Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Pharmaceutical Management of Secondary Hyperparathyroidism and the Role of Surgery: A 5-Year Retrospective Study.

Background and Objectives: Secondary hyperparathyroidism (SHPT) poses a common condition among patients with chronic kidney disease (CKD) due to the chronic stimulation of the parathyroid glands as a result of persistently low calcium levels. As a first option for medical treatment, vitamin D receptor analogs (VDRAs) and calcimimetic agents are generally used. Apart from cinacalcet, which is orally taken, in recent years, another calcimimetic agent, etelcalcetide, is being administered intravenously during dialysis. Materials and Methods: In a 5-year retrospective study between 2018 and 2023, 52 patients undergoing dialysis were studied. The aim of this study is to highlight the possible effects and/or benefits that intravenously administered calcimimetic agents have on CKD patients. A total of 34 patients (65.4%) received cinacalcet and etelcalcetide while parathormone (PTH) and calcium serum levels were monitored on a monthly basis. Results: A total of 29 out of 33 patients (87.9%) that received treatment with etelcalcetide showed a significant decrease in PTH levels, which rose up to 57% compared to the initial values. None of the included patients needed to undergo parathyroidectomy (PTx) due to either extremely high and persistent PTH levels or severe side effects of the medications. It is generally strongly advised that parathyroidectomies should be performed by an expert surgical team. In recent years, a significant decrease in parathyroidectomies has been recorded globally, a fact that is mainly linked to the constantly wider use of new calcimimetic agents. This decrease in parathyroidectomies has resulted in an important decrease in complications occurring in cervical surgeries (e.g., perioperative hemorrhage and nerve damage). Conslusions: Despite the fact that these surgical complications cannot be easily compared to the pharmaceutical side effects, the recorded decrease in parathyroidectomies is considered to be notable, especially in cases of relapse where a difficult reoperation would be considered based on previously published guidelines.

Multiscale effects of the calcimimetic drug, etelcalcetide on bone health of rats with secondary hyperparathyroidism induced by chronic kidney disease.

Chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT) heightens fracture risk through impaired mineral homeostasis and elevated levels of uremic toxins (UTs), which in turn enhance bone remodeling. Etelcalcetide (Etel), a calcium-sensing receptor (CaSR) agonist, suppresses parathyroid hormone (PTH) in hyperparathyroidism to reduce excessive bone resorption, leading to increased bone mass. However, Etel's effect on bone quality, chemical composition, and strength is not well understood. To address these gaps, we established a CKD-SHPT rat model and administered Etel at a human-equivalent dose concurrently with disease induction. The effects on bone and mineral homeostasis were compared with a CKD-SHPT (vehicle-treated group) and a control group (rats without SHPT). Compared with vehicle-treated CKD-SHPT rats, Etel treatment improved renal function, reduced circulating UT levels, improved mineral homeostasis parameters, decreased PTH levels, and prevented mineralization defects. The upregulation of mineralization-promoting genes by Etel in CKD-SHPT rats might explain its ability to prevent mineralization defects. Etel preserved both trabecular and cortical bones with attendant suppression of osteoclast function, besides increasing mineralization. Etel maintained the number of viable osteocytes to the control level, which could also contribute to its beneficial effects on bone. CKD-SHPT rats displayed increased carbonate substitution of matrix and mineral, decreased crystallinity, mineral-to-matrix ratio, and collagen maturity, and these changes were mitigated by Etel. Further, Etel treatment prevented CKD-SHPT-induced deterioration in bone strength and mechanical behavior. Based on these findings, we conclude that in CKD-SHPT rats, Etel has multiscale beneficial effects on bone that involve remodeling suppression, mineralization gene upregulation, and preservation of osteocytes.

Roles of Parathyroid Hormone and Fibroblast Growth Factor 23 in Advanced Chronic Kidney Disease.

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.

Skeletal parathyroid hormone hyporesponsiveness: a neglected, but clinically relevant reality in chronic kidney disease.

