A real-world study of denosumab-related hypocalcaemia based on the US food and Drug Administration Adverse Event Reporting System database

doi:10.21203/rs.3.rs-5283355/v1

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A real-world study of denosumab-related hypocalcaemia based on the US food and Drug Administration Adverse Event Reporting System database

https://doi.org/10.21203/rs.3.rs-5283355/v1

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Objective

Review and discuss the risk factors for denosumab-induced hypocalcaemia through the US Food and Drug Administration Adverse Event Reporting System (FAERS)database.

Methods

Using the FAERS database from January 2010 to December 2023, we selected "hypocalcaemia" as the preferred term, "denosumab" as the targeted drug. We used the reporting odds ratio (ROR) based on disproportionality analysis to assess the association between the drug and adverse events. Logistic regression was conducted to identify risk factors for hypocalcaemia. Subgroups were based on dosage, indications, age, gender, and presence of chronic kidney disease. The onset time and the distribution were evaluated.

Results

We identified 2395 cases of denosumab-induced hypocalcaemia after removing duplicates. The odds ratio (OR) for patients with chronic kidney disease(CKD) was 4.21 (1.62–9.01), 2.38(1.99–2.83) for males, and 3.22 (2.06–5.24) for Xgeva(120mg-denosumab) compared to Prolia(60mg-denosumab). The tumor-related group had a 7.11-fold (5.13–10.15) increased risk, while the osteoporosis group had a 5.67-fold (3.25–10.27) increased risk. The adolescent group had a 3.28-fold (1.68–5.96) increased risk, while the elderly group showed a 0.82-fold(0.70–0.96) decreased risk. The median onset of hypocalcaemia with elderly patients was 16 days (7-62) and longer than the patients age from 18 to 65 (12days(5.75‐35),P < 0.05). The onset primarily occurs within two weeks after treatment except for the patients with CKD, whose onset had a constant incidence over time.

Conclusion

Xgeva, adolescents, males, tumor-related indications, and presence of chronic kidney disease were risk factors for denosumab-induced hypocalcaemia. Extended monitoring is recommended for patients with elderly age and CKD.

Patients with chronic kidney disease, males, and adolescents are at higher risk for denosumab-induced hypocalcaemia. Extended monitoring is needed for the elderly and CKD patients.

Denosumab represents a significant advancement in the treatment of osteoporosis and offers a novel mechanism of action compared to other treatment methods. It is a human monoclonal antibody that inhibits bone resorption by binding to the receptor activator of nuclear factor kappa-β ligand (RANKL) (1). This inhibition of RANKL prevents the activation of RANK on osteoclasts, reducing bone resorption and increasing bone density(2). Denosumab is available in two formulations: Prolia, which is a 60mg formulation, and Xgeva, which is a 120mg formulation. Prolia has effectively reduced the risk of vertebral, hip, and non-vertebral fractures in postmenopausal women(3). Additionally, denosumab can be used in patients with osteoporosis caused by various factors, in men at high risk of fracture receiving androgen deprivation therapy for non-metastatic prostate cancer, and in women at high risk of fracture receiving adjuvant aromatase inhibitor therapy for breast cancer to increase bone mass. Xgeva can be used in multiple myeloma, in patients with bone metastases from solid tumors, giant cell tumors of bone, and malignancy-induced hypercalcemia.

Hypocalcaemia caused by denosumab is a significant issue, particularly for individuals with chronic kidney disease (CKD) and those receiving hemodialysis. The U.S. Food and Drug Administration (FDA) has issued a boxed warning regarding the risk of severe hypocalcaemia in patients with advanced CKD who are taking the osteoporosis medication Prolia (denosumab). This risk is exceptionally high in patients on dialysis or those with mineral and bone disorders. Bird et al. included 1,523 patients with chronic kidney disease, and the results revealed a significant difference in the occurrence of severe hypocalcaemia between those treated with denosumab (41.1%) and those treated with oral bisphosphonates (2.0%) over 12 weeks (4).

The study highlights the importance of identifying risk factors for severe hypocalcaemia caused by denosumab, a drug commonly used to treat osteoporosis. Although the initial stages of denosumab-induced hypocalcaemia may not show any symptoms, it is necessary to manage the condition effectively. The study reviewed cases of denosumab-induced hypocalcaemia reported in the FDA Adverse Event Reporting System (FAERS), a vast database that collects voluntarily reported post-marketing adverse reactions to FDA-approved drugs. This database's comprehensive nature ensures the practical review of multiple cases of drug-related side effects, including denosumab-induced hypocalcaemia, as demonstrated by this study.

2.1 Data collection

The study is structured as an observational, retrospective disproportionality analysis, a well-established concept in pharmacovigilance used to evaluate the likelihood of an association between denosumab and hypocalcaemia.(5) The FAERS data were obtained from the FAERS Quarterly Data Extract Files, which can be accessed at https://fis.fda.gov/extensions/FPD-QDE-FAERS/ FPD-QDE-FAERS.html. Our analysis included all reports recorded in FAERS from the first quarter (Q1) of 2010 to fourth quarter(Q4) 2023, in accordance with the FDA approval time for denosumab.

The FAERS database comprised seven data files.: patient demographic information (DEMO), drug information (DRUG), adverse event information (REAC), patient outcome information (OUTC), report source information (RPSR), drug therapy date information (THER), and drug indication (INDI).(6) The data was imported into the MySQL software (v8.0; Oracle, Sweden), and the deduplication process was conducted prior to statistical analysis. The primary ID served as the primary key connecting various data files, while the case ID was selected as the key filter in our study to eliminate duplicate records.(7) We identified cases by using specific search terms for the drug and hypocalcaemia, which can be found in Table 1. We selected the role_cod as PS (Primary suspected). We excluded cases lacking information on patient age, gender, or indication for use from the final analysis. A flow diagram illustrating the sequential steps of data extraction, processing, and analysis was presented in figure 1.

Table 1: This table represents the various search terms for the drug and primary term associated with denosumab as reported to the FAERS database that were included in our study.

