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Kamimura Y, Ikegami K, Kizaki H, Imai S, Hori S. Exploration of factors affecting denosumab-induced hypocalcemia in male patients with osteoporosis using a hospital-based administrative claims database. Maturitas 2025; 193:108190. [PMID: 39765200 DOI: 10.1016/j.maturitas.2024.108190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 11/19/2024] [Accepted: 12/26/2024] [Indexed: 01/25/2025]
Abstract
OBJECTIVES Factors affecting denosumab-induced hypocalcemia in male patients with osteoporosis remain unclear because of the small patient population. Nevertheless, it is important to explore male-specific risk factors. This study aimed to identify the factors affecting the development of denosumab-induced hypocalcemia in male patients with osteoporosis and compare them with those in female patients with osteoporosis. STUDY DESIGN This retrospective, observational study used data from a hospital-based administrative claims database. Patients with osteoporosis undergoing denosumab treatment between April 2008 and May 2020 were enrolled. Data on age, inpatient/outpatient status, laboratory data, drug use, and disease status were collected. MAIN OUTCOME MEASURES Patients were classified as those with hypocalcemia and without hypocalcemia, and variables with P < 0.2 and missing proportions <30 % on univariate analysis were entered into multivariate logistic regression analysis. The multiple imputation method was used to compensate for missing data. RESULTS Overall, 175 males and 1335 females were included in the analysis, and hypocalcemia developed in 52 and 247 patients, respectively. In the multivariate analysis, prior use of preventive medicine (calcium supplements or activated vitamin D) decreased the risk of osteoporosis only in male patients. Low corrected levels of calcium and albumin and low estimated glomerular filtration rates increased the risk in both sexes. CONCLUSIONS Prior use of preventive medicine may be a factor that decreases the risk of denosumab-induced hypocalcemia in male patients. Low corrected levels of calcium and albumin, and low estimated glomerular filtration rates are common risk factors in both male and female patients.
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Affiliation(s)
- Yuto Kamimura
- Division of Drug Informatics, Keio University Faculty of Pharmacy, Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
| | - Keisuke Ikegami
- Division of Drug Informatics, Keio University Faculty of Pharmacy, Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
| | - Hayato Kizaki
- Division of Drug Informatics, Keio University Faculty of Pharmacy, Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
| | - Shungo Imai
- Division of Drug Informatics, Keio University Faculty of Pharmacy, Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
| | - Satoko Hori
- Division of Drug Informatics, Keio University Faculty of Pharmacy, Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
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Rotman-Pikielny P, Barzilai-Yosef L, Ramaty E, Braginski-Shapira S, Meron MK, Lurie TH. Parathyroid hormone levels following denosumab vs. zoledronic acid therapy for osteoporosis. Bone 2025; 193:117407. [PMID: 39863008 DOI: 10.1016/j.bone.2025.117407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/08/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025]
Abstract
The objective of this retrospective, database study was to characterize the rate, magnitude and timeline of increases in parathyroid hormone (PTH) levels post-denosumab (DMAb) vs. zoledronic acid (ZA) injection in patients with osteoporosis and near normal baseline PTH. Included were osteoporotic females, ≥50 years, initiating treatment with 60 mg DMAb or 5 mg ZA. PTH levels within 6-months post-DMAb or 12-months post-ZA injection were extracted from the electronic database of a 4.5 million-member health maintenance organization. The indication for PTH measurements was unknown. Exclusion criteria were creatinine >2 mg/dL, vitamin D < 50 nmol/L or parathyroid hormone level > 1.5 × upper limit of normal (ULN). Among 3317 women, 1992 received DMAb and 1325 ZA. The DMAb group was older (73.3 ± 8.5 vs. 69.8 ± 8.6 years, p < 0.001) and more patients treated with DMAb compared with patients treated with ZA had prior non-vertebral fractures (7.7 % vs. 5.2 %, p < 0.01) and had previously been treated with osteoporosis medication (56.3 % vs. 50.3 %, p < 0.001). Among the patients, 14.9 % had at least one post-treatment PTH > 1.5 ULN. Of 7273 post-treatment PTH tests, 62.6 % were within normal limits, while 24.8 % were mildly elevated at 1.01-1.5 ULN. Two-months after both treatments, >1.5 ULN PTH levels peaked at ∼20 %. Elevated PTH was associated with eGFR < 60 mL/min/1.73 m2 and comorbidities. In conclusion, most PTH levels post-DMAb or ZA in osteoporotic patients with baseline PTH < 1.5 ULN, were within normal range. PTH increased to >1.5 ULN in 14.9 % of patients; peaking in the first 2-months post-treatment and declining thereafter. Elevated PTH may be related to anti-resorptive effects and is not medication specific. PTH measurements in the first few months post-DMAb and ZA therapy should be limited.
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Affiliation(s)
- Pnina Rotman-Pikielny
- Institute of Endocrinology, Diabetes and Metabolism, Meir Medical Center, Kfar Saba, Israel; Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel.
| | - Liat Barzilai-Yosef
- Institute of Endocrinology, Diabetes and Metabolism, Meir Medical Center, Kfar Saba, Israel
| | - Erez Ramaty
- Institute of Endocrinology, Diabetes and Metabolism, Meir Medical Center, Kfar Saba, Israel
| | | | - Michal Kasher Meron
- Institute of Endocrinology, Diabetes and Metabolism, Meir Medical Center, Kfar Saba, Israel; Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
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Bird ST, Gelperin K, Smith ER, Jung TH, Lyu H, Thompson A, Easley O, Naik KB, Zhao Y, Kambhampati R, Wernecke M, Niak A, Zemskova M, Chillarige Y, Kelman JA, Graham DJ. The Effect of Denosumab on Risk for Emergently Treated Hypocalcemia by Stage of Chronic Kidney Disease : A Target Trial Emulation. Ann Intern Med 2025; 178:29-38. [PMID: 39556837 DOI: 10.7326/m24-0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND There is a paucity of data on treatment of osteoporosis in patients with advanced chronic kidney disease (CKD). OBJECTIVE To assess the risk for emergently treated hypocalcemia with denosumab by stage of CKD and presence of CKD-mineral and bone disorder (CKD-MBD). DESIGN Target trial emulation. SETTING Medicare fee-for-service data with prescription drug coverage, 2012 to 2020. PARTICIPANTS Female patients aged 65 years or older initiating denosumab, oral bisphosphonates, or intravenous (IV) bisphosphonates for osteoporosis. MEASUREMENTS Hospital and emergency department admissions (that is, emergent care) for hypocalcemia were assessed in the first 12 treatment weeks. Inverse probability of treatment weighted cumulative incidence and weighted risk differences (RDs) were calculated. RESULTS A total of 361 453 patients treated with denosumab, 829 044 treated with oral bisphosphonates, and 160 413 treated with IV bisphosphonates were identified. Risk for emergently treated hypocalcemia with denosumab versus oral bisphosphonates increased with worsening CKD stage (P < 0.001), with greatest risk among dialysis-dependent (DD) patients (3.01% vs. 0.00%; RD, 3.01% [95% CI, 2.27% to 3.77%]) and non-dialysis-dependent (NDD) patients with CKD stages 4 and 5 (0.57% vs. 0.03%; RD, 0.54% [CI, 0.41% to 0.68%]). Among patients with stages 4 and 5 CKD (NDD + DD), denosumab had a greater risk for emergently treated hypocalcemia versus oral bisphosphonates in those with CKD-MBD (1.53% vs. 0.02%; RD, 1.51% [CI, 1.21% to 1.78%]) than in those without CKD-MBD (0.22% vs. 0.03%; RD, 0.19% [CI, 0.08% to 0.31%]). Denosumab also showed increased risk compared with IV bisphosphonates. LIMITATION Generalizability to men and non-Medicare populations. CONCLUSION Risk for emergently treated hypocalcemia with denosumab increased with worsening CKD stage and was highest in DD patients and those with CKD-MBD. PRIMARY FUNDING SOURCE U.S. Food and Drug Administration.
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Affiliation(s)
- Steven T Bird
- Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (S.T.B., K.G., A.N., D.J.G.)
| | - Kate Gelperin
- Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (S.T.B., K.G., A.N., D.J.G.)
| | | | - Tae Hyun Jung
- Division of Biometrics 7, Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (T.H.J., Y.Z.)
| | - Hai Lyu
- Acumen, Burlingame, California (E.R.S., H.L., K.B.N., M.W., Y.C.)
| | - Aliza Thompson
- Division of Cardiology and Nephrology, Office of Cardiology, Hematology, Endocrinology, and Nephrology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (A.T., R.K.)
| | - Olivia Easley
- Division of General Endocrinology, Office of Cardiology, Hematology, Endocrinology, and Nephrology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (O.E., M.Z.)
| | - Kushal B Naik
- Acumen, Burlingame, California (E.R.S., H.L., K.B.N., M.W., Y.C.)
| | - Yueqin Zhao
- Division of Biometrics 7, Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (T.H.J., Y.Z.)
| | - Rekha Kambhampati
- Division of Cardiology and Nephrology, Office of Cardiology, Hematology, Endocrinology, and Nephrology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (A.T., R.K.)
| | - Michael Wernecke
- Acumen, Burlingame, California (E.R.S., H.L., K.B.N., M.W., Y.C.)
| | - Ali Niak
- Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (S.T.B., K.G., A.N., D.J.G.)
| | - Marina Zemskova
- Division of General Endocrinology, Office of Cardiology, Hematology, Endocrinology, and Nephrology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (O.E., M.Z.)
| | | | - Jeffrey A Kelman
- Centers for Medicare & Medicaid Services, Washington, DC (J.A.K.)
| | - David J Graham
- Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland (S.T.B., K.G., A.N., D.J.G.)
