Tubular calcium, magnesium, and phosphate excretion during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy: A prospective study.

OBJECTIVES: Hypocalcemia, hypomagnesemia, and hyperphosphatemia are common electrolyte disturbances in perinatal asphyxia (PA). Different reasons have been proposed for these electrolyte disturbances. This study investigated the effect of the urinary excretion of calcium (Ca), magnesium (Mg), and phosphorus (P) on the serum levels of these substances in babies who were treated using therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) caused by PA. This study sheds light on the pathophysiology that may cause changes in the serum values of these electrolytes. METHODS: This study included 21 healthy newborns (control group) and 38 patients (HIE group) who had undergone therapeutic hypothermia due to HIE. Only infants with a gestational age of 36 weeks and above and a birth weight of 2000 g and above were evaluated. The urine and serum Ca, Mg, P, and creatinine levels of all infants were evaluated at 24, 48, and 72 h. RESULTS: The lower serum Ca value and the higher serum P value of the HIE group were found to be statistically significant compared to the control group (p<0.05). There was no significant difference in serum Mg values between the groups. However, hypomagnesemia was detected in five patients from the HIE group. The urine excretion of FeCa and FeMg at 24 h, and FeP excretion at 48 and 72 h were found to be significantly higher in the HIE group compared to the control group. CONCLUSIONS: This study determined that the urinary excretion of Ca, Mg, and P has an effect on the serum Ca, Mg, and P levels of infants with HIE.

Case Report: Severe Hypocalcemic Episodes Due to Autoimmune Enteropathy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic disorder, associated with endocrine deficiencies and non-endocrine involvement. Gastrointestinal (GI) manifestations appear in approximately 25% of patients and are the presenting symptom in about 10% of them. Limited awareness among pediatricians of autoimmune enteropathy (AIE) caused by destruction of the gut endocrine cells in APECED patients delays diagnosis and appropriate therapy. We describe an 18-year-old female presenting at the age of 6.10 years with hypoparathyroidism, oral candidiasis and vitiligo. The clinical diagnosis of APECED was confirmed by sequencing the autoimmune regulator-encoding (AIRE) gene. Several characteristics of the disease-Hashimoto's thyroiditis, Addison's disease, diabetes mellitus type 1 and primary ovarian insufficiency-developed over the years. She had recurrent episodes of severe intractable hypocalcemia. Extensive GI investigations for possible malabsorption, including laboratory analyses, imaging and endoscopy with biopsies were unremarkable. Revision of the biopsies and chromogranin A (CgA) immunostaining demonstrated complete loss of enteroendocrine cells in the duodenum and small intestine, confirming the diagnosis of AIE. Management of hypocalcemia was challenging. Only intravenous calcitriol maintained calcium in the normal range. Between hypocalcemic episodes, the proband maintained normal calcium levels, suggesting a fluctuating disease course. Repeated intestinal biopsy revealed positive intestinal CgA immunostaining. The attribution of severe hypocalcemic episodes to AIE emphasizes the need for increased awareness of this unique presentation of APECED. The fluctuating disease course and repeated intestinal biopsy showing positive CgA immunostaining support a reversible effect of GI involvement. CgA immunostaining is indicated in patients with APECED for whom all other investigations have failed to reveal an explanation for the malabsorption.

Use of pre-operative calcium and vitamin D supplementation to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy: a systematic review.

OBJECTIVE: This systematic review aimed to establish the evidence behind the use of pre-operative calcium, vitamin D or both calcium and vitamin D to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy. METHOD: This review included prospective clinical trials on adult human patients that were published in English and which studied the effects of pre-operative supplementation with calcium, vitamin D or both calcium and vitamin D on the rate of post-operative hypocalcaemia following total thyroidectomy. RESULTS: Seven out of the nine trials included reported statistically significantly reduced rates of post-operative laboratory hypocalcaemia (absolute risk reduction, 13-59 per cent) and symptomatic hypocalcaemia (absolute reduction, 11-40 per cent) following pre-operative supplementation. CONCLUSION: Pre-operative treatment with calcium, vitamin D or both calcium and vitamin D reduces the risk of post-operative hypocalcaemia and should be considered in patients undergoing total thyroidectomy.

Symptomatic hypocalcemia after treatment for hyperthyroidism in a woman with chromosome 22q11.2 deletion syndrome complicated by Graves' disease: longitudinal changes in the number of subsets of CD4 and CD8 lymphocytes after thyroidectomy.