DRUG

'XGEVA','XGEVA DENOSUMAB ','ERIBULIN XGEVA','XGEVA 120MG','DENOSUMAB XGEVA ','XGEVA DENOSUMAB ','XGEVA 120 MG SOLUZIONE INIETTABILE','XGEVA 120 INJVLST 70MG ML FLACON 1 7ML','XGEVA BENEFIBRE','XGEVA INJ','XGEVASC','CRANBERRY DENOSUMAB XGEVA ','XGEVA INJECTIONS','XGEVA BONE BUILDER','XGEVA AMGEN EUROPE B V ','DENOSUMAB SOLUTION FOR INJECTION PROLIA XGEVA','DENOSUMAB XGEVA','XXGEVA','XGEVA FL INJ ','METFORMIN XGEVA ATORVASTATIN','VITAMIN B12 XGEVA','BONE ESSENTI VIT D XGEVA CODEINE SULF','VITAMIN D3 XGEVA','XGEVA SINGLE USE VIAL FOR S C USE ONLY PRESERVATIVE FREE ','EXGEVA','XGEVA 120 MG 1 7 ML','DECADRON OXYCODONE XGEVA','XGEVA 70G ML','XGEVA P FCS','XARELTA XGEVA','XGEVA P','XGEVA CALCIUM','XGEVA SINGLE USE VIAL FOR S C USE ONLY PRESERVATIVE FREE ','XGEVA PROCHLORPERAZINE','XGEVA SC 120MG 1 7ML','XGEVA 120 MG 1 7 ML','XGEVA SINGLE USE VIAL FOR S C USE ONLY PRESERVATIVE FREE ','XGEVA 120 MG 1 7 ML SUBQ ONCE MONTHLY','XGEVA 120 MG 1 7 ML ORAL','XGEVA 120MG 1 7ML SQ','XGEVA 120MG 1 7ML SQ','XGEVA 120 MG 1 7ML','XGEVA 120MG 0 7ML','XGEVA SQ','FASLODEX VITAMIN D XGEVA MULTIVITAMIN','XGEVA 120MG 1 7 SUBCUTANEOUS','XGEVA 120MG 1 7ML SUBCUTANEOUS','XGEVA 120 MG 1 7ML SC','XGEVA SC','XGEVA CALTRATE GABAPENTIN XTAMPZA VENLAFAXINE VITAMIN D3','XGEVA SINGLE USE VIAL FOR S C USE ONLY PRESERVATIVE FREE','XGEVA ','XGEVA 120 1 7ML VIAL','XGEVA 120 MG 1 7 VIAL','KETOCONAZOLE 2 XGEVA 120MG 1 7ML','XGEVA INJECTION','XGEVA 120MG VIAL','XGEVA SOL 120MG 1 7ML','XGEVA SOL','XGEVA SUBCUTANEOUS','XGEVA BISPHOSPHONATE ','XGEVA SQ SOLUTION','XGEVA DENOSUMAB 120MG SUBQ Q 28D X 12 CYCLES V6 0','XGEVA DENOSUMAB','XGEVA AMGEN','XGEVA DENOSUMAB 120MG AMGEN','XGEVA XGEVA ','XGEVA 120MG 1 7ML SOLUTION','EXGEVA NON ABBOTT ','XGEVA DENOSUMAB','XGEVA DENSUMAB ','XGEVA DENOSUMAB INJECTION','XGEVA DENOSUMAB','XGEVA 120 MG','XGEVA SINGLE USE VIAL','AMG 162','PROLIA','PROLIA SYRINGE','PROLIA SOL 60MG ML','PROLIA AMGEN','PROLIA DENOSUMAB INJECTION AMGEN','PROLIA INJECTION','PROLIAPFS 60MG NOVARTIS','PROLIA DENOSUMAB AMGEN','DENOSUMAB PROLIA ','PROLIA DENOSUMAB ','PROLIA 60MG ML AMGEN','PROLIA 60MG ML SYRINGE','PROLIA INJECTION AMGEN','PROLIA DENOSUMAB ','PROLIA SOLUTION','PROLIA SOLUTION FOR INJECTION','PROLIA INFUSION VITAMIN D','KYPROLIA','PROLIA PRE FILLED SYRINGE PRESERVATIVE FREE ','DENOSUMAB PROLIA SUBQ ','PROLIA PFS','CHEMOTHERAPY PROLIA INJECTIONS NEXIUM TOPAMAX IMITREX','PROLIA PEN','PROLIA PRE FILLED SYRINGE PRESERVATIVE FREE','PROLIA CALCIUM','E INVALID PROLIA','PROLIA PRE FILLED SYRINGE PRESERVATIVE FREE','GENERIC PROLIA','PROLIA 60 MG SOLUTION FOR INJECTION IN A PRE FILLED SYRINGE','PROLIA 60 MG SOLUCION INYECTABLE EN UNA JERINGA PRECARGADA','METOPROLIAL','PROLIA 60 MG SOLUTION INJECTABLE','TO RPH KNOWLEDGE PROLIA IS ONLY ACTIVE MEDICATION','PROLIA PRE FILLED SYRINGE PRESERVATIVE FREE ','PROLIA 60 MG SOLUTION INJECTABLE EN SERINGUE PR REMPLIE','PROLIA 60MG PFS','PROLIA 6','PROLIA PREFILLED SYRINGE','PROLIA TWICE A YEAR','PROLIA 60 MG INJEKTIONSVATSKA LOSNING I FORFYLLD SPRUTA','PROLIA SOL 60 MG ML','PREDNISONE PROLIA','LASIX PROLIA ONDANSETRON','PROLIA INJECTION EVERY 6 MONTHS','NAPROSYNM PROLIA','PROLIA FS','PROLIA 60 MG ML SYRG INJECTION','PROLIA 60MG EVERY 6 MONTHS','PROLIA HFA','PROLIA PRE FILLED PRESERVATIVE FREE','PROLIA SUBCUT SOLUTION 60MG','PROLIA 60 MG SOLUCION INYECTABLE EN JERINGA PRECARGADA 1 JERINGA PREC','PROLIA PRE FILLED PRESERVATIVE FREE ','PROLIA 60 MG SOLUCION INYECTABLE EN JERINGA PRECARGADA 1 JERINGA PRE','DENOSUMAB INJVLST 60MG ML PROLIA 60 INJVLST 60MG ML WWSP 1ML','PROLIA Q 6MO','PROLIA PRE FILLED SYRINGE','DS PROLIA','PROLIA 60 MG SOLUCION INYECTABLE EN JERINGA PRECARGADA','PROLIA SC','PROLIA 60 MG SOLUCION INYECTABLE EN JERINGA PRECARGADA 1 JERINGA P ','PROLIA SOL','PROLIA FOR BONES','PROLIA DANOSUMAB ','AZILECT PROLIA','PROLIA PRE FILLEDSYRINGE PRESERVATIVE FREE','PROLIA 60MG 1ML','PROLIA SUBCUTANEOUS SOLUTION PREFIL','ABO PROLIA','PROLIA SC DENOSUMAB ','PROLIA BEGAN 10 5 20 ','PROLIA 60 MG SOLUCION INYECTABLE EN JERINGA PRECARGADA ','PROLIA SOS','PROLIA 60MG ML Q 6MO','PROLIA PRE FILLEDSYRINGE PRESERVATIVE FREE','DENOSUMAB PROLIA 60 MG AMGEN','PROLIA ADMINISTERED IN HOSPITAL PROLIA TO BE GIVEN 2X YEAR ONLY TOOK','PROLIA PROLIA DENOSUMAB INJECTION','PROLIA ','PROLIA 60 MG SQ EVERY 6 MONTHS AMGEN','PROLIA INJECTION FORM ','PROLIA DENOSUMAB INJECTION','PROLIA 60MG PFS PROLIA AMGEN','SELENIUM PROLIA','PROLIA PROLIA PLUS','PROLIA AMGEN ','PROLIA 60 MG IN 1 ML SOLUTION AMGDEN','PROLIA DENOSUMAB DENOSUMAB ','PROLIA 60 MG ML SYRINGE','PROLIA DENOSUMABE 60MG ML','PROLIA 60MG ML AMIGEN','DENOSUMAB','PROLISA DENOSUMAB ','DENOSUMAB DENOSUMAB RANMARK ','DENOSUMAB 120MG 1 7 ML','DENOSUMAB INJVIST','DENOSUMAB DENOSUMAB ','BLINDED DENOSUMAB','XEGEVA DENOSUMAB ','DENOSUMAB INJVLST','DENOSUMAB 60MG AMGEN','RANMARK DENOSUMAB ','DENOSUMAB HERCEPTIN','DENOSUMAB GENETICAL RECOMBINATION ','PRALIA DENOSUMAB ','DENOSUMAB DS','DENOSUMAB 60MG ML','DENOSUMAB INJVLST 60MG ML','DENOSUMAB SUBCUT','DENOSUMAB X GEVA','DENOSUMAB 60MG','DENOSUMAB GENETICAL RECOMBINATION ','DENOSUMAB SOLUTION FOR INJECTION','DENOSUMABUM','DENOSUMAB 60MG SC EVERY 6 MONTHS','DENOSUMAB 8418A ','DENOSUMAB HOSPIRA','SYRINGE DENOSUMAB RCH ','DENOSUMAB PER MAAND','DENOSUMAB 60MG SUB CUTA','EXCHEVIA DENOSUMAB','DENOSUMAB 60 MG INYECTABLE 1 ML 1 JERINGA PRECARGADA','DENOSUMAB 60MG SUB Q EVERY 6 MO','DENOSUMAB INJECTION','DENOSUMAB DENOSUMAB 120MG 1 7ML INJ ','2178348 GLOBALC3SEP20 DENOSUMAB','DENOSUMAB 120 MG','DENOSUMAB INJVLST 70MG ML BRAND NAME NOT SPECIFIEDDENOSUMAB INJVL ','DENOSUMAB SOLUTION','DENOSUMAB DENOSUMAB 120MG 1 7ML INJ','ESENTRA DENOSUMAB ','ZOMETA DENOSUMAB','DENOSUMAB 50 MG','DENOSUMAB SQ','DENOSUMAB PRIOR TO STUDY DRUG ADMINISTRATION','DENOSUMAB COMPARATOR FOSAMAX ','DENOSUMAB BLINDED','DENOSUMAB COMPARATOR ZOMETA BLINDED ','DENOSUMAB STUDY PROCEDURE','DENOSUMAB DENOSUMAB UNKNOWN ','ZGEVA DENOSUMAB ','DENOSUMAB DENOSUMAB ','DDENOSUMAB',

