Hypocalcaemia in patients with prostate cancer treated with a bisphosphonate or denosumab: prevention supports treatment completion

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tetany 1 endocrinologydiseases
Denosumab 3 endocrinologydiseasesdrugs
cholecalciferol 6 endocrinologydiseasesdrugs
ergocalciferol 4 endocrinologydiseasesdrugs
hypocalcaemia 89 endocrinologydiseases
hypoparathyroidism 4 endocrinologydiseases
secondary hyperparathyroidism 2 endocrinologydiseases
calcitriol 7 endocrinologydiseasesdrugs
calcium carbonate 1 endocrinologydiseasesdrugs
calcium chloride 4 endocrinologydiseasesdrugs
hyperparathyroidism 2 endocrinologydiseases
zoledronic acid 17 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
Denosumab 4981 resorption, almost half of patients with prostate cancer and bone metastases could develop a SRE [[4]]. Denosumab is a more efficacious inhibitor of bone resorption than zoledronic acid and has shown superiority in
Denosumab 11341 induce osteoblasts to produce osteoclast inhibitory factors, and cause apoptosis of osteoclasts [[26]]. Denosumab is a monoclonal antibody against RANKL that disrupts signalling through RANK, thus preventing tumour-mediated
Denosumab 15938 to the active form (calcitriol), resulting in the reduced intestinal absorption of calcium [[39]]. Denosumab is a useful therapeutic option for patients with advanced cancer and renal insufficiency or CKD because,
calcitriol 6853 area.Main textDiagnosing hypocalcaemiaCalcium homeostasis is mediated by the effect of active vitamin D ( calcitriol ) and parathyroid hormone (PTH) on the gastrointestinal (GI) absorption of calcium, renal excretion of
calcitriol 15859 causes a reduction in the activity of 1-α-hydroxylase and conversion of vitamin D to the active form ( calcitriol ), resulting in the reduced intestinal absorption of calcium [[39]]. Denosumab is a useful therapeutic
calcitriol 23284 hydroxylated in the liver to form calcidiol and then in the kidneys to form the biologically active form, calcitriol [[49]]. Vitamin D deficiency is defined as a serum calcidiol concentration below 20 ng/ml (50 nmol/l),
calcitriol 26391 [[54]].Vitamin D can be given as ergocalciferol or cholecalciferol, or as the active metabolites alfacalcidol or calcitriol [[55]]. Ergocalciferol and cholecalciferol are both recommended for the treatment and prevention of
calcitriol 26829 patients with severe renal insufficiency (glomerular filtration rate < 30 ml/min); therefore, calcitriol or alfacalcidol should be administered for the treatment of hypocalcaemia in these patients [[57]].
calcitriol 26955 should be administered for the treatment of hypocalcaemia in these patients [[57]]. Treatment with calcitriol or alfacalcidol can lead to rapid changes in serum calcium levels, so patients should be monitored closely
calcitriol 33148 calcium supplements (as described above) and vitamin D (e.g., 50,000 IU each week for 8 weeks or calcitriol 0.5–1 μg/day for patients with hypoparathyroidism) as needed [[18]]. Treatment should be repeated
calcium carbonate 29073 adverse events are common in patients taking calcium supplements [[61]]. Compared with calcium citrate, calcium carbonate is more often associated with GI symptoms [[48]]. Although most GI adverse events are mild, a meta-analysis
calcium chloride 22900 receiving proton pump inhibitors [[48]]. Other calcium forms in supplements include calcium gluconate, calcium chloride , calcium lactate, calcium phosphate, and calcium citrate malate [[45], [46]].The main circulating form
calcium chloride 31008 juice250 ml195 Calcium-fortified cereals30 g137 Calcium-fortified bread40 g191aOnly if set with calcium chloride (E509) or calcium sulphate (E516)Treating hypocalcaemiaMild hypocalcaemiaPatients with mild hypocalcaemia
calcium chloride 32602 monitor these patients closely [[18]].Intravenously administered calcium gluconate (10%) is preferred to calcium chloride , which is a strong irritant. It can be given as repeated 50–100 ml boluses in 5% dextrose or by continuous
calcium chloride 32755 be given as repeated 50–100 ml boluses in 5% dextrose or by continuous infusion [[16], [67]]. If calcium chloride is given, it should be administered via a central line to prevent irritation of veins [[67]]. In order
