Early vs late initiation of sodium glycerophosphate: Impact on hypophosphatemia in preterm infants <32 weeks.

BACKGROUND & AIMS: Early electrolyte and mineral imbalances have emerged as a conspicuous problem in very preterm babies since the revision of nutrition guidelines and the eventual implementation of early aggressive parenteral nutrition (PN). We opted to carry out a study with the introduction of phosphorus as sodium glycerophosphate in PN from the first day onward to reveal the impact on serum phosphorus and calcium levels following the surge in the incidence of hypercalcemia and hypophosphatemia. METHODS: In this single-center, prospective, observational cohort study, inborn babies <32 gestational weeks and <1500 g between August 2017 and July 2018 were enrolled consecutively. Infants born in the first 6-month of this period were initiated PN (Early phosphorus group) containing phosphorus (1 mmol P as sodium glycerophosphate/100 ml PN) immediately after birth, and in the latter six-months, mineral-free standard PN (Control group) was commenced up until 48 h of life. Parenteral nutritional prescriptions of both groups were similar in terms of macro and micronutrient intakes except for early phosphorus, calcium, and sodium. Serum mineral and electrolyte levels were measured on Days 1-3-7 and compared between the groups. The primary outcome was the presence of hypophosphatemia in the first week of life. The secondary outcome was hypercalcemia, preterm morbidity, and mortality. RESULTS: A total of 261 infants were included in this study. There were 130 babies in Early phosphorus group and 131 in control group. Gestational ages (28.79 ± 2.1 vs 28.46 ± 2.2 weeks, respectively) and birth weights (1138 ± 273 vs 1090 ± 274 g, respectively) were similar in the groups. Mean serum phosphorus levels were higher on all days in Early phosphorus group (p < 0.001). Early phosphorus group had a lower incidence of hypophosphatemia on days 1-3 and 7 (p < 0.001). The percentage of hypercalcemic infants was significantly lower in Early phosphorus group on day 3 (p < 0.001). No difference was noted in terms of hypernatremia in the groups. CONCLUSIONS: Adding phosphorus to PN in the first hours of life reduced the frequency of hypophosphatemia and hypercalcemia without any surge in hypernatremia or morbidity. Nutrition guidelines need to be revised accordingly in terms of early mineral/electrolyte supplementation.

Impact of anion exchange adsorbents on regional citrate anticoagulation.

INTRODUCTION: Heparin and citrate are commonly used anticoagulants in membrane/adsorption based extracorporeal liver support systems. However, anion exchange resins employed for the removal of negatively charged target molecules including bilirubin may also deplete these anticoagulants due to their negative charge. The aim of this study was to evaluate the adsorption of citrate by anion exchange resins and the impact on extracorporeal Ca2+ concentrations. METHODS: Liver support treatments were simulated in vitro. Citrate and Ca2+ concentrations were measured pre and post albumin filter as well as pre and post adsorbents. In addition, batch experiments were performed to quantify citrate adsorption. RESULTS: Pre albumin filter target Ca2+ concentrations were reached well with only minor deviations. Citrate was adsorbed by anion exchange resins, resulting in a higher Ca2+ concentration downstream of the adsorbent cartridges during the first hour of treatment. CONCLUSIONS: The anion exchange resin depletes citrate, leading to an increased Ca2+ concentration in the extracorporeal circuit, which may cause an increased risk of clotting during the first hour of treatment. An increase of citrate infusion during the first hour of treatment should therefore be considered to compensate for the adsorption of citrate.

Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.

The bioactive vitamin D3, 1α,25(OH)2D3, plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D3 leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)2D3 synthesis, but are poorly efficient. In this study, we identify WBP4 as a new VDR interactant, and demonstrate that it controls VDR subcellular localization. Moreover, we show that the vitamin D analogue ZK168281 enhances the interaction between VDR and WBP4 in the cytosol, and normalizes the expression of VDR target genes and serum calcium levels in 1α,25(OH)2D3-intoxicated mice. As ZK168281 also blunts 1α,25(OH)2D3-induced VDR signaling in fibroblasts of a patient with impaired vitamin D degradation, this VDR antagonist represents a promising therapeutic option for 1α,25(OH)2D3-induced hypercalcemia.