Primary Term

HYPOCALCAEMIA

2.2 statistical analysis

2.2.1 the reporting odds ratio for denosumab-induced hypocalcaemia

To provide a comprehensive analysis, we employed descriptive statistics to summarize the demographic and clinical characteristics of all patients, presented as categorical variables [N (%)]. Our review covered a range of information, such as patient age, gender, indication for denosumab use, diagnosis of chronic kidney disease, and whether patients received a 60mg Prolia or 120mg Xgeva dose of denosumab. We used the reporting odds ratio (ROR) based on disproportionality analysis to assess the association between the drug and adverse events. We constructed a 2x2 contingency table and calculated the reporting odds ratio for denosumab-induced hypocalcaemia using the total number of reported cases (see Table 2).

Table 2:the algorithms used for signal detection for denosumab-induced hypocalcaemia
	Hypocalcaemia	No Hypocalcaemia
Denosumab	a=2395	b=304780
No Denosumab	c=11285	d=46386006

2x2 contingency table that was used for calculating the reporting odds ratio. ROR = ad/bc;a, number of reports containing both the suspect drug(denosumab) and the suspect adverse event(hypocalcaemia); b, number of reports containing the suspect adverse event with other medications (except the drug of denosumab); c, number of reports containing the suspect drug with other adverse drug reactions (except the event of hypocalcaemia); d, number of reports containing other drugs and other adverse events.

2.2.2 subgroup analysis and logistic regression analysis

The study executed subgroup analyses to identify potential risk factors for hypocalcaemia. These factors included age, gender, presence of chronic renal dysfunction, indication, and drug dosage. Age was sorted into three subgroups: adolescents (<18 years), elderly individuals (>65 years), and a control group (18 to 65 years). Drug dosage was classified as either 60mg Prolia or 120mg Xgeva.

The indication subgroups were categorized as osteoporosis, tumor-related, and prophylaxis groups for control. Indications in FAERS are coded using the preferred terms (PTs) from standardized Medical Dictionary for Regulatory Activities (MedDRA), which contains 27 system organ classes (SOCs), 1783 high level terms(HLTs) and 22499 PTs. The SOC is a collection of similar medical terms at the high grouping level, the highest level of the hierarchical structure, providing the widest range of concepts for data retrieval. HLT is a collection of similar medical terms at the preferred term level, which are generalized terms that are associated with subordinate PTs through anatomical, pathological, physiological, aetiological, or functional features for data retrieval and expression, and are superordinate to preferred terms PTs. Indication subgroups were categorized based on SOC and HLT levels(relevant terms see Table 3), with HLTs related to “METABOLIC BONE DISORDERS” classified as the osteoporosis group, SOCs related to “NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)” classified as the tumor-related group, and HLTs related to " PROPHYLACTIC PROCEDURES NEC" classified as the control group. The research team then conducted risk-odd analyses to ascertain the reporting odds ratio of hypocalcaemia for each subgroup. Finally, logistic regression was utilized to statistically analyze the odds ratio (OR) of multiple risk factors leading to hypocalcaemia.

Table 3: subgroup setup according to MedDRA® SOC and HLT levels*
term in MedDRA	name	subgroup for indication
HLT levels	PROPHYLACTIC PROCEDURES NEC	control group
HLT levels	METABOLIC BONE DISORDERS	osteoporosis group
SOC levels	NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)	tumor-related group

*MedDRA® (Medical Dictionary for Regulatory Activities) is a standardized terminology used for classifying medical and adverse event data related to drugs. It includes multiple hierarchical classifications, notably SOC (System Organ Class) and HLT (High-Level Term). SOC (System Organ Class): SOC is the highest level in MedDRA, used to categorize all medical events related to a specific organ or system. Each SOC contains a group of related HLTs. HLT (High-Level Term):HLT is a secondary-level term used to describe more specific medical events. They typically group similar symptoms or diseases, facilitating the classification of particular adverse events.

2.2.3 time-to-onset analysis

The time-to-onset was defined as the time from the start of drug medication to the occurrence of hypocalcaemia. Subsequent to the exclusion of reports lacking onset time data, an analysis was performed on the remaining reports. The cumulative incidence of hypocalcaemia was determined through the Kaplan-Meier method. The log-rank test was utilized to compare the difference in the cumulative incidence of hypocalcaemia among subgroups.

The time-to-onset data was evaluated based on the median, quartiles, and Weibull shape parameter (WSP) tests. The occurrence rate of adverse events after the start of treatment depends on the drug's mechanism of action and often changes over time. In contrast, adverse events unrelated to drug treatment occur at a constant rate. The WSP test can determine the rate of change in the occurrence rate of adverse events. The scale parameter α of the Weibull distribution determines the scale of the distribution; a larger α value stretches the distribution, while a smaller α value compresses the distribution. The shape parameter β of the Weibull distribution determines the shape of the curve. In the analysis, the shape parameter β of the Weibull distribution was used to represent the hazard without a reference population as follows: when the shape parameter β was <1 and its 95%CI was <1, the hazard was considered to have decreased over time(early failure); when the shape parameter β was equal to or nearly 1 and its 95%CI included the value 1, the hazard was estimated to constantly occur over time(random failure); and when the shape parameter β was >1 and it’s 95%CI excluded the value 1, the hazard was considered to increase over time (wear-out failure). The median onset time difference between subgroups was evaluated using the Wilcoxon rank-sum test. Statistical analysis and plotting were performed using R statistical software, version 4.3.1 (R Foundation for Statistical Computing). This report was prepared following the STROBE checklist. ( freely available on the website at http://www.strobe-statement.org).