cholecalciferol 23150 [[49]]. Vitamin D also exists in two inactive forms, namely vitamin D2 (ergocalciferol) and vitamin D3 ( cholecalciferol ), which are hydroxylated in the liver to form calcidiol and then in the kidneys to form the biologically
cholecalciferol 25194 Practice Guidelines recommend that these patients should be treated with 50,000 IU of ergocalciferol or cholecalciferol weekly for 8 weeks or 6000 IU daily until a serum calcidiol level above 75 nmol/l is achieved. This
cholecalciferol 26329 starting therapy with an inhibitor of bone resorption [[54]].Vitamin D can be given as ergocalciferol or cholecalciferol , or as the active metabolites alfacalcidol or calcitriol [[55]]. Ergocalciferol and cholecalciferol
cholecalciferol 26429 cholecalciferol, or as the active metabolites alfacalcidol or calcitriol [[55]]. Ergocalciferol and cholecalciferol are both recommended for the treatment and prevention of vitamin D deficiency [[52]], although cholecalciferol
cholecalciferol 26540 cholecalciferol are both recommended for the treatment and prevention of vitamin D deficiency [[52]], although cholecalciferol is the more potent of the two agents [[56]] and is thus prescribed more commonly than ergocalciferol.
cholecalciferol 31247 grade 1) should be treated with oral calcium and vitamin D supplements: calcium (1 g) and vitamin D ( cholecalciferol at least 800 IU) should be given twice daily [[65]]. Patients who are vitamin D deficient and who do
ergocalciferol 23118 form of vitamin D is calcidiol [[49]]. Vitamin D also exists in two inactive forms, namely vitamin D2 ( ergocalciferol ) and vitamin D3 (cholecalciferol), which are hydroxylated in the liver to form calcidiol and then in
ergocalciferol 25176 Society Clinical Practice Guidelines recommend that these patients should be treated with 50,000 IU of ergocalciferol or cholecalciferol weekly for 8 weeks or 6000 IU daily until a serum calcidiol level above 75 nmol/l
ergocalciferol 26311 deficient before starting therapy with an inhibitor of bone resorption [[54]].Vitamin D can be given as ergocalciferol or cholecalciferol, or as the active metabolites alfacalcidol or calcitriol [[55]]. Ergocalciferol and
ergocalciferol 26642 cholecalciferol is the more potent of the two agents [[56]] and is thus prescribed more commonly than ergocalciferol . The normal conversion of vitamin D to its active form is compromised in patients with severe renal
zoledronic acid 1179 ‘prostate cancer’, ‘bone-targeted agents’, ‘anti-resorptive agents’, ‘bisphosphonates’, ‘ zoledronic acid ’, ‘denosumab’, ‘hypocalcaemia’, and ‘hypocalcemia’. Additional references were suggested
zoledronic acid 3969 metastases, respectively (Amgen, data on file).Inhibitors of bone resorption, such as the bisphosphonate zoledronic acid and the fully human monoclonal antibody against the receptor activator of nuclear factor kappa B ligand
zoledronic acid 5047 metastases could develop a SRE [[4]]. Denosumab is a more efficacious inhibitor of bone resorption than zoledronic acid and has shown superiority in the prevention of SREs [[3], [10]]. Both agents have been associated with
zoledronic acid 5251 associated with an increased risk of hypocalcaemia, but the risk is greater with denosumab than with zoledronic acid , consistent with the greater efficacy of denosumab to inhibit bone resorption and reduce skeletal morbidity
zoledronic acid 6521 ‘prostate cancer’, ‘bone-targeted agents’, ‘anti-resorptive agents’, ‘bisphosphonates’, ‘ zoledronic acid ’, ‘denosumab’, ‘hypocalcaemia’, and ‘hypocalcemia’. Additional references relevant to
zoledronic acid 11012 [[25]].Hypocalcaemia has been reported as an adverse event associated with the use of bisphosphonates (such as zoledronic acid ) and denosumab. Bisphosphonates are analogues of a natural regulator of bone metabolism, pyrophosphonate.
zoledronic acid 11772 and clinical data indicate that denosumab is a more efficacious inhibitor of osteoclast activity than zoledronic acid [[11]] and has shown superiority in the prevention of SREs compared with zoledronic acid [[3], [10]].
