Denosumab-induced hypocalcemia in patients with solid tumors and renal dysfunction: a multicenter, retrospective, observational study.

BACKGROUND: Bone metastases are frequently observed in advanced cancer, and bone modifying agents are used to prevent or treat skeletal-related events. Zoledronic acid is contraindicated in patients with severe renal impairment (Ccr < 30 mL/min), but it is not completely known whether denosumab can be used in them. We aimed to determine the association between renal function and hypocalcemia development during denosumab treatment. METHODS: We included patients with solid cancer and bone metastases who started denosumab treatment between April 2017 and March 2019. They were classified into four groups based on creatinine clearance (Ccr; mL/min): normal (Ccr ≥ 80), mild (50 ≤ Ccr ˂80), moderate (30 ≤ Ccr ˂50), and severe (Ccr ˂30). Hypocalcemia was evaluated using the Common Terminology Criteria for Adverse Events (v5.0) based on the albumin-adjusted serum calcium levels; its incidence (stratified by renal function) and risk factors were investigated using a Chi-square test and logistic regression analysis. RESULTS: Of 524 patients (age: 69 ± 11 years; 303 men), 153 had a normal renal function and 222, 117, and 32 had mild, moderate, and severe renal dysfunction. The albumin-adjusted serum calcium level was higher than the measured (total) calcium level in most patients. The incidence of grade ≥ 1 hypocalcemia was 32.0% in the normal group and 37.4%, 29.9%, and 62.5% in the mild, moderate, and severe renal dysfunction groups, respectively. It was, therefore, higher in the severe renal dysfunction groups than in the normal group (P = 0.002). The incidence of grade ≥ 3 hypocalcemia did not differ significantly among the groups. Pre-treatment low serum calcium levels and severe renal dysfunction were risk factors for hypocalcemia. CONCLUSIONS: Evaluating denosumab-induced hypocalcemia required albumin adjustment, and its incidence was high among patients with severe renal dysfunction. Reduced serum calcium levels and severely impaired renal function were associated with an elevated hypocalcemia risk.

Long-Term Efficacy and Safety of Upacicalcet in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism: Open-Label 52-Week Study.

INTRODUCTION: Upacicalcet is a novel injectable calcimimetic. This phase 3 multicenter open-label study aimed to assess the long-term efficacy and safety of upacicalcet in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). METHODS: Japanese HD patients with serum intact parathyroid hormone (iPTH) levels >240 pg/mL and corrected calcium (cCa) levels ≥8.4 mg/dL were enrolled. Upacicalcet with a dose range of 25-300 µg was administered after each dialysis for 52 weeks. The main efficacy endpoint was the percentage of patients achieving the target iPTH level (60-240 pg/mL). RESULTS: A total of 157 patients were enrolled, of whom 138 completed the study. Overall, 94.2% of patients achieved the target serum iPTH level at week 52. Neither symptomatic hypocalcemia nor cCa level <7.5 mg/dL occurred despite the negligible increase of concomitant vitamin D receptor activators and calcium carbonate. Upacicalcet improved the control of serum phosphate (P) and calcium levels regardless of baseline PTH levels and decreased intact fibroblast growth factor-23 levels. The largest parathyroid glands shrank, irrespective of their baseline volume or prior calcimimetic usage. Upacicalcet was well tolerated, with no adverse events requiring dose reduction. CONCLUSION: This is the first study to show that a calcimimetic improves serum P and cCa control without inducing severe hypocalcemia in patients with iPTH levels ≤300 pg/mL. Upacicalcet is efficacious in HD patients with mild-to-severe SHPT, with few safety concerns.

Ratios of calcium to citrate administration in blood transfusion for traumatic hemorrhage: A retrospective cohort study.