A Lipid-Based Nanocarrier Containing Active Vitamin D3 Ameliorates NASH in Mice via Direct and Intestine-Mediated Effects on Liver Inflammation.

The gut-liver axis may be involved in non-alcoholic steatohepatitis (NASH) progression. Pathogen-associated molecular patterns leak through the intestinal barrier to the liver via the portal vein to contribute to NASH development. Active vitamin D3 (1,25(OH)2D3) is a potential therapeutic agent to enhance the intestinal barrier. Active vitamin D3 also suppresses inflammation and fibrosis in the liver. However, the adverse effects of active vitamin D3 such as hypercalcemia limit its clinical use. We created a nano-structured lipid carrier (NLC) containing active vitamin D3 to deliver active vitamin D3 to the intestine and liver to elicit NASH treatment. We found a suppressive effect of the NLC on the lipopolysaccharide-induced increase in permeability of an epithelial layer in vitro. Using mice in which NASH was induced by a methionine and choline-deficient diet, we discovered that oral application of the NLC ameliorated the permeability increase in the intestinal barrier and attenuated steatosis, inflammation and fibrosis in liver at a safe dose of active vitamin D3 at which the free form of active vitamin D3 did not show a therapeutic effect. These data suggest that the NLC is a novel therapeutic agent for NASH.

Serum calcium derangements in neonates with moderate to severe hypoxic ischemic encephalopathy and the impact of therapeutic hypothermia: a cohort study.

Background: Perinatal hypoxia is a recognized cause of hypocalcemia in neonates in the first 3 days of life. Therapeutic hypothermia (TH) promotes neuroprotection by decreasing calcium influx into the cells during the reperfusion phase thereby increase serum calcium levels. This study examines the trends of serum calcium levels in neonates with hypoxic ischemic encephalopathy (HIE) and the effect of TH.Material and methods: A retrospective cohort study of neonates with moderate to severe HIE admitted to level III neonatal intensive care units (NICU's) in Calgary between September 2011 and October 2015. HIE was staged using modified Sarnat scoring system. Ionized calcium levels were followed in the first 3 days of age.Results: One hundred thirteen neonates admitted with the diagnosis of moderate to severe HIE were included; 89 (79%) underwent TH. Hypercalcemia was significantly higher with TH 57 (64%) compared to 8 (33%) in noncooled group (p = .007). Hypocalcemia was less in TH group; 11 (12%) compared to 5 (21%) in non TH group. Hypo/hypercarbia did not alter the serum calcium levels. Furthermore; there was no increase in the incidence of intracranial hemorrhage, clinical or electrographic seizures, antiepileptic drug use, or hypoxic/ischemic MRI changes with calcium derangements.Conclusion: The incidence of hypocalcemia was reduced by almost half and hypercalcemia was significantly increased with TH in the first 3 days of life. The reduction in hypocalcemia and the increase in hypercalcemia may be attributed to the neuroprotective effect of TH.

Long-term effects on PTH and mineral metabolism of 1.25 versus 1.75 mmol/L dialysate calcium in peritoneal dialysis patients: a meta-analysis.