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Kritzinger J, Wyse J, Karaplis A. Severe hypophosphataemia and hypocalcaemia following intravenous ferric derisomaltose and denosumab administration. BMJ Case Rep 2024; 17:e262595. [PMID: 39694647 DOI: 10.1136/bcr-2024-262595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Serum calcium and phosphorus levels are tightly regulated by the calciotropic hormone parathyroid hormone, fibroblast growth factor 23 and 1,25(OH)2 vitamin D. Commonly prescribed therapies for iron-deficiency anaemia (IDA) such as ferric carboxymaltose and ferric derisomaltose (FDM) have been shown to disrupt phosphorus homeostasis, resulting in hypophosphataemia. Similarly, denosumab use can result in hypocalcaemia due to the inhibition of osteoclastic maturation, activity and survival. Here, we report the development of severe hypophosphataemia and hypocalcaemia in a patient with osteoporosis and IDA following treatment with denosumab and FDM. The patient remained asymptomatic; however, supplementation with calcium, phosphorus and calcitriol replacement was required prior to eventual normalisation of serum levels. Often concomitantly prescribed, little guidance exists regarding electrolyte disturbances following the administration of FDM and denosumab. While hypophosphataemia and hypocalcaemia are relatively uncommon when prescribed individually, synergistic effects likely exist that warrant regular monitoring and occasional supplementation.
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Affiliation(s)
| | - Jonathan Wyse
- Division of Gastroenterology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Andrew Karaplis
- Division of Endocrinology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
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Hirai T, Mori Y, Ogura T, Kondo Y, Sakazaki Y, Ishitsuka Y, Sudo A, Iwamoto T. Influence of loop diuretics on denosumab-induced hypocalcaemia in osteoporosis: a retrospective observational analysis. J Pharm Health Care Sci 2024; 10:60. [PMID: 39334301 PMCID: PMC11437979 DOI: 10.1186/s40780-024-00380-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND We examined whether denosumab-induced hypocalcaemia is evident in osteoporosis when given loop diuretics that promote urinary calcium excretion. METHODS Japanese Spontaneous Adverse Drug Event Reports was analyzed to examine signals for denosumab-induced hypocalcaemia co-administered loop diuretics. We retrospectively included osteoporotic patients to detect predictors for denosumab-induced hypocalcaemia (corrected calcium level < 8.5 mg/dL) using multivariate logistic regression analysis. We compared differences in corrected calcium levels (ΔCa = nadir-baseline). RESULTS A significant signal for hypocalcaemia was detected (Reporting odds ratio = 865.8, 95% confidence interval [95% CI]: 596.8 to 1255.9, p < 0.0001). Among 164 patients (hypocalcaemia, 12%), loop diuretics have a significant association with hypocalcaemia (odds ratio [OR] = 6.410, 95% CI: 1.005 to 40.90, p = 0.0494). However, hypocalcaemia was found to be lower in high corrected calcium levels at baseline (OR = 0.032, 95% CI: 0.005 to 0.209, p < 0.0001) and calcium and vitamin D supplementation (OR = 0.285, 95% CI: 0.094 to 0.868, p = 0.0270). In the non-hypocalcaemia, ΔCa decreased significantly in the denosumab plus loop diuretics than in the denosumab alone (-0.9 [-1.3 to -0.7] mg/dL vs. -0.5 [-0.8 to -0.3] mg/dL, p = 0.0156). However, ΔCa remained comparable in the hypocalcaemia despite loop diuretics co-administration (-1.0 [-1.2 to -0.8] mg/dL vs. -0.8 [-1.5 to -0.7] mg/dL, p = 0.7904). CONCLUSIONS Loop diuretics may predispose to developing denosumab-induced hypocalcaemia.
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Affiliation(s)
- Toshinori Hirai
- Department of Pharmacy, Faculty of Medicine, Mie University Hospital, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
- Department of Pharmacy, Tokyo Medical and Dental University Hospital, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Yukari Mori
- Department of Pharmacy, Faculty of Medicine, Mie University Hospital, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Toru Ogura
- Clinical Research Support Center, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Yuki Kondo
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, Kumamoto, 862-0973, Japan
| | - Yuka Sakazaki
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, Kumamoto, 862-0973, Japan
| | - Yoichi Ishitsuka
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, Kumamoto, 862-0973, Japan
| | - Akihiro Sudo
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oehonmachi, Chuo-ku, Kumamoto, Kumamoto, 862-0973, Japan
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Takuya Iwamoto
- Department of Pharmacy, Faculty of Medicine, Mie University Hospital, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
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Abu-Jwead A, Fisher DL, Goldabart A, Yoel U, Press Y, Tsur A, Fraenkel M, Baraf L. Safety of In-hospital Parenteral Antiosteoporosis Therapy Following a Hip Fracture: A Retrospective Cohort. J Endocr Soc 2024; 8:bvae172. [PMID: 39416429 PMCID: PMC11481011 DOI: 10.1210/jendso/bvae172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Indexed: 10/19/2024] Open
Abstract
Purpose To assess the safety of zoledronic acid (ZOL) and denosumab (Dmab) administered following hip fracture in a hospital setting. Methods Patients older than 65 years were treated by a fracture liaison service following hip fracture. Generally, patients who had a glomerular filtration rate (eGFR) > 35 mL/min were treated with ZOL, whereas patients who had previously received bisphosphonates or had a eGFR between 20 and 35 mL/min were treated with Dmab. Adverse events included hypocalcemia (calcium corrected for albumin less than 8.5 mg/day), renal functional impairment (0.5 mg/dL or more increase in serum creatinine) within 30 days of treatment, or a fever (>38 °C) within 48 hours of drug administration. Results Two hundred twenty-eight and 134 patients were treated with ZOL and Dmab, respectively. Mean body temperature was elevated following ZOL administration (0.18 °C P < .001) but remained below 38 °C. Hypocalcemia occurred in 18% and 29% of the ZOL and Dmab groups, respectively (P = .009). Renal functional impairment was observed in 9 and 6 patients (4% and 5%) in the ZOL and Dmab groups, respectively (P = .8). Pretreatment calcium above 9.3 mg/dL was associated with a lower risk of posttreatment hypocalcemia (odds ratio 0.30, 95% confidence interval 0.13-0.68, P = .004). While the absolute risk of hypocalcemia was higher in the Dmab group, multivariate analysis did not find that the choice of drug was predictive of hypocalcemia. Conclusion In-hospital parenteral osteoporosis treatment was rarely associated with fever or renal function impairment but was associated with hypocalcemia. Posttreatment hypocalcemia risk did not vary significantly between patients receiving ZOL or Dmab.
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Affiliation(s)
- Alaa Abu-Jwead
- Goldman Medical School at the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - David L Fisher
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
| | - Adi Goldabart
- Clinical Research Center, Soroka University Medical Center, Beer Sheva 84101, Israel
| | - Uri Yoel
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Yan Press
- Geriatric Department, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Anat Tsur
- Department of Endocrinology and Metabolism, Clalit Health Services, Jerusalem 9310604, Israel
- The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9190500, Israel
| | - Merav Fraenkel
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Lior Baraf
- Endocrinology, Soroka University Medical Center, Beer Sheva 84101, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel
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7
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Siddiqui AH, Shaikh M, Salman A, Fahim MAA, Batool F, Mari T, Musani S, Fareed M, Rehan R, Hassni A, Nizami U, Amir A, Moeed A, Surani SR. Incidence and predictors of hypocalcemia in end-stage renal disease patients on denosumab therapy: A systematic review and meta-analysis. World J Meta-Anal 2024; 12:97256. [DOI: 10.13105/wjma.v12.i3.97256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/20/2024] [Accepted: 08/26/2024] [Indexed: 09/13/2024] Open
Abstract
BACKGROUND Denosumab inhibits the receptor activator of nuclear factor kappa-ligand. It markedly increases bone mineral density and has been proven to reduce the risk of fractures. However, numerous adverse effects, notably hypocalcemia, are prevalent in patients with end-stage renal disease (ESRD).
AIM To analyze the incidence and predictors of hypocalcemia caused by denosumab compared to control in patients with ESRD.
METHODS We conducted this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. PubMed, Scopus, Cochrane Central, and EMBASE were systematically searched from inception through March 2024. All original studies investigating the effects of denosumab on patients with ESRD compared to control were extracted. The primary outcomes of our study were the incidence of mild, severe, and very severe hypocalcemia. Secondary outcomes included serum levels of intact parathyroid hormone, calcium, and phosphate. The results were pooled and analyzed using a random-effects model.
RESULTS Seven articles comprising 3240 patients were included in our study. Patients treated with denosumab had a significantly increased incidence of mild hypocalcemia [risk ratio (RR): 2.79; 95% confidence interval (CI): 0.99-7.91; P = 0.05; I² = 37%] and of very severe hypocalcemia (RR: 9.58; 95%CI: 1.58-57.98; P = 0.01; I² = 49%). However, an increase in the occurrence of severe hypocalcemia was non-significant (RR: 4.23; 95%CI: 0.47-38.34; P = 0.20; I² = 96%). Alternatively, denosumab showed a significant decrease in serum intact parathyroid hormone [mean difference (MD): -433.20, 95%CI: -775.12 to -91.28, I2 = 98%, P= 0.01], while there was a non-significant decrease in phosphate (MD: -0.47, 95%CI: -1.35 to 0.41, I2 = 88%, P = 0.30) and calcium levels (MD: -0.33, 95%CI: -0.95 to 0.29, I2 = 94%, P = 0.29).
CONCLUSION Our study demonstrated that denosumab is significantly associated with mild and very severe hypocalcemia in patients with ESRD making it necessary to detect and prevent this side effect of treatment.