3.1 Descrptive analysis

From January 2010 to December 2023, 18,400,744 adverse event reports were available in the FAERS database. After data cleaning and analysis, we identified 148,038 reported adverse events associated with denosumab. Among these, we identified 2,395 reports of denosumab-induced hypocalcaemia and summarized the clinical characteristics of these patients (see Table 4). There were 1,242 female cases, accounting for 50.04% of the total, and 1,045 cases in patients over 65, accounting for 42.9%. The average age was 69.16 ± 16.3 years.

Table 4

subgroups descriptive review of denosumab induced hypocalcaemia
	subgroup	N	%
Gender	F	1242	51.86%
	M	810	33.82%
Age	< 18	39	1.63%
	18ཞ65	417	17.41%
	> 65	1045	43.63%
Indication	Osteoporosis-relate	815	34.03%
	Tumor-relate	682	28.48%
dosage	60mg prolia	1144	47.77%
	120mg xgeva	1007	42.05%
CKD	chronic kidney disease	25	1.04%
	without chronic kidney disease	2370	98.96%

3.2 Subgroup analysis and logistic regression analysis

We conducted subgroup analyses based on potential risk factors for denosumab-induced hypocalcaemia, considering the clinical characteristics identified in the screening results. Subgroups were defined based on age, gender, indication, drug formulation, and the presence of chronic kidney disease.

We calculated the overall reporting odds ratio (ROR) for denosumab-induced hypocalcaemia to be 32.30 (95%CI: 30.90-33.76), as indicated by the disproportionate analysis. The RORs for each subgroup are shown in Fig. 2. Among them, the ROR for hypocalcaemia was higher in males (86.73,95%CI:80.42–93.55) and younger patients(158.83,95%CI:114.30-220.71)compared to females and elderly patients. Patients with chronic kidney disease had a significantly higher ROR(144.83, 95%CI:97.01-216.26). The Xgeva formulation had a significantly higher ROR(89.51, 95%CI:83.71–95.73) than the Prolia formulation, and the tumor-related group had a higher ROR(44.42,95%CI:41.00-48.13) than the osteoporosis treatment group.

Logistic regression analysis was performed to calculate the odds ratios (OR) and the P-value for each risk factor. The details of the logistic regression analysis are shown in Table 5. The OR for male patients was 2.38 (1.99–2.83) compared to female patients. The OR for Xgeva(120mg denosumab) was 3.22 (2.06–5.24) compared to Prolia(60mg denosumab). The indications subgroup was categorized into three groups: osteoporosis group, tumor-related group, and prophylaxis group as control. The results showed that the tumor-related group had a 7.11-fold (5.13–10.15) increased risk of hypocalcaemia compared to the control group, while the osteoporosis group had a 5.67-fold (3.25–10.27) increased risk. The age subgroup consisted of three age ranges: the adolescent group below 18 years, the elderly group of 65 years and older, and the younger group of 18–65 as control. The results showed that the adolescent group had a 3.28-fold (1.68–5.96) increased risk of hypocalcaemia with control, while the elderly group showed a 0.82-fold(0.70–0.96) decreased risk with control. The schematic diagram of the logistic regression analysis is shown in Fig. 3.

Table 5

The logistic regression results for the occurrence of hypocalcemia following the use of denosumab
Dependent: Hypocalcaemia	subgroup	no_Hypocalcaemia	Hypocalcaemia	OR (univariable)	OR (multivariable)
AGE	18 ~ 65	11416 (97.8)	253 (2.2)	-	-
	65 < Age	34989 (98.5)	550 (1.5)	0.71 (0.61–0.83, p < 0.001)	0.82 (0.70–0.96, p = 0.013)
	Age < 18	63 (82.9)	13 (17.1)	9.31 (4.85–16.58, p < 0.001)	3.28 (1.68–5.96, p < 0.001)
GENDER	Female	40099 (98.7)	512 (1.3)	-	-
	Male	6369 (95.4)	304 (4.6)	3.74 (3.23–4.32, p < 0.001)	2.38 (1.99–2.83, p < 0.001)
CKD	nonCKD	46366 (98.3)	810 (1.7)	-	-
	CKD	102 (94.4)	6 (5.6)	3.37 (1.31–7.06, p = 0.004)	4.21 (1.62–9.01, p = 0.001)
indication	Prophylactic	3655 (99.0)	38 (1.0)	-	-
	Osteoporosis	37948 (98.8)	448 (1.2)	1.14 (0.83–1.61, p = 0.454)	5.67 (3.25–10.27, p < 0.001)
	Tumor_related	4865 (93.6)	330 (6.4)	6.52 (4.72–9.30, p < 0.001)	7.11 (5.13–10.15, p < 0.001)
dosage	prolia	38704 (98.8)	461 (1.2)	-	-
	xgeva	7764 (95.6)	355 (4.4)	3.84 (3.33–4.42, p < 0.001)	3.22 (2.06–5.24, p < 0.001)

3.3 Time-to-onset analysis and cumulative incidence:

Among the 2,395 cases of denosumab-induced hypocalcaemia, 639 cases had data on the time-to-onset. The distribution of time to onset for these cases is shown in Fig. 4, which demonstrates that 313 patients(48.98%) experienced onset within 2 weeks after medication.

The Kaplan-Meier curves for the difference subgroups were shown in Fig. 5. The cumulative incidence of hypocalcaemia significantly differed between elderly patients and patients aged from 18 to 65.(log-rank test, p < 0.05), whereas hypocalcaemia show no significant difference between other subgroups. Elderly patients(over 65) treated with denosumab showed a significantly longer time-to onset of hypocalcaemia(median:16days, range:7‐62days) than the patients aged from 18 to 65 (median:12days, range:5.75‐35days, P < 0.05).

The WSP test results for each subgroup are summarized in Table 6. In the WSP test for denosumab-induced hypocalcaemia, the lower 95% confidence interval limit for the shape parameter in almost all subgroups, excluding those diagnosed with CKD, was less than 1, suggesting an early failure type. This suggests that the probability of denosumab-induced hypocalcaemia decreases over time. In the WSP test for the patients with CKD, the shape parameter β(0.93) was nearly 1, and its 95%CI included the value 1, suggesting a random failure type. This indicates that the risk of denosumab-induced hypocalcemia in individuals with CKD remains stable over time, without a gradual decline in occurrence.

