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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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Riesco-Bárcena C, Ivorra-Cortés J, Grau-García E, González-Puig L, Leal S, Huaylla A, Román-Ivorra J. [Hyperparathyroidism in patients with low bone mineral density treated with zoledronic acid or denosumab]. Med Clin (Barc) 2024; 163:595-599. [PMID: 39384494 DOI: 10.1016/j.medcli.2024.07.020] [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: 04/16/2024] [Revised: 07/16/2024] [Accepted: 07/20/2024] [Indexed: 10/11/2024]
Abstract
OBJECTIVE To analyze the prevalence of hyperparathyroidism in patients treated with zoledronic acid (ZA) or denosumab, its relationship with other parameters and how it affects on bone mineral density (BMD) evolution. METHODS Retrospective observational study in patients with osteoporosis or osteopenia and high risk of fracture, who have received denosumab or ZA for at least two years. Patients diagnosed with hyperparathyroidism or glomerular filtration rate <30ml/min at baseline visit were excluded from the study. RESULTS Ninety patients (ZA: 54.44%) were included. 18.36% of ZA-treated patients had elevated PTH levels at some time compared to 36.58% denosumab-treated patients (p>0.05). Patients with persistently elevated PTH were 6.13% in the AZ group and 19.51% in the denosumab group (p<0.04). We found a statistically significant inverse association between elevated PTH levels, glomerular filtration rate (p=0.007), and albumin-corrected calcium (p <0.001). We did not find an association between hyperparathyroidism and BMD evolution. CONCLUSIONS A high incidence of hyperparathyroidism was observed in patients treated with AZ and especially denosumab. Hyperparathyroidism correlated inversely with glomerular filtration rate and albumin-corrected calcium. Elevated PTH does not appear to affect short-term bone mineral density evolution.
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Affiliation(s)
- Carmen Riesco-Bárcena
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - José Ivorra-Cortés
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España.
| | - Elena Grau-García
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Luis González-Puig
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Samuel Leal
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Anderson Huaylla
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - José Román-Ivorra
- Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España
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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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Ali M, Kim YS. A comprehensive review and advanced biomolecule-based therapies for osteoporosis. J Adv Res 2024:S2090-1232(24)00215-7. [PMID: 38810908 DOI: 10.1016/j.jare.2024.05.024] [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: 03/26/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND The prevalence of osteoporosis (OP) on a global scale is significantly elevated that causes life threatening issues. The potential of groundbreaking biomolecular therapeutics in the field of OP is highly encouraging. The administration of biomolecular agents has the potential to mitigate the process of bone demineralization while concurrently augmenting the regenerative capacity of bone tissue, thereby facilitating a personalized therapeutic approach. Biomolecules-based therapies showed promising results in term of bone mass protection and restoration in OP. AIM OF REVIEW We summarized the recent biomolecular therapies with notable progress in clinical, demonstrating the potential to transform illness management. These treatments frequently utilize different biomolecule based strategies. Biomolecular therapeutics has a targeted character, which results in heightened specificity and less off-target effects, ultimately leading to increased patient outcomes. These aspects have the capacity to greatly enhance the management of OP, thus resulting in a major enhancement in the quality of life encountered by individuals affected by this condition.
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Affiliation(s)
- Maqsood Ali
- Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chungnam 31151, Republic of Korea
| | - Yong-Sik Kim
- Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chungnam 31151, Republic of Korea; Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Chungnam 31151, Republic of Korea.
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Kim H, Lee EJ, Woo S, Rho S, Jung JY. Effect of Denosumab on Bone Health, Vascular Calcification, and Health-Related Quality of Life in Hemodialysis Patients with Osteoporosis: A Prospective Observational Study. J Clin Med 2024; 13:1462. [PMID: 38592300 PMCID: PMC10934499 DOI: 10.3390/jcm13051462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/26/2024] [Accepted: 02/29/2024] [Indexed: 04/10/2024] Open
Abstract
Background: Osteoporosis is common in hemodialysis (HD) patients, contributing to cardiovascular risks. Limited research exists on denosumab's efficacy in this group. Our study explores denosumab's effects on bone turnover markers (BTMs) and vascular calcification in chronic kidney disease-mineral bone disorder (CKD-MBD) patients. Methods: In a prospective single-center study, we investigated the effects of denosumab over 2 years on 30 HD patients from a cohort of 185. Annual assessments of bone mineral density (BMD), vascular calcification, and health-related quality of life (HRQL) were conducted and compared with an untreated group. Mineral and bone parameters were analyzed at specific intervals in the treatment group. Results: Denosumab notably raised femoral BMD in the initial year. Most bone turnover markers (BTMs) decreased, except for osteocalcin. Changes in T50 correlated with BTMs. Pre-denosumab supplementation of calcium and vitamin D helped manage mineral imbalances. Post denosumab, parathyroid hormone (PTH) levels increased initially, stabilizing after 3 months. No significant changes occurred in vascular calcification or HRQL. Conclusions: Denosumab exhibited varying effects on BMD improvement, with a stronger impact in the first year that diminished in the second year. Early PTH monitoring was crucial, and extending the administrative period may enhance BMD outcomes compared to the general population.