BACKGROUND: This study aimed to compare 1.25 and 1.75 mmol/L dialysate calcium for their effects on parathyroid hormone (PTH) and mineral metabolism in peritoneal dialysis (PD). METHODS: The PubMed, Cochrane Library, and EmBase databases were searched from inception to October 2016. Methodological quality assessment of the included studies was performed using the risk of bias tool of the Review Manager software. The meta-analysis was carried out with the Stata12.0 software. Subgroup analysis was performed by study design [randomized controlled trial (RCT) and non-RCT]. Odds ratios or standardized mean differences were used to assess the outcome measures, including intact parathyroid hormone (i-PTH) levels, serum total calcium amounts, ionized calcium levels, phosphate concentrations, and peritonitis episodes. RESULTS: Seven studies were enrolled in the synthesized analysis, including 4 RCTs and 3 non-RCTs. All studies compared 1.25 mmol/L and 1.75 mmol/L dialysate calcium for PD. Pooled analysis revealed that 1.75 mmol/L dialysate calcium significantly reduced i-PTH levels compared with the 1.25 mmol/L dose in PD patients. However, 1.25 mmol/L dialysate calcium was superior to the 1.75 mmol/L dose in decreasing the levels of serum total calcium and ionized calcium in PD patients. No significant differences in phosphate amounts and peritonitis episodes were observed between the two groups. CONCLUSION: These findings indicated that 1.75 mmol/L dialysate calcium is more appropriate for PD patients with secondary hyperparathyroidism. Meanwhile, 1.25 mmol/L dialysate calcium is more favorable to PD patients with secondary hypercalcemia. However, further well-designed and high-quality studies are required to validate these findings.

Activation of the calcium sensing receptor attenuates TRPV6-dependent intestinal calcium absorption.

Plasma calcium (Ca2+) is maintained by amending the release of parathyroid hormone and through direct effects of the Ca2+ sensing receptor (CaSR) in the renal tubule. Combined, these mechanisms alter intestinal Ca2+ absorption by modulating 1,25-dihydroxy vitamin D3 production, bone resorption, and renal Ca2+ excretion. The CaSR is a therapeutic target in the treatment of secondary hyperparathyroidism and hypocalcemia a common complication of calcimimetic therapy. The CaSR is also expressed in intestinal epithelium, however, a direct role in regulating local intestinal Ca2+ absorption is unknown. Chronic CaSR activation decreased expression of genes involved in Ca2+ absorption. In Ussing chambers, increasing extracellular Ca2+ or basolateral application of the calcimimetic cinacalcet decreased net Ca2+ absorption across intestinal preparations acutely. Conversely, Ca2+ absorption increased with decreasing extracellular Ca2+ concentration. These responses were absent in mice expressing a non-functional TRPV6, TRPV6D541A. Cinacalcet also attenuated Ca2+ fluxes through TRPV6 in Xenopus oocytes when co-expressed with the CaSR. Moreover, the phospholipase C inhibitor, U73122, prevented cinacalcet-mediated inhibition of Ca2+ flux. These results reveal a regulatory pathway whereby activation of the CaSR in the basolateral membrane of the intestine directly attenuates local Ca2+ absorption via TRPV6 to prevent hypercalcemia and help explain how calcimimetics induce hypocalcemia.

A practical self-made device in parathyroid autotransplantation for patients with secondary hyperparathyroidism.

OBJECTIVE: Secondary hyperparathyroidism (sHPT) is one of the most serious complications in patients on long-term hemodialysis. These patients may suffer from metabolic bone diseases, severe atherosclerosis, and undesirable cardiovascular events. Endoscopic parathyroidectomy with autotransplantation is a treatment option for those who do not respond to clinical management. This study aimed to investigate practical use of a self-made device in parathyroid autotransplantation for patients with sHPT, and to compare this device with ordinary surgical scissors. METHODS: A total of 15 patients with sHPT were treated with endoscopic parathyroidectomy and autotransplantation. Pieces of parathyroid tissue were squeezed in our self-made device and injected into the brachioradialis muscle. Sixteen patients with sHPT who were treated with traditional parathyroid transplantation served as controls. Serum levels of parathyroid hormone, alkaline phosphatase, calcium, phosphorus and intact parathyroid hormone were measured before and after surgery. RESULTS: Preoperative symptoms were alleviated, and serum parathyroid hormone and alkaline phosphatase levels, hyperphosphatemia, and hypercalcemia were improved or normalized in all of the patients in both groups. Pathological examinations showed that parathyroid cells remained active. CONCLUSION: Application of our squeezing device is an economic, effective, and safe method in endoscopic parathyroidectomy and autotransplantation for patients with sHPT.

[Update 2017 of the KDIGO guidelines on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). What are the real changes?]