Table 6

Weibull shape parameter test of time-to-onset for hypocalcaemia associated with different subgroups
Hypocalcaemia(subgroup)		Case Reports	Median(d) (25%-75%)	p	Scale parameter:α(95%CI)	Shape parameter:β (95%CI)	TYPE
drug	Denosumab	639	15(7–57)	0.3	51.34(43.81–58.86)	0.56(0.53–0.59)	Early Failure
	aged from 18 to 65	172	12(5.75-35)	0.043	38.74(27.07–50.40)	0.53(0.47–0.58)	Early Failure
age	aged elderly than 65	489	16(7–62)		55.26(45.80-64.71)	0.55(0.51–0.59)	Early Failure
	chronic kidney disease	21	15(7–28)	0.13	24.88(12.75–37.02)	0.93(0.66–1.20)	Random Failure
diagnosis	without chronic kidney disease	630	15(7–61)		52.66(44.80-60.53)	0.56(0.53–0.59)	Early Failure
	female	368	14(7-48.25)	0.75	50.35(40.16–60.53)	0.54(0.50–0.58)	Early Failure
gender	male	276	19(7–28)		52.57(41.48–63.65)	0.59(0.55–0.64)	Early Failure
	tumor related	280	17(7-74.5)	0.38	55.74(43.35–68.12)	0.56(0.51–0.61)	Early Failure
indication	osteporosis	272	14(7-39.75)		47.24(36.05–58.44)	0.53(0.49–0.58)	Early Failure
	Xgeva	247	17(7–63)	0.51	49.65(38.31-61.00)	0.58(0.53–0.63)	Early Failure
dosage	Prolia	315	14(7–38)		44.62(35.00-54.23)	0.55(0.50–0.59)	Early Failure

4.1 Denosumab and hypocalcaemia

Hypocalcaemia is a well-known adverse event associated with the use of denosumab, particularly in patients with severe renal impairment(4). FDA adds Boxed Warning for increased risk of severe hypocalcaemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia (denosumab). Several studies have highlighted the occurrence of severe hypocalcaemia following denosumab administration(8–10). Denosumab has been reported to cause profound hypocalcaemia, even in patients with normocalcaemia despite calcium and vitamin D supplementation(11). It has been observed that denosumab is more likely to induce hypocalcaemia compared to bisphosphonates(12). The incidence of hypocalcaemia with denosumab has been reported to range from 5.2–20.8% (13–15) .

The risk factors for denosumab-induced hypocalcaemia include renal impairment, vitamin D deficiency, and malignancy(16–18). Calcium and vitamin D supplementation have been recommended before and after denosumab administration to mitigate the risk of hypocalcaemia (19,20). Vitamin D deficiency has also been identified as a significant risk factor for developing hypocalcaemia associated with denosumab(21,22). Additionally, factors such as reduced creatinine clearance, higher baseline levels of bone turnover markers, and high bone turnover status have been identified as risk factors for denosumab-induced hypocalcaemia(23–25). Our reseach also found that males, adolescents, and tumor-related patients have a higher incidence of hypocalcaemia, which may be related to higher baseline levels of bone turnover.

Despite efforts to prevent hypocalcaemia, severe cases have been reported, necessitating close monitoring and proactive management(26). Identifying risk factors associated with denosumab-induced hypocalcaemia is essential to mitigate its impact(27). Denosumab-induced hypocalcaemia can be asymptomatic initially, making it crucial to identify risk factors for severe hypocalcaemia to guide clinical management effectively (28). The prevalence of hypocalcaemia induced by denosumab in patients with osteoporosis, even with adequate calcium and vitamin D supplementation, underscores the need for careful monitoring and proactive measures(29). Our study aimed to investigate the risk factors for denosumab-induced hypocalcaemia by analyzing 2,395 cases identified from the FDA Adverse Event Reporting System (FAERS) database. We conducted subgroup analysis considering gender, age, various indications, chronic kidney disease (CKD), and drug formulations. Our findings suggest that younger age, male gender, presence of CKD, tumor-related indications, and the use of Xgeva formulation are potential risk factors for developing hypocalcaemia in patients treated with denosumab.".

4.2 Gender

Gender plays a significant role in the occurrence of hypocalcaemia induced by denosumab. Research indicates that the male sex was associated with denosumab-induced hypocalcaemia (13). This finding is further supported by our study that reported an increased odd ratio of hypocalcaemia in male patients receiving denosumab. Furthermore, a study on predictors for the development of denosumab-induced hypocalcaemia in cancer patients found that male gender was a significant factor associated with this condition(30). Moreover, while some studies have shown that gender may not have a significant effect on hypocalcaemia, other research contradicts this by indicating that the female gender is associated with a higher risk of transient hypocalcaemia(31). A multivariate analysis of over 5000 patients showed that the female gender had an odds ratio of 1.9 for transient hypocalcaemia(32). This suggests that gender differences play a role in the development of hypocalcaemia following certain medical interventions.

4.3 Age

Bird reported a markedly higher incidence of severe hypocalcaemia in older female dialysis-dependent patients aged 65 years or older with denosumab compared to oral bisphosphonates. These findings suggest that elderly age groups may have a higher risk of experiencing hypocalcaemia when treated with denosumab. The incidence of hypocalcaemia caused by denosumab appears to be higher in adolescent individuals(aged under 18) and lower in elderly patients(aged over 65), based on our research. Nickolas identified that younger age was a risk factor for hypocalcaemia induced by denosumab, particularly in patients with more severe kidney failure, lower baseline serum calcium, and parathyroid hormone levels. Young patients who receive denosumab are more likely to experience hypocalcaemia. One possible reason is that most young patients are not receiving denosumab for osteoporosis but rather for tumors-related indications. Additionally, young patients may also have a higher bone turnover state. Therefore, it is particularly important to monitor and prevent hypocalcaemia in young patients, especially those under the age of 18.

4.4 Prolia and xgeva

Denosumab has two different trade names: Prolia and Xgeva. Prolia is utilized for osteoporosis treatment and is administered subcutaneously at a dosage of 60 mg every 6 months. On the other hand, Xgeva is employed for bone metastases and solid tumors, given at a higher dose of 120 mg monthly (33). The difference between the two denosumab dosages, Prolia and Xgeva, lies in their intended use and dosing regimens. Prolia, administered every 6 months at a lower dose, is primarily indicated for osteoporosis treatment. In contrast, Xgeva, given monthly at a higher dose, is specifically used for bone metastases and complications in patients with solid tumors. This distinction in dosing and indications reflects the tailored approach denosumab offers in addressing different bone-related conditions, ensuring optimal therapeutic outcomes based on the specific medical needs of the patients.

There are currently no studies reporting the incidence of hypocalcaemia for prolia and xgeva. Our research indicates that the incidence of hypocalcaemia is higher with Xgeva compared to Prolia. This may be due to the fact that Xgeva is primarily used for indications related to tumor patients with more dosage, including giant cell tumors and bone metastasis patients, who often experience high turnover states. Therefore, they have a higher likelihood of developing hypocalcaemia.

4.5 CKD

Denosumab-induced hypocalcaemia is a significant concern, particularly in patients with chronic kidney disease (CKD) and those undergoing hemodialysis. Patients with CKD are prone to denosumab-induced hypocalcaemia, possibly because their ability to absorb calcium from the gastrointestinal tract is impaired, relying primarily on bones as a calcium source. Denosumab inhibits osteoclasts, restricting the body's ability to mobilize calcium from bones, leading to hypocalcaemia in these patients. Studies have highlighted the association between denosumab treatment and hypocalcaemia, with CKD G4–5 and male sex being identified as risk factors for denosumab-induced hypocalcaemia (34). It is crucial to be vigilant in correcting denosumab-induced hypocalcaemia promptly, especially in the presence of cardiac dysfunction (35). In CKD patients, hypocalcaemia induced by denosumab can be a critical issue, emphasizing the importance of preemptive administration of active vitamin D to eligible CKD patients before initiating denosumab to prevent hypocalcaemia(36). In patients undergoing hemodialysis, denosumab administration has been linked to severe hypocalcaemia, necessitating close monitoring and appropriate management strategies (37). Risk analysis studies have shown that renal dysfunction may not necessarily be a direct risk factor for denosumab-induced hypocalcaemia, highlighting the complexity of managing this adverse event (38).