zoledronic acid 11861 activity than zoledronic acid [[11]] and has shown superiority in the prevention of SREs compared with zoledronic acid [[3], [10]]. Consistent with the potent action of denosumab, in a combined analysis of three clinical
zoledronic acid 12010 potent action of denosumab, in a combined analysis of three clinical trials comparing denosumab and zoledronic acid in patients with bone metastases from solid tumours (including prostate cancer) or multiple myeloma,
zoledronic acid 12204 cancer) or multiple myeloma, hypocalcaemia of any grade occurred more frequently with denosumab than with zoledronic acid (9.6% vs. 5%, respectively) (Fig. 1) [[11]].Fig. 1Proportion of patients receiving denosumab or zoledronic
zoledronic acid 12317 acid (9.6% vs. 5%, respectively) (Fig. 1) [[11]].Fig. 1Proportion of patients receiving denosumab or zoledronic acid who developed hypocalcaemia of any grade. Figure reproduced with permission from Body et al. Eur J Cancer
zoledronic acid 13000 of 125 patients with bone metastases (including 92 patients with prostate cancer) who were receiving zoledronic acid showed that hypocalcaemia of any grade occurred in 18.5% of the patients with prostate cancer. Of patients
zoledronic acid 16068 therapeutic option for patients with advanced cancer and renal insufficiency or CKD because, in contrast to zoledronic acid , it is not excreted by the kidneys and requires no dose adjustment for renal insufficiency [[6], [40]].
zoledronic acid 17493 treatment initiation (Fig. 3) and occurs earlier in patients receiving denosumab than in those receiving zoledronic acid ; in phase III trials, the median time to hypocalcaemia of grade 2 or higher was 3.8 months with denosumab
zoledronic acid 17637 median time to hypocalcaemia of grade 2 or higher was 3.8 months with denosumab and 6.5 months with zoledronic acid [[11]]. Similar findings have been reported in real-world studies; a retrospective chart review of 55
zoledronic acid 20376 calcium and/or vitamin D is associated with fewer hypocalcaemia adverse events for patients receiving zoledronic acid or denosumab. Use of these supplements [recommended doses: calcium ≥ 500 mg/day; vitamin D ≥ 400
zoledronic acid 20627 /day] has been shown to lower the risk of developing hypocalcaemia by 27% or 40% in patients receiving zoledronic acid or denosumab, respectively (Fig. 4) [[11]]. This reduction in risk is impressive given that, in this
Select Disease Character Offset Disease Term Instance
hyperparathyroidism 7192 hypocalcaemia has many potential causes, such as vitamin D deficiency (which can lead to secondary hyperparathyroidism ), abnormal magnesium or phosphate levels, and partial or complete hypoparathyroidism [[14], [15]]. Hypocalcaemia
hyperparathyroidism 15710 resorption [[21], [29]]. This increased risk of hypocalcaemia likely results from CKD-induced secondary hyperparathyroidism [[21]]. Additionally, CKD causes a reduction in the activity of 1-α-hydroxylase and conversion of vitamin
hypocalcaemia 703 delay the progression of bone pain. However, these agents are associated with an increased risk of hypocalcaemia , which, although often mild and transient, can be serious and life-threatening. Here we provide practical
hypocalcaemia 854 transient, can be serious and life-threatening. Here we provide practical advice on managing the risk of hypocalcaemia in patients with advanced prostate cancer who are receiving treatment with bone resorption inhibitors.