Chromosome 22q11.2 deletion syndrome is a multisystem genetic disorder that presents with hypocalcemia due to congenital hypoparathyroidism; cardiovascular, renal, and facial anomalies; and skeletal defects. This syndrome is also associated with an increased risk of autoimmune disease. We report here on a 33-year-old Japanese woman with 22q11.2 deletion syndrome complicated by Graves' disease. The patient had facial abnormalities and a history of a surgical procedure for a submucous cleft palate at age 3 years. At age 33, the patient was diagnosed with Graves' disease because both hyperthyroidism and thyroid stimulating hormone receptor antibody were present. The patient's serum calcium level was within the normal range, but symptomatic hypocalcemia developed 1 month after treatment with methimazole was started for thyrotoxicosis. Methimazole was discontinued because it caused liver dysfunction, so the patient underwent total thyroidectomy to treat her Graves' disease. We examined longitudinal changes in the number of subsets of CD4 and CD8 lymphocytes, including regulatory T (T reg) cells and PD-1+CD4+ and PD-1+CD8+ T cells, after treatment by total thyroidectomy. A flowcytometry analysis demonstrated that circulating PD-1+CD4+ and PD-1+CD8+ T cells gradually decreased over time, as did circulating T reg cells and circulating CD19+ B cells. These findings suggest that PD-1-positive CD4+ and CD8+ T cells and T reg cells may have been associated with the autoimmunity in our patient with chromosome 22q11.2 deletion syndrome complicated by Graves' disease.

Hypocalcemia is associated with adverse clinical course in patients with upper gastrointestinal bleeding.

Acute non-variceal upper gastrointestinal bleeding (NV-UGIB) is associated with significant morbidity and mortality. Early and efficient risk stratification can facilitate management and improve outcomes. We aimed to determine whether the level of ionized calcium (Ca++), an essential co-factor in the coagulation cascade, is associated with the severity of bleeding and the need for advanced interventions among these patients. This was a retrospective single-center cohort study of all patients admitted due to NV-UGIB. The primary outcome was transfusion of ≥ 2 packed red blood cells, arterial embolization, or emergency surgery. Secondary outcomes included (1) transfusion of ≥ 2 packed red blood cells, (2) arterial embolization, or emergency surgery, and (3) all-cause in-hospital mortality. Multivariable logistic regression was performed to determine whether Ca++ was an independent predictor of these adverse outcomes. 1345 patients were included. Hypocalcemia was recorded in 604 (44.9%) patients. The rates of primary adverse outcome were significantly higher in the hypocalcemic group, 14.4% vs. 5.1%, p < 0.001. Secondary outcomes-multiple transfusions, need for angiography or surgery, and mortality were also increased (9.9% vs. 2.3%, p < 0.001, 5.3% vs. 2.8%, p = 0.03, and 33.3% vs. 24.7%, p < 0.001, respectively). Hypocalcemia was an independent predictor of primary and all the secondary outcomes, except mortality. Hypocalcemia in high-risk hospitalized patients with NV-UGIB is common and independently associated with adverse outcomes. Ca++ monitoring in this population may facilitate the rapid identification of high-risk patients. Trials are needed to assess whether correction of hypocalcemia will lead to improved outcomes.

Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.

Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.

Impact of low serum calcium at hospital admission on SARS-CoV-2 infection outcome.

BACKGROUND: Calcium is an essential ion for pathogen survival and virulence and is involved in the regulation of the inflammatory response. Hypocalcemia is a common laboratory finding in critically ill patients. Data regarding levels of calcium in SARS-CoV-2 infection is scarce. Patients with SARS-CoV-2 infection who present with hypocalcemia could have a worse outcome. METHODS: We performed a retrospective analysis of hospitalized patients with SARS-CoV-2 infection and included all patients who had any serum calcium measurement in the first 72h since hospital admission. The main objective was to investigate the relation of low serum calcium with adverse outcome, measured by the requirement of high oxygen support - defined as high flow nasal cannula oxygen, non-invasive mechanical ventilation and/or invasive ventilation - intensive care unit admission or death. RESULTS: A total of 316 patients were included in the study. Median age was 65 years (IQR 55-74); 65% were men. Hypocalcemia within 72h since hospital admission was present in 63% of patients. A higher number of patients in the hypocalcemia group required high oxygen support during hospitalization (49% vs 32%; p=0,01) and were admitted to the ICU (42% vs 26%; p=0,005). No differences in mortality were observed between groups. CONCLUSIONS: Hypocalcemia is frequent in hospitalized patients with SARS-CoV-2 infection and can identify patients who will have a worse outcome. More studies are needed to understand the role of calcium metabolism in SARS-CoV-2 infection and to address the clinical implications and therapeutic interventions it might have.