Guidelines for the assessment, diagnosis and therapy of the alterations that characterize the CKD-MBD are an important support in the clinical practice of the nephrologist. Compared to the KDIGO guidelines published in 2009, the 2017 update made changes on some topics on which there was previously no strong evidence both in terms of diagnosis and therapy. The recommendations include the diagnosis of bone anomalies in CKD-MBD and the treatment of mineral metabolism abnormalities with particular regard to hyperphosphataemia, calcium levels, secondary hyperparathyroidism and anti-resorptive therapies. The Italian Study Group on Mineral Metabolism, in reviewing the 2017 recommendations, aimed to assess the weight of the evidence that led to this update. In fact, on some topics there has not been a substantial difference on the degree of evidence compared to the previous guidelines. The Italian Study Group emphasizes the points that may still reserve critical issues, including interpretation, and invites an evaluation that is articulated and personalized for each patient.

[New scenarios in secondary hyperparathyroidism: etelcalcetide. Position paper of Nephrologists form Lombardy].

Bone mineral abnormalities (defined as Chronic Kidney Disease Mineral Bone Disorder; CKD-MBD) are prevalent and associated with a substantial risk burden and poor prognosis in CKD population. Several lines of evidence support the notion that a large proportion of patients receiving maintenance dialysis experience a suboptimal biochemical control of CKD-MBD. Although no study has ever demonstrated conclusively that CKD-MBD control is associated with improved survival, an expanding therapeutic armamentarium is available to correct bone mineral abnormalities. In this position paper of Lombardy Nephrologists, a summary of the state of art of CKD-MBD as well as a summary of the unmet clinical needs will be provided. Furthermore, this position paper will focus on the potential and drawbacks of a new injectable calcimimetic, etelcalcetide, a drug available in Italy since few months ago.

Long-term effects of low calcium dialysates on the serum calcium levels during maintenance hemodialysis treatments: A systematic review and meta-analysis.

Hypercalcemia and hyperparathyroidism in patients receiving maintenance hemodialysis (MHD) can cause the progression of cardiovascular diseases (CVD) and mineral bone disorders (MBD). The KDIGO recommends the dialysates with a calcium (Ca) concentration of 1.25-1.5 mmol/L for MHD treatments, but the optimal concentration remains controversial. Here, we conducted a systematic review and a meta-analysis of seven randomized controlled trials examining a total of 622 patients to investigate the optimal concentration for MHD for 6 months or longer. The dialysates with a low Ca concentration (1.125 or 1.25 mmol/L) significantly lowered the serum Ca and raised the intact parathyroid hormone levels by 0.52 mg/dL (95% confidence interval, 0.20-0.85) and 39.59 pg/mL (14.80-64.38), respectively, compared with a high Ca concentration (1.50 or 1.75 mmol/L). Three studies showed that a low concentration was preferred for lowering arterial calcifications or atherosclerosis in different arteries, but one study showed that coronary arterial calcifications increased with a low concentration. Two studies showed contradictory outcomes in terms of MBD. Our meta-analysis showed that a dialysate with a low Ca concentration lowered the serum Ca levels in patients receiving long-term MHD, but further studies are needed to determine the optimal Ca concentration in terms of CVD and MBD.

Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update.

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis. Methods: Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations. Recommendations: The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.

Current opinions on nephrolithiasis associated with primary hyperparathyroidism.

Nephrolithiasis is a common urological disease and could be secondary to primary hyperparathyroidism (PHPT). PHPT is traditionally characterised with hypercalcaemia. Recently, a normocalcemic PHPT has been officially recognised at the International Workshops. Regarding this new phenotype, nephrolithiasis is frequently found in studies that evaluate low bone mass. However, until now, no study on aetiology of nephrolithiasis considered normocalcemic PHPT. Hypercalciuria related to PHPT is considered as an important risk factor of stone formation in hypercalcemic PHPT, but the precise relationships between hypercalcemic PHPT and nephrolithiasis and between normocalcemic PHPT and nephrolithiasis remain unclear. In patients with hypercalcemic PHPT, after a surgical cure of PHPT, the renal calcium excretion and stone recurrence rate reduce but remain higher above health controls. This finding implies that abnormalities not caused by PHPT also probably affect stone formation. According to the new guideline, the presence of stones indicates the need for parathyroidectomy in patients with either hypercalcemic or normocalcemic PHPT unless contraindications exist. Patients with contraindications for parathyroidectomy or those who do not want to receive parathyroidectomy should be monitored for signs of disease progression and given of medical management. Moreover, due to decreased but significantly higher frequency of nephrolithiasis above those of healthy controls, patients with nephrolithiasis associated with PHPT after parathyroidectomy still should be motivated to explore strategies to prevent stone occurrence.