PURPOSE OF REVIEW: Defining the optimal parathyroid hormone (PTH) target in chronic kidney disease (CKD) is challenging, especially for bone outcomes, due to the substantial variability in the skeleton's response to PTH. Although PTH hyporesponsiveness is as integral a component of CKD-mineral bone disorder as elevated PTH levels, clinical awareness of this condition is limited. In this review, we will discuss factors and mechanisms contributing to PTH hyporesponsiveness in CKD. This knowledge may provide clues towards a personalized approach to treating secondary hyperparathyroidism in CKD. RECENT FINDINGS: Indicates a link between disturbed phosphate metabolism and impaired skeletal calcium sensing receptor signaling as an important mediator of PTH hyporesponsiveness in CKD. Further, cohort studies with diverse populations point towards differences in mineral metabolism control, rather than genetic or environmental factors, as drivers of the variability of PTH responsiveness. IN SUMMARY: Skeletal PTH hyporesponsiveness in CKD has a multifactorial origin, shows important interindividual variability, and is challenging to estimate in clinical practice. The variability in skeletal responsiveness compromises PTH as a biomarker of bone turnover, especially when considering populations that are heterogeneous in ethnicity, demography, kidney function, primary kidney disease and mineral metabolism control, and in patients treated with bone targeting drugs.

The Effects of Parathyroidectomy vs Medical Treatments for Secondary Hyperparathyroidism in Patients Undergoing Dialysis: A Meta-Analysis.

OBJECTIVE: The management of secondary hyperparathyroidism in patients undergoing dialysis is debated, with uncontrolled parathyroid hormone (PTH) levels becoming more common despite the expanded use of medical treatments like cinacalcet. This study examines the clinical benefits of parathyroidectomy vs medical treatment in reducing mortality and managing key laboratory parameters in patients undergoing dialysis. METHODS: PubMed, Embase, Cochrane, Scopus, and Web of Science databases were searched for cohort studies or randomized controlled trials published before August 18, 2023. We included studies with comparative arms, specifically medical treatment vs surgical intervention. Patients with a history of kidney transplant were excluded. Outcomes were analyzed using hazard ratios (HRs) for mortality and weighted mean differences (WMD) for laboratory parameters. RESULTS: Twenty-three studies involving 24 398 patients were analyzed. The pooled meta-analysis has shown a significant reduction in all-cause (HR, 0.47; 95% confidence interval [CI], 0.35-0.61) and cardiovascular mortality (HR, 0.58; 95% CI, 0.40-0.84) for parathyroidectomy vs medical treatments. Subgroup analysis showed that parathyroidectomy was associated with a greater reduction in mortality in patients with a PTH level over 585 pg/mL (HR, 0.37; 95% CI, 0.24-0.58). No mortality difference was found when all patients in the medical group received cinacalcet alongside standard medical treatment (HR, 1.02; 95% CI, 0.49-2.11). Parathyroidectomy also led to a larger decrease in PTH (WMD, 1078 pg/mL; 95% CI, 587-1569), calcium (WMD, 0.86 mg/dL; 95% CI, 0.43-1.28), and phosphate (WMD, 0.74 mg/dL; 95% CI, 0.32-1.16). CONCLUSION: Parathyroidectomy may offer a survival advantage compared to medical management in patients with severe secondary hyperparathyroidism.

Capsiate ameliorates secondary hyperparathyroidism by improving insulin sensitivity and inhibiting angiogenesis.