hypocalcaemia 1219 agents’, ‘anti-resorptive agents’, ‘bisphosphonates’, ‘zoledronic acid’, ‘denosumab’, ‘ hypocalcaemia ’, and ‘hypocalcemia’. Additional references were suggested by the authors.Main textAmong patients
hypocalcaemia 1399 by the authors.Main textAmong patients with advanced cancer receiving a bisphosphonate or denosumab, hypocalcaemia occurs most frequently in those with prostate cancer, although it can occur in patients with any tumour
hypocalcaemia 1766 patients with bone metastases from solid tumours. Consequently, denosumab is more likely to induce hypocalcaemia than the bisphosphonates. Likewise, various bisphosphonates have differing potencies for the inhibition
hypocalcaemia 1925 bisphosphonates have differing potencies for the inhibition of bone resorption, and thus the risk of hypocalcaemia varies between different bisphosphonates. Other risk factors for the development of hypocalcaemia include
hypocalcaemia 2023 of hypocalcaemia varies between different bisphosphonates. Other risk factors for the development of hypocalcaemia include the presence of osteoblastic metastases, vitamin D deficiency, and renal insufficiency. Hypocalcaemia
hypocalcaemia 2296 both preventable and manageable. Serum calcium concentrations should be measured, and any pre-existing hypocalcaemia should be corrected, before starting treatment with inhibitors of bone resorption. Once treatment has
hypocalcaemia 2635 monitored during treatment with bisphosphonates or denosumab, particularly in patients at high risk of hypocalcaemia . If hypocalcaemia is diagnosed, patients should receive treatment with calcium and vitamin D.ConclusionWith
hypocalcaemia 2653 treatment with bisphosphonates or denosumab, particularly in patients at high risk of hypocalcaemia. If hypocalcaemia is diagnosed, patients should receive treatment with calcium and vitamin D.ConclusionWith preventative
hypocalcaemia 2862 preventative strategies and treatment, patients with prostate cancer who are at risk of, or who develop, hypocalcaemia should be able to continue to benefit from treatment with bisphosphonates or denosumab.BackgroundBone
hypocalcaemia 5187 superiority in the prevention of SREs [[3], [10]]. Both agents have been associated with an increased risk of hypocalcaemia , but the risk is greater with denosumab than with zoledronic acid, consistent with the greater efficacy
hypocalcaemia 5624 metastases from solid tumours who were receiving denosumab, four patients discontinued treatment because of hypocalcaemia [[12]].Patients with prostate cancer and osteoblastic metastases who are receiving treatment with inhibitors
hypocalcaemia 5801 metastases who are receiving treatment with inhibitors of bone resorption are at a particularly high risk of hypocalcaemia [[11]]. Although often mild and transient, hypocalcaemia can also present as a serious and life-threatening
hypocalcaemia 5858 resorption are at a particularly high risk of hypocalcaemia [[11]]. Although often mild and transient, hypocalcaemia can also present as a serious and life-threatening condition, which can lead to treatment interruption
hypocalcaemia 6030 condition, which can lead to treatment interruption or cessation. However, with proper patient monitoring, hypocalcaemia can be prevented and treated. In this review, we provide practical advice on managing the risk of hypocalcaemia
hypocalcaemia 6142 hypocalcaemia can be prevented and treated. In this review, we provide practical advice on managing the risk of hypocalcaemia in patients with advanced prostate cancer who are receiving treatment with bone resorption inhibitors.
hypocalcaemia 6561 agents’, ‘anti-resorptive agents’, ‘bisphosphonates’, ‘zoledronic acid’, ‘denosumab’, ‘ hypocalcaemia ’, and ‘hypocalcemia’. Additional references relevant to the topics of focus in the review were
hypocalcaemia 6773 were suggested by the authors based on their expert knowledge of the therapy area.Main textDiagnosing hypocalcaemia Calcium homeostasis is mediated by the effect of active vitamin D (calcitriol) and parathyroid hormone
hypocalcaemia 7093 osteoclast/osteoblast activity in the skeleton (which is the main calcium sink in the body) [[13]]. Consequently, hypocalcaemia has many potential causes, such as vitamin D deficiency (which can lead to secondary hyperparathyroidism),