BACKGROUND: Massive transfusion with citrated blood products causes hypocalcemia, which is associated with mortality. Recognition of this problem has led to increased calcium administration; however, the optimal dosing is still unknown. STUDY DESIGN AND METHODS: This retrospective, single-center study included level 1 trauma patients in 2019 and 2020 who underwent an operation within 12 h of arrival and received a transfusion. Preoperative and intraoperative administrations were totaled to calculate the ratio of administered calcium to the number of blood transfusions for each patient. The citrate content of each blood component was estimated to calculate a second ratio, the ratio of administered calcium to administered citrate. Receiver Operating Characteristic (ROC) curves were performed on both ratios to determine the optimal cutoff values for predicting severe hypocalcemia (ionized calcium <0.9 mmol/L) and hypercalcemia (>1.35 mmol/L) at the end of the intraoperative period. RESULTS: A total of 506 trauma activations were included, receiving a mean of 17.4 citrated blood products and 16.3 mmol of calcium (equivalent to 2400 mg of calcium chloride). No ratio was statistically significant in differentiating severely hypocalcemic patients from the rest. A calcium to blood ratio of 0.903 mmol of administered calcium per citrated blood product differentiated hypercalcemic patients from the rest. DISCUSSION: Quantifying received calcium and citrated blood products was insufficient to predict severe hypocalcemia, suggesting other contributions to hypocalcemia. We demonstrated an upper-limit ratio for calcium administration in traumatic hemorrhage; however, further studies are required to determine what calcium dosing regimen results in the best outcomes.

Higher Doses of Calcium Associated With Survival in Trauma Patients.

INTRODUCTION: Calcium is required for coagulation, cardiac output, and peripheral vascular resistance. Between 85% and 94% of trauma patients treated with massive blood transfusion develop hypocalcemia.1 The aim of this study is to evaluate the relationship between increased intravenous calcium administration during massive transfusion and improved survival of trauma patients. METHODS: We performed a retrospective analysis of trauma patients who received massive transfusion over a 2-y period. Doses of elemental calcium administered per unit of blood product transfused were calculated by calcium to blood product ratio (CBR). Chi-square test evaluated association between coagulopathy and 30-d mortality. Two-sample t-test evaluated association between CBR and coagulopathy. Bivariate regression analysis evaluated association between CBR and blood products transfused per patient. Multivariable logistic regression analysis, controlling for age, sex, coagulopathy, and Injury Severity Score evaluated the association between CBR and mortality. RESULTS: The study included 77 patients. Coagulopathy was associated with increased 30-d mortality (P < 0.05). Patients who survived had higher CBR than those who died (P < 0.05). CBR was associated with a significant reduction in total blood products transfused per patient (P < 0.05). CBR was not associated with coagulopathy (P = 0.24). Multivariable logistic regression analysis demonstrated that Injury Severity Score ≥16, coagulopathy and decreased CBR were significant predictors of mortality (P < 0.05). CBR above 50 mg was a predictor of survival (P < 0.05). CONCLUSIONS: Higher doses of calcium given per blood product transfused were associated with improved 30-d survival and decreased blood product transfusions.

An update on the use of near-infrared autofluorescence imaging in endocrine surgical procedures.

Over the past decade, near-infrared autofluorescence (NIRAF) imaging has been a major breakthrough in endocrine surgery. Although initial focus was directed at the parathyroid glands, subsequent work has also shown that non-parathyroid neuroendocrine tumors also possess autofluorescence properties. The aim of this review is to present an update and synopsis about NIRAF applications in various endocrine surgical procedures. Methodology includes a review of the literature supplemented with expert opinion. Overall, our review reveals that the use of NIRAF may provide the surgeon with adjunctive critical information that has the potential to change the conduct of many various endocrine surgical procedures.

Calcium supplementation during trauma resuscitation: a propensity score-matched analysis from the TraumaRegister DGU®.