Denosumab-associated hypocalcemia: Does gender play a role?

OBJECTIVE: It is well recognized that the presentation, treatment, and outcomes of various diseases may differ between men and women. We recently reported a 7.4% rate of denosumab-associated hypocalcemia in community-dwelling osteoporotic patients. This study sought to investigate the role of gender in this complication. STUDY DESIGN: Retrospective community-dwelling cohort. METHOD: The databases of a large health maintenance organization were searched for adult patients treated with denosumab for osteoporosis in 2010-2018. Rates and predictors of denosumab-associated hypocalcemia (serum calcium ≤8.5 mg/mL) were analyzed by gender. RESULTS: The cohort included 1871 women and 134 men. Compared with the women, the men were characterized by older median age (81 vs. 77 years, p = 0.005), higher likelihood to receive denosumab as a first-line treatment (22% vs. 6%, p < 0.001), less treatment with calcium supplements (42% vs. 53%, p = 0.012), and lower median eGFR level (66.1 vs. 79.8 mL/min/1.73m2, p < 0.001). Denosumab-associated hypocalcemia developed in 133 women (7.1%) and 16 men (11.9%) (p = 0.04); the drug was discontinued in 75% and 61%, respectively. The strongest predictors of hypocalcemia in women were levels of pretreatment albumin-adjusted serum calcium (OR 0.08, 95% CI (0.04, 0.14)) and creatinine (OR 2.43, 95% CI (1.45, 4.05)). There were no predictors in men. On propensity matching of 126 men and 126 women, gender was not a predictor of hypocalcemia. CONCLUSION: Denosumab-treated men were significantly older than treated women and had a lower eGFR and more advanced osteoporosis. These findings suggest that selection bias rather than male genderper se underlies the higher rate of denosumab-associated hypocalcemia in men.

Preoperative Vitamin D Supplementation in Patients With Vitamin D Deficiency Undergoing Total Thyroidectomy.

BACKGROUND: Transient hypocalcemia due to parathyroid gland or vessel manipulation is a common complication following thyroidectomy. Considering the role of 25-hydroxyvitamin D (25(OH)D) in calcium hemostasis, this study aimed to evaluate the effect of preoperative vitamin D supplementation on hypocalcemia incidence in thyroidectomy patients. METHODS: In this randomized clinical trial, 100 patients scheduled for total thyroidectomy and suffering from preoperative moderate or severe vitamin D deficiency were enrolled. Patients were randomly allocated to either study or control groups using the sealed envelope method. Patients in the study group received vitamin D3 50,000-unit pearl weekly for 4 weeks prior to the operation. The control group received placebo. Total and ionized serum calcium levels were checked before surgery, the day after surgery, and 2 weeks postoperatively. RESULTS: No significant difference was observed in terms of demographic data. During serial total calcium checks (5 episodes), total calcium levels changed significantly in patients who had received vitamin D supplements compared to the control group (P = 0.043). Symptomatic hypocalcemia incidence was significantly lower in patients supplemented with 25-hydroxyvitamin D (25(OH)D) (P = 0.04). Also, the requirement for intravenous calcium administration in order to treat the hypocalcemia symptoms was significantly lower in the study in comparison to the control group (P = 0.03). CONCLUSIONS: Vitamin D supplementation in patients with vitamin D deficiency might lead to a lower incidence of early-onset symptomatic hypocalcemia; hence, requiring less calcium supplementation for the management of hypocalcemia.

Overdosage of Calcarea phosphorica causes severe hypocalcaemia in a toddler.

A four-year-old girl presented with accidental ingestion of 200 tablets of Calcarea phosphorica. Although she was asymptomatic, she was found to have marked hypocalcaemia with a prolonged QTc interval on electrocardiogram. She was successfully treated with intravenous calcium, followed by oral maintenance.