Cardiovascular manifestations of primary hyperparathyroidism: a narrative review.

Data on cardiovascular disease in primary hyperparathyroidism (PHPT) are controversial; indeed, at present, cardiovascular involvement is not included among the criteria needed for parathyroidectomy. Aim of this narrative review is to analyze the available literature in an effort to better characterize cardiovascular involvement in PHPT. Due to physiological effects of both parathyroid hormone (PTH) and calcium on cardiomyocyte, cardiac conduction system, smooth vascular, endothelial and pancreatic beta cells, a number of data have been published regarding associations between symptomatic and mild PHPT with hypertension, arrhythmias, endothelial dysfunction (an early marker of atherosclerosis), glucose metabolism impairment and metabolic syndrome. However, the results, mainly derived from observational studies, are inconsistent. Furthermore, parathyroidectomy resulted in conflicting outcomes, which may be linked to several potential biases. In particular, differences in the methods utilized for excluding confounding co-existing cardiovascular risk factors together with differences in patient characteristics, with varying degrees of hypercalcemia, may have contributed to these discrepancies. The only meta-analysis carried out in PHPT patients, revealed a positive effect of parathyroidectomy on left ventricular mass index (a predictor of cardiovascular mortality) and more importantly, that the highest pre-operative PTH levels were associated with the greatest improvements. In normocalcemic PHPT, it has been demonstrated that cardiovascular risk factors are almost similar compared to hypercalcemic PHPT, thus strengthening the role of PTH in the cardiovascular involvement. Long-term longitudinal randomized trials are needed to determine the impact of parathyroidectomy on cardiovascular diseases and mortality in PHPT.

Sevelamer versus calcium-based phosphate binders for chronic kidney disease. / Sevelamer comparado con quelantes de fósforo en base a calcio para la insuficiencia renal crónica.

Chronic kidney disease-mineral and bone disorder is prevalent. There is controversy regarding whether calcium-based phosphate binders or sevelamer - a non-calcium phosphate binder – constitute a better therapeutic alternative. Searching in Epistemonikos database, which is maintained by screening multiple information sources, we identified 12 systematic reviews comprising 61 studies of which 41 correspond to randomized trials addressing the question of this article. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded sevelamer may decrease hypercalcemia, but with a higher incidence of gastrointestinal effects than calcium based phosphate binders. It is unclear if there are differences in mortality because the certainty of the evidence is very low.

Los trastornos minerales y óseos asociados a la enfermedad renal crónica son frecuentes. Para su tratamiento existen quelantes de fósforo en base a calcio y otros no cálcicos como el sevelamer, pero no está claro cuál constituye una mejor opción. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples fuentes de información, identificamos 12 revisiones sistemáticas que en conjunto incluyen 61 estudios primarios, de los cuales 41 corresponden a ensayos aleatorizados. Extrajimos los datos, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Concluimos que el sevelamer, en comparación con los quelantes de fósforo en base a calcio, podría disminuir los eventos de hipercalcemia, pero con una mayor incidencia de efectos gastrointestinales. Por otra parte, no está claro si existen diferencias en cuanto a mortalidad porque la certeza de la evidencia es muy baja.

Severe hypercalcaemia and hypophosphataemia with an optimised preterm parenteral nutrition formulation in two epochs of differing phosphate supplementation.