BACKGROUND: In major trauma patients, hypocalcemia is associated with increased mortality. Despite the absence of strong evidence on causality, early calcium supplementation has been recommended. This study investigates whether calcium supplementation during trauma resuscitation provides a survival benefit. METHODS: We conducted a retrospective analysis using data from the TraumaRegister DGU® (2015-2019), applying propensity score matching to balance demographics, injury severity, and management between major trauma patients with and without calcium supplementation. 6 h mortality, 24 h mortality, and in-hospital mortality were considered as primary outcome parameters. RESULTS: Within a cohort of 28,323 directly admitted adult major trauma patients at a European trauma center, 1593 (5.6%) received calcium supplementation. Using multivariable logistic regression to generate propensity scores, two comparable groups of 1447 patients could be matched. No significant difference in early mortality (6 h and 24 h) was observed, while in-hospital mortality appeared higher in those with calcium supplementation (28.3% vs. 24.5%, P = 0.020), although this was not significant when adjusted for predicted mortality (P = 0.244). CONCLUSION: In this matched cohort, no evidence was found for or against a survival benefit from calcium supplementation during trauma resuscitation. Further research should focus on understanding the dynamics and kinetics of ionized calcium levels in major trauma patients and identify if specific conditions or subgroups could benefit from calcium supplementation.

Identification of novel risk factors for postoperative severe hypocalcemia in patients with primary hyperparathyroidism undergoing parathyroidectomy: a case control study.

BACKGROUND: Patients with primary hyperparathyroidism (PHPT) are at risk for severe hypocalcemia (SH) following parathyroidectomy (PTX), but limited data exist on the predictors of SH. We aimed to identify risk factors for early postoperative SH after PTX in patients with PHPT and to evaluate the predictive value of clinical parameters. METHODS: A retrospective review of patients with PHPT who underwent PTX between January 2010 and December 2022 was performed. A total of 46 patients were included in the study, with 15 (32.6%) experiencing postoperative SH, 19 (41.3%) having calculi in the ureter or kidney, and 37 (80.4%) having osteoporosis. Patients were divided into SH and non-SH groups based on postoperative serum calcium levels. Preoperative biochemical indicators, bone turnover markers, and renal function parameters were analyzed and correlated with postoperative SH. RESULTS: Statistically significant (P < 0.05) differences were found in preoperative serum calcium (serum Ca), intact parathyroid hormone, serum phosphorus (serum P), serum Ca/P, percentage decrease of serum Ca, total procollagen type 1 intact N-terminal propeptide, osteocalcin (OC), and alkaline phosphatase levels between the two groups. Multivariate analysis showed that serum P (odds ratio [OR] = 0.989; 95% confidence interval [95% CI] = 0.981-0.996; P = 0.003), serum Ca (OR = 0.007; 95% CI = 0.001-0.415; P = 0.017), serum Ca/P (OR = 0.135; 95% CI = 0.019-0.947; P = 0.044) and OC levels (OR = 1.012; 95% CI = 1.001-1.024; P = 0.036) were predictors of early postoperative SH. The receiver operating characteristic curve analysis revealed that serum P (area under the curve [AUC] = 0.859, P < 0.001), serum Ca/P (AUC = 0.735, P = 0.010) and OC (AUC = 0.729, P = 0.013) had high sensitivity and specificity. CONCLUSION: Preoperative serum P, serum Ca/P and osteocalcin levels may identify patients with PHPT at risk for early postoperative SH after PTX.

Pamidronate-induced irreversible symptomatic hypocalcemia in a dog with hypercalcemia after glucocorticoid withdrawal: a case report.

BACKGROUND: Pamidronate is used for the treatment of hypercalcemia. However, a rare but potential adverse event of pamidronate treatment is hypocalcemia. This report describes an unusual case of severe, irreversible hypocalcemia after a single injection of pamidronate for the treatment of hypercalcemia due to glucocorticoid withdrawal in a dog. CASE PRESENTATION: An 11-year-old castrated male Maltese dog presented with anorexia, vomiting, and diarrhea (day 0). The patient had calcinosis cutis throughout the body, calcification of intraabdominal organs, mild azotemia, and severe hypercalcemia. The severe calcification was attributed to long-term glucocorticoid administration, which was discontinued 1 month before presentation. Fluid therapy, diuretics, calcitonin, and a single intravenous injection of pamidronate were used for the treatment of hypercalcemia. On day 14, normocalcemia was achieved, but renal failure occurred. On day 20, severe and irreversible hypocalcemia occurred, and on day 42, the patient was euthanized at the owner's request because of worsened hypocalcemia and renal failure. CONCLUSIONS: Although hypocalcemia is an extremely rare adverse event of bisphosphonate treatment, bisphosphonates like pamidronate can result in potentially life-threatening conditions according to the patient's underlying conditions. Therefore, the patient's condition should be closely monitored and any underlying conditions should be carefully evaluated before initiating the treatment for hypercalcemia using pamidronate.

