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Intravenous bisphosphonates are widely used to treat osteoporosis and bone metastasis in cancer patients
The risk of hypocalcaemia is a rare but underestimated side effect of anti-resorptive treatment. Clinically apparent hypocalcaemia is mostly related to high-dose treatment with zoledronate and denosumab in cancer patients
Particular caution is...
Context in source publication
Context 1
... should have minimum enteral doses of 1'200 mg of calcium and 800 IU of vitamin D or corresponding supplements [35]. Furthermore, we recommend monitoring the nutri- tional status (e.g., by calculating the NRS) and to ade- quately correct malnutrition, since special attention with bisphosphonate treatment should be taken in malnourished patients, as it has been illustrated in case 1, 2 and 6 (table 4). Although the problem of hypocalcaemia is allegedly known, the high frequency of severe electrolyte imbalance presenting in a short time period to our clinic was worri- some. ...
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Introduction
The use of bisphosphonates is increasing, for treatment of hypercalcemia and pain in cancer, and post-menopausal osteoporosis and also to decrease the risk of skeletal morbidity in multiple myeloma and metastatic breast cancer.
Case report
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Purpose:
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Methods:
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Citations
... [19] In a review of the literature, Kreutle et al. reported that the true incidence of hypocalcaemia was difficult to measure with bisphosphonate therapy. [20] Broadbent et al. have described a case report of severe symptomatic hypocalcaemia following bisphosphonate therapy in a patient with advanced cancer, pointing to the significance of assessment of this ion status in palliative care. [21] Hypocalcaemia can be caused by myriad mechanisms, and there is a dearth of literature about its prevalence in the palliative care cancer population. ...
Objectives
Our research aimed to examine the characteristics of palliative oncology patients hospitalised through an emergency to look for the symptom profile, characteristics of dyselectrolytemia and blood investigations, and possible associations with mortality.
Materials and Methods
After institutional review board approval, a retrospective, observational study of patients hospitalised in our tertiary care specialty oncology hospital was undertaken. Records of hospitalised cancer patients admitted from the emergency department under palliative care from January 2019 to October 2021 were examined. As all admissions during this period were through emergency due to institution COVID-19 protocols, all elective admissions were excluded from the study. Data collected included patient characteristics, blood investigations, and comorbid history of systemic diseases and factors that could be associated with electrolyte imbalance.
Results
There were 157 emergency admissions during the study period. A majority were patients with solid tumours (92.4%). Pain was the most frequent cardinal symptom, along with other symptoms (68/157) or in isolation (33/157), followed by reduced oral intake (32/157) and altered sensorium (24/157). sixty-six patients died within the hospitalisation period. On long-term follow-up, only 8 (5.1%) were surviving. Hyponatraemia (43%), Hypoalbuminaemia (66%), and altered renal function (33.1%) were prevalent. We observed a weak positive correlation between sodium levels and outcome (r = 0.199, P = 0.016) and a strong positive correlation between albumin levels and survival outcomes (r = 0.329, P = 0.000). Patients with normal albumin had a higher chance of survival (odds ratio: 33.1225, 95% confidence interval: 3.415–321.20, P = 0.003).
Conclusion
Pain-reduced oral intake and altered sensorium are common emergency symptoms in oncology palliative care. Mortality is high in these patients. Hyponatraemia, hypoalbuminaemia, and deranged renal functions were commonly seen. Normal sodium and albumin levels were associated with higher chances of survival, and the association was strong for serum albumin levels. This may have prognostic utility.
... Symptomatic hypocalcemia should be treated with intravenous calcium gluconate or oral calcium supplements. Based on several clinical observations, calcium and vitamin D status should be assessed before intravenous administration and corrected if needed [29,30]. Osteonecrosis of the jaws has been reported in adults treated with bisphosphonates but not in pediatric patients [31]. ...