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Affiliation(s)
- Abdul Hannan Siddiqui
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Misbah Shaikh
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Afia Salman
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Muhammad Ahmed Ali Fahim
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Fizzah Batool
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Tahreem Mari
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Sarah Musani
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Muneeb Fareed
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Rooma Rehan
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Amna Hassni
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Urooj Nizami
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Ayesha Amir
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Abdul Moeed
- Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Sindh, Pakistan
| | - Salim R Surani
- Department of Medicine & Pharmacology, Texas A&M University, College Station, TX 77843, United States
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8
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Yoo YS, Kim MG, Park HJ, Chae MY, Choi YJ, Oh CK, Son CG, Lee EJ. Additional effects of herbal medicine combined with bisphosphonates for primary osteoporosis: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1413515. [PMID: 39346562 PMCID: PMC11427380 DOI: 10.3389/fphar.2024.1413515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 08/26/2024] [Indexed: 10/01/2024] Open
Abstract
Background Osteoporosis (OP) is a significant medical issue associated with population aging. Recent research on herbal medicines (HMs) for OP has been increasing, with these therapies sometimes used in conjunction with bisphosphonates (BPs), the standard treatment for OP. We conducted a systematic review and meta-analysis to evaluate the effects of combining HMs with BPs on improving bone mineral density (BMD) in patients with primary OP. Methods We searched nine databases-PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure Wanfang, KISS, Kmbase, Science On, and Oasis-up to 31 August 2023. We selected randomized controlled trials (RCTs) comparing BMD between HMs plus BPs and BPs alone in primary OP. A meta-analysis with BMD as the primary outcome was performed using RevMan version 5.4. Study quality and evidence certainty were assessed through Cochrane's risk of bias2 and GRADE. Results Out of 43 RCTs involving 4,470 participants (mean age 65.8 ± 6.6 years), 35 RCTs with 3,693 participants were included in the meta-analysis. The combination of HMs and BPs was found to be more effective in improving BMD compared to BPs alone, with improvements of 0.10 g/cm2 at the lumbar spine (33 RCTs, 95% CI: 0.07-0.12, p < 0.001, I2 = 93%) and 0.08 g/cm2 at the femoral neck (20 RCTs, 95% CI: 0.05-0.12, p < 0.001, I2 = 94%), though this result was associated with high heterogeneity, high risk of bias, and very low certainty of evidence. Conclusion Our data suggest the possibility that combining HMs with BPs may improve BMD in primary OP more effectively than using BPs alone. However, the results should be interpreted with caution due to the high heterogeneity and low quality of the studies included in the review. Therefore, further well-designed RCTs are needed to confirm these findings. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023392139.
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Affiliation(s)
- Young-Seo Yoo
- College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Min-Gyeong Kim
- College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Hee-Joo Park
- College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Min-Young Chae
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Yu-Jin Choi
- Institute of Bioscience and Integrative Medicine, Department of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Chae-Kun Oh
- Department of Herbal Formula, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Chang-Gue Son
- Institute of Bioscience and Integrative Medicine, Department of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
| | - Eun-Jung Lee
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Daejeon University, Daejeon, Republic of Korea
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9
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Diab DL, Watts NB. The use of denosumab in osteoporosis - an update on efficacy and drug safety. Expert Opin Drug Saf 2024; 23:1069-1077. [PMID: 39262109 DOI: 10.1080/14740338.2024.2386365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 07/03/2024] [Indexed: 09/13/2024]
Abstract
INTRODUCTION Denosumab (Prolia) is a fully human monoclonal antibody against the receptor activator of the nuclear factor kappaB ligand. It is a potent antiresorptive agent that reduces osteoclastogenesis. AREAS COVERED Denosumab has been shown to improve bone mineral density and reduce the incidence of new fractures in postmenopausal women and men. It is also used in the treatment of glucocorticoid-induced osteoporosis, as well as for the prevention of bone loss and reduction of fracture risk in men receiving androgen deprivation therapy for non-metastatic prostate cancer and women receiving adjuvant aromatase inhibitor therapy for breast cancer. Initial safety concerns included infections, cancer, skin reactions, cardiovascular disease, hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures; however, further study and experience provide reassurance on these issues. Anecdotal reports have raised concerns about an increased risk of multiple vertebral fractures following discontinuation of denosumab. EXPERT OPINION Although bisphosphonates are often selected as initial therapy for osteoporosis, denosumab may be an appropriate initial therapy in patients at high risk for fracture, including older patients who have difficulty with the dosing requirements of oral bisphosphonates, as well as patients who are intolerant of, unresponsive to, or have contraindications to other therapies. Additional data is needed to address questions regarding treatment duration and discontinuation.
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Affiliation(s)
- Dima L Diab
- College of Medicine, Cincinnati VA Medical Center, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH, USA
| | - Nelson B Watts
- Mercy Health Osteoporosis and Bone Health Services, Cincinnati, OH, USA
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10
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Ikegami K, Imai S, Yasumuro O, Tsuchiya M, Henmi N, Suzuki M, Hayashi K, Miura C, Abe H, Kizaki H, Funakoshi R, Sato Y, Hori S. External Validation and Update of the Risk Prediction Model for Denosumab-Induced Hypocalcemia Developed From a Hospital-Based Administrative Database. JCO Clin Cancer Inform 2024; 8:e2400078. [PMID: 39008783 PMCID: PMC11371100 DOI: 10.1200/cci.24.00078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 04/23/2024] [Accepted: 05/10/2024] [Indexed: 07/17/2024] Open
Abstract
PURPOSE Denosumab is used to treat patients with bone metastasis from solid tumors, but sometimes causes severe hypocalcemia, so careful clinical management is important. This study aims to externally validate our previously developed risk prediction model for denosumab-induced hypocalcemia by using data from two facilities with different characteristics in Japan and to develop an updated model with improved performance and generalizability. METHODS In the external validation, retrospective data of Kameda General Hospital (KGH) and Miyagi Cancer Center (MCC) between June 2013 and June 2022 were used and receiver operating characteristic (ROC)-AUC was mainly evaluated. A scoring-based updated model was developed using the same data set from a hospital-based administrative database as previously employed. Selection of variables related to prediction of hypocalcemia was based on the results of external validation. RESULTS For the external validation, data from 235 KGH patients and 224 MCC patients were collected. ROC-AUC values in the original model were 0.879 and 0.774, respectively. The updated model consisting of clinical laboratory tests (calcium, albumin, and alkaline phosphatase) afforded similar ROC-AUC values in the two facilities (KGH, 0.837; MCC, 0.856). CONCLUSION We developed an updated risk prediction model for denosumab-induced hypocalcemia with small interfacility differences. Our results indicate the importance of using data from plural facilities with different characteristics in the external validation of generalized prediction models and may be generally relevant to the clinical application of risk prediction models. Our findings are expected to contribute to improved management of bone metastasis treatment.
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Affiliation(s)
- Keisuke Ikegami
- Keio University Faculty of Pharmacy/Graduate School of Pharmaceutical Sciences, Tokyo, Japan
| | - Shungo Imai
- Keio University Faculty of Pharmacy/Graduate School of Pharmaceutical Sciences, Tokyo, Japan
| | - Osamu Yasumuro
- Department of Pharmacy, Kameda General Hospital, Chiba, Japan
| | - Masami Tsuchiya
- Keio University Faculty of Pharmacy/Graduate School of Pharmaceutical Sciences, Tokyo, Japan
- Department of Pharmacy, Miyagi Cancer Center, Miyagi, Japan
| | - Naomi Henmi
- Department of Pharmacy, Miyagi Cancer Center, Miyagi, Japan
| | - Mariko Suzuki
- Department of Pharmacy, Miyagi Cancer Center, Miyagi, Japan
| | | | - Chisato Miura
- Department of Pharmacy, Miyagi Cancer Center, Miyagi, Japan
| | - Haruna Abe
- Department of Pharmacy, Miyagi Cancer Center, Miyagi, Japan
| | - Hayato Kizaki
- Keio University Faculty of Pharmacy/Graduate School of Pharmaceutical Sciences, Tokyo, Japan
| | | | - Yasunori Sato
- Department of Biostatistics, Keio University School of Medicine, Tokyo, Japan
| | - Satoko Hori
- Keio University Faculty of Pharmacy/Graduate School of Pharmaceutical Sciences, Tokyo, Japan
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11
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Yamamoto A, Nagao M, Nishizaki Y, Maeda E, Ishijima M. Risk factors for nonresponse to 2 years of denosumab administration in patients with osteoporosis: A retrospective single-center cohorts study. Health Sci Rep 2024; 7:e1993. [PMID: 38585014 PMCID: PMC10995440 DOI: 10.1002/hsr2.1993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 04/09/2024] Open
Abstract
Background and Aims To investigate the factors associated with changes in bone mineral density (BMD) and the incidence of fractures in osteoporotic patients treated with denosumab. Methods This retrospective study included 162 osteoporotic patients treated with denosumab for 24 months between 2013 and 2019. Patients were divided according to the changes in BMD as nonresponders (NL group: <3% increase in lumbar spine BMD [LBMD], NH group: <0% increase in femoral neck BMD [FNBMD]) or responders (RL group: ≥3% increase in LBMD, RH group: ≥0% increase in FNBMD). Results The respective changes in the LBMD and FNBMD after 24 months of denosumab treatment were 9.3% (95% confidence interval [CI]: 8.1-10.6) and 3.3% (95% CI: 2.1-4.5). Twenty-eight (17.3%) patients were in the NL group, and 134 (82.7%) were in the RL group. A history of bisphosphonate treatment was a risk factor for being in the NL group (odds ratio [OR]: 3.84, 95% CI: 1.38-10.71, p = 0.007; adjusted OR: 3.21, 95% CI: 1.01-10.19, p = 0.048). Although the NH (n = 48; 30.8%) and RH (n = 108; 69.2%) groups had similar baseline characteristics, the NH group had a significantly higher baseline FNBMD than the RH group (p = 0.003). The change in FNBMD was negatively associated with the FNBMD at baseline (r = -0.34, p < 0.001). No new osteoporotic fractures occurred in either group during follow-up. Conclusion In osteoporotic patients receiving denosumab treatment, a history of bisphosphonate treatment was a risk factor for a lack of increase in LBMD, and a higher FNBMD at baseline was negatively associated with the change in FNBMD.