Clinical and molecular characteristics of two Italian kindreds with hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome.

PURPOSE: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disease characterized by the triad of hypoparathyroidism, deafness, and renal abnormalities. The disorder is caused by the haploinsufficiency of the zinc finger transcription factor GATA3 and exhibits a great clinical variability with an age-dependent penetrance of each feature. We report two unrelated kindreds whose probands were referred to our outpatient clinic for further evaluation of hypoparathyroidism. METHODS: The proband of family 1, a 17-year-old boy, was referred for severe hypocalcemia (5.9 mg/dL) incidentally detected at routine blood tests. Abdomen ultrasound showed bilateral renal cysts. The audiometric evaluation revealed the presence of bilateral moderate hearing loss although the patient could communicate without any problem. Conversely, the proband of family 2, a 19-year-old man, had severe symptomatic hypocalcemia complicated by epileptic seizure at the age of 14 years; his past medical history was remarkable for right nephrectomy at the age of 4 months due to multicystic renal disease and bilateral hearing loss diagnosed at the age of 18 years. RESULTS: Based on clinical, biochemical, and radiologic data, HDR syndrome was suspected and genetic analysis of the GATA3 gene revealed the presence of two pathogenetic variants in exon 3, c.404dupC and c.431dupG, in the proband of family 1 and 2, respectively. CONCLUSION: HDR syndrome is a rare cause of hypoparathyroidism and must be excluded in all patients with apparently idiopathic hypoparathyroidism. A correct diagnosis is of great importance for early detection of other HDR-related features and genetic counseling.

Features of patients and fracture risk in hypoparathyroidism; a single center study.

PURPOSE: Patients with hypoparathyroidism (hypoPT) have low bone turnover and high bone mineral density (BMD). However, data on fracture risk are conflicting. The objectives of this study were: 1. To describe clinical/biochemical characteristics of hypoPT patients followed at a single medical center. 2. To identify postsurgical hypoPT patients and investigate their fracture rate compared with gender/age-matched post-surgical normocalcemic patients. METHODS: Retrospective analysis of patient's medical records treated at the tertiary medical center in 2010-2021 identified by computerized medical database search. RESULTS: The cohort included 133 patients (91% women, mean age 64 ± 13 years) of whom 105 (79%) had post-thyroidectomy hypoparathyroidism and the remainder had an autoimmune/idiopathic/other etiology. Mean follow-up time was 21 ± 12 and 27 ± 12 years, respectively. The control group included 142 post-thyroidectomy patients without hypoparathyroidism. Patients in the postsurgical hypoparathyroidism group were older and had higher calcium and PTH levels at diagnosis than the non-surgical hypoPT patients. Comparing the postsurgical hypoPT and postsurgical normocalcemic control patients revealed a significantly higher BMD in the hypoPT group. Yet, fracture rates were 31% in the postsurgical hypoparathyroidism group and 21% in the control group (P = 0.1) over a similar median follow-up period (17 and 18.4 years, respectively). In both groups the most common fracture site was the spine (50% and 70%, respectively; p = 0.33), mainly nonclinical morphometric fractures. Higher phosphorus blood level was associated with increased fracture risk. CONCLUSIONS: The relatively high BMD in patients with postsurgical hypoparathyroidism is not associated with lower fracture risk. Silent morphometric fractures are quite common in this group of patients.

Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro.

PURPOSE: Hypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro. METHODS: C2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated. RESULTS: The combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells. CONCLUSIONS: Our results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

FT4 is a novel indicator for risk assessment of severe hypocalcemia following parathyroidectomy.