4.6 Indications

Denosumab has shown promise as a therapeutic option for tumor-related indications, particularly in the management of giant cell tumors of the bone (GCTB). Several studies have investigated the efficacy and safety of denosumab in treating GCTB, shedding light on its potential benefits and limitations. A systematic review and meta-analysis by Yayan (39) focused on the impact of denosumab on tumor size reduction in patients with GCTB. The study aimed to compare patients who experienced tumor progression with denosumab treatment to those who saw a reduction in tumor size, providing valuable insights into the effectiveness of denosumab in managing GCTB. However, caution is advised in the application of denosumab therapy for GCTB, as highlighted in a review by (40). The review emphasizes the need for careful consideration and monitoring when using denosumab in GCTB treatment to mitigate potential pitfalls associated with its use.

Hypocalcaemia is a significant concern associated with denosumab when used for tumor-related indications, particularly in patients with bone metastases. In a study by Smith(41), denosumab significantly prolonged bone metastasis-free survival in men with castration-resistant prostate cancer, highlighting its efficacy in this patient group. However, denosumab use in male patients with bone metastases may lead to an increased risk of hypocalcaemia, as demonstrated in studies such as those by Ikegami et al(26), emphasizing the importance of monitoring and managing calcium levels in this population. Several studies have explored the incidence, management, and implications of denosumab-induced hypocalcaemia in this context. A study by Henry et al (42) analyzed data from patients with advanced cancer receiving denosumab and reported a higher incidence of hypocalcaemia events compared to those receiving zoledronic acid. The study highlighted the importance of monitoring and managing hypocalcaemia in patients undergoing denosumab treatment for bone metastases. Furthermore, Saito et al.(38) emphasized the typical adverse effect of hypocalcaemia induced by denosumab, underscoring the need for pharmaceutical intervention and strict management systems to normalize serum calcium levels and prevent exacerbation of hypocalcaemia. In a case report by Flood et al.(43), a patient with metastatic prostate cancer presented with severe hypophosphatemia and hypocalcaemia following denosumab administration, highlighting the potential for severe adverse effects associated with denosumab use in this patient population. Moreover, Pittman et al. (44)discussed the incidence of hypocalcaemia in denosumab-treated patients with bone metastases from solid tumors, noting that most hypocalcaemia events were asymptomatic and resolved within a few weeks. This underscores the importance of close monitoring and proactive management of hypocalcaemia in patients receiving denosumab for tumor-related indications.

4.7 The time to onset

The onset of hypocalcaemia after denosumab administration typically occurs within the first 2 weeks, with the risk persisting for several weeks to months(13–15). Furthermore, studies have shown that denosumab-induced hypocalcaemia is more common and occurs earlier compared to bisphosphonates like zoledronic acid (45,46). Our research revealed that elderly patients had a later onset of hypocalcaemia compared to younger patients. Patients with chronic kidney disease showed no increase or decrease in the probability of developing hypocalcaemia over time, demonstrating a random failure type. In other words, hypocalcaemia could occur at any time after medication in this subgroup, rather than an early failure pattern seen in other subgroups where onset clustered within 2 weeks after medication and then gradually declined over time.

The risk of hypocalcaemia with denosumab is a concern that necessitates careful monitoring and management, especially in patients with predisposing factors such as Xgeva(120mg dose denosumab), adolescents, males, tumor-related indications, and diagnosis of chronic kidney disease. Strategies to mitigate the risk of hypocalcaemia associated with denosumab treatment may include optimizing calcium intake, monitoring serum calcium levels, and providing supplementation with vitamin D analogues or calcium carbonate as needed(47,48). Healthcare providers should be vigilant for symptoms of hypocalcaemia in patients receiving denosumab, particularly during the early stages of treatment for at least two weeks, to promptly address any imbalances and prevent complications. Extended hypocalcaemia prophylaxis is warranted for patients with chronic kidney disease receiving denosumab.

Our study highlights several shortcomings of the FAERS database and areas for potential improvement. First, frequent duplication of reported cases made data analysis challenging and time-consuming. Roughly 50% of all reported cases had complete demographics/ information necessary for this analysis, and all reported cases lacked a descriptive value of hypocalcaemia, glomerular filtration rate (GFR) of the patients with CKD. Under-reporting of ADRs and specific details in the FAERS database is known to occur. Undoubtedly this could impact data analysis and arguably limit the utility of the calculated reporting odds ratio. Additionally, media attention and the recent publication of an adverse drug reaction in the literature might affect reporting behaviors. While a more robust, well-defined data source could confer more reliable information about denosumab-induced hypocalcaemia, the large number of cases reported in this series is useful to shed further light on this important and frequently encountered ADR from denosumab. Finally, it is possible that certain instances of hypocalcaemia recorded in the FAERS database may not be directly caused by denosumab medication, which could potentially affect the outcomes.

In conclusion, an evaluation of the FAERS database for denosumab-induced hypocalcaemia identified over 2300 reported cases. This is the largest reported case series to date. Our study explored the possible risk factor for denosumab-induced hypocalcaemia based on the FDA database. Chronic kidney disease, male, tumor-related indications, drug formation of Xgeva, and age less than 18 years were high-risk factors for denosumab-induced hypocalcaemia, with chronic kidney disease having the highest odd ratio, followed by tumor-related indications and the use of Xgeva. Due to the FDA database's inability to provide specific blood calcium values for hypocalcaemia, additional research is needed to explore the relationship between extend of hypocalcaemia and the risk factor.

Ethical Approval: not applicable.

Funding: This study was funded by Foreign Cooperation Project of Science and Technology, Fujian Province(2023I0014) and Joint Funds for the Innovation of Science and Technology, Fujian Province(2020Y9104). All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Availability of data and materials: The data for this study primarily come from the FDA Adverse Event Reporting System (FAERS). The FAERS database collects reports of adverse events associated with drugs and biological products, including patient safety data, drug usage information, and relevant clinical details. This data provides crucial support for our research, ensuring the reliability and validity of our findings.In utilizing the FAERS database, we adhered to the relevant usage guidelines and ensured the integrity and accuracy of the data to support our research conclusions.

Author Contribution

Nanxin Zhang wrote the initial draft, and made significant revisions.Xinyu Fang reviewed the design and implementation of experiments, collected and organized data, and assisted in manuscript writing.Yiming Lin conducted the literature review and theoretical framework, providing important academic guidance.Qiang Li participated in data analysis and interpretation of results, and assisted in manuscript revisions and figures edit.Wenming Zhang supervised the entire research process and conducted a comprehensive review and revision of the final manuscript.