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Affiliation(s)
- Akiko Yamamoto
- Clinical Translational ScienceJuntendo University Graduate School of MedicineTokyoJapan
| | - Masashi Nagao
- Clinical Translational ScienceJuntendo University Graduate School of MedicineTokyoJapan
- Medical Technology Innovation CenterJuntendo UniversityTokyoJapan
- Department of Medicine for Orthopaedics and Motor OrganJuntendo University Graduate School of MedicineTokyoJapan
- Department of Sports MedicineJuntendo University School of Sports and Health ScienceChibaJapan
| | - Yuji Nishizaki
- Clinical Translational ScienceJuntendo University Graduate School of MedicineTokyoJapan
- Medical Technology Innovation CenterJuntendo UniversityTokyoJapan
| | - Eri Maeda
- Department of Medicine for Orthopaedics and Motor OrganJuntendo University Graduate School of MedicineTokyoJapan
- Department of Orthopaedic SurgeryJuntendo Tokyo Koto Geriatric Medical CenterTokyoJapan
| | - Muneaki Ishijima
- Department of Medicine for Orthopaedics and Motor OrganJuntendo University Graduate School of MedicineTokyoJapan
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12
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Bitar ZI, Hajjiah AMA, Maadarani OS, Elzoueiry MM, Gohar MR, Abdelfatah M, Alabdali F. Hypocalcemia in Patients With Osteoporosis and Normal Renal Function, Treated With Denosumab, a Retrospective Analysis. Nutr Metab Insights 2024; 17:11786388231223604. [PMID: 38205220 PMCID: PMC10775727 DOI: 10.1177/11786388231223604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Objective The reported hypocalcemia in postmenopausal women with osteoporosis who received Denosumab was low (0.05%-1.7% to 7.4%). The major prediction factors were vitamin D and calcium levels and renal function. The objective is to evaluate the incidence of hypocalcemia in patients with osteoporosis, normal renal function, and vitamin D who received Denosumab. Method A retrospective analysis was conducted using the medical records (2022-2023). We looked for hypocalcemia (albumin-adjusted calcium lower than 2.2 mmol/L). Results Two hundred one postmenopausal women diagnosed with osteoporosis and received denosumab treatment were included. All patients received vitamin D3 capsules and calcium supplementation. The mean age of the patient was 75.7 ± 7.0 years (56-91 years). Hypocalcemia was observed in 46 (23%) patients following a subcutaneous dose of Denosumab 60 mg. Median calcium was 2.25 mmol/L (minimum: 0.890 mmol/L, maximum: 2.6 mmol/L). Fourteen (30.4%) patients had severe hypocalcemia (<1.8 mmol/L) and required parenteral correction. A comparison between hypocalcemia and patients with normal calcium indicated that the significant predictor of hypocalcemia was pretreatment parathyroid hormone levels (9.9 ± 11.8vs 7.6 ± 2.56 pmol/L, respectively; P < .005). The prognostic role of parathyroid hormone for the denosumab-associated hypocalcemia was assessed using ROC curve analysis. For the cut-off value of Parathyroid hormone = 6.8 pmol/L, giving serum parathyroid measurement an AUC of 0.668 (0.599-0.737) - P = .0007; sensitivity 85%; specificity 52%. Conclusion Hypocalcemia induced by the denosumab treatment is more prevalent than previously shown in patients with osteoporosis receiving adequate calcium and vitamin D supplements. An elevated parathyroid hormone predicts hypocalcemia related to denosumab therapy in patients with normal calcium and vitamin D levels.
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Affiliation(s)
| | | | | | | | | | | | - Fawaz Alabdali
- Endocrinology and Diabetic Unit, Ahmadi Hospital, Kuwait Oil Company, Ahmadi, Kuwait
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13
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Spångeus A, Rydetun J, Woisetschläger M. Prevalence of denosumab-induced hypocalcemia: a retrospective observational study of patients routinely monitored with ionized calcium post-injection. Osteoporos Int 2024; 35:173-180. [PMID: 37750930 PMCID: PMC10786736 DOI: 10.1007/s00198-023-06926-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/19/2023] [Indexed: 09/27/2023]
Abstract
We assessed the prevalence of hypocalcemia after denosumab injections in a real-world cohort routinely monitored for calcium during up to 7.5 years of treatment. Among 1096 injections in 242 patients, 6.3% resulted in hypocalcemia, and was independent of the injection number. Severe hypocalcemia was rare (1%). PURPOSE To assess the prevalence of and risk factors for hypocalcemia after administration of denosumab in a patient cohort routinely monitored for ionized calcium after each dose. METHODS In this retrospective observational study, we analyzed denosumab-induced hypocalcemia in a real-world cohort who were routinely followed up with ionized calcium pre- and post-injection (within 31 days after injection) during the period 2011 to 2020. RESULTS In total, we included data from 1096 denosumab injections in 242 individuals (1-15 injections per patient). The mean age for the first injection was 74 ± 10 years, and 88% were female. Post-injection hypocalcemia occurred after 6.3% of all injections (4.6% mild, 0.6% moderate, and 1.1% severe) and was independent of the number of injections (rate of hypocalcemia varied from 3-8%). Risk factors for hypocalcemia were male sex, severe renal failure, pre-injection hypocalcemia, hypomagnesemia, hypophosphatemia, and vitamin D insufficiency. Furthermore, older age was not associated with an increased hypocalcemia risk. CONCLUSIONS Denosumab-induced hypocalcemia is a prevalent adverse event, which occurs independently of the number of injections. However, severe hypocalcemia is a rare occurrence, and severe renal failure and nutritional status appear to be important predictive factors. Magnesium and phosphate might add value in the pre-injection risk assessment; however, this observation needs to be confirmed in larger cohorts.
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Affiliation(s)
- Anna Spångeus
- Department of Acute Internal Medicine and Geriatrics, Department of Medical and Health Sciences, Linköping University Hospital, Linköping University, Building 444, Level 11, Campus US, 581 83, Linköping, Sweden.
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
| | - Johan Rydetun
- Department of Acute Internal Medicine and Geriatrics, Department of Medical and Health Sciences, Linköping University Hospital, Linköping University, Building 444, Level 11, Campus US, 581 83, Linköping, Sweden
| | - Mischa Woisetschläger
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Department of Radiology, Linköping University Hospital, Linköping, Sweden
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14
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Muhandiramge J, Lee V, Tran M, Ho L. Interaction between ferric carboxymaltose and denosumab causing severe hypocalcaemia and hypophosphataemia in a patient without chronic kidney disease. Intern Med J 2023; 53:1273-1276. [PMID: 37384573 DOI: 10.1111/imj.16156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 04/25/2023] [Indexed: 07/01/2023]
Abstract
Coadministration of ferric carboxymaltose and denosumab may cause hypocalcaemia and hypophosphataemia; however, this interaction is not well-described in the literature and has typically been described in patients with chronic kidney disease (CKD). We present a case of this interaction in a patient without preexisting CKD. We suggest the use of alternative iron preparations and an interval of at least 4 weeks between administrations.
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Affiliation(s)
- Jaidyn Muhandiramge
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Austin Health, Melbourne, Victoria, Australia
| | - Vivian Lee
- Austin Health, Melbourne, Victoria, Australia
| | - Monica Tran
- Austin Health, Melbourne, Victoria, Australia
| | - Lannie Ho
- Austin Health, Melbourne, Victoria, Australia
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15
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Dadana S, Gundepalli S, Kondapalli A. Severe Refractory Hypocalcemia Caused by Denosumab. Cureus 2023; 15:e39866. [PMID: 37404446 PMCID: PMC10315058 DOI: 10.7759/cureus.39866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2023] [Indexed: 07/06/2023] Open
Abstract
Denosumab is a fully human monoclonal antibody that binds to the receptor activator of nuclear factor kappa-Β ligand, an essential cytokine factor in bone resorption, which reduces bone resorption and has been shown to decrease the incidence of skeletal-related events in patients with malignancy and bone metastasis. Severe hypocalcemia is a rare and life-threatening adverse effect of denosumab therapy. Here, we discuss the case of a patient with stage 4 estrogen receptor-positive, progesterone receptor-negative, human epidermal growth factor receptor 2-negative breast cancer who was on treatment with denosumab for bony metastases and presented with severe refractory hypocalcemia.
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Affiliation(s)
- Sriharsha Dadana
- Internal Medicine, Cheyenne Regional Medical Center, Cheyenne, USA
| | - Sai Gundepalli
- Internal Medicine, Cheyenne Regional Medical Center, Cheyenne, USA
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16
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Tsai TY, You ZH, Tsai SF, Wu MJ, Yu TM, Chuang YW, Lin YC, Deng YL, Hsu CY, Chen CH. Adverse Effects of Denosumab in Kidney Transplant Recipients: A 20-Year Retrospective Single-Center Observation Study in Central Taiwan. Transplant Proc 2023:S0041-1345(23)00145-8. [PMID: 37055293 DOI: 10.1016/j.transproceed.2023.03.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/13/2023] [Indexed: 04/15/2023]
Abstract
BACKGROUND Bone loss can be noted in kidney transplantation recipients (KTRs) and can be related to fracture events. Denosumab, a potent monoclonal antibody to RANK ligand, increases lumbar bone mineral density. However, safety data for denosumab remain limited regarding transplant recipients. Hypocalcemia and increased genital tract infections have been mentioned as adverse effects in KTRs after being prescribed denosumab. METHODS We retrospectively analyzed the electronic medical records of KTRs during the recent 20 years who had been prescribed antiresorptive therapy and were >18 years old. Medical records and their clinical data were reviewed and analyzed. We compared the frequency of adverse effects between denosumab with other antiresorptive therapies. RESULTS A total of 70 KTRs were enrolled, with 46 patients being given denosumab and the first injection being noted on October 31, 2014. No significant differences were seen in mortality rate, opportunistic infection, pneumonia, or genitourinary tract infection. One diagnosis of osteonecrosis of the jaw was noted in the denosumab group (2.2%). A higher incidence of hypocalcemia (<8.4 mg/dL) was noted in the denosumab group (34.8%), and a higher but nonsignificant difference in the incidence of severe hypocalcemia was also noted in the group. CONCLUSIONS Denosumab may be considered as safe as other antiresorptive therapies for KTRs. However, more hypocalcemia events have been noted, so medical personnel may need to be cautious when prescribing its use.
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Affiliation(s)
- Tsung-Yin Tsai
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital Chiayi Branch, Chiayi, Taiwan
| | - Zi-Hong You
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital Chiayi Branch, Chiayi, Taiwan
| | - Shang-Feng Tsai
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Ming-Ju Wu
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan
| | - Tung-Min Yu
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ya-Wen Chuang
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yung-Chieh Lin
- Department of Urology, Hsinchu Branch, MacKay Memorial Hospital, New Taipei, Taiwan
| | - Ya-Lian Deng
- Department of Nursing, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chiann-Yi Hsu
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Cheng-Hsu Chen
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; Department of Life Science, Tunghai University, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan.