Hungry bone syndrome after parathyroidectomy in end-stage renal disease patients: review of an alkaline phosphatase-based treatment protocol.

AIM: Hyperparathyroidism in chronic kidney disease-mineral and bone disorder is associated with significant morbidity and mortality. Parathyroidectomy is widely carried out as treatment despite complications such as hypocalcaemia post-surgery. Our centre has been using an ALP-based protocol to replace calcium postoperatively to prevent hypocalcaemia. We aim to describe and audit our calcium replacement protocol post-parathyroidectomy METHODS: We, retrospectively, analyse 167 end-stage kidney disease patients who had parathyroidectomy with auto-implantation in Singapore General Hospital between January 2008 and December 2013. Their calcium replacement postoperatively was initiated upon patient arrival back in ward on the same day of surgery based on their pre-op ALP prior to occurrence of hypocalcaemia. Patient demographics, surgical and laboratory parameters were reviewed from medical records. Changes in calcium postoperatively were reported to look for incidence of calcium derangement. RESULTS: Mean calcium levels between pre-operation day and post-operation day 7 ranged from 2.31 to 2.70 mmol/L. Decline in serum calcium was common in all patients prior to starting calcium replacement. Eighteen patients (10.9%) experienced hypocalcaemia immediately post-operation prior to commencement of IV calcium replacement. Patients with immediate post-operation hypocalcaemia had lower pre-operation calcium but higher pre-operation alkaline phosphatase (ALP) and pre-operation intact parathyroid hormone. Hypercalcaemia is common likely from aggressive IV calcium replacement using the protocol. The average length of stay for patients prior to calcium stabilization and discharge was 9 days. CONCLUSION: Implementation of an ALP-based prophylactic calcium replacement protocol with daily serum calcium monitoring can ameliorate severe hypocalcaemia post-parathyroidectomy.

Effect of subclinical and clinical hypocalcemia and dietary cation-anion difference on rumination activity in periparturient dairy cows.

Rumination involves a complex series of muscle contractions that bring a bolus of ingesta to the mouth for further mastication before it is swallowed again. Healthy cows ruminate 8 to 9 h/d. Hypocalcemia is known to disrupt nerve and muscle function. Our hypothesis was that hypocalcemia in periparturient cows would reduce rumination activity. Twenty-six Holstein cows entering their third lactation or greater were fed a control diet [dietary cation-anion difference (DCAD) = +196 mEq/kg of dry matter (DM)] or a low DCAD diet supplemented with anions (DCAD = -9 mEq/kg of DM) prepartum. Periparturient plasma Ca concentration and rumination rate were determined. Four of 12 control cows developed clinical milk fever, necessitating intravenous Ca therapy. Rumination rate decreased in all cows around the time of calving. Rumination rate on the first and second day of lactation was highly correlated with the cow's plasma Ca concentration on the first day of lactation. In one of our statistical models, a normocalcemic cow was defined as a cow whose plasma Ca concentration remained above 2.00 mM. Cows were retrospectively classified as normocalcemic, subclinically hypocalcemic, or clinically hypocalcemic (milk fever). Only 4 cows were considered normocalcemic, and all had been fed the low DCAD diet. Normocalcemic cows spent more time ruminating on the first day after calving than subclinically hypocalcemic cows or cows with milk fever. Cows with milk fever had a lower rumination rate than normocalcemic cows through d 3 of lactation. Rumination activity in cows with milk fever was almost nondetectable in the hours before and after intravenous Ca treatment for an extended period, despite the return of muscle function that allowed the cows to stand and eructate following treatment. Other statistical models using different definitions of normocalcemia gave qualitatively similar results. Diet had a great effect on plasma Ca concentration and rumination rate. Even when cows with clinical milk fever were removed from the control cow data set, cows on the low DCAD diet had significantly greater plasma Ca concentrations in the first 36 h after calving and a higher rumination rate on d 1 of lactation (248 ± 26 min) than control cows (158 ± 32 min).

Lower serum calcium and pre-onset blood pressure elevation in cerebral hemorrhage patients undergoing hemodialysis.