Secondary hyperparathyroidism has a significant impact on the overall well-being of the body. Capsiates, known for their antioxidant and metabolic properties, have emerged as a promising alternative treatment for secondary hyperparathyroidism. This study aims to evaluate the effects and mechanisms of capsiates in the treatment of secondary hyperparathyroidism. To achieve our research objectives, we conducted a study on patients' serum and examined changes in metabolic markers using serum metabolomics. We induced secondary hyperparathyroidism in rat through dietary intervention and divided them into four groups. The first group, referred to as the Parathyroid Hormone (PTH) group, received a low-calcium and high-phosphate diet (0.2% calcium, 1.2% phosphorus). The second group served as the control group, receiving a standard phosphate and calcium diet (0.6% calcium, 0.6% phosphorus). The third group, called the capsiates group, consisted of rat from the control group treated with capsiates (intraperitoneal injection of 2 mg/kg capsiates for 2 weeks after 2 weeks of dietary intervention). The fourth group was the capsiates-treated PTH group. Subsequently, we conducted ribose nucleic acid (RNA) sequencing on parathyroid gland cells and evaluated serum thyroxine levels, oxidative stress, expression of proteins associated with vascular neogenesis, measurement of SOD, GSH and 3-nitrotyrosine, micro-CT and histological staining. The serum metabolomic data revealed a significant decrease in capsiate levels in the secondary hyperparathyroidism group. Administration of capsiates to PTH rat resulted in increased calcium levels compared to the PTH group. Additionally, the PTH + Capsiates group showed significantly lower levels of PTH and phosphate compared to the PTH group. The PTH group exhibited a notable increase in the quantity and size of mitochondria compared to the control group. Following capsiates administration to the PTH group, there was a significant reduction in the number of mitochondria and length of microvilli, but an increase in the size of mitochondria compared to the PTH group. Sequencing analysis revealed that vascular endothelial growth factor (VEGF) and Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) play crucial roles in this process. Vascular-related variables and downstream signalling were significantly elevated in hyperthyroidism and were alleviated with capsaicin treatment. Finally, combining capsiates with the PTH group improved bone mineral density, Tb.N, BV.TV, Cs.Th, Tt.Ar, OPG, Ob.TV and Oc.TV, as well as the mineral apposition rate, but significantly decreased Tb.Sp and Receptor Activator for Nuclear Factor-κ B Ligand (RANKL) compared to the PTH group. The findings suggest that capsiates can improve secondary hyperparathyroidism and ameliorated osteoporosis outcomes by inhibiting angiogenesis and reducing oxidative stress.

Effectiveness of calcimimetics on fractures in dialysis patients with secondary hyperparathyroidism: meta-analysis of randomized trials.

INTRODUCTION: This study aimed to assess the effectiveness of calcimimetics in reducing the risk of fractures in dialysis patients with secondary hyperparathyroidism (SHPT). MATERIAL AND METHODS: A comprehensive literature search was conducted using PubMed, Embase, and Cochrane Library for articles published through December 9, 2023. The quality of each trial was evaluated using the Cochrane Collaboration tool. Meta-analysis was performed using a random-effects model, and effect measures across studies were synthesized. The risk ratio (RR) and 95% confidence interval (CI) were used to quantify the risk of fracture. RESULTS: We identified seven studies involving 6481 dialysis patients with SHPT. The administration of calcimimetics reduced fracture incidence compared to placebo or conventional treatment (RR: 0.50, 95% CI 0.29-0.88, p = 0.02). Calcimimetics demonstrated a low number needed to treat (NNT) to prevent an incident fracture (NNT: 47). CONCLUSION: The use of calcimimetics offers a significant benefit in reducing the risk of fractures in patients undergoing dialysis with SHPT.

Calcimimetics treatment strategy for serum calcium and phosphate management in patients with secondary hyperparathyroidism undergoing dialysis: A systematic review and meta-analysis of randomized studies.

INTRODUCTION: Several calcimimetics, other than cinacalcet, are commercially available; however, their effects on calcium and phosphate levels have not yet been fully studied. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the impact of calcimimetics on the management of serum calcium and phosphate levels in patients with secondary hyperparathyroidism undergoing dialysis. METHODS: A systematic literature search through October 2023 and a meta-analysis were conducted on the effects of upacicalcet, etelcalcetide, evocalcet, and cinacalcet on serum calcium and phosphate levels in patients with secondary hyperparathyroidism undergoing dialysis; we searched PubMed, Ovid MEDLINE, and the Cochrane Central Register of Controlled Trials, and 21 studies comprising 6371 patients undergoing dialysis were included. RESULTS: Participants treated with calcimimetics had lower serum calcium and phosphate levels than placebo. CONCLUSION: Calcimimetics significantly reduced serum calcium and phosphate levels compared to placebo in patients with secondary hyperparathyroidism undergoing dialysis, independent of therapeutic strategy or concomitant vitamin D treatment.

Denosumab Decreases Epicardial Adipose Tissue Attenuation in Dialysis Patients with Secondary Hyperparathyroidism and Low Bone Mass.