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Affiliation(s)
- Hyunsook Kim
- Department of Health Sciences and Technology, Gachon University, Incheon 21565, Republic of Korea;
| | - Eun Ju Lee
- Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Republic of Korea; (E.J.L.); (S.W.)
| | - Siyun Woo
- Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Republic of Korea; (E.J.L.); (S.W.)
| | - Sohee Rho
- Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Republic of Korea; (E.J.L.); (S.W.)
| | - Ji Yong Jung
- Department of Health Sciences and Technology, Gachon University, Incheon 21565, Republic of Korea;
- Division of Nephrology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Republic of Korea; (E.J.L.); (S.W.)
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6
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Orford NR, Bone A, Kotowicz MA, Bailey M, Pasco JA, Maiden M, Kakho N, Cattigan C, Nichonghaile M, Jones C, Hodgson C, Nair P, Center J, Bellomo R. A pilot feasibility randomised controlled trial of bone antiresorptive agents on bone turnover markers in critically ill women. Sci Rep 2024; 14:2071. [PMID: 38267490 PMCID: PMC10810087 DOI: 10.1038/s41598-024-52607-1] [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: 08/22/2023] [Accepted: 01/21/2024] [Indexed: 01/26/2024] Open
Abstract
Critical illness is associated with increased bone turnover, loss of bone density, and increased risk of fragility fractures. The impact of bone antiresorptive agents in this population is not established. This trial examined the efficacy, feasibility, and safety of antiresorptive agents administered to critically ill women aged fifty years or greater. Women aged 50 years or greater admitted to an intensive care unit for at least 24 h were randomised to receive an antiresorptive agent (zoledronic acid or denosumab) or placebo, during critical illness and six months later (denosumab only). Bone turnover markers and bone mineral density (BMD) were monitored for 1 year. We studied 18 patients over 35 months before stopping the study due to the COVID-19 pandemic. Antiresorptive medications decreased the bone turnover marker type 1 cross-linked c-telopeptide (CTX) from day 0 to 28 by 43% (± 40%), compared to an increase of 26% (± 55%) observed with placebo (absolute difference - 69%, 95% CI - 127% to - 11%), p = 0.03). Mixed linear modelling revealed differences in the month after trial drug administration between the groups in serum CTX, alkaline phosphatase, parathyroid hormone, and phosphate. Change in BMD between antiresorptive and placebo groups was not statistically analysed due to small numbers. No serious adverse events were recorded. In critically ill women aged 50-years and over, antiresorptive agents suppressed bone resorption markers without serious adverse events. However, recruitment was slow. Further phase 2 trials examining the efficacy of these agents are warranted and should address barriers to enrolment.Trial registration: ACTRN12617000545369, registered 18th April 2017.
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Affiliation(s)
- Neil R Orford
- Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Australia.
- Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine (SPPHPM), Monash University, Melbourne, Australia.
- IMPACT-Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
- Department of Critical Care, University of Melbourne, Melbourne, Australia.
| | - Allison Bone
- Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Australia
- Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine (SPPHPM), Monash University, Melbourne, Australia
| | - Mark A Kotowicz
- IMPACT-Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia
- Department of Medicine-Western Health, The University of Melbourne, Melbourne, Australia
| | - Michael Bailey
- Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine (SPPHPM), Monash University, Melbourne, Australia
| | - Julie A Pasco
- IMPACT-Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia
- Department of Medicine-Western Health, The University of Melbourne, Melbourne, Australia
| | - Matthew Maiden
- Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Australia
| | - Nima Kakho
- Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Australia
| | - Claire Cattigan
- Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Australia
| | - Martina Nichonghaile
- Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Australia
| | - Claire Jones
- Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Australia
| | - Carol Hodgson
- Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine (SPPHPM), Monash University, Melbourne, Australia
| | - Priya Nair
- Intensive Care Unit, St Vincent's Hospital Sydney, Sydney, Australia
- Garvan Institute of Medical Research, Sydney, Australia
| | - Jacqueline Center
- Intensive Care Unit, St Vincent's Hospital Sydney, Sydney, Australia
- Garvan Institute of Medical Research, Sydney, Australia
| | - Rinaldo Bellomo
- Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine (SPPHPM), Monash University, Melbourne, Australia
- Department of Critical Care, University of Melbourne, Melbourne, Australia
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7
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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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Abduelkarem AR, Guella A, Hamrouni AM, Hassanein MM, Nasr A, Rana O. Denosumab Use in Chronic Kidney Disease Associated Osteoporosis: A Narrative Review. Risk Manag Healthc Policy 2023; 16:1809-1813. [PMID: 37719685 PMCID: PMC10503558 DOI: 10.2147/rmhp.s426869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/06/2023] [Indexed: 09/19/2023] Open
Abstract
Chronic kidney disease (CKD) and hemodialysis (HD) patients have a high incidence of bone disease and increased fracture risk, making effective management of their bone health a clinical challenge. Denosumab, a human monoclonal antibody, has been investigated as a therapeutic option in this patient population. In this review, we summarize the current evidence on the efficacy and safety of denosumab in CKD and HD patients. A comprehensive search of the relevant literature was conducted, including randomized controlled trials, observational studies, and meta-analyses. The findings suggest that denosumab reduces the risk of fractures and improves bone mineral density in all stages of CKD. The results of this review support the use of denosumab as a promising option for managing bone disease in CKD and HD patients.