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17
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Khan AA, AbuAlrob H, Al-Alwani H, Ali DS, Almonaei K, Alsarraf F, Bogoch E, Dandurand K, Gazendam A, Juby AG, Mansoor W, Marr S, Morgante E, Myslik F, Schemitsch E, Schneider P, Thain J, Papaioannou A, Zalzal P. Post hip fracture orthogeriatric care-a Canadian position paper addressing challenges in care and strategies to meet quality indicators. Osteoporos Int 2023; 34:1011-1035. [PMID: 37014390 DOI: 10.1007/s00198-022-06640-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/12/2022] [Indexed: 04/05/2023]
Abstract
INTRODUCTION Osteoporosis is a major disease state associated with significant morbidity, mortality, and health care costs. Less than half of the individuals sustaining a low energy hip fracture are diagnosed and treated for the underlying osteoporosis. OBJECTIVE A multidisciplinary Canadian hip fracture working group has developed practical recommendations to meet Canadian quality indicators in post hip fracture care. METHODS A comprehensive narrative review was conducted to identify and synthesize key articles on post hip fracture orthogeriatric care for each of the individual sections and develop recommendations. These recommendations are based on the best evidence available today. CONCLUSION Recommendations are anticipated to reduce recurrent fractures, improve mobility and healthcare outcomes post hip fracture, and reduce healthcare costs. Key messages to enhance postoperative care are also provided.
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Affiliation(s)
- Aliya A Khan
- Department of Medicine, Division of Endocrinology and Metabolism and Geriatrics, McMaster University, Hamilton, ON, Canada.
| | - Hajar AbuAlrob
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada
- Department of Medicine, Division of Geriatric Medicine, McMaster University, Hamilton, ON, Canada
| | - Hatim Al-Alwani
- Department of Medicine, Division of Endocrinology and Metabolism and Geriatrics, McMaster University, Hamilton, ON, Canada
| | - Dalal S Ali
- Department of Medicine, Division of Endocrinology and Metabolism and Geriatrics, McMaster University, Hamilton, ON, Canada
| | - Khulod Almonaei
- Department of Medicine, Division of Endocrinology and Metabolism and Geriatrics, McMaster University, Hamilton, ON, Canada
| | - Farah Alsarraf
- Department of Medicine, Division of Endocrinology and Metabolism and Geriatrics, McMaster University, Hamilton, ON, Canada
| | - Earl Bogoch
- Department of Surgery, Division of Orthopaedic Surgery, University of Toronto, Toronto, ON, Canada
| | - Karel Dandurand
- Department of Medicine, Division of Endocrinology and Metabolism and Geriatrics, McMaster University, Hamilton, ON, Canada
| | - Aaron Gazendam
- Department of Surgery, Division of Orthopaedic Surgery, McMaster University, Hamilton, ON, Canada
| | - Angela G Juby
- Department of Medicine, Division of Geriatric Medicine, University of Alberta, Edmonton, AB, Canada
| | - Wasim Mansoor
- Trillium Health Partners, University of Toronto, Toronto, ON, Canada
| | - Sharon Marr
- Department of Medicine, Division of Geriatric Medicine, McMaster University, Hamilton, ON, Canada
| | - Emmett Morgante
- Bone Research and Education Center Patient Support Program and Education Coordinator, Oakville, ON, Canada
| | - Frank Myslik
- Division of Emergency Medicine, Western University, London, ON, Canada
| | - Emil Schemitsch
- Department of Surgery, Division of Orthopaedic Surgery, Western University, London, ON, Canada
| | - Prism Schneider
- Department of Surgery, Division of Orthopaedic Surgery, University of Calgary, Calgary, AB, Canada
| | - Jenny Thain
- Department of Medicine, Division of Geriatric Medicine, Western University, London, ON, Canada
| | - Alexandra Papaioannou
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada
- Department of Medicine, Division of Geriatric Medicine, McMaster University, Hamilton, ON, Canada
| | - Paul Zalzal
- Department of Surgery, Division of Orthopaedic Surgery, McMaster University, Hamilton, ON, Canada
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18
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Cowan A, Jeyakumar N, McArthur E, Fleet JL, Kanagalingam T, Karp I, Khan T, Muanda FT, Nash DM, Silver SA, Thain J, Weir MA, Garg AX, Clemens KK. Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study. J Bone Miner Res 2023; 38:650-658. [PMID: 36970786 DOI: 10.1002/jbmr.4804] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/28/2023] [Accepted: 03/21/2023] [Indexed: 04/11/2023]
Abstract
Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Andrea Cowan
- ICES, Toronto, Canada
- Department of Medicine, Western University, London, Canada
| | - Nivethika Jeyakumar
- ICES, Toronto, Canada
- Lawson Health Research Institute, London Health Sciences Centre, London, Canada
| | - Eric McArthur
- ICES, Toronto, Canada
- Lawson Health Research Institute, London Health Sciences Centre, London, Canada
| | - Jamie L Fleet
- Lawson Health Research Institute, London Health Sciences Centre, London, Canada
- Department of Physical Medicine and Rehabilitation, Western University, London, Canada
- Schulich School of Medicine and Dentistry, Western University, London, Canada
- St. Joseph's Health Care London, London, Canada
| | | | - Igor Karp
- Department of Epidemiology & Biostatistics, Western University, London, Canada
| | - Tayyab Khan
- Department of Medicine, Western University, London, Canada
- St. Joseph's Health Care London, London, Canada
| | | | - Danielle M Nash
- ICES, Toronto, Canada
- Lawson Health Research Institute, London Health Sciences Centre, London, Canada
- Department of Epidemiology & Biostatistics, Western University, London, Canada
| | | | - Jenny Thain
- Department of Medicine, Western University, London, Canada
- St. Joseph's Health Care London, London, Canada
| | - Matthew A Weir
- ICES, Toronto, Canada
- Department of Medicine, Western University, London, Canada
- Lawson Health Research Institute, London Health Sciences Centre, London, Canada
| | - Amit X Garg
- ICES, Toronto, Canada
- Department of Medicine, Western University, London, Canada
- Lawson Health Research Institute, London Health Sciences Centre, London, Canada
- Schulich School of Medicine and Dentistry, Western University, London, Canada
- Department of Epidemiology & Biostatistics, Western University, London, Canada
| | - Kristin K Clemens
- ICES, Toronto, Canada
- Department of Medicine, Western University, London, Canada
- Lawson Health Research Institute, London Health Sciences Centre, London, Canada
- Schulich School of Medicine and Dentistry, Western University, London, Canada
- St. Joseph's Health Care London, London, Canada
- Department of Epidemiology & Biostatistics, Western University, London, Canada
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Awang MH, Hatta SFWM, Mohamad AF, Ghani RA. Denosumab-induced hypocalcemia post bariatric surgery-a severe and protracted course: a case report. J Med Case Rep 2023; 17:73. [PMID: 36859300 PMCID: PMC9979455 DOI: 10.1186/s13256-023-03764-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/05/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND Denosumab is known to cause abnormalities in calcium homeostasis. Most of such cases have been described in patients with underlying chronic kidney disease or severe vitamin D deficiency. Previous bariatric surgery could also contribute to hypocalcemia and deterioration in bone health. CASE PRESENTATION We present a case of a 61-year-old Malay female with worsening bilateral limb weakness, paresthesia, and severe carpopedal spasm a week after receiving subcutaneous denosumab for osteoporosis. She had a history of gastric bypass surgery 20 years ago. Post gastric bypass surgery, she was advised and initiated on lifelong calcium, vitamin D, and iron supplementations that she unfortunately stopped taking 5 years after surgery. Her last serum blood tests, prior to initiation on denosumab, were conducted in a different center, and she was told that she had a low calcium level; hence, she was advised to restart her vitamin and mineral supplements. Laboratory workup revealed severe hypocalcemia (adjusted serum calcium of 1.33 mmol/L) and mild hypophosphatemia (0.65 mmol/L), with normal magnesium and renal function. Electrocardiogram showed a prolonged QTc interval. She required four bolus courses of intravenous calcium gluconate, and three courses of continuous infusions due to retractable severe hypocalcemia (total of 29 vials of 10 mL of 10% calcium gluconate intravenously). In view of her low vitamin D level of 33 nmol/L, she was initiated on a loading dose of cholecalciferol of 50,000 IU per week for 8 weeks. However, despite a loading dose of cholecalciferol, multiple bolus courses, and infusions of calcium gluconate, her serum calcium hovered around only 1.8 mmol/L. After 8 days of continuous intravenous infusions of calcium gluconate, high doses of calcitriol 1.5 μg twice daily, and 1 g calcium carbonate three times daily, her serum calcium stabilized at approximately 2.0 mmol/L. She remained on these high doses for over 2 months, before they were gradually titrated down to ensure sustainability of a safe calcium level. CONCLUSION This case report highlights the importance of screening for risk factors for iatrogenic hypocalcemia and ensuring normal levels before initiating denosumab. The patient history of bariatric surgery could have worsened the hypocalcemia, resulting in a more severe presentation and protracted response to oral calcium and vitamin D supplementation.
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Affiliation(s)
- Mohd Hazriq Awang
- grid.412259.90000 0001 2161 1343Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia
| | | | - Aimi Fadilah Mohamad
- grid.412259.90000 0001 2161 1343Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia
| | - Rohana Abdul Ghani
- grid.412259.90000 0001 2161 1343Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia
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Pharmacological Interventions Targeting Pain in Fibrous Dysplasia/McCune-Albright Syndrome. Int J Mol Sci 2023; 24:ijms24032550. [PMID: 36768871 PMCID: PMC9916440 DOI: 10.3390/ijms24032550] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 02/03/2023] Open
Abstract
Fibrous dysplasia (FD) is a rare, non-inherited bone disease occurring following a somatic gain-of-function R201 missense mutation of the guanine-nucleotide binding protein alpha subunit stimulating activity polypeptide 1 (GNAS) gene. The spectrum of the disease ranges from a single FD lesion to a combination with extraskeletal features; an amalgamation with café-au-lait skin hyperpigmentation, precocious puberty, and other endocrinopathies defines McCune-Albright Syndrome (MAS). Pain in FD/MAS represents one of the most prominent aspects of the disease and one of the most challenging to treat-an outcome driven by (i) the heterogeneous nature of FD/MAS, (ii) the variable presentation of pain phenotypes (i.e., craniofacial vs. musculoskeletal pain), (iii) a lack of studies probing pain mechanisms, and (iv) a lack of rigorously validated analgesic strategies in FD/MAS. At present, a range of pharmacotherapies are prescribed to patients with FD/MAS to mitigate skeletal disease activity, as well as pain. We analyze evidence guiding the current use of bisphosphonates, denosumab, and other therapies in FD/MAS, and also discuss the potential underlying pharmacological mechanisms by which pain relief may be achieved. Furthermore, we highlight the range of presentation of pain in individual cases of FD/MAS to further describe the difficulties associated with employing effective pain treatment in FD/MAS. Potential next steps toward identifying and validating effective pain treatments in FD/MAS are discussed, such as employing randomized control trials and probing new pain pathways in this rare bone disease.