INTRODUCTION: Denosumab preceding elective surgery is an alternative option when parathyroidectomy is not immediately possible. Denosumab (an osteoprotegerin mimic) may play a role in the cardiovascular system, which is reflected in the features of epicardial adipose tissue (EAT) and coronary artery calcification (CAC). METHODS: We investigated the effects of denosumab on EAT attenuation (EATat) and CAC in dialysis patients with secondary hyperparathyroidism (SHPT). This cohort study included patients on dialysis with SHPT. The baseline characteristics of dialysis patients and propensity score-matched non-dialysis patients were compared. Computed tomography scans of the dialysis patients (dialysis group with denosumab, n = 24; dialysis group without denosumab, n = 21) were obtained at baseline and at 6 months of follow-up. RESULTS: At baseline, the dialysis group patients had a higher EATat-median (-71.00 H ± 10.38 vs. -81.60 H ± 6.03; p < 0.001) and CAC (1,223 A [248.50-3,315] vs. 7 A [0-182.5]; p < 0.001) than the non-dialysis group. At follow-up, the dialysis group without denosumab showed an increase in Agatston score (1,319.50 A [238.00-2,587.50] to 1,552.00 A [335.50-2,952.50]; p = 0.001) without changes in EATat-median (-71.33 H ± 11.72 to -70.86 H ± 12.67; p = 0.15). The dialysis group with denosumab showed no change in Agatston score (1,132.2 A [252.25-3,260.5] to 1,199.50 A [324.25-2,995]; p = 0.19) but a significant decrease of EATat-median (-70.71 H ± 9.30 to -74.33 H ± 10.28; p = 0.01). CONCLUSIONS: Denosumab may reverse EATat and retard CAC progression in dialysis patients with SHPT.

Cost-Effectiveness and Clinical Outcomes of Secondary Hyperparathyroidism Treatments in Patients with Chronic Kidney Disease.

The study addresses the challenge of treating secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, focusing on the cost-effectiveness of surgical versus pharmacological interventions. Conducting a retrospective analysis on 152 CKD patients with SHPT at the Third People's Hospital of Chengdu, the study matched 80 patients into two groups: 40 undergoing parathyroidectomy with autotransplantation (PTX + AT) and 40 treated with calcimimetics. PTX + AT was more effective in alleviating symptoms, particularly bodily pain, and demonstrated greater cost-effectiveness over a long-term period compared to calcimimetics. This was especially significant in patients with PTH levels > 1800 pg/mL and hyperphosphatemia. Despite similar initial costs, PTX + AT led to a substantial decrease in expenses during the 2-5 years post-treatment period, PTX + AT results in an ICER of -RMB 26.71/QALY for the first post-treatment year and -RMB-111.9k/QALY for the 2-5 year period, indicating cost-effectiveness with reduced long-term costs. The study also found an increased economic burden in managing patients with hyperphosphatemia. Surgical intervention (PTX + AT) is advocated as the primary treatment strategy for severe SHPT in CKD patients, owing to its long-term economic and clinical advantages. The results underscore the need for a severity-based approach in treating SHPT.

Multicentre, open-label, randomised, controlled trial to compare early intervention with calcimimetics and conventional therapy in preventing coronary artery calcification in patients with secondary hyperparathyroidism (UPCOMING): a study protocol.

