining 656 articles were screened, and 175 irrelevant articles were omitted.
Of the remaining 481 articles, the full texts of twelve were unavailable, and another 457 were discarded due to meeting other exclusion criteria.Eventually, twelve high-quality articles entered the meta-analysis process (Figure 1).Three of the twelve reviewed studies were conducted in the US, three in Spain, and one each in Brazil, Japan, Russia, Italy, Portugal, and the Netherlands.Among them, seven were cohort studies, and five were randomized controlled trials (RCTs) (Table 1).The serum calcium level showed a significant reduction in patients on dialysis after cinacalcet treatment [SMD: -1.32 (95% CI: -2.64, -0.01)] (Figure 2).
In sub-group analysis, the effectiveness of cinacalcet in lowering the serum calcium level in dialysis patients was verified at a daily dose of 30 to 60 mg [SMD: -0.83 (95% CI: -1.25, -0.42)].In addition, the patients who were administered cinacalcet for a duration of 24 months had a significantly reduced calcium level [SMD: -1.26 (95% CI: -1.66, -0.87)].In an analysis by disease type, cinacalcet use in dialysis patients noticeably affected their calcium levels [SMD: -0.83 (95% CI: -1.19, -0.47)].However, this was not the case in hemodialysis patients.Significant changes were not reported in other subgroups analyzed (Table 2).
As presented in Figure 7, the publication bias plot     Yarahmadi M et al was statistically non-significant, and no bias occurred during the literature search (P =0.954).Consequently, the literature search process was carried out thoroughly and successfully.

Discussion
Overall, the study results suggest that cinacalcet use causes a reduction in serum calcium, phosphorus, Ca×P product, and PTH levels in dialysis patients.A sub-group analysis also confirmed the cinacalcet efficacy in lowering the calcium levels of patients at a dose of 30-60 mg/day and a duration of 24 months.Chandran et al conducted a meta-analysis of RCTs, including 940 patients with PHPT.They found that cinacalcet administration for up to 28 weeks decreases serum calcium levels compared to placebo [RR: 20 (95% CI: 6.04-68.52)].Additionally, serum PTH levels declined following two weeks and up to 28 weeks of cinacalcet treatment.Similarly, the cohort studies revealed the normalization of the serum calcium levels in 76% of patients regardless of treatment length (25).In a meta-analysis by Greeviroj et al with 10031 dialysis patients, cinacalcet treatment reduced serum calcium, phosphate, and PTH levels.However, the osteogenesis biomarkers (bone alkaline phosphatase and osteocalcin) remained unchanged (26).The results of the above studies corroborate those of the present meta-analysis.
According to a meta-analysis by Ng et al involving 28   Consistent with the meta-analysis by Ng et al, the present meta-analysis also reported reduced levels of calcium and PTH.However, the phosphate levels showed a reduction which contradicted their findings.The observed inconsistency can be due to the difference in type and sample size of studied patients, the dose, and the duration of cinacalcet use.
Wang et al presented a meta-analysis of 8481 chronic kidney disease patients and concluded that when compared to the control group, cinacalcet administration reduced the incidence of parathyroidectomy (RR: 0.48, 95% CI: 0.40, 0.50) while elevating the hypocalcemia risk (RR: 8.48, 95% CI: 6.37, 11.29) (28).Another meta-analysis by Garside et al, including 846 patients on dialysis, evaluated the effect of cinacalcet in treating secondary hyperparathyroidism.The results indicated the higher effectiveness of cinacalcet in achieving the PTH target level (40% versus 5% in the placebo group; P < 0.001).Moreover, the cinacalcet group experienced a 90% drop in Ca×P product compared to the 1% reduction in the placebo group (29).In a meta-analysis by Palmer et al on dialysis patients, cinacalcet had a minor effect on all-cause mortality (0.97 [95% CI: 0.89, 1.05]) and prevented the incidence of parathyroidectomy (0.49 [95% CI: 0.40-0.59])and hypercalcemia (0.23 [95% CI: 0.05-0.97])(30).The findings of these three studies agree with those of the present meta-analysis and thus can verify the efficacy of cinacalcet in dialysis patients.

Conclusion
Cinacalcet administration can lower serum calcium, phosphorus, Ca×P product, and PTH in dialysis patients.Hence, one can infer the effectiveness of cinacalcet in treating hypercalcemia and hyperparathyroidism in these patients.Considering the findings of the present metaanalysis, cinacalcet administration at a daily dose of 30-60 mg for two years seems beneficial for dialysis patients with hypercalcemia.However, further research is required to confirm its efficacy for patients undergoing hemodialysis.Given the limitation of the reviewed studies, future researchers are encouraged to conduct further research on this topic to evaluate the relationship between age and gender with cinacalcet use, thereby overcoming the restrictions of this study.

Limitations
This meta-analysis faces some limitations.1) The lack of reporting of hyperparathyroidism type in some reviewed studies hindered further sub-group analysis of the cinacalcet impact on primary and secondary hyperparathyroidism. 2) Due to the limited number of articles and the similarity of the age range in reviewed studies, we could neither classify the studies based on the age range of patients nor assess the association between age variable and cinacalcet effectiveness in patients. 3) The reviewed articles did not address the gender-specific impact of cinacalcet use on variables such as calcium, phosphorus, and PTH among men and women and only reported the overall results.For this reason, the association between gender and cinacalcet efficacy in patients remains unknown, resulting in considerable heterogeneity among the studies.
Yarahmadi M et al checklist, and its protocol was registered on the PROSPERO (International Prospective Register of Systematic Reviews) website with (ID: CRD42023428774).Besides, ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the author.
Funding/Support None.

Figure 1 .
Figure 1.The process of entering the studies into the systematic review and meta-analysis.

Figure 2 .
Figure 2. Forest plot showing calcium level changes after the administration of cinacalcet.

Figure 3 .
Figure 3. Forest plot showing parathyroid hormone level changes after the administration of cinacalcet.

Figure 4 .
Figure 4. Forest plot showing phosphorus level changes after the administration of cinacalcet.

Figure 5 .
Figure 5. Forest plot showing Ca×P product changes after the administration of cinacalcet.

Figure 6 .
Figure 6.Forest plot showing alkaline phosphatase level changes after the administration of cinacalcet.

Table 1 .
Summary of article information

Table 2 .
The effect of cinacalcet on serum calcium level, based on different subgroups