OBJECTIVE: To analyze the risk factors associated with the development of severe hypocalcemia (SH) in patients who have undergone parathyroidectomy (PTX). METHODS: This research involved patients with chronic kidney disease-secondary hyperparathyroidism who underwent PTX between June 1, 2021, and May 31, 2023. SH was characterized by a serum total calcium (tCa) level below 1.8 mmol/L. This study aimed to analyze differences in preoperative laboratory findings and clinical manifestations between patients with and without SH. Logistic regression analysis was used to identify potential risk factors associated with the development of SH. RESULTS: The incidence of SH was 23% (n = 176). Significant differences were observed in free thyroxine (FT4), free triiodothyronine, alanine aminotransferase, osteocalcin, tCa, alkaline phosphatase (ALP), C-terminal cross-linked telopeptide of type I collagen, and parathyroid hormone between the SH and non-SH groups. The three independent risk factors for SH were tCa [odds ratio (OR) 0.063, 95% confidence interval (95% CI) 0.006-0.663], ALP (OR 1.003, 95% CI 1.001-1.005), and FT4 (OR 0.439, 95%CI 0.310-0.621). The area under the curve, sensitivity, specificity, and overall accuracy of this model were 0.904 (95% CI 0.856-0.952), 46.3%(95% CI 32.0%-61.3%), 94.8% (95% CI 89.7%-97.5%), and 83.5% (95% CI 77.3%-88.3%), respectively. CONCLUSION: The preoperative level of FT4 plays a crucial role in predicting the risk of SH after PTX. The combined FT4-ALP-tCa model demonstrates the ability to predict SH risk, providing valuable insights for customizing calcium supplementation strategies and improving clinical decision-making.

Development of a tool to calculate the probability of hypocalcemia after total thyroidectomy: a prospective study.

PURPOSE: This study aimed to evaluate the ability of the percentage of decrease in serum PTH level in the first 8 h after total thyroidectomy (TT) to predict hypocalcemia requiring Ca supplementation and develop a tool to predict it. METHODS: 97 patients who underwent TT with measurement of preoperative parathyroid hormone (PTH) levels were prospectively evaluated 1 and 8 h after TT; postoperative magnesium (Mg2PO) and phosphorus levels were evaluated on the 2nd day after surgery. The percentage of decrease in PTH level 1 h (%dPTH1h) and 8 h (%dPTH8h) postoperatively and predictors of hypocalcemia requiring Ca supplementation were evaluated and an equation was developed to predict this outcome. RESULTS: %dPTH1h (p = 0.002), %dPTH8h (p = 0.001) and (Mg2PO) (p < 0.01) were isolated predictors of postoperative hypocalcemia requiring Ca supplementation. The data obtained led to the development of two tools to predict this complication. CONCLUSIONS: The percentage of decrease in PTH level 1 h and 8 h postoperatively and the magnesium level on the 2nd day after surgery were predictors of more severe hypocalcemia, and an auxiliary tool for predicting this complication was developed.

Electrolyte disorders related emergencies in children.

This article provides a comprehensive overview of electrolyte and water homeostasis in pediatric patients, focusing on some of the common serum electrolyte abnormalities encountered in clinical practice. Understanding pathophysiology, taking a detailed history, performing comprehensive physical examinations, and ordering basic laboratory investigations are essential for the timely proper management of these conditions. We will discuss the pathophysiology, clinical manifestations, diagnostic approaches, and treatment strategies for each electrolyte disorder. This article aims to enhance the clinical approach to pediatric patients with electrolyte imbalance-related emergencies, ultimately improving patient outcomes.Trial registration This manuscript does not include a clinical trial; instead, it provides an updated review of literature.

Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET® in Japan: a new-user cohort study.

BACKGROUND: In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function. METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group). RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period. CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.

Effect of 2 dosages of prepartum cholecalciferol injection on blood minerals, vitamin D metabolites, and milk production in multiparous dairy cows: A randomized clinical trial.