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Integrated Osteoporosis Care to Reduce Denosumab-Associated Hypocalcemia for Patients with Advanced Chronic Kidney Disease and End-Stage Renal Disease. Healthcare (Basel) 2023; 11:healthcare11030313. [PMID: 36766888 PMCID: PMC9914883 DOI: 10.3390/healthcare11030313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/18/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023] Open
Abstract
The incidence of hypocalcemia is high in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) undergoing denosumab treatment. Since 2018, we have carried out a "multidisciplinary integrated care program for osteoporosis among patients with CKD and ESRD" in our hospital. The aim of this study was to compare the incidence of denosumab-associated hypocalcemia among patients with advanced CKD and ESRD before and after the integrated care program. We retrospectively reviewed the records of patients on their first dose of denosumab treatment from January 2012 to December 2021. A total of 3208 patients were included in our study. Among the 3208 patients, there were 101 dialysis patients, 150 patients with advanced CKD (stage 4 and 5), and 2957 patients with an estimated glomerular filtration rate (eGFR) higher than or equal to 30. The incidence of post-treatment severe hypocalcemia (corrected calcium level less than 7.0 mg/dl) within 30 days was significantly higher in the dialysis and advanced CKD group than in patients with an eGFR higher than or equal to 30 (6.9% vs. 2.0% vs. 0.1%, respectively, p < 0.001). Based on the results of the multivariate regression model, poor renal function (p < 0.05) and lower baseline corrected calcium level (p < 0.05) were associated with severe hypocalcemia within 30 days following the first dose of denosumab treatment. The incidence of post-treatment severe hypocalcemia within 30 days in advanced CKD and dialysis patients was significantly lower after the integrated care program (6.8% vs. 0.8%, p < 0.05). Our study shows that multidisciplinary integrated care may reduce the incidence rate of denosumab-associated severe hypocalcemia among patients with advanced CKD and ESRD.
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Artoni de Carvalho JA, Magalhães LR, Polastri LM, Batista IET, de Castro Bremer S, Caetano HRDS, Rufino MN, Bremer-Neto H. Prebiotics improve osteoporosis indicators in a preclinical model: systematic review with meta-analysis. Nutr Rev 2022; 81:nuac097. [PMID: 36474436 DOI: 10.1093/nutrit/nuac097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024] Open
Abstract
CONTEXT Studies using experimental models have demonstrated that prebiotics are involved in antiosteoporotic mechanisms. OBJECTIVE This study was conducted to determine the impact of supplementation with prebiotics in the basal diet of ovariectomized rats with induced osteoporosis as a preclinical model. METHODS A comprehensive systematic search was carried out in the electronic databases PubMed, Science Direct, Web of Science, Scielo, and Google through March 2022 for studies that investigated the impact of prebiotics on bone mineral density (BMD), bone mineral content (BMC), and bone biomechanics. RESULTS The search returned 844 complete articles, abstracts, or book chapters. After detailed screening, 8 studies met the inclusion criteria. Rats (n = 206), were randomly divided between control and treatment groups. Weighted mean differences (WMDs) with the 95%CIs were used to estimate the combined effect size. Compared with the control group, dietary intake of prebiotics significantly increased bone density in the BMD subgroups, with WMDs as follows: 0.03 g/cm3, 95%CI, 0.01-0.05, P < 0.00001, n = 46; and 0.00 g/cm2, 95%CI, 0.00-0.02, P < 0.00001, n = 81; total BMD: WMD, 0.01, 95%CI, 0.01-0.02, P < 0.00001, n = 127; bone content in BMC: WMD, 0.02 g, 95%CI, 0.00-0.04, P = 0.05, n = 107; and the 3-point-bend test: WMD, 15.20 N, 95%CI, 5.92-24.47, P = 0.00001, n = 120. CONCLUSION Prebiotics improve indicators of osteoporosis, BMD, BMC, and bone biomechanics in ovariectomized rats. More studies are needed to increase the level of evidence. SYSTEMIC REVIEW REGISTRATION Systematic Review Protocol for Animal Intervention Studies.
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Affiliation(s)
- João Alberto Artoni de Carvalho
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Leticia Rocha Magalhães
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Laryssa Mayara Polastri
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Ingrid Eloise Trombine Batista
- Department of Orthopedics and Traumatology, Medicine School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | | | - Heliard Rodrigues Dos Santos Caetano
- Department of Functional Sciences, Health Technology Assessment Nucleus of the Medical School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Marcos Natal Rufino
- Department of Functional Sciences, Health Technology Assessment Nucleus of the Medical School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
| | - Hermann Bremer-Neto
- Department of Functional Sciences, Health Technology Assessment Nucleus of the Medical School of Presidente Prudente, Western Sao Paulo University, Presidente Prudente, São Paulo, Brazil
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Inose H, Kato T, Tomizawa S, Ariga A, Motoyoshi T, Fukushima K, Takahashi K, Yoshii T, Okawa A. Impact of romosozumab on serum calcium concentration and factors predicting the fluctuations in calcium concentration upon romosozumab administration: A multicenter retrospective study. Bone Rep 2022; 17:101635. [DOI: 10.1016/j.bonr.2022.101635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/02/2022] [Accepted: 11/06/2022] [Indexed: 11/09/2022] Open
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Definition, Assessment, and Management of Vitamin D Inadequacy: Suggestions, Recommendations, and Warnings from the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Nutrients 2022; 14:nu14194148. [PMID: 36235800 PMCID: PMC9573415 DOI: 10.3390/nu14194148] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/23/2022] [Accepted: 09/30/2022] [Indexed: 11/07/2022] Open
Abstract
In the recent years, both the prescriptions of serum 25(OH)D levels assay, and vitamin D supplementation are constantly increasing, as well as the costs to be incurred relating to these specific aspects. As in many other countries, the risk of vitamin D deficiency is particularly high in Italy, as recently confirmed by cohort studies in the general population as well as in patients with metabolic bone disorder. Results confirmed the North-South gradient of vitamin D levels described among European countries, despite the wide use of supplements. Although vitamin D supplementation is also recommended by the Italian Medicine Agency for patients at risk for fragility fracture or for initiating osteoporotic medication, the therapeutic gap for osteoporosis in Italy is very high. There is a consistent proportion of osteoporotic patients not receiving specific therapy for osteoporosis following a fragility fracture, with a poor adherence to the recommendations provided by national guidelines and position paper documents. The failure or inadequate supplementation with vitamin D in patients on antiresorptive or anabolic treatment for osteoporosis is thought to further amplify the problem and exposes patients to a high risk of re-fracture and mortality. Therefore, it is important that attention to its possible clinical consequences must be given. Thus, in light of new evidence from the literature, the SIOMMMS board felt the need to revise and update, by a GRADE/PICO system approach, its previous original recommendations about the definition, prevention, and treatment of vitamin D deficiency in adults, released in 2011. Several key points have been here addressed, such as the definition of the vitamin D status: normality values and optimal values; who are the subjects considered at risk of hypovitaminosis D; opportunity or not of performing the biochemical assessment of serum 25(OH)D levels in general population and in subjects at risk of hypovitaminosis D; the need or not to evaluate baseline serum 25(OH)D in candidate subjects for pharmacological treatment for osteoporosis; how and whether to supplement vitamin D subjects with hypovitaminosis D or candidates for pharmacological treatment with bone active agents, and the general population; how and whether to supplement vitamin D in chronic kidney disease and/or chronic liver diseases or under treatment with drugs interfering with hepatic metabolism; and finally, if vitamin D may have toxic effects in the subject in need of supplementation.
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25
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Boots JMM, Quax RAM. High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment. Drug Saf 2022; 45:1019-1036. [PMID: 36068430 PMCID: PMC9492608 DOI: 10.1007/s40264-022-01216-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2022] [Indexed: 11/22/2022]
Abstract
The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron-Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.
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Affiliation(s)
- Johannes M M Boots
- Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, The Netherlands.
| | - Rogier A M Quax
- Department of Internal Medicine, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, The Netherlands
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26
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Osteoporosis and Fragility Fractures: currently available pharmacological options and future directions. Best Pract Res Clin Rheumatol 2022; 36:101780. [PMID: 36163230 DOI: 10.1016/j.berh.2022.101780] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. The average lifetime risk of a 50-year-old woman to suffer a fracture of the spine, hip, proximal humerus, or distal forearm has been estimated at close to 50%. In general, pharmacological treatment is recommended in patients who suffered a fragility fracture because their risk of suffering a subsequent fracture is increased dramatically. Therefore, many guidelines recommend pharmacological treatment in patients without a prevalent fracture if their fracture probability is comparable to or higher than that of a person of the same age with a prevalent fracture. The present review aims to highlight currently available pharmacological treatment options and their antifracture efficacy including safety aspects. Drug classes discussed comprise bisphosphonates, selective estrogen receptor modulators, parathyroid hormone peptides and derivatives, humanized monoclonal antibodies, and estrogens and gestagens and their combinations. Furthermore, a brief glimpse is provided into a potentially promising treatment option that involves mesenchymal stem cells.