INTRODUCTION: Coronary artery and heart valve calcification is a risk factor for cardiovascular death in haemodialysis patients, so calcification prevention should be started as early as possible. Treatment with concomitant calcimimetics and low-dose vitamin D receptor activators (VDRAs) is available, but not enough evidence has been obtained on the efficacy of this regimen, particularly in patients with short dialysis duration. Therefore, this study will evaluate the efficacy and safety of early intervention with upacicalcet, a calcimimetic used to prevent coronary artery calcification in this patient population. METHODS AND ANALYSIS: This multicentre, open-label, randomised, parallel-group controlled study will compare an early intervention group, which received upacicalcet and a low-dose VDRA, with a conventional therapy group, which received a VDRA. The primary endpoint is a change in log coronary artery calcium volume score from baseline to 52 weeks. The main inclusion criteria are as follows: (1) age 18 years or older; (2) dialysis is planned or dialysis duration is less than 60 months; (3) intact parathyroid hormone (PTH) >240 pg/mL or whole PTH level>140 pg/mL; (4) serum-corrected calcium≥8.4 mg/dL and (5) Agatston score >30. The main exclusion criteria are as follows: (1) history of parathyroid intervention or fracture in the past 12 weeks; (2) history of myocardial infarction, stroke or leg amputation in the past 12 weeks; (3) history of coronary angioplasty and (4) heart failure of New York Heart Association class III or worse. ETHICS AND DISSEMINATION: The study will comply with the Declaration of Helsinki and the Japanese Clinical Trials Act. The study protocol has been approved by the Fujita Health University Certified Review Board (file no. CR22-052). Written informed consent will be obtained from all participants. Study results will be presented in academic meetings and peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: jRCTs041220126.

Comparative Effectiveness of Alternative Treatment Approaches to Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis: An Observational Trial Emulation.

RATIONALE & OBJECTIVE: Optimal approaches to treat secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis (HD) have yet to be established in randomized controlled trials (RCTs). STUDY DESIGN: Two observational clinical trial emulations. SETTING & PARTICIPANTS: Both emulations included adults receiving in-center HD from a national dialysis organization. The patients who had SHPT in the period between 2009 and 2014, were insured for≥180 days by Medicare as primary payer, and did not have contraindications or poor health status limiting theoretical trial participation. EXPOSURE: The parathyroid hormone (PTH) Target Trial emulation included patients with new-onset SHPT (first PTH 300-600pg/mL), with 2 arms defined as up-titration of either vitamin D sterols or cinacalcet within 30 days (lower target) or no up-titration (higher target). The Agent Trial emulation included patients with a PTH≥300 pg/mL while on≥6µg weekly of vitamin D sterol (paricalcitol equivalent dose) and no prior history of cinacalcet. The 2 arms were defined by the first dose or agent change within 30 days (vitamin D-favoring [vitamin-D was up-titrated] vs cinacalcet-favoring [cinacalcet was added] vs nondefined [neither applies]). Multiple trials per patient were allowed in trial 2. OUTCOME: The primary outcome was all-cause death over 24 months; secondary outcomes included cardiovascular (CV) hospitalization or the composite of CV hospitalization or death. ANALYTICAL APPROACH: Pooled logistic regression. RESULTS: There were 1,152 patients in the PTH Target Trial (635 lower target and 517 higher target). There were 2,726 unique patients with 6,727 patient trials in the Agent Trial (6,268 vitamin D-favoring trials and 459 cinacalcet-favoring trials). The lower PTH target approach was associated with reduced adjusted hazard of death (HR, 0.71 [95% CI, 0.52-0.93]), CV hospitalization (HR, 0.78 [95% CI, 0.63-0.98]), and their composite (HR, 0.74 [95% CI, 0.61-0.89]). The cinacalcet-favoring approach demonstrated lower adjusted hazard of death compared to the vitamin D-favoring approach (HR, 0.79 [95% CI, 0.62-0.99]), but not of CV hospitalization or the composite outcome. LIMITATIONS: Potential for residual confounding; low use of cinacalcet with low power. CONCLUSIONS: SHPT management that is focused on lower PTH targets may lower mortality and CV disease in patients receiving HD. These findings should be confirmed in a pragmatic randomized trial. PLAIN-LANGUAGE SUMMARY: Optimal approaches to treat secondary hyperparathyroidism (SHPT) have not been established in randomized controlled trials. Data from a national dialysis organization was used to identify patients with SHPT in whom escalated treatment may be indicated. The approach to treatment was defined based on observed upward titration of SHPT-controlling medications: earlier titration (lower target) versus delayed titration (higher target); and the choice of medication (cinacalcet vs vitamin D sterols). In the first trial emulation, we estimated a 29% lower rate of death and 26% lower rate of cardiovascular disease or death for patients managed with a lower versus higher target approach. Cinacalcet versus vitamin D-favoring approaches were not consistently associated with outcomes in the second trial emulation. This observational study suggests the need for additional clinical trials of SHPT treatment intensity.