The objective of the present study was to evaluate the effect of 2 dosages of prepartum cholecalciferol injection on blood minerals, vitamin D metabolites, and milk production. Cows entering their second or greater lactation (n = 158) were randomly assigned to a control group (CON) or one of 2 treatment groups receiving either 6 × 106 IU (6VitD) or 12 × 106 IU (12VitD) cholecalciferol intramuscularly on d 275 ± 1.2 (SD) of gestation. Concentrations of serum total Ca (tCa), phosphate, and Mg were determined on 1, 2, 3, 5, 7, and 10 d in milk (DIM). For a subsample of 30 cows entering the third lactation (n = 10/group), these samples were analyzed for cholecalciferol, 25-hydroxycholecalciferol (25-OHD3), and 24,25-dihydroxycholecalciferol (24,25-[OH]2D3). In these cows, we also determined 1,25-dihydroxycholecalciferol (1,25-[OH]2D3), the biologically most active metabolite, on 1, 2, 3, and 5 DIM. Repeated measures ANOVA was performed to evaluate the effect of different dosages of cholecalciferol on blood minerals, vitamin D metabolites, and milk yield over the first 5 test days after calving. Binary outcomes such as retained placenta and metritis were analyzed using a chi-squared test. Although the 12VitD treatment increased tCa concentrations on 1, 2, and 3 DIM compared with CON, administration of 6VitD increased tCa concentrations only on 1 DIM. Compared with CON cows and 6VitD cows, 12VitD cows had greater serum phosphate concentration during the first 10 DIM. Furthermore, 6VitD cows had greater serum phosphate concentrations compared with CON cows. On the contrary, 12VitD cows had lower serum Mg concentrations during the first 10 DIM compared with CON and 6VitD cows. Cholecalciferol was increased by the treatment and decreased quickly until 10 DIM. In respect to 25-OHD3, the 6VitD treatment resulted in a 4.1-fold increase in comparison to the CON group, while a 6.5-fold increase was observed in 12VitD animals. The vitamin D metabolite 24,25-(OH)2D3 increased linearly with 25-OHD3 serum levels, resulting in the highest concentrations in the 12VitD group. An increase of 1,25-(OH)2D3 until 3 DIM was observed in all cows. However, this rise was most pronounced in the CON group. The incidence of retained placenta was 1.9%, 11.5%, and 29.6%, and that of metritis was 11.5%, 15.4%, and 31.5% for CON, 6VitD, and 12VitD cows, respectively. Although none of the treated cows exerted clinical signs of hypocalcemia, one cow in CON incurred clinical hypocalcemia. Cows of the 12VitD group had a lower milk yield over the first 5 monthly test days compared with the control and 6VitD group (42.2 ± 0.5, 42.0, ± 0.5 and 40.7 ± 0.5 kg for control cows, 6VitD cows and 12VitD cows, respectively). Although no negative side effects were observed in 6VitD cows, we do not recommend the general application of 6 × 106 IU cholecalciferol before calving as positive effects on calcium homeostasis were marginal and restricted to the first DIM. The present findings confirm that the application of 12 × 106 IU cholecalciferol negatively affected milk production on this farm.

Effects of timing of oral calcium administration on milk production in high-producing early-lactation Holstein cows.

Supplementation of oral Ca via blanket administration of an oral Ca bolus at 0 and 24 h after calving has shown limited success in increasing production and minimizing adverse health events. Recent evidence that reductions in blood Ca at 4 d in milk (DIM) are more closely associated with negative outcomes than hypocalcemia at 0 to 24 h postpartum might explain this lack of Ca bolus efficacy. Therefore, our primary objective was to explore the effect of delayed oral Ca bolus supplementation on milk production, with secondary objectives of exploring the effects on disease incidence and postpartum blood Ca dynamics. We conducted a randomized controlled trial on multiparous Holstein cows (n = 998) from 4 herds in New York. At calving, cows were randomly assigned to 1 of 3 treatment groups: (1) control, no supplemental Ca at or around parturition (CON; n = 343); (2) conventional bolus, an oral Ca bolus containing 43 g of Ca at calving and 24 h later (BOL-C; n = 330); or (3) delayed bolus, an oral Ca bolus containing 43 g of Ca at 48 and 72 h after calving (BOL-D; n = 325). We created generalized linear mixed models to analyze differences in milk yield for the first 10 wk of lactation and serum total Ca (tCa) at 1 and 4 DIM between treatment groups; multivariable Poisson regression models were used to analyze adverse event outcomes (metritis, displaced abomasum, herd removal, or a combination of one or more of the 3) in the first 30 DIM. Milk yield increased by week and was not affected by treatment. However, a treatment by parity group interaction for milk yield showed that BOL-D cows in the third parity produced more milk than third-parity BOL-C or CON cows (BOL-D = 52.0 kg/d, 95% confidence interval [50.6, 53.4] kg/d, BOL-C = 47.9 [46.3, 49.5] kg/d, CON = 49.8 [48.2, 51.2] kg/d). The incidence of adverse health events was similar between treatments (BOL-D = 3.7%, BOL-C = 3.7%, CON = 3.6%). Serum tCa was lower at 1 than 4 DIM, and we detected no difference in tCa between treatment groups. Our findings suggest that delaying oral Ca bolus supplementation has limited influence on blood Ca concentrations but may be beneficial to cohorts of cows as a targeted prophylactic supplement to support milk production.