OBJECTIVE: To compare in two epochs of differing phosphate provision serum calcium, phosphate, potassium, and sodium concentrations and the frequency of abnormality of these electrolytes and of sepsis in preterm infants who received an optimised higher amino acid-content formulation. DESIGN AND SETTING: Retrospective cohort study at a single tertiary-level neonatal unit. PATIENTS: Preterm infants given parenteral nutrition (PN) in the first postnatal week during two discrete 6-month epochs in 2013-2014. INTERVENTIONS: In epoch 1 the Ca2+:PO4 molar ratio of the PN formulation was ~1.3-1.5:1 (1.7 mmol Ca2+ and 1.1 mmol PO4 per 100 mL aqueous phase) and in epoch 2 was 1.0:1 via extra phosphate supplementation (1.7 mmol Ca2+ and 1.7 mmol PO4 per 100 mL). MAIN OUTCOME MEASURES: Peak calcium and nadir phosphate and potassium concentrations, and proportions with severe hypercalcaemia (Ca2+ >3.0 mmol/L), hypophosphataemia (PO4<1.5 mmol/L), and hypokalaemia (K+ <3.5 mmol/L) within the first postnatal week. RESULTS: In epoch 2, peak calcium concentrations were lower than in epoch 1 (geometric means: 2.83 mmol/L vs 3.09 mmol/L, p value<0.0001), fewer babies were severely hypercalcaemic (10/49, 20%, vs 31/51, 61%, p value<0.0001); nadir plasma phosphate concentrations were higher (means: 1.54 mmol/L vs 1.32 mmol/L, p value=0.006), and there were fewer cases of hypophosphataemia (17/49, 35% vs 31/51, 61%, p value=0.009) and hypokalaemia (12/49, 25% vs 23/51, 45%, p value=0.03). CONCLUSIONS: Reverting from a PN Ca2+:PO4 molar ratio of 1.3-1.5:1 to a ratio of 1.0:1 was associated with a lower incidence and severity of hypophosphataemia and hypercalcaemia. For preterm infants given higher concentrations of amino acids (≥2.5 g/kg/day) from postnatal day 1, an equimolar Ca2+:PO4 ratio may be preferable during the first postnatal week.

Liver-Directed Embolization for the Long-Term Control of Hypercalcemia of Malignancy in Metastatic Breast Cancer.

Hypercalcemia of malignancy is a common complication of certain types of cancers. No standard therapies exist for the treatment of hypercalcemia secondary to paraneoplastic syndromes that result in the long-term control of serum calcium levels. We report a case of metastatic breast cancer with parathyroid hormone-related protein associated with hypercalcemia of malignancy that was treated with transarterial embolization of the hepatic metastatic lesions.

Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours.

The purpose of this meta-analysis was to evaluate the efficacy of denosumab, compared with zoledronic acid (ZA), in delaying skeletal-related events (SREs) and enhancing overall survival in patients with advanced solid tumours and bone metastases. A systematic literature search of several electronic databases, including PubMed, Medline, Embase, the Cochrane Library, CKNI and Web of Science with Conference Proceedings, was performed. Only randomised controlled trials assessing denosumab in comparison with ZA, in patients with advanced solid tumours and metastatic-stage disease, were included. The primary outcome was the time to first SRE. The risk of developing subsequent on-study SREs and overall survival were also evaluated. Three randomised controlled trials with a total of 5,544 patients with advanced solid tumours and bone metastases were included in the meta-analysis. There were 2,776 patients treated with denosumab and 2,768 treated with ZA. The pooled analysis showed that denosumab was superior to ZA in delaying time to first on-study SRE (odds ratio [OR]: 0.82; 95% CI: 0.75-0.89, p < 0.0001) and multiple SREs (risk ratio: 0.81; 95% CI: 0.74-0.88, p < 0.0001). However, no significant difference was found in overall survival improvement between denosumab and ZA (OR: 1.02; 95% CI: 0.91-1.15, p = 0.71). This meta-analysis indicates that denosumab is superior to ZA in delaying SREs for patients with bone metastases. No significant difference was observed between denosumab and ZA, regarding overall survival. We support denosumab as a potential novel treatment option for the management of bone metastases in advanced solid tumours.