We report a 4-year-old with Gorham–Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old girl presented with back pain after falling on her back 2 months prior. Thoracolumbar spine X-ray revealed diffuse compression spinal fractures in T9-L2. Magnetic resonance imaging (MRI) confirmed multiple compression fractures at T9-L5 and revealed a paraspinal mass along the T1-L1 level. Based on clinical, radiological, and histopathological findings, Gorham–Stout disease was diagnosed. Treatment with sirolimus (0.5 mg twice daily, 1.6 mg/m2) was initiated and intravenous bisphosphonate (pamidronate, 1 mg/kg for 3 days, total 3 mg/kg every 4 months) was added for back pain; she had immediate improvement in back pain. After 9 months with this treatment, she had a mild increase in paraspinal lymphangiomatosis and aggravation in T9-L5 compression fractures; atenolol was administered. The patient underwent 11 months of combination treatment with bisphosphonate, sirolimus, and atenolol, and MRI showed mild degree of reduction in the paraspinal lesions at L1-L5. The patient is currently in stable condition with no back pain or side effects. The triple combination treatment with bisphosphonate, sirolimus, and atenolol may be helpful in stabilizing the disease course of GSD.
... The likely mechanism behind this is the effect that bisphosphonates have on lowering the serum calcium concentration. Bisphosphonates cause osteoclast apoptosis, leading to decreased calcium release from bone and possible hypocalcemia, (34) a known cause for prolonged QT interval on ECG. (35) Hypocalcemia, which was observed in four of five described case studies, (24,(26)(27)(28) decreases influx of calcium into myocytes phase 2 of the cardiac action potential, (36,37) prolonging ventricular repolarization, which is reflected in an ECG as a prolonged QT interval. ...
Bisphosphonates are first-line treatments for several bone and mineral disorders. Studies have reported an increased incidence of serious atrial fibrillation in patients receiving bisphosphonates, however, uncertainty remains as to if electrical disturbances are precipitated by bisphosphonates. We aimed to review the literature for studies reporting electrocardiogram findings in patients receiving intravenous bisphosphonates for any indication. We searched MEDLINE and EMBASE from inception until January 14, 2023, for studies reporting electrocardiogram parameters following intravenous bisphosphonate infusion. We excluded studies that only reported atrial fibrillation. Study quality was assessed using the Newcastle-Ottawa scale. Continuous data were meta-analysed if reported in at least two studies. Random-effects models were fitted and reported as standardised mean difference (SMD) with 95% confidence intervals (95%CI). We found 1,083 unique records, of which 11 met our inclusion and exclusion criteria. Studies had a low to low/moderate risk of bias. Six prospective cohort studies were included in the meta-analysis. Five studies used zoledronic acid, while one study used pamidronate. Most studies (n=4) were conducted in postmenopausal women with osteoporosis, one study was conducted in patients with bone metastases, and one study in children with osteoporosis secondary to cerebral palsy. Study populations ranged from n=15 to n=116. QTc was significantly longer post-infusion (SMD = 0.46 milliseconds [95%CI: 0.80 to 0.11]; n=67 patients, k=2 studies, τ2 = 0). There were no differences in heart rate, P wave (maximum), P wave (minimum), P wave dispersion, PR interval, QRS duration, QTc, QTc (maximum), QTc (minimum) and QTc dispersion. The correlation between pre- and post-infusion QTc was not significant (p=0.93). Overall, there is a weak association between intravenous bisphosphonate infusion and a QTc interval prolongation. However, there is insufficient evidence to support an association between intravenous bisphosphonate and any ECG variable changes, which may precipitate atrial fibrillation. This article is protected by copyright. All rights reserved.
... Cette carence va donc favoriser une hypocalcémie induite par les bisphosphonates. Le dosage ainsi que la substitution en calcium et vitamine D sont donc impératifs avant traitement par acide zolédronique [13], mais ne sont pas systématiquement réalisés [14]. ...
... Dieser Mangel begünstigt daher die Bisphosponatbedingte Hypokalzämie. Die Messung sowie die Substitution von Kalzium und Vitamin D sind darum vor der Behandlung mit Zoledronsäure unverzichtbar [13], sie werden aber nicht systematisch durchgeführt [14]. ...