Effect of Paricalcitol Combined with Cinacalcet on Calcium and Phosphorus Metabolism in Patients Receiving Maintenance Hemodialysis.

This study was designed to compare the beneficial effects of paricalcitol combined with or without cinacalcet on calcium and phosphorus metabolism in patients undergoing maintenance hemodialysis (MHD). A total of 140 patients who received MHD in our hospital from March 2021 to March 2022 were randomly divided into a control group (intravenous paricalcitol, n = 70) and a test group (intravenous paricalcitol combined with oral cinacalcet, n = 70). Clinical baseline data and relevant laboratory parameters before treatment were compared. Additionally, calcium, phosphorus, intact parathyroid hormone in serum were measured and compared between the 2 groups before treatment and 1, 2, 3, 4, 5, 6, 9, 10, and 12 months after treatment. As a result, comparison before treatment demonstrated no significant difference in baseline data such as age, sex, and most laboratory parameters between the 2 groups (P > .05), but there was a significant difference in mean corpuscular volume (P < .001). The serum phosphorus level decreased and calcium level increased significantly in the 2 groups after treatment, while the intact parathyroid hormone level showed no significant change within 12 months of treatment (P > .05). In addition, the combined treatment for 6-12 months caused a much lower phosphorus level (P < .05) and higher calcium level (P < .05) than the treatment with paricalcitol alone, and the difference increased with the extension of treatment time. Collectively, paricalcitol combined with cinacalcet, which is more effective than paricalcitol alone, has a positive effect on calcium and phosphorus metabolism in patients receiving MHD.

Safety of cinacalcet in children and adolescents with chronic kidney disease-mineral bone disorder: systematic review and proportional meta-analysis of case series.

BACKGROUND: Mineral and bone disease in children with chronic kidney disease can cause abnormalities in calcium, phosphorus, parathyroid hormone, and vitamin D and when left untreated can result in impaired growth, bone deformities, fractures, and vascular calcification. Cinacalcet is a calcimimetic widely used as a therapy to reduce parathyroid hormone levels in the adult population, with hypocalcemia among its side effects. The analysis of safety in the pediatric population is questioned due to the scarcity of randomized clinical trials in this group. OBJECTIVE: To assess the onset of symptomatic hypocalcemia or other adverse events (serious or non-serious) with the use of cinacalcet in children and adolescents with mineral and bone disorder in chronic kidney disease. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: The bibliographic search identified 2699 references from 1927 to August/2023 (57 LILACS, 44 Web of Science, 686 PubMed, 131 Cochrane, 1246 Scopus, 535 Embase). Four references were added from the bibliography of articles found and 12 references from the gray literature (Clinical Trials). Of the 77 studies analyzed in full, 68 were excluded because they did not meet the following criteria: population, types of studies, medication, publication types and 1 article that did not present results (gray literature). PARTICIPANTS AND INTERVENTIONS: There were 149 patients aged 0-18 years old with Chronic Kidney Disease and mineral bone disorder who received cinacalcet. STUDY APPRAISAL AND SYNTHESIS METHODS: Nine eligible studies were examined for study type, size, intervention, and reported outcomes. RESULTS: There was an incidence of 0.2% of fatal adverse events and 16% of serious adverse events (p < 0.01 and I2 = 69%), in addition to 10.7% of hypocalcemia, totaling 45.7% of total adverse events. LIMITATIONS: There was a bias in demographic information and clinical characteristics of patients in about 50% of the studies and the majority of the studies were case series. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: If used in the pediatric population, the calcimimetic cinacalcet should be carefully monitored for serum calcium levels and attention to possible adverse events, especially in children under 50 months. SYSTEMATIC REVIEW REGISTRATION NUMBER (PROSPERO REGISTER): CRD42019132809.

Parathyroidectomy: still the best choice for the management of severe secondary hyperparathyroidism.