Milk component ratios and their associations with energy balance indicators and serum calcium concentration in early-lactation spring-calving pasture-based dairy cows.

Indirect assessment of metabolic status using milk samples provides a non-invasive and objective tool for cow-level health monitoring. Milk fat-to-protein ratio (FPR) has been commonly evaluated as an indirect measure for negative energy balance (EB) in confined dairy cows. However, milk component ratios have not been explored for their association with pasture-based cows' metabolic status. The objectives of this observational study were to 1) describe milk component ratios from 0 to 45 d postpartum, 2) evaluate the associations between milk component ratios [FPR, fat-to-lactose (FLR), protein-to-lactose (PLR)] and indicators of EB (serum ß-hydroxybutyrate (BHB) concentration at 5-45 d postpartum and body condition score (BCS) change during the transition period), and 3) evaluate the associations between milk component ratios and serum Ca concentration 0-4 d postpartum in spring-calving dairy cows from pasture-based commercial farms. Milk component ratios were determined on samples collected before AM or PM milkings from 548 cows at 0-45 d postpartum (n = 970). Serum BHB and Ca determinations were performed in blood samples collected at the time of milk sample collection at 5-45 d postpartum (n = 918) and 0-4 d postpartum (n = 50), respectively; and BCS change was calculated using BCS assigned between 29 d prepartum and 45 d postpartum (n = 851). Cows' calving date, parity (1st, 2nd-3rd or ≥ 4th) and breed (Holstein-Friesian or dairy crossbred) information was obtained from the farm records. Data was analyzed by multiple linear regression. Average milk FPR, FLR and PLR were 0.70, 0.53 and 0.72, respectively. Milk FPR linearly increased while milk FLR linearly decreased postpartum both at a rate of 0.004 units per day; milk PLR decreased 0.05 units per day for the first 30 d postpartum and moderately increased afterward. Milk FPR and FLR were 0.71 and 0.52 units lower before AM than PM milking, respectively; while milk PLR was similar before AM and PM milking. Milk FPR and FLR were 0.07 to 0.10 units higher for 2nd-3rd compared with 1st and ≥ 4th parity cows. Milk PLR was 0.03 units greater for ≥ 4th compared with 2nd-3rd and 1st parity cows. Further, crossbred cows had 0.07, 0.08 and 0.03 higher milk FPR, FLR and PLR than Holstein-Friesian cows, respectively. Moderate to high P-values along with moderate to small estimated slopes and wide 95% confidence intervals were observed for the associations between milk component ratios and indicators of EB. A positive linear association was observed between milk FPR and serum Ca concentration within 4 d postpartum; milk FPR increased 0.31 units per each mmol/L increase in serum Ca concentration. Cows with low serum Ca concentration within 4 d postpartum had 0.27 units lower milk FPR compared with cows at or above the threshold (2.12 mmol/L), and tended to have 0.15 units lower milk FPR compared with cows at or above the threshold (2.00 mmol/L). In conclusion, further research is needed to reach conclusions on the association between milk component ratios determined before milking and EB indicators. The potential of milk FPR for monitoring blood Ca status warrants further investigation in early-lactation pasture-based dairy cows.

Patterns of periparturient rumination and activity time in multiparous Holstein cows with and without dyscalcemia in early lactation.