... Different drugs causing tetany include bisphosphonates, denosumab, cisplatin, antiepileptics (e.g., phenytoin and phenobarbitone), aminoglycosides, diuretics, and PPIs. [70][71][72][73][74][75][76][77][78][79][80][81] Kanamycin is reported to cause Gitelman-like syndrome along with tetany. 82 Puri et al. reported tetany in an extensively drug-resistant tuberculosis patient due to capreomycin use which was associated with hypokalemia, hypocalcemia, and hypomagnesemia. ...
Introduction:
Awareness regarding the etiological spectrum of tetany is poor among physicians. Because of poor awareness, tetany is underdiagnosed and undertreated.
Materials and methods:
Databases like PubMed, PubMed Central, Scopus, and Google Scholar are searched to identify peer-reviewed articles on tetany. Case reports, case series, and original articles are analyzed to identify different causes of tetany prevalent in the community. Different causes found are analyzed and tabulated, and finally, a flowchart is made on the approach for diagnosing different underlying pathologies of tetany.
Results:
Both metabolic and respiratory alkalosis are important causes of tetany because of reduced ionized calcium levels. Gitelman syndrome (GS) is associated with metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria, and frequently causes normocalcemic tetany. Recurrent vomiting and primary hyperaldosteronism also cause tetany due to metabolic alkalosis. Hyperventilation syndrome (HVS) leads to respiratory alkalosis and is a frequent cause of tetany. Hyperventilation-induced tetany is also seen after spinal anesthesia and in respiratory disorders like asthma. Vitamin D deficiency (VDD), primary hypoparathyroidism, and pseudohypoparathyroidism (PHP) (1a, 1b, and 2) cause hypocalcemic tetany. Hypomagnesemia causes hypocalcemia and tetany due to peripheral parathyroid hormone resistance and impaired parathyroid hormone secretion. Drugs causing tetany include bisphosphonates, denosumab, cisplatin, antiepileptics, aminoglycosides, diuretics, etc. Tetany is also seen in acute pancreatitis, dengue, falciparum malaria, hyperemesis gravidarum, tumor lysis syndrome (TLS), massive blood transfusion, etc. Conclusion: The spectrum of disorders associated with tetany is diverse. Awareness of different causes will help early and proper diagnosis of tetany.
... Therefore it may lead to mild secondary hyperparathyroidism. Increased PTH cause increased renal reabsorption of calcium, and 1,25(OH) 2 D production leading to increased intestinal absorption of calcium 4 . So the patients with vitamin D or renal impairment may not be able to correct hypocalcaemia and may become symptomatic. ...
Zoledronic acid is a parenteral long acting bisphosphonate that has been used widely in the management of osteoporosis, bone metastasis and malignancy induced hypocalcaemia. Zoledronic acid is well tolerated but rarely severe hypocalcaemia and nephrotoxicity may occur. Here we report a case of 62 year male patient of metastatic Ca prostate who had severe hypocalcaemia after receiving intravenous zoledronic acid and docetaxel. Patient was hospitalized and managed with intravenous calcium supplementation and remained admitted for several days. Post recovery he was again started on zoledronic acid therapy and chemotherapy.
... In the literature, analysis of ZA-induced hypocalcemia is scarce but reports that this situation prevails in cancer patients, involving specific mechanisms [34]. There are little data on the feasibility of initiating ZA treatment despite 25(OH)D insufficiency. ...
Objective:
Zoledronic acid (ZA) is an antiosteoporotic drug that has been proven to reduce mortality after a hip fracture (HF). ZA is however underused with older HF patients. One possible cause may be the high prevalence of severe renal failure and hypocalcemia which contraindicate ZA administration. The aim of this study was to assess the prevalence of these 2 contraindications in patients aged 75 years or older admitted into an orthogeriatric (OG) unit after a low-energy HF. The secondary objective was to assess the prevalence of situations in which ZA must be used with caution.