BACKGROUND: Asymptomatic blood pressure (BP) elevation may be associated with cerebral hemorrhage (CH); however, few studies have investigated this association. We aimed to evaluate BP elevation before CH in hemodialysis (HD) patients and elucidate its associated factors. METHODS: We reviewed HD patients treated for CH at our hospital between 2008 and 2019 (CH group). The control group comprised HD patients treated at Nagasaki Renal Center between 2011 and 2012. Data were obtained from medical records and three consecutive HD charts, made immediately before CH. HD1 was the session closest to onset, followed by HD2 and HD3. Systolic and mean BP were evaluated at the beginning of HD, and factors associated with BP elevation were investigated. RESULTS: The CH and control groups included 105 and 339 patients, respectively. Systolic and mean BP at HD1 were significantly higher than those at baseline (HD2 + HD3) in the CH group by 5 and 3 mmHg, respectively (P < 0.001). Multiple linear regression analysis showed that lower calcium levels were significantly associated with BP elevation in the CH group (P < 0.05). The CH group was sub-divided by June 2013; the latter group had lower calcium levels (9.2 mg/dL) and a marked systolic BP difference from baseline (+ 10 mmHg) compared with the former (9.5 mg/dL and - 4 mmHg). CONCLUSION: Asymptomatic BP elevation was observed in HD patients before CH; this elevation was associated with lower serum calcium levels and observed more frequently in the recent era. The precise mechanism underlying this effect remains unknown.

Hypocalcemia-Induced Slowing of Human Sinus Node Pacemaking.

Each heartbeat is initiated by cyclic spontaneous depolarization of cardiomyocytes in the sinus node forming the primary natural pacemaker. In patients with end-stage renal disease undergoing hemodialysis, it was recently shown that the heart rate drops to very low values before they suffer from sudden cardiac death with an unexplained high incidence. We hypothesize that the electrolyte changes commonly occurring in these patients affect sinus node beating rate and could be responsible for severe bradycardia. To test this hypothesis, we extended the Fabbri et al. computational model of human sinus node cells to account for the dynamic intracellular balance of ion concentrations. Using this model, we systematically tested the effect of altered extracellular potassium, calcium, and sodium concentrations. Although sodium changes had negligible (0.15 bpm/mM) and potassium changes mild effects (8 bpm/mM), calcium changes markedly affected the beating rate (46 bpm/mM ionized calcium without autonomic control). This pronounced bradycardic effect of hypocalcemia was mediated primarily by ICaL attenuation due to reduced driving force, particularly during late depolarization. This, in turn, caused secondary reduction of calcium concentration in the intracellular compartments and subsequent attenuation of inward INaCa and reduction of intracellular sodium. Our in silico findings are complemented and substantiated by an empirical database study comprising 22,501 pairs of blood samples and in vivo heart rate measurements in hemodialysis patients and healthy individuals. A reduction of extracellular calcium was correlated with a decrease of heartrate by 9.9 bpm/mM total serum calcium (p < 0.001) with intact autonomic control in the cross-sectional population. In conclusion, we present mechanistic in silico and empirical in vivo data supporting the so far neglected but experimentally testable and potentially important mechanism of hypocalcemia-induced bradycardia and asystole, potentially responsible for the highly increased and so far unexplained risk of sudden cardiac death in the hemodialysis patient population.

Hypocalcemic cardiomyopathy: a rare presenting manifestation of hypoparathyroidism.

Hypoparathyroidism patients present with features of hypocalcemia like carpopedal spasm, numbness and paresthesias but hypocalcemic cardiomyopathy leading to congestive heart failure (CHF) is a rare presentation. We present here a case of 55-year-old Asian man who was a known case of dilated cardiomyopathy for 6 months, presented with the chief complaints of shortness of breath on exertion and decreased urine output. On general physical examination, features suggestive of CHF were seen. Chvostek and Trousseau's sign was positive. The patient had a history of cataract surgery of both eyes 15 years ago. Further investigations revealed hypocalcemia. Echo showed severe global hypokinesia of left ventricle with left ventricle ejection fraction 15%. This CHF was refractory to conventional treatment, though, with calcium supplementation, the patient improved symptomatically. On follow-up after 3 months, an improvement was seen in the echocardiographic parameters with ejection fraction improving to 25%.

Comparison of hypocalcemia rates between LigaSure and clamp-and-tie hemostatic technique in total thyroidectomies.