Dyscalcemia, defined as reduced blood Ca at 4 DIM, is associated with reduced milk production and reproduction and an increased risk of negative health events. Cowside testing of blood Ca to diagnose dyscalcemia is difficult, and alternative methods to identify dyscalcemia are needed. Our objectives were to explore differences in periparturient rumination and activity time between cows with and without dyscalcemia and use activity and rumination variables to identify dyscalcemia. We performed a retrospective cohort analysis on data collected from multiparous Holstein cows (n = 182) from 2 herds in New York. Cows were affixed with ear or neck loggers to record daily activity (arbitrary units [AU]/d, defined by manufacturer) and rumination (min/d) times. Daily activity and rumination times were collected from 14 d before calving until 14 DIM. No cows received supplemental calcium or experienced clinical hypocalcemia during the study period. A blood sample was collected at 4 DIM and analyzed for total calcium concentration, and cows were subsequently classified as dyscalcemic if total calcium was ≤2.2 mmol/L (n = 57) or eucalcemic if total calcium was >2.2 mmol/L (n = 125). Linear mixed models were used to analyze differences in pre- and postpartum activity and rumination times between the calcemic groups. Logistic regression models were used to identify the probability of dyscalcemia from activity and rumination time variables from 0 to 4 DIM. Prepartum activity time was similar between eucalcemic and dyscalcemic cows (402.0 ± 10.4 AU/d and 395.1 ± 14.5 AU/d, respectively). Postpartum eucalcemic cows had greater activity time than dyscalcemic cows (436.1 ± 10.7 vs. 407.8 ± 14.7 AU/d, respectively). Prepartum rumination time was similar between eucalcemic and dyscalcemic cows (512.6 ± 9.8 min/d vs. 504.2 ± 14 min/d, respectively). Postpartum eucalcemic cows had greater rumination time than dyscalcemic cows (512.3 ± 10.5 min/d vs. 480.5 ± 15 min/d, respectively). Logistic regression models yielded AUC values ranging from 0.71 to 0.79, sensitivities of 17.5% to 40.3%, specificities of 91.2% to 94.4%, accuracy of 70.3% to 77.0%, positive predictive values of 59.0 to 76.0%, and negative predictive values of 72.0% to 78.0%. Our findings suggest that differences exist in postpartum activity and rumination times between cows that experience dyscalcemia and those that remain eucalcemic. Utilizing activity and rumination time data in the immediate postpartum period shows utility in identifying cows with dyscalcemia, which could aid in management decisions that ameliorate the associated negative outcomes; however, further work is needed to optimize their capabilities.

A prospective cross-sectional study on hypocalcemia after total thyroidectomy in patients with Graves' disease: insights on secondary hyperparathyroidism.

PURPOSE: To investigate the parathyroid function and calcium (Ca) levels in the secondary hyperparathyroidism (SHPT) state in patients with Graves' disease. METHODS: We examined 31 consecutive patients with Graves' disease without chronic kidney disease, who were treated with total thyroidectomy. The patients were divided into a normal parathyroid hormone (PTH) group (NPTH group; n = 19) with a PTH level ≤ 65 pg/mL, and a secondary hyperparathyroidism group (SHPT group; n = 12), with a PTH level > 65 pg/mL. The PTH and Ca-related parameters were examined and the risk factors for postoperative hypocalcemia were analyzed. RESULTS: The preoperative Ca level was significantly lower (2.24 ± 0.06 vs. 2.31 ± 0.07 mmol/L, p < 0.05) in the SHPT group than in the NPTH group. The reduction in PTH, 1,25-dihydroxyvitamin D (1,25(OH)2D), and Ca levels from the preoperative day to the next morning was significantly greater in the SHPT group than in the NPTH group (p < 0.05). When intraoperative factors were included, the decrease in the PTH level alone was significant. SHPT was a significant factor in determining the extent of PTH reduction. CONCLUSIONS: Hyperfunctioning parathyroid glands in the SHPT state were more susceptible to postoperative PTH reduction, which, combined with low preoperative Ca levels, increased the risk of postoperative hypocalcemia in patients with Graves' disease.