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27
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Cohen A, Chacko B. Severe hypocalcaemia following denosumab and iron infusion. Nephrology (Carlton) 2022; 27:781-782. [PMID: 35746864 PMCID: PMC9543461 DOI: 10.1111/nep.14078] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/09/2022] [Indexed: 01/26/2023]
Affiliation(s)
- Adrienne Cohen
- Nephrology and Transplantation Unit, John Hunter Hospital, Newcastle, New South Wales, Australia
| | - Bobby Chacko
- Nephrology and Transplantation Unit, John Hunter Hospital, Newcastle, New South Wales, Australia.,School of Medicine and Public Health, University of Newcastle, New South Wales, Australia
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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] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- Rebecca Tai
- Department of Aged Care The University of Melbourne Austin Health Melbourne Australia
| | - Nadia Mouchaileh
- Pharmacy Department Austin Health Heidelberg Australia
- Faculty of Pharmacy and Pharmaceutical Sciences Monash University Clayton Australia
| | - Celia Ting
- Department of Aged Care Austin Health Melbourne Australia
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Abstract
PURPOSE OF REVIEW This review provides suggestions for the evaluation of patients with osteoporosis in order to assure that the diagnosis is correct, to identify potentially correctable conditions contributing to skeletal fragility and fracture risk, and to assist in individualizing management decisions. RECENT FINDINGS Some patients who appear to have osteoporosis have another skeletal disease, such as osteomalacia, that requires further evaluation and treatment that is different than for osteoporosis. Many patients with osteoporosis have contributing factors (e.g., vitamin D deficiency, high fall risk) that should be addressed before and after starting treatment to assure that treatment is effective and safe. Evaluation includes a focused medical history, skeletal-related physical examination, assessment of falls risk, appropriate laboratory tests, and rarely transiliac double-tetracycline labeled bone biopsy. Evaluation of patients with osteoporosis before starting treatment is essential for optimizing clinical outcomes.
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Affiliation(s)
- E Michael Lewiecki
- New Mexico Clinical Research & Osteoporosis Center, 300 Oak St. NE, Albuquerque, NM, 87106, USA.
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30
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Park SY, Kim J, Chung HY. Denosumab-induced hypocalcemia in a patient with hyperthyroidism: a case report. Osteoporos Int 2022; 33:305-308. [PMID: 34232341 PMCID: PMC8758617 DOI: 10.1007/s00198-021-06059-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 06/29/2021] [Indexed: 11/26/2022]
Abstract
Denosumab is a humanized monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab is an effective treatment for osteoporosis but can cause hypocalcemia. We present a case of denosumab-induced hypocalcemia in a patient with hyperthyroidism with a high bone turnover state. A 48-year-old postmenopausal woman was diagnosed with hyperthyroidism and osteoporosis and received antithyroid drugs (propylthiouracil 200 mg/day) and denosumab. After 2 months of taking medication, the patient complained of numbness and tingling in the hands and feet and was diagnosed with hypocalcemia (calcium, 5.8 mg/dL; ionized calcium, 0.83 mmol/L). Alfacalcidol (0.5 μg/day) and calcium carbonate (3000 mg/day) were prescribed. Subsequently, the patient's symptoms improved, and her serum calcium level normalized. The risk of denosumab-induced hypocalcemia may be increased in patients with diseases related to high bone turnover, such as hyperthyroidism; therefore, caution is needed.
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Affiliation(s)
- S Y Park
- Department of Endocrinology and Metabolism, Kyung Hee University Hospital, Seoul, Republic of Korea
| | - J Kim
- Department of Endocrinology and Metabolism, Chaum, Seoul, Republic of Korea
| | - H Y Chung
- Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul, 05278, Republic of Korea.
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Xing Y, Ju S, Sun M, Xiang S. Case report: Denosumab-associated acute heart failure in patients with cardiorenal insufficiency. Front Endocrinol (Lausanne) 2022; 13:970571. [PMID: 36187135 PMCID: PMC9515392 DOI: 10.3389/fendo.2022.970571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/29/2022] [Indexed: 11/20/2022] Open
Abstract
Denosumab is a pivotal treatment for postmenopausal women with osteoporosis. Although its clinical use is generally well tolerated by patients, denosumab in patients with renal insufficiency may increase the risk of hypocalcemia. Thus, we have to consider the population of denosumab in the treatment of osteoporosis and preventive measures for related complications. In a patient with cardiorenal insufficiency, we reported a case of denosumab-induced hypocalcemia complicated by acute left heart failure due to delayed administration of active vitamin D and calcium supplements. The patient's symptoms did not improve after anti-heart failure treatment. However, after adequate calcium and vitamin D supplementation subsequently, the patient's symptoms of heart failure were rapidly relieved, and the serum calcium level returned to normal within three weeks. Therefore, our case showed that the application of denosumab in patients requires assessment of cardiac and renal function, timely calcium and vitamin D supplementation, and enhanced monitoring of serum calcium levels to prevent acute left heart failure induced by denosumab-related hypocalcemia.
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Priddy C, Li J. The role of the Nrf2/Keap1 signaling cascade in mechanobiology and bone health. Bone Rep 2021; 15:101149. [PMID: 34869801 PMCID: PMC8626578 DOI: 10.1016/j.bonr.2021.101149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/06/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
In conjunction with advancements in modern medicine, bone health is becoming an increasingly prevalent concern among a global population with an ever-growing life expectancy. Countless factors contribute to declining bone strength, and age exacerbates nearly all of them. The detrimental effects of bone loss have a profound impact on quality of life. As such, there is a great need for full exploration of potential therapeutic targets that may provide antiaging benefits and increase the life and strength of bone tissues. The Keap1-Nrf2 pathway is a promising avenue of this research. The cytoprotective and antioxidant functions of this pathway have been shown to mitigate the deleterious effects of oxidative stress on bone tissues, but the exact cellular and molecular mechanisms by which this occurs are not yet fully understood. Presently, refined animal and loading models are allowing exploration into the effect of the Keap1-Nrf2 pathway in a tissue-specific or even cell-specific manner. In addition, Nrf2 activators currently undergoing clinical trials can be utilized to investigate the particular cellular mechanisms at work in this cytoprotective cascade. Although the timing and dosing of treatment with Nrf2 activators need to be further investigated, these activators have great potential to be used clinically to prevent and treat osteoporosis.
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Affiliation(s)
- Carlie Priddy
- Department of Biology, Indiana University – Purdue University Indianapolis, Indianapolis, IN, USA
| | - Jiliang Li
- Department of Biology, Indiana University – Purdue University Indianapolis, Indianapolis, IN, USA
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33
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Gopaul A, Kanagalingam T, Thain J, Khan T, Cowan A, Sultan N, Clemens KK. Denosumab in chronic kidney disease: a narrative review of treatment efficacy and safety. Arch Osteoporos 2021; 16:116. [PMID: 34319515 DOI: 10.1007/s11657-021-00971-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 06/04/2021] [Indexed: 02/03/2023]
Abstract
UNLABELLED People with chronic kidney disease (CKD) are at high risk of bone fractures. In this review, we summarize the complexity of fracture prevention in CKD, describe the usefulness of a medication called denosumab, and review its safety in this population. Our article will help doctors manage brittle bones in CKD and encourage researchers to conduct more studies to improve bone health in CKD. PURPOSE Patients with CKD are at increased risk of fragility fractures and associated consequences. We discuss the complexity of fracture prevention in CKD, summarize the efficacy and safety of denosumab, and provide an approach to denosumab-induced hypocalcemia. METHODS Using predefined terms, we searched PubMed, MEDLINE, and Google Scholar for studies on fracture prevention in CKD and the efficacy and safety of denosumab. We included observational studies, randomized controlled trials (RCTs), meta-analyses, evidence-based reviews, and clinical practice guidelines. RESULTS The diagnosis of osteoporosis and prevention of related fragility fractures is complex in CKD, particularly in those with advanced and end-staged kidney disease (ESKD). Prior to initiating denosumab, it is important to assess for and optimize CKD-mineral and bone disorders (CKD-MBD). In observational studies and small RCTs, denosumab has been shown to improve bone mineral density and reduce bone turnover in CKD, but there have been no studies focused upon its fracture efficacy. Denosumab-induced hypocalcemia has also been reported, which disproportionately impacts those with ESKD. Risk factors for hypocalcemia with denosumab use in CKD include lower baseline serum calcium and 25 hydroxyvitamin D and both low and high bone turnover. Choosing the "right patient" for denosumab, supplementing with calcium and vitamin D, adjusting calcium dialysate, and close clinical monitoring are essential if considering this drug. CONCLUSION With optimization of CKD-MBD, calcium and vitamin D supplementation, and close monitoring, denosumab can be considered in CKD. There are however opportunities to better understand its fracture efficacy and safety in an RCT setting.
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Affiliation(s)
- Aquila Gopaul
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Tharsan Kanagalingam
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Jenny Thain
- Division of Geriatrics, Western University, London, ON, Canada
| | - Tayyab Khan
- Division of Endocrinology and Metabolism, Western University, London, ON, Canada.,St. Joseph's Health Care London, London, ON, Canada
| | - Andrea Cowan
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Nabil Sultan
- Division of Nephrology, Western University, London, ON, Canada.,London Health Sciences Centre, London, ON, Canada
| | - Kristin K Clemens
- Division of Endocrinology and Metabolism, Western University, London, ON, Canada. .,St. Joseph's Health Care London, London, ON, Canada. .,Department of Epidemiology and Biostatistics, Western University, London, ON, Canada. .,Lawson Health Research Institute, London, ON, Canada. .,ICES, Ontario, Canada.