hypocalcaemia 7493 life-threatening crises [[16]]; the Common Terminology Criteria for Adverse Events (CTCAE) define grades of hypocalcaemia from mild (grade 1) to severe (grade 5) (Table 1) [[17]].Table 1Common Terminology Criteria for Adverse
hypocalcaemia 7630 severe (grade 5) (Table 1) [[17]].Table 1Common Terminology Criteria for Adverse Events grading of hypocalcaemia [[17]]GradeTotal corrected calcium concentration, mmol/l (mg/dl)12.0–2.1 (8.0–LLN)21.75 to < 2.0
hypocalcaemia 7846 (7.0 to < 8.0)31.5 to < 1.75 (6.0 to < 7.0)4< 1.5 (< 6.0)5If death occurs as a result of hypocalcaemia LLN lower limit of normalExtracellular calcium is required for the normal functioning of muscles and
hypocalcaemia 7996 normalExtracellular calcium is required for the normal functioning of muscles and nerves. Thus, signs and symptoms of hypocalcaemia include muscle twitching, spasms, tingling, and numbness, and patients with severe hypocalcaemia may
hypocalcaemia 8093 of hypocalcaemia include muscle twitching, spasms, tingling, and numbness, and patients with severe hypocalcaemia may develop tetany, seizures, and cardiac dysrhythmias [[18]]. The development of neuromuscular excitability
hypocalcaemia 8433 experience a rapid fall in serum calcium concentration are often symptomatic, whereas those who develop hypocalcaemia gradually may be asymptomatic, with hypocalcaemia being diagnosed as an incidental biochemical finding
hypocalcaemia 8483 are often symptomatic, whereas those who develop hypocalcaemia gradually may be asymptomatic, with hypocalcaemia being diagnosed as an incidental biochemical finding [[18]]. However, if asymptomatic hypocalcaemia
hypocalcaemia 8583 hypocalcaemia being diagnosed as an incidental biochemical finding [[18]]. However, if asymptomatic hypocalcaemia is not treated, long-term consequences can include neuropsychiatric symptoms, cataract formation, and
hypocalcaemia 9154 calcium concentration must be corrected for albumin concentration in order to confirm a diagnosis of hypocalcaemia [[16]]. This is particularly important in patients with advanced cancer in whom albumin levels are frequently
hypocalcaemia 9939 of creatinine, phosphate, magnesium, vitamin D, and PTH levels is also recommended when diagnosing hypocalcaemia in order to identify other underlying causes of low serum calcium concentrations [[16]].Identifying
hypocalcaemia 10086 underlying causes of low serum calcium concentrations [[16]].Identifying patients who are at high risk of hypocalcaemia It is rare for patients with cancer to develop hypocalcaemia as a direct result of the primary tumour
hypocalcaemia 10146 [[16]].Identifying patients who are at high risk of hypocalcaemiaIt is rare for patients with cancer to develop hypocalcaemia as a direct result of the primary tumour [[23]]. However, low calcium concentrations are quite frequently
hypocalcaemia 10532 retrospective analyses, conducted before the introduction of bisphosphonate or denosumab treatment, hypocalcaemia was reported in 5–13% of patients with bone metastases, depending on the formula used to correct for
hypocalcaemia 10695 metastases, depending on the formula used to correct for albumin levels. Among these patients, 35% had hypocalcaemia of grade 1, 60% grade 2, and 5% grade 3 or higher [[25]]. Prevalence was highest among individuals with
hypocalcaemia 10887 highest among individuals with prostate cancer and bone metastases; 13–27% of these patients developed hypocalcaemia [[25]].Hypocalcaemia has been reported as an adverse event associated with the use of bisphosphonates
hypocalcaemia 12127 in patients with bone metastases from solid tumours (including prostate cancer) or multiple myeloma, hypocalcaemia of any grade occurred more frequently with denosumab than with zoledronic acid (9.6% vs. 5%, respectively)
hypocalcaemia 12347 (Fig. 1) [[11]].Fig. 1Proportion of patients receiving denosumab or zoledronic acid who developed hypocalcaemia of any grade. Figure reproduced with permission from Body et al. Eur J Cancer 2015;51:1812–21 under
hypocalcaemia 12597 (https://creativecommons.org/licenses/by-nc-nd/4.0/) [[11]]Real-world data suggest that the incidence of hypocalcaemia associated with bisphosphonates or denosumab may be higher than has been reported in clinical trials.