BACKGROUND: Postoperative hypocalcemia (PH) is a serious complication after total thyroidectomy. This study aimed to compare PH rates between LigaSure Small Jaw (LSJ) and clamp-and-tie hemostatic technique in patients undergoing total thyroidectomy. METHODS: Four hundred twenty patients were divided into two groups: group L (210 patients) performed with LSJ and group C (210 patients) with clamp-and-tie technique. Serum ionized calcium (iCa) was measured before and 12, 24, 48, 72 hours after surgery. PH was defined as iCa lower than 4.2 mg/dL in at least two measurements. RESULTS: There was no significant difference between groups in sex, age, extent of surgery, pathology, and the strategy of intraoperative management of parathyroid glands (PG). The PH rate was significantly lower in group L compared to group C (22.9% vs 32.4%, P = .03). CONCLUSIONS: Compared to clamp-and-tie technique, LigaSure is superior to decrease PH rate after total thyroidectomy.

Clinical Presentation of Hypoparathyroidism.

Parathyroid hormone (PTH) is one of the major hormones that regulates serum calcium. Hypoparathyroidism occurs when PTH secretion is insufficient. The main symptoms of hypoparathyroidism are the result of low blood calcium levels, hypocalcemia, which interferes with normal muscle contraction and nerve conduction. As a result, people with hypoparathyroidism can experience paresthesia, an unpleasant tingling sensation around the mouth and in the hands and feet, as well as muscle cramps and severe spasms known as "tetany" that affect the hands and feet. Many also report a number of other subjective symptoms. Hypocalcemia can be the cause of medical emergencies, for example seizures, severe irregularities in the normal heart beat, as well as laryngospasm, stridor, bronchospasm, and wheezing.

Dysregulated Mineral Metabolism in AKI.

Dysregulated mineral metabolism is a nearly universal sequalae of acute kidney injury (AKI). Abnormalities in circulating mineral metabolites observed in patients with AKI include hypocalcemia, hyperparathyroidism, hyperphosphatemia, decreased vitamin D metabolite levels, and increased fibroblast growth factor 23 levels. We review the pathophysiology of dysregulated mineral metabolism in AKI with a focus on calcium, phosphate, parathyroid hormone, and vitamin D metabolites. We discuss how mineral metabolite levels can serve as novel prognostic markers for incident AKI and other related outcomes in various clinical settings. Finally, we discuss how vitamin D metabolites potentially could be used as novel therapeutic agents for AKI prevention and treatment.

Impaired residual renal function predicts denosumab-induced serum calcium decrement as well as increment of bone mineral density in non-severe renal insufficiency.

Denosumab treatment of osteoporotic patients, except those with severe renal insufficiency, reduced cCa levels. Low baseline cCa, low estimated glomerular filtration rate, and high bone turnover increased the risk of lower cCa, while increasing bone mineral density. Pretreatment with antiresorptive agents was beneficial in reducing the risk of hypocalcemia. INTRODUCTION: Although denosumab-induced hypocalcemia has been frequently observed in patients with chronic kidney disease (CKD) stages 4-5D being treated with denosumab for osteoporosis, few studies have assessed the risk factors for serum-corrected calcium (cCa) reductions in patients with non-severe renal insufficiency. This study assessed the risk factors for reduced cCa concentration following denosumab administration and analyzed factors predictive of changes in bone mineral density (BMD). METHODS: Seventy-seven osteoporotic patients, not including those with CKD stages 4-5D, were treated with 60 mg denosumab once every 6 months. Biochemical parameters and BMD were analyzed from prior to the initial dose until 1 month after the second dose. RESULTS: Following the first administration of denosumab, cCa levels decreased, reaching a minimum on day 7. Multiple linear regression analyses showed that baseline cCa, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, tartrate-resistant acid phosphatase-5b (TRACP-5b), and bone alkaline phosphatase (BAP) or pretreatment with antiresorptive agents were significant factors independently associated with the absolute reduction in cCa from baseline to day 7 (ΔcCa0-7 days). ΔcCa0-7 days after the second dose of denosumab was significantly lower than that after the first dose. After 6 months of denosumab treatment, both LS-BMD and FN-BMD significantly increased from baseline. LS-BMD and FN-BMD correlated significantly with baseline TRACP-5b or BAP and eGFR, respectively. CONCLUSIONS: Both low eGFR and high bone turnover were independent risk factors for denosumab-induced cCa decrement, and for increases in BMD. Pretreatment with antiresorptive agents may reduce the risk of hypocalcemia.