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Seasonal Variation and Global Public Interest in the Internet Searches for Osteoporosis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6663559. [PMID: 34189139 PMCID: PMC8195644 DOI: 10.1155/2021/6663559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/01/2021] [Accepted: 03/18/2021] [Indexed: 12/01/2022]
Abstract
Background To ascertain the seasonal pattern and global public interest in osteoporosis by evaluating search term popularity changes of the disease over a decade. Methods We applied Google Trends to retrieve search popularity scores for the term “osteoporosis” between January 01, 2004, and December 31, 2019. Cosinor analyses were conducted to examine the seasonality of osteoporosis, and analysis on osteoporosis-related topics including hot topics and rising-related topics was also performed. Results The cosinor analyses demonstrated a statistically significant seasonal variation in relative search volume of the “osteoporosis” in the world (p = 0.0083), USA (p < 0.001), UK (p < 0.001), Canada (p < 0.001), Ireland (p < 0.001), Australia (p < 0.001), and New Zealand (p < 0.001), with a peak in the late winter months and trough in the summer months. The peaks in late winter and valley in summer presented an approximately 6-month difference between hemispheres. The top 11 rising topics were denosumab, FRAX, hypocalcaemia, zoledronic acid, ibandronic acid, osteomyelitis, osteopenia, osteoarthritis, bone, calcium, and bone density. Conclusions Google search query volumes related to osteoporosis follow strong seasonal patterns with late winter peaks and summer troughs. Further studies aimed at elucidating the possible mechanisms behind seasonality in osteoporosis are needed. Moreover, Internet data including the top rising topics may alert physicians to strengthen the propaganda of osteoporosis timely, so as to further promote the development of public health interventions.
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Kim BT. Efficacy and safety of calcium and vitamin D supplementation to prevent osteoporotic fracture. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2021. [DOI: 10.5124/jkma.2021.64.4.305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Dietary supplementation of calcium and vitamin D has been deemed one of the most important tools to fight against osteoporotic fractures increasing with aging of the population globally. Reports from early clinical trials demonstrated that supplementation of calcium and vitamin D for patients with osteoporosis can reduce the incidence of fragility fractures by decreasing bone loss and falls. However, following trials failed to demonstrate the efficacy of calcium and vitamin D for the prevention of osteoporotic fractures, questioning the need of calcium and vitamin D supplementation. Even metanalyses and system reviews presented opposite conclusions , depending on clinical trials included. Recent studies reported that excessive calcium supplement can increase cardiovascular risk such as non-fatal myocardial infarction and that excessive vitamin D supplement can produce more frequent falls than it is supposed to be. However, in spite of some arguments regarding the efficacy and safety of calcium and vitamin D supplementation, it seems to be essential to provide 800 to 1,000 mg elementary calcium and 800 to 1,000 IU vitamin D for the elderly whose intake of calcium and vitamin D is insufficient to prevent osteoporotic fracture.
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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. Sci Rep 2021; 11:978. [PMID: 33441770 PMCID: PMC7806964 DOI: 10.1038/s41598-020-80243-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 12/18/2020] [Indexed: 12/13/2022] Open
Abstract
This retrospective study was undertaken to identify predictors for the development of hypocalcaemia even with prophylactic administration of calcium and vitamin D, and to help guide future strategies to improve the safety, efficacy, and QOL of patients receiving denosumab. Between January 2016 and February 2020, a total of 327 advanced cancer patients at our hospital who were receiving denosumab were enrolled. Variables associated with the development of hypocalcaemia were extracted from the clinical records. The level of hypocalcaemia was evaluated using CTCAE version 5. Multivariate ordered logistic regression analysis was performed to identify predictors for the development of hypocalcaemia. Optimal cut off thresholds were determined using ROC analysis. Values of P < 0.05 (2-tailed) were considered significant. 54 patients have developed hypocalcemia (≥ Grade 1). Significant factors identified included concomitant use of vonoprazan [odds ratio (OR) = 3.74, 95% confidence interval (CI) 1.14–12.26; P = 0.030], dexamethasone (OR = 2.45, 95%CI 1.14–5.42; P = 0.022), pre-treatment levels of serum calcium (OR = 0.27, 95%CI 0.13–0.54; P < 0.001), ALP/100 (OR = 1.04, 95%CI 1.01–1.07; P = 0.003), and haemoglobin (OR = 0.79, 95%CI 0.68–0.93; P = 0.004). ROC curve analysis revealed that the threshold for pre-treatment levels of serum calcium was ≤ 9.3 mg/dL, ALP was ≥ 457 U/L, and haemoglobin was ≤ 10.4 g/dL. In conclusion, concomitant use of vonoprazan or dexamethasone, and pre-treatment levels of serum calcium (low), ALP (high) and haemoglobin (low) were identified as significant predictors for the development of denosumab-induced hypocalcaemia.
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Affiliation(s)
- Yuko Kanbayashi
- Department of Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan. .,Department of Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan. .,Departments of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Koichi Sakaguchi
- Departments of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Fumiya Hongo
- Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Ishikawa
- Department of Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.,Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yusuke Tabuchi
- Department of Pharmacy, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Osamu Ukimura
- Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tetsuya Taguchi
- Department of Outpatient Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.,Departments of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Kim KJ, Hong N, Lee S, Kim M, Rhee Y. A Simple-to-Use Score for Identifying Individuals at High Risk of Denosumab-Associated Hypocalcemia in Postmenopausal Osteoporosis: A Real-World Cohort Study. Calcif Tissue Int 2020; 107:567-575. [PMID: 32920682 DOI: 10.1007/s00223-020-00754-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/01/2020] [Indexed: 12/23/2022]
Abstract
Since denosumab-associated hypocalcemia occurs infrequently, data on its incidence and risk factors are limited. We aimed to evaluate risk factors and develop a useful score for identifying individuals at risk of denosumab-associated hypocalcemia. In this retrospective cohort, 790 consecutive female patients who received 60 mg denosumab at least once between 2016 and 2017 were analyzed. Based on biochemical records from a large-scale single-center, mild and moderate hypocalcemia were defined as albumin-corrected calcium (cCa) levels < 8.5 and < 8.0 mg/dL (< 2.12 and < 2.0 mmol/L), respectively. Mild and moderate hypocalcemia were observed in 8.2% and 1.0% patients, respectively. Patients who developed mild hypocalcemia had lower baseline cCa (8.9 vs. 9.3 mg/dL and 2.22 vs. 2.32mmo/L) and estimated glomerular filtration rate (75.0 vs. 83.2 mL/min/1.73 m2) and more frequent loop diuretic use (10.8% vs. 4.4%; all p < 0.05). In multivariate analysis, low baseline cCa (OR 1.29; 95% CI 1.20-1.40) and chronic kidney disease (CKD) stages 3b-5 were associated with elevated mild hypocalcemia risk (OR 2.92; 95% CI 1.38-6.20). Loop diuretics use was associated with mild hypocalcemia (OR 2.61; 95% CI 1.11-6.18) by univariate analysis, independent of baseline cCa and CKD stage. A scoring approach identified two risk groups: (1) patients without CKD (eGFR ≥ 45) and cCa < 8.5 mg/dL (2.12 mmol/L) and (2) patients with CKD (eGFR < 45) and cCa < 9.5 mg/dL (2.37 mmol/L).
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Affiliation(s)
- Kyoung Jin Kim
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Namki Hong
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Seunghyun Lee
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Miryung Kim
- Department of Internal Medicine, Wonju Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Yumie Rhee
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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Diker-Cohen T, Amitai O, Shochat T, Shimon I, Tsvetov G. Denosumab-associated hypocalcemia: Does gender play a role? Maturitas 2020; 142:17-23. [PMID: 33158483 DOI: 10.1016/j.maturitas.2020.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/20/2020] [Accepted: 07/03/2020] [Indexed: 10/23/2022]
Abstract
OBJECTIVE It is well recognized that the presentation, treatment, and outcomes of various diseases may differ between men and women. We recently reported a 7.4% rate of denosumab-associated hypocalcemia in community-dwelling osteoporotic patients. This study sought to investigate the role of gender in this complication. STUDY DESIGN Retrospective community-dwelling cohort. METHOD The databases of a large health maintenance organization were searched for adult patients treated with denosumab for osteoporosis in 2010-2018. Rates and predictors of denosumab-associated hypocalcemia (serum calcium ≤8.5 mg/mL) were analyzed by gender. RESULTS The cohort included 1871 women and 134 men. Compared with the women, the men were characterized by older median age (81 vs. 77 years, p = 0.005), higher likelihood to receive denosumab as a first-line treatment (22% vs. 6%, p < 0.001), less treatment with calcium supplements (42% vs. 53%, p = 0.012), and lower median eGFR level (66.1 vs. 79.8 mL/min/1.73m2, p < 0.001). Denosumab-associated hypocalcemia developed in 133 women (7.1%) and 16 men (11.9%) (p = 0.04); the drug was discontinued in 75% and 61%, respectively. The strongest predictors of hypocalcemia in women were levels of pretreatment albumin-adjusted serum calcium (OR 0.08, 95% CI (0.04, 0.14)) and creatinine (OR 2.43, 95% CI (1.45, 4.05)). There were no predictors in men. On propensity matching of 126 men and 126 women, gender was not a predictor of hypocalcemia. CONCLUSION Denosumab-treated men were significantly older than treated women and had a lower eGFR and more advanced osteoporosis. These findings suggest that selection bias rather than male genderper se underlies the higher rate of denosumab-associated hypocalcemia in men.
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Affiliation(s)
- Talia Diker-Cohen
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, Petach Tikva 4941492, Israel; Department of Medicine A, Rabin Medical Center - Beilinson Hospital, Petach Tikva 4941492, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997802, Israel.
| | - Oren Amitai
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997802, Israel; Clalit Healthcare Services, Dan-Petach Tikva District, Israel.
| | - Tzippy Shochat
- Statistical Consulting Unit, Rabin Medical Center - Beilinson Hospital, Petach Tikva 4941492, Israel.
| | - Ilan Shimon
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, Petach Tikva 4941492, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997802, Israel.
| | - Gloria Tsvetov
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, Petach Tikva 4941492, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997802, Israel.
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Ho P, Tan EF, Su S, Mallya J. Correspondence to "Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?". Osteoporos Int 2020; 31:1597. [PMID: 32533194 DOI: 10.1007/s00198-020-05491-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 06/03/2020] [Indexed: 11/29/2022]
Affiliation(s)
- P Ho
- Department of Geriatric Medicine, Khoo Teck Puat Hospital, Singapore, Singapore.
| | - E F Tan
- Department of Geriatric Medicine, Khoo Teck Puat Hospital, Singapore, Singapore
| | - S Su
- Department of Geriatric Medicine, Khoo Teck Puat Hospital, Singapore, Singapore
| | - J Mallya
- Department of Geriatric Medicine, Khoo Teck Puat Hospital, Singapore, Singapore
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