hypocalcaemia 12812 Retrospective studies of patients treated with denosumab have reported an incidence of 9–22% for hypocalcaemia of grade 2 or higher [[21], [28]–[30]]. A 12-month observational study of 125 patients with bone metastases
hypocalcaemia 13028 metastases (including 92 patients with prostate cancer) who were receiving zoledronic acid showed that hypocalcaemia of any grade occurred in 18.5% of the patients with prostate cancer. Of patients with any tumour type,
hypocalcaemia 13145 any grade occurred in 18.5% of the patients with prostate cancer. Of patients with any tumour type, hypocalcaemia of grade 3 or 4 occurred in 4% [[31]]. The higher incidence of hypocalcaemia encountered in real-world
hypocalcaemia 13222 with any tumour type, hypocalcaemia of grade 3 or 4 occurred in 4% [[31]]. The higher incidence of hypocalcaemia encountered in real-world studies compared with clinical trials may reflect poor adherence to guidelines
hypocalcaemia 13503 clinical practice [[12]]. Although both clinical trial data and real-world evidence suggest that severe hypocalcaemia is a relatively rare occurrence, it can be a serious, life-threatening condition that requires hospitalization
hypocalcaemia 13714 hospitalization and administration of intravenous calcium [[28]]. However, hospital admissions due to hypocalcaemia associated with inhibitors of bone resorption remain low, suggesting that such cases are often mild
hypocalcaemia 13940 [[30]].Analysis of data from phase III clinical trials has identified several factors that increase the risk of hypocalcaemia [[11]]. Hypocalcaemia associated with inhibitors of bone resorption has been shown to occur in patients
hypocalcaemia 14347 presence of osteoblastic metastases have been shown to associate significantly with an increased risk of hypocalcaemia [[11]]. By inhibiting bone resorption and preventing the release of calcium from bone, bisphosphonates
hypocalcaemia 14940 measurements for albumin levels. Moreover, vitamin D deficiency is associated with an increased risk of hypocalcaemia following treatment with inhibitors of bone resorption [[33], [34]] and is common in elderly people
hypocalcaemia 15537 filtration rate < 30 ml/min) or stage 4 or 5 chronic kidney disease (CKD) have an increased risk of hypocalcaemia associated with treatment involving inhibitors of bone resorption [[21], [29]]. This increased risk
hypocalcaemia 15654 associated with treatment involving inhibitors of bone resorption [[21], [29]]. This increased risk of hypocalcaemia likely results from CKD-induced secondary hyperparathyroidism [[21]]. Additionally, CKD causes a reduction
hypocalcaemia 16223 requires no dose adjustment for renal insufficiency [[6], [40]]. However, owing to the high risk of hypocalcaemia in patients with severe renal insufficiency, we advise caution when considering such patients for treatment
hypocalcaemia 16627 type I collagen and bone-specific alkaline phosphatase) at baseline are also at an increased risk of hypocalcaemia [[11]]. Additionally, patients with pre-existing hypocalcaemia, associated with impaired parathyroid
hypocalcaemia 16690 baseline are also at an increased risk of hypocalcaemia [[11]]. Additionally, patients with pre-existing hypocalcaemia , associated with impaired parathyroid function, have a high risk of developing hypocalcaemia following
hypocalcaemia 16783 pre-existing hypocalcaemia, associated with impaired parathyroid function, have a high risk of developing hypocalcaemia following treatment with inhibitors of bone resorption [[41]].Preventing hypocalcaemiaHypocalcaemia
hypocalcaemia 16870 of developing hypocalcaemia following treatment with inhibitors of bone resorption [[41]].Preventing hypocalcaemia Hypocalcaemia associated with inhibitors of bone resorption is avoidable in most cases (Fig. 2). With
hypocalcaemia 17262 associated with increased mortality [[2]].Fig. 2Recommendations for the prevention and treatment of hypocalcaemia Although hypocalcaemia can occur at any time during therapy, it is most frequently reported within 6 months
hypocalcaemia 17284 increased mortality [[2]].Fig. 2Recommendations for the prevention and treatment of hypocalcaemiaAlthough hypocalcaemia can occur at any time during therapy, it is most frequently reported within 6 months of treatment initiation
hypocalcaemia 17550 receiving denosumab than in those receiving zoledronic acid; in phase III trials, the median time to hypocalcaemia of grade 2 or higher was 3.8 months with denosumab and 6.5 months with zoledronic acid [[11]]. Similar