Savvidou OD, Bolia IK, Chloros GD, Papanastasiou J, Koutsouradis P, Papagelopoulos PJ. Denosumab: Current Use in the Treatment of Primary Bone Tumors. Orthopedics (2017) doi: 10.3928/01477447-20170627-04
Brown JP, Reid IR, Wagman RB, Kendler DL, Miller PD, Jensen JB, Bolognese MA, Daizadeh N, Valter I, F. Zerbini CA, et al. Effects of Up to 5 Years of Denosumab Treatment on Bone Histology and Histomorphometry: The FREEDOM Study Extension. Journal of Bone and Mineral Research (2014) doi: 10.1002/jbmr.2236
Chavassieux P, Portero-Muzy N, Roux J-P, Horlait S, Dempster DW, Wang A, Wagman RB, Chapurlat R. Reduction of Cortical Bone Turnover and Erosion Depth After 2 and 3 Years of Denosumab: Iliac Bone Histomorphometry in the FREEDOM Trial. Journal of Bone and Mineral Research (2019) doi: 10.1002/jbmr.3631
Bird ST, Smith ER, Gelperin K, Jung TH, Thompson A, Kambhampati R, Lyu H, Zhao H, Zhao Y, Zhu Y, et al. Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients. JAMA (2024) 331:491. doi: 10.1001/jama.2023.28239
Ali Z, Ismail M, Khan F, Sajid H. Association of H1-antihistamines with torsade de pointes: a pharmacovigilance study of the food and drug administration adverse event reporting system. Expert Opinion on Drug Safety (2020) 20:101–108. doi: 10.1080/14740338.2021.1846717
Shu Y, Ding Y, Dai B, Zhang Q. A real-world pharmacovigilance study of axitinib: data mining of the public version of FDA adverse event reporting system. Expert Opinion on Drug Safety (2021) 21:563–572. doi: 10.1080/14740338.2022.2016696
Wu B, Luo M, Wu F, He Z, Li Y, Xu T. Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS. Frontiers in Pharmacology (2022) 13: doi: 10.3389/fphar.2022.692828
Farinola N, Kanjanapan Y. Denosumab‐induced Hypocalcaemia in High Bone Turnover States of Malignancy and Secondary Hyperparathyroidism From Renal Failure. Internal Medicine Journal (2013) doi: 10.1111/imj.12283
Gunawan F, George E, Kotowicz MA. Denosumab-Induced Hypocalcaemia in Metastatic Castrate-Resistant Prostate Cancer. Endocrinology Diabetes and Metabolism Case Reports (2019) doi: 10.1530/edm-19-0063
Imatoh T, Sai K, Takeyama M, Segawa K, Yamashita T, Nakashima N, Yokoi H, Hiramatsu T, Kimura M, Hori K, et al. Evaluating the Impact of Regulatory Action on Denosumab‐induced Hypocalcaemia in Japan. Journal of Clinical Pharmacy and Therapeutics (2019) doi: 10.1111/jcpt.13004
Adhikaree J, Newby Y, Sundar S. Denosumab Should Be the Treatment of Choice for Bisphosphonate Refractory Hypercalcaemia of Malignancy. BMJ Case Reports (2014) doi: 10.1136/bcr-2013-202861
Body J, Moos R von, Niepel D, Tombal B. Hypocalcaemia in Patients With Prostate Cancer Treated With a Bisphosphonate or Denosumab: Prevention Supports Treatment Completion. BMC Urology (2018) doi: 10.1186/s12894-018-0393-9
Shrosbree J, Elder GJ, Eisman JA. Acute Hypocalcaemia Following Denosumab in Heart and Lung Transplant Patients With Osteoporosis. Internal Medicine Journal (2018) doi: 10.1111/imj.13744
Eshak N, Abdelnabi M, Benjanuwattra J, Ismail A, Leelaviwat N, Culberson J. Refractory Shock Secondary to Denosumab-Induced Severe Hypocalcaemia. European Journal of Case Reports in Internal Medicine (2022) doi: 10.12890/2022_003706
Zeng W, Swee DS. Severe and Refractory Hypocalcaemia Secondary to Osteoblastic Bone Metastases in Bladder Signet Ring Carcinoma: A Case Report and Literature Review. Medicine (2022) doi: 10.1097/md.0000000000029731
Body J-J, Niepel D, Tonini G. Hypercalcaemia and Hypocalcaemia: Finding the Balance. Supportive Care in Cancer (2017) doi: 10.1007/s00520-016-3543-1
Saleem S, Patel S, Ahmed A, Saleem N. Denosumab Causing Severe, Refractory Hypocalcaemia in a Patient With Chronic Kidney Disease. BMJ Case Reports (2018) doi: 10.1136/bcr-2017-224068
Tai R, Mouchaileh N, Ting C. Hypocalcaemia and Hypophosphataemia Following Denosumab and IV Ferric Carboxymaltose in an Older Patient With Normal Renal Function. Journal of Pharmacy Practice and Research (2022) doi: 10.1002/jppr.1791
Huynh A, Baker S, Stewardson AJ, Johnson D. Denosumab‐associated Hypocalcaemia: Incidence, Severity and Patient Characteristics in a Tertiary Hospital Setting. Pharmacoepidemiology and Drug Safety (2016) doi: 10.1002/pds.4045
Cuthbertson L. Severe Hypocalcaemia After Denosumab and Intravenous Iron: A Cautionary Tale. Internal Medicine Journal (2023) doi: 10.1111/imj.16261
Blackley SV, Anderson K, Berg JP. A Case of Denosumab-Induced Hypocalcaemia in a Patient With Non-Metastatic Prostate Cancer and Renal Impairment. The Journal of the Royal College of Physicians of Edinburgh (2015) doi: 10.4997/jrcpe.2015.209
Watthanasuntorn K, Abid H, Gnanajothy R. Severe Hypocalcaemia Following Denosumab in a Patient With Cancer With Vitamin D Deficiency. BMJ Case Reports (2018) doi: 10.1136/bcr-2018-226727
Ishikawa K, Nagai T, Sakamoto K, Ohara K, Eguro T, H I, Toyoshima Y, Kokaze A, Toyone T, Inagaki K. High Bone Turnover Elevates the Risk of Denosumab-Induced Hypocalcemia in Women With Postmenopausal Osteoporosis. Therapeutics and Clinical Risk Management (2016) doi: 10.2147/tcrm.s123172
Ishikawa K, Nagai T, Tsuchiya K, Oshita Y, Kuroda T, H I, Tani S, Dodo Y, Toyone T, Inagaki K. High Bone Turnover Status as a Risk Factor in Symptomatic Hypocalcemia Following Denosumab Treatment in a Male Patient With Osteoporosis. Clinical Interventions in Aging (2018) doi: 10.2147/cia.s180614
Moos R von, Costa L, Gonzalez-Suarez E, Terpos E, Niepel D, Body J-J. Management of Bone Health in Solid Tumours: From Bisphosphonates to a Monoclonal Antibody. Cancer Treatment Reviews (2019) doi: 10.1016/j.ctrv.2019.05.003
Ikegami K, Hashiguchi M, Kizaki H, Yasumuro O, Funakoshi R, Hori S. Development of Risk Prediction Model for Grade 2 or Higher Hypocalcemia in Patients With Bone Metastasis Treated With Denosumab Plus Cholecalciferol (Vitamin D )/Calcium Supplement. The Journal of Clinical Pharma (2022) 62:1151–1159. doi: 10.1002/jcph.2057