INTRODUCTION: Management of secondary hyperparathyroidism (SHPT) is a challenging endeavor with several factors contruibuting to treatment failure. Calcimimetic therapy has revolutionized the management of SHPT, leading to changes in indications and appropriate timing of parathyroidectomy (PTX) around the world. METHODS: We compared response rates to clinical vs. surgical approaches to SHPT in patients on maintenance dialysis (CKD 5D) and in kidney transplant patients (Ktx). A retrospective analysis of the one-year follow-up findings was carried out. CKD 5D patients were divided into 3 groups according to treatment strategy: parathyroidectomy, clinical management without cinacalcet (named standard - STD) and with cinacalcet (STD + CIN). Ktx patients were divided into 3 groups: PTX, CIN (cinacalcet use), and observation (OBS). RESULTS: In CKD 5D we found a significant parathormone (PTH) decrease in all groups. Despite all groups had a higher PTH at baseline, we identified a more pronounced reduction in the PTX group. Regarding severe SHPT, the difference among groups was evidently wider: 31%, 14% and 80% of STD, STD + CIN, and PTX groups reached adequate PTH levels, respectively (p<0.0001). Concerning the Ktx population, although the difference was not so impressive, a higher rate of success in the PTX group was also observed. CONCLUSION: PTX still seems to be the best treatment choice for SHPT, especially in patients with prolonged diseases in unresourceful scenarios.

Impact of Parathyroidectomy Versus Oral Cinacalcet on Bone Mineral Density in Patients on Peritoneal Dialysis With Advanced Secondary Hyperparathyroidism: The PROCEED Pilot Randomized Trial.

RATIONALE & OBJECTIVE: Parathyroidectomy and calcimimetics have been used to reduce fracture risk in patients with kidney failure and advanced secondary hyperparathyroidism (SHPT), but direct comparisons of these treatment approaches have not been implemented. This pilot study compared their effects on bone mineral density (BMD) in this patient population. STUDY DESIGN: A prospective pilot open-label randomized trial. SETTING & PARTICIPANTS: 65 patients receiving maintenance peritoneal dialysis with advanced SHPT recruited from 2 university-affiliated hospitals in Hong Kong. INTERVENTIONS: Total parathyroidectomy with forearm autografting versus oral cinacalcet treatment for 12 months. OUTCOME: Prespecified secondary end points including changes in BMD z and T scores of femoral neck, lumbar spine, and distal radius 12 months after treatment initiation and also categorized as osteopenia or osteoporosis according to the World Health Organization. RESULTS: Both total parathyroidectomy and cinacalcet significantly improved BMD of the lumbar spine and femoral neck over 12 months, but the total parathyroidectomy group had a greater increase than the cinacalcet-treated group (P<0.001). The proportion of study participants classified as having osteopenia/osteoporosis by femoral neck T-score fell from 78.2% to 51.7% in the total parathyroidectomy group (P<0.001) and from 65.7% to 52.0% in cinacalcet-treated group after 12 months (P=0.7). The proportion of participants with a T-score at the lumbar spine classified as osteopenia/osteoporosis fell from 53.1% to 31.0% in the total parathyroidectomy group (P=0.01) and from 59.4% to 53.8% with cinacalcet (P=0.3). No significant change was observed in BMD T or z score of the distal radius over 12 months with either intervention. LIMITATIONS: Bone histology was not assessed, and the study duration was 12 months. CONCLUSIONS: A large proportion of peritoneal dialysis patients with advanced SHPT had low bone densities and osteopenia/osteoporosis. Total parathyroidectomy increased the BMD of the lumbar spine and femoral neck and reduced osteopenia/osteoporosis more than oral cinacalcet. FUNDING: Grants from academic (The University of Hong Kong Research) and not-for-profit (Hong Kong Society of Nephrology) entities. REGISTRATION: Registered at Clinicaltrials.gov with study number NCT01447368. PLAIN-LANGUAGE SUMMARY: It is not known whether oral cinacalcet and surgical parathyroidectomy differ in their effects on bone parameters in patients with advanced secondary hyperparathyroidism (SHPT) receiving peritoneal dialysis. This pilot randomized trial evaluated the effect of medical versus surgical therapy on bone mineral densities (BMD) as prespecified secondary study end points. The findings showed that a large proportion of peritoneal dialysis patients with advanced SHPT had low bone densities and osteopenia/osteoporosis. Parathyroidectomy increased the BMD of the lumbar spine and femoral neck more than cinacalcet over 12 months. Parathyroidectomy reduced the proportion of patients with osteopenia/osteoporosis at the lumbar spine and femoral neck more than cinacalcet after 12 months. Neither intervention led to an increase in the BMD of the distal radius over 12 months.