Methods:
Our retrospective descriptive monocentric study was performed in an OG unit on a cohort of elderly patients hospitalized for HF from August 2015 to August 2017. Prevalence of hypocalcemia lower than 2 mmol/L and Cockcroft creatinine clearance lower than 35 mL/min was recorded.
Results:
Among the 194 patients admitted for HF, 136 patients (mean age 86 ± 5.6 years; 101 women) were included. The mean length of hospital stay was 15 ± 9 days. 111 (81.5%) had no contraindications to ZA administration. More than 80% presented situations in which ZA had to be used with caution, including 25(OH)D deficiency (20%).
Conclusion:
The majority of subjects aged 75 years or older admitted to hospital after an HF seem to have no contraindication for ZA administration during their immediate postoperative hospital stay. The hospitalization period after HF repair gives the opportunity to give most of them this treatment to improve their prognosis, taking into account situations in which ZA must be used with caution.
... The only re-analysis 17 of pivotal RCTs of bisphosphonates in participants with CKD excluded those with baseline abnormal serum calcium or phosphate levels and did not report on hypocalcaemia. Case reports 140,141 have suggested an association between bisphosphonate use and symptomatic hypocalcaemia, but bigger, better-designed cohort studies have failed to demonstrate this. Instead, they have confirmed an asymptomatic reduction in serum calcium following the initiation of bisphosphonate therapy, but with no clinical consequences. ...
Background
Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.
Objectives
The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.
Design
This was a new-user cohort study design with propensity score matching.
Setting and data sources
Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1–3 and from the Danish Odense University Hospital Databases for work package 4.
Participants
Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m ² were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m ² within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1–3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1–4.
Interventions/exposure
Bisphosphonate use, identified from primary care prescriptions (for work packages 1–3) or pharmacy dispensations (for work package 4), was the main exposure.
Main outcome measures
Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.
Results
Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.
Limitations
Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.
Conclusions
Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.
Future work
Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data.
Study registration
This study is registered as EUPAS10029.
Funding
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.
... Nevertheless, long-term BP use is associated with multiple rare but severe adverse effects. More specifically, adverse effects include events of the gastrointestinal tract, such as abdominal pain, nausea, dyspepsia, vomiting and diarrhea [6], osteonecrosis of the jaw [7] and the maxillae [8], osteonecrosis of the external ear canal [9], hypocalcaemia [10,11], atypical femoral fractures [12] or subtrochanteric fractures [13], carpal tunnel syndrome [14], renal failure [15], oesophageal cancer [16], uveitis with macular edema [17], interface dermatitis [18], orbital inflammation [19] and non-contact allergenic drug-induced baboon syndrome [20]. Recently, according to Cibickova et al. [21] experimental evidence has been provided that supports the idea of alendronate inhibiting cholesterol biosynthesis on the central nervous system. ...
Background:
Bisphosphonates (BPs) are forceful inhibitors of osteoclast-mediated bone resorption. Long-term BP use is associated with multiple rare but severe adverse effects. The objective of this study was to investigate the possible effects of BPs in the structure of femoral nerve. Specimens from the femoral nerve of ten female 12-month old Wistar rats were used as control group and ten female 12-month old Wistar rats to which Alendronate (Fosamax, Merck) was administered per os for 13 weeks, were used as research group. Samples were observed under a Transmission Electron Microscope. G ratio measurements and statistical analysis with SPSS program were also performed.
Results:
The control group showed no major changes of the nerve's histologic image, with the exception of some spots of thickness of the nerve myelin sheath. The research group showed major morphological changes which varied from partial disorganization or thickening of the myelin to severe myelin thickening and axon strangulation. A statistically significant difference of the G ratio between the two groups was observed.
Conclusions:
The reported values (found in literature) for the morphologic measurements of the femoral nerve in Wistar rats are not complying with the ones we found in our study. There was a significant reduction of all three variables (the mean axon like diameter, the myelin thickness, G ratio) studied in the femoral nerve of the research group in contrast to control group. Our study demonstrates a possible correlation between alendronate administration and femoral nerve's function, nevertheless due to the small specimen further research is needed.