Okada N, Kawazoe K, Teraoka K, Kujime T, Abe M, Shinohara Y, Minakuchi K. Identification of the Risk Factors Associated With Hypocalcemia Induced by Denosumab. Biological and Pharmaceutical Bulletin (2013) doi: 10.1248/bpb.b13-00496
Ikesue H, Tsuji T, Hata K, Watanabe H, Mishima K, Uchida M, Egashira N, Miyamoto T, Baba E, Akashi K, et al. Time Course of Calcium Concentrations and Risk Factors for Hypocalcemia in Patients Receiving Denosumab for the Treatment of Bone Metastases From Cancer. Annals of Pharmacotherapy (2014) doi: 10.1177/1060028014539919
Bitar ZI. Hypocalcemia in Patients With Osteoporosis and Normal Renal Function, Treated With Denosumab, a Retrospective Analysis. Nutrition and Metabolic Insights (2024) doi: 10.1177/11786388231223604
Kanbayashi Y, Sakaguchi K, Hongo F, Ishikawa T, Tabuchi Y, Ukimura O, Takayama K, Taguchi T. Predictors for Development of Denosumab-Induced Hypocalcaemia in Cancer Patients With Bone Metastases Determined by Ordered Logistic Regression Analysis. Scientific Reports (2021) doi: 10.1038/s41598-020-80243-y
Özoğul B, Akçay MN, Akçay G, Bulut O. Factors Affecting Hypocalcaemia Following Total Thyroidectomy: A Prospective Study. Eurasian Journal of Medicine (2014) doi: 10.5152/eajm.2014.03
Harris A, Prades E, Ткачук ОЮ, Zeitoun H. Better Consenting for Thyroidectomy: Who Has an Increased Risk of Postoperative Hypocalcaemia? European Archives of Oto-Rhino-Laryngology (2016) doi: 10.1007/s00405-016-4084-4
Qaisi M, Hargett J, Loeb M, Brown JJ, Caloss R. Denosumab Related Osteonecrosis of the Jaw With Spontaneous Necrosis of the Soft Palate: Report of a Life Threatening Case. Case Reports in Dentistry (2016) doi: 10.1155/2016/5070187
Hsu C, Chen L, Chen K-H. Osteoporosis in Patients With Chronic Kidney Diseases: A Systemic Review. International Journal of Molecular Sciences (2020) doi: 10.3390/ijms21186846
Dave V, Chiang C, Booth J, Mount PF. Hypocalcemia Post Denosumab in Patients With Chronic Kidney Disease Stage 4-5. American Journal of Nephrology (2015) doi: 10.1159/000380960
Nitta K, Yajima A, Tsuchiya K. Management of Osteoporosis in Chronic Kidney Disease. Internal Medicine (2017) doi: 10.2169/internalmedicine.8618-16
Hiramatsu R, Ubara Y, Sawa N, Hoshino J, Hasegawa E, Kawada M, Imafuku A, Sumida K, Mise K, Hayami N, et al. Denosumab for Low Bone Mass in Hemodialysis Patients: A Noncontrolled Trial. American Journal of Kidney Diseases (2015) doi: 10.1053/j.ajkd.2015.03.012
Saito Y, Takekuma Y, Sugawara M. Risk Analysis of Denosumab-Induced Hypocalcemia in Bone Metastasis Treatment: Renal Dysfunction Is Not a Risk Factor for Its Incidence in a Strict Denosumab Administration Management System With Calcium/Vitamin D Supplementation. Biological and Pharmaceutical Bulletin (2021) doi: 10.1248/bpb.b21-00653
Yayan J. Denosumab for Effective Tumor Size Reduction in Patients With Giant Cell Tumors of the Bone: A Systematic Review and Meta-Analysis. Cancer Control (2020) doi: 10.1177/1073274820934822
Li H, Gao J, Gao Y-S, Lin N, Zheng M, Ye Z. Denosumab in Giant Cell Tumor of Bone: Current Status and Pitfalls. Frontiers in Oncology (2020) doi: 10.3389/fonc.2020.580605
Smith MR, Saad F, Coleman RE, Shore ND, Fizazi K, Tombal B, Miller K, Sieber P, Karsh LI, Damião R, et al. Denosumab and Bone-Metastasis-Free Survival in Men With Castration-Resistant Prostate Cancer: Results of a Phase 3, Randomised, Placebo-Controlled Trial. The Lancet (2012) doi: 10.1016/s0140-6736(11)61226-9
Henry DH, Vadhan‐Raj S, Hirsh V, Moos R von, Hungria V, Costa L, Woll PJ, Scagliotti GV, Smith GH, Feng A, et al. Delaying Skeletal-Related Events in a Randomized Phase 3 Study of Denosumab Versus Zoledronic Acid in Patients With Advanced Cancer: An Analysis of Data From Patients With Solid Tumors. Supportive Care in Cancer (2013) doi: 10.1007/s00520-013-2022-1
Flood M, Rowley M, Basnet A. Diagnosis and Management of Denosumab-Induced Hypocalcemia and Hypophosphatemia in the Setting of Metastatic Prostate Cancer. Cureus (2022) doi: 10.7759/cureus.20928
Pittman K, Antill Y, Goldrick A, Goh JC, De Boer RH. Denosumab: Prevention and Management of Hypocalcemia, Osteonecrosis of the Jaw and Atypical Fractures. Asia-Pacific Journal of Clinical Oncology (2016) doi: 10.1111/ajco.12517
McLachlan J, Marx G, Bridgman M. Severe Symptomatic Hypocalcaemia Following a Single Dose of Denosumab. The Medical Journal of Australia (2013) doi: 10.5694/mja13.10038
C. Teng JT, Abell SK, Hicks RJ, Hofman MS, Sachithanandan N, McKelvie P, MacIsaac RJ. Protracted Hypocalcaemia Following a Single Dose of Denosumab in Humoral Hypercalcaemia of Malignancy Due to PTHrP‐secreting Neuroendocrine Tumour. Clinical Endocrinology (2014) doi: 10.1111/cen.12519
Hori M, Yasuda K, Takahashi H, Kondo C, Shirasawa Y, Ishimaru Y, Sekiya Y, Morozumi K, Maruyama S. Effects of Bone Turnover Status on the Efficacy and Safety of Denosumab Among Haemodialysis Patients. Scientific Reports (2022) doi: 10.1038/s41598-022-12029-3
Inderjeeth C, Inderjeeth KA. Osteoporosis in Older People. Journal of Pharmacy Practice and Research (2021) doi: 10.1002/jppr.1743

No competing interests reported.

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A real-world study of denosumab-related hypocalcaemia based on the US food and Drug Administration Adverse Event Reporting System database

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Abstract

Objective

Methods

Results

Conclusion

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Key Points

1. Introduction

2. Materials and Methods

3. Results

3.1 Descrptive analysis

3.2 Subgroup analysis and logistic regression analysis

3.3 Time-to-onset analysis and cumulative incidence:

4. Discussion

4.1 Denosumab and hypocalcaemia

4.2 Gender

4.3 Age

4.4 Prolia and xgeva

4.5 CKD

4.6 Indications

4.7 The time to onset

5. Conclusion

Declarations

Author Contribution

References

Additional Declarations

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