hypocalcaemia 17844 review of 55 patients with advanced cancer who were receiving denosumab found that, in most patients, hypocalcaemia developed shortly after treatment administration (median 16 days) and after a median of one injection
hypocalcaemia 18131 patients with cancer who received a median of 3–6 cycles of denosumab, found that the incidence of hypocalcaemia of any grade was higher during the first course of therapy (16.7%) than in second or later courses (6.1%)
hypocalcaemia 18418 in patients with bone metastases from breast cancer or prostate cancer showed that the incidence of hypocalcaemia did not increase with longer exposure to denosumab [[42]].Fig. 3First occurrence of hypocalcaemia by
hypocalcaemia 18516 of hypocalcaemia did not increase with longer exposure to denosumab [[42]].Fig. 3First occurrence of hypocalcaemia by time period in patients receiving denosumab (n = 313) [[11]]To prevent hypocalcaemia in patients
hypocalcaemia 18608 occurrence of hypocalcaemia by time period in patients receiving denosumab (n = 313) [[11]]To prevent hypocalcaemia in patients receiving a bisphosphonate or denosumab, serum vitamin D and albumin-corrected (or ionized)
hypocalcaemia 18810 albumin-corrected (or ionized) calcium concentrations should be measured before treatment initiation. Pre-existing hypocalcaemia must be corrected before treatment initiation [[5], [6]]. For patients with a substantial tumour burden
hypocalcaemia 19408 patients and that additional monitoring should be conducted in patients with suspected symptoms of hypocalcaemia and in those at high risk of hypocalcaemia [[6]]. However, in clinical practice, we recommend such monitoring
hypocalcaemia 19451 should be conducted in patients with suspected symptoms of hypocalcaemia and in those at high risk of hypocalcaemia [[6]]. However, in clinical practice, we recommend such monitoring following the initial dose of a bisphosphonate
hypocalcaemia 19635 following the initial dose of a bisphosphonate or denosumab only in patients who are at a high risk of hypocalcaemia , such as those who are critically ill or who have renal insufficiency. Nevertheless, we do recommend
hypocalcaemia 19948 bisphosphonate or denosumab. Additionally, patients should be counselled on the signs and symptoms of hypocalcaemia and encouraged to report symptoms indicative of this condition [[6]]. Monitoring allows early detection
hypocalcaemia 20069 encouraged to report symptoms indicative of this condition [[6]]. Monitoring allows early detection of hypocalcaemia and hence the correction of serum calcium concentration before administering further doses of a bisphosphonate
hypocalcaemia 20324 vitamin D supplementsPreventative supplementation with calcium and/or vitamin D is associated with fewer hypocalcaemia adverse events for patients receiving zoledronic acid or denosumab. Use of these supplements [recommended
hypocalcaemia 20577 vitamin D ≥ 400 International Units (IU) /day] has been shown to lower the risk of developing hypocalcaemia by 27% or 40% in patients receiving zoledronic acid or denosumab, respectively (Fig. 4) [[11]]. This
hypocalcaemia 20963 D at any time during the study (excluding those who reported supplement use only after their first hypocalcaemia event) [[11]].Fig. 4Hypocalcaemia risk in patients receiving calcium and/or vitamin supplementation
hypocalcaemia 21381 with a minimum of 500 mg calcium daily and 400 IU vitamin D daily is required [[6]]. When managing hypocalcaemia risk in patients with bone metastases from prostate cancer, it is important to note that those receiving
hypocalcaemia 26900 rate < 30 ml/min); therefore, calcitriol or alfacalcidol should be administered for the treatment of hypocalcaemia in these patients [[57]]. Treatment with calcitriol or alfacalcidol can lead to rapid changes in serum
hypocalcaemia 27390 denosumab, measures should be taken to maximise adherence to calcium and vitamin D supplements: the risk of hypocalcaemia and the importance of adherence to supplements should be discussed with patients, and serum calcium
hypocalcaemia 29816 [[64]], but we advise regular monitoring of vitamin D levels in patients who are at a high risk of hypocalcaemia and those for whom poor adherence to supplementation is suspected.Table 2Foods rich in calcium [[44],
hypocalcaemia 31067 cereals30 g137 Calcium-fortified bread40 g191aOnly if set with calcium chloride (E509) or calcium sulphate (E516)Treating hypocalcaemia Mild hypocalcaemiaPatients with mild hypocalcaemia (asymptomatic grade 1) should be treated with oral
hypocalcaemia 31085 bread40 g191aOnly if set with calcium chloride (E509) or calcium sulphate (E516)Treating hypocalcaemiaMild hypocalcaemia Patients with mild hypocalcaemia (asymptomatic grade 1) should be treated with oral calcium and vitamin