Uso de cinacalcet en hiperparatiroidismo secundario: evaluación del estado nutricional, lipídico e inflamatorio en enfermedad renal crónica / Use of cinacalcet in secondary hyperparathyroidism: assessment of nutritional, lipid and inflammatory status in chronic kidney disease

Introducción: observaciones en líneas celulares sugieren que el uso de cinacalcet podría asociarse con un aumento de grasa corporal y del estado inflamatorio y una alteración del metabolismo lipídico. Sin embargo, al escalar el modelo a nivel clínico se desconoce la ocurrencia de estos efectos. Objetivos: analizar el efecto de la terapia con cinacalcet sobre parámetros antropométricos, inflamatorios y lipídicos en pacientes renales con hiperparatiroidismo secundario (HPT2). Métodos: estudio observacional con dos aproximaciones. El estudio retrospectivo incluyó 89 pacientes que iniciaron tratamiento de cinacalcet desde el año 2018 con un seguimiento máximo de 36 meses. Se analizaron variables de índice de masa corporal (IMC), circunferencia de cintura, pliegue tricipital, paratohormona (PTH) y perfil bioquímico. El estudio prospectivo incluyó 52 pacientes que iniciaron tratamiento con cinacalcet desde el año 2020 con un seguimiento de 12 meses. Se analizaron variables de IMC, PTH, perfil lipídico y proteína C reactiva (PCR). Resultados: en el estudio retrospectivo, el IMC fue de 27 kg/m2, con un 62 % de exceso de peso y un 65 % de los pacientes con riesgo cardiovascular elevado. Cinacalcet redujo la PTH un 12 % luego de seis meses (p < 0,01) y el calcio sérico disminuyó un 3,4 % al final del seguimiento (p = 0,04). En el estudio prospectivo, el IMC fue de 26,8 kg/m2, con un 60 % de exceso de peso. La PTH disminuyó un 8,4 % luego de seis meses. El colesterol total, el colesterol LDL y los triglicéridos disminuyeron en un 6,8 %, 12,5 % y 5,5 %, respectivamente, al finalizar el seguimiento. Conclusiones: el estado nutricional prevalente es el exceso de peso. En pacientes con HPT2 cinacalcet mejora el control de la PTH sin provocar cambios en parámetros antropométricos, lipídicos e inflamatorios. (AU)

Introduction: observations in cell lines suggest that the use of cinacalcet could be associated with increase in body fat, inflammatory state, and alteration in lipid metabolism. However, when scaling the model to the clinical level, the occurrence of these effects is unknown. Objectives: to analyze the effect of cinacalcet therapy on anthropometric, inflammatory and lipid parameters in renal patients with secondary hyperparathyroidism (SHPT). Methods: observational study with two approaches. The retrospective study included 89 patients who started cinacalcet treatment since 2018 with a maximum follow-up of 36 months. Body mass index (BMI) variables, waist circumference, tricipital skinfold, parathyroid hormone (PTH), and biochemical profile were analyzed. The prospective study included 52 patients who started cinacalcet treatment since 2020 with a 12-month follow-up. BMI, PTH, lipid profile, and PCR variables were analyzed. Results: in the retrospective study, BMI was 27 kg/m2, with 62 % overweight and 65 % of patients with high cardiovascular risk. Cinacalcet reduced PTH by 12 % after six months (p < 0.01) and serum calcium decreased by 3.4 % at the end of follow-up (p = 0.04). According to the prospective study, BMI was 26.8 kg/m2 , with 60 % overweight. PTH decreased by 8.4 % after six months. Total cholesterol, LDL cholesterol, and triglycerides decreased by 6.8 %, 12.5 %, and 5.5 %, respectively, at the end of follow-up. Conclusions: the prevalent nutritional status is excess weight. In patients with SHPT, cinacalcet improves PTH control without causing changes in anthropometric, lipid, and inflammatory parameters. (AU)