hypocalcaemia 31117 chloride (E509) or calcium sulphate (E516)Treating hypocalcaemiaMild hypocalcaemiaPatients with mild hypocalcaemia (asymptomatic grade 1) should be treated with oral calcium and vitamin D supplements: calcium (1 g)
hypocalcaemia 32033 recommend that treatment with inhibitors of bone resorption be continued in patients who experience grade 1 hypocalcaemia .Severe hypocalcaemiaFor symptomatic or at-risk patients [[11]], or those possibly/probably non-compliant
hypocalcaemia 32054 inhibitors of bone resorption be continued in patients who experience grade 1 hypocalcaemia.Severe hypocalcaemia For symptomatic or at-risk patients [[11]], or those possibly/probably non-compliant with oral calcium
hypocalcaemia 33010 salts, phosphate and bicarbonate should not be infused with the calcium [[16]]. Patients with severe hypocalcaemia should also receive oral calcium supplements (as described above) and vitamin D (e.g., 50,000 IU each
hypocalcaemia 33315 as needed [[18]]. Treatment should be repeated until symptoms have subsided. It should be noted that hypocalcaemia can be prolonged, so continuous administration of a dilute solution of calcium for a few days may be
hypocalcaemia 33719 administration is recommended because the rapid elevation of serum calcium concentration required to correct hypocalcaemia can result in cardiac arrhythmia [[18]].Retrospective analysis of patients treated for denosumab-associated
hypocalcaemia 33841 result in cardiac arrhythmia [[18]].Retrospective analysis of patients treated for denosumab-associated hypocalcaemia found that the median time from detection of hypocalcaemia to normocalcaemia was 33 days (range: 9–92 days)
hypocalcaemia 33900 patients treated for denosumab-associated hypocalcaemia found that the median time from detection of hypocalcaemia to normocalcaemia was 33 days (range: 9–92 days) [[28]]. However, the time to normalization of serum
hypocalcaemia 34503 treatment with inhibitors of bone resorption be delayed in patients who experience grade 2 or higher hypocalcaemia ; treatment can be continued once a patient has had a stable normal calcium level for a minimum of 4 weeks.
hypocalcaemia 34665 had a stable normal calcium level for a minimum of 4 weeks. In patients who have experienced severe hypocalcaemia , serum calcium levels should be measured 2 weeks after reinitiating treatment with an inhibitor of
hypocalcaemia 34861 with an inhibitor of bone resorption, and monthly thereafter. Our recommendations for the treatment of hypocalcaemia are summarised in Fig. 2.ConclusionHypocalcaemia associated with the use of bisphosphonates and denosumab
hypocalcaemia 35448 measures, patients with advanced prostate cancer, including those with additional risk factors for hypocalcaemia , should be able to continue to benefit from treatment with these agents
hypoparathyroidism 7278 to secondary hyperparathyroidism), abnormal magnesium or phosphate levels, and partial or complete hypoparathyroidism [[14], [15]]. Hypocalcaemia can range in severity from mild asymptomatic cases to acute life-threatening
hypoparathyroidism 8792 formation, and raised intracranial pressure [[18]]. Such cases predominantly occur in patients with chronic hypoparathyroidism [[19]].Measuring calcium concentrationsApproximately 50% of serum calcium exists in an unbound ionized
hypoparathyroidism 31654 3 months [[65]]. It is important to check whether a patient is hypomagnesaemic, which induces functional hypoparathyroidism leading to low serum calcium levels [[66]]. If a patient is hypomagnesaemic, precipitating drugs should
hypoparathyroidism 33194 vitamin D (e.g., 50,000 IU each week for 8 weeks or calcitriol 0.5–1 μg/day for patients with hypoparathyroidism ) as needed [[18]]. Treatment should be repeated until symptoms have subsided. It should be noted that
secondary hyperparathyroidism 7182 Consequently, hypocalcaemia has many potential causes, such as vitamin D deficiency (which can lead to secondary hyperparathyroidism ), abnormal magnesium or phosphate levels, and partial or complete hypoparathyroidism [[14], [15]]. Hypocalcaemia
secondary hyperparathyroidism 15700 bone resorption [[21], [29]]. This increased risk of hypocalcaemia likely results from CKD-induced secondary hyperparathyroidism [[21]]. Additionally, CKD causes a reduction in the activity of 1-α-hydroxylase and conversion of vitamin
tetany 8119 muscle twitching, spasms, tingling, and numbness, and patients with severe hypocalcaemia may develop tetany , seizures, and cardiac dysrhythmias [[18]]. The development of neuromuscular excitability depends on

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