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Affiliation(s)
- Abduelmula R Abduelkarem
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Adnane Guella
- Department of Nephrology, University Hospital Sharjah, Sharjah, United Arab Emirates
| | - Amar M Hamrouni
- Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain, United Arab Emirates
| | - Mohammed M Hassanein
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
| | - Ahmed Nasr
- Pharmacy Department, University Hospital Sharjah, Sharjah, United Arab Emirates
| | - Owais Rana
- Department of Internal Medicine, University Hospital Sharjah, Sharjah, United Arab Emirates
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9
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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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10
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Kotecha J, Fardeen KM, Mirzazadeh M. Hyperparathyroidism Following Denosumab and Zoledronate Therapy in a Secondary Care Setting. J Clin Rheumatol 2023; 29:101-104. [PMID: 35981297 DOI: 10.1097/rhu.0000000000001894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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11
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Abstract
Primary hyperparathyroidism (PHPT) is classically characterized by hypercalcemia with elevated or inappropriately normal parathyroid hormone (PTH) levels. Elevated PTH levels in the presence of normal calcium levels are not infrequently found during the evaluation of metabolic bone disorders or kidney stone disease. This can be caused by secondary hyperparathyroidism (SHPT) or normocalcemic primary hyperparathyroidism (NPHPT). NPHPT is due to autonomous parathyroid function whereas SHPT is caused by a physiologic stimulation to PTH secretion. Many medical conditions and medications can contribute to SHPT, and differentiation between SHPT and NPHPT may be difficult. Cases are presented to illustrate examples. In this paper, we review the distinction between SHPT and NPHPT as well as end organ effects of NPHPT and outcomes of surgery in NPHPT. We suggest that the diagnosis of NPHPT be made only after careful exclusion of causes of SHPT and consideration of medications that can increase PTH secretion. Further, we advise a conservative approach to surgery in NPHPT.
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Affiliation(s)
- Joseph L Shaker
- Correspondence: Joseph L. Shaker, MD, W129N7155 Northfield Dr, Menomonee Falls, WI 53051, USA.
| | - Robert A Wermers
- Department of Medicine and Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA
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12
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Lin Y, Yang H, Yang X, Guo C, Yang S, Yang G, Wu Q, Pan C, Sun C, Li C, He L, Huang J, Pei Q. Biosimilarity of HS-20090 to Denosumab in healthy Chinese subjects: a randomized, double-blinded, pharmacokinetics/pharmacodynamics study. Expert Opin Investig Drugs 2022; 31:1125-1132. [DOI: 10.1080/13543784.2022.2123737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Yaqi Lin
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, China
- Department of Pharmacy, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Heng Yang
- Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyan Yang
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Can Guo
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Shuang Yang
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Guoping Yang
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Qiong Wu
- Department of Hansoh Medical Development Group, Hansoh Pharmaceutical Group Co. Ltd, Shanghai, China
| | - Chao Pan
- Department of Hansoh Medical Development Group, Hansoh Pharmaceutical Group Co. Ltd, Shanghai, China
| | - Changan Sun
- Department of Hansoh Medical Development Group, Hansoh Pharmaceutical Group Co. Ltd, Shanghai, China
| | - Chuan Li
- Department of Hansoh Medical Development Group, Hansoh Pharmaceutical Group Co. Ltd, Shanghai, China
| | - Liangliang He
- Department of Hansoh Medical Development Group, Hansoh Pharmaceutical Group Co. Ltd, Shanghai, China
| | - Jie Huang
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Qi Pei
- Department of Pharmacy, the Third Xiangya Hospital, Central South University, Changsha, China
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13
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Chavassieux P, Chapurlat R. Interest of Bone Histomorphometry in Bone Pathophysiology Investigation: Foundation, Present, and Future. Front Endocrinol (Lausanne) 2022; 13:907914. [PMID: 35966102 PMCID: PMC9368205 DOI: 10.3389/fendo.2022.907914] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Despite the development of non-invasive methods, bone histomorphometry remains the only method to analyze bone at the tissue and cell levels. Quantitative analysis of transiliac bone sections requires strict methodologic conditions but since its foundation more 60 years ago, this methodology has progressed. Our purpose was to review the evolution of bone histomorphometry over the years and its contribution to the knowledge of bone tissue metabolism under normal and pathological conditions and the understanding of the action mechanisms of therapeutic drugs in humans. The two main applications of bone histomorphometry are the diagnosis of bone diseases and research. It is warranted for the diagnosis of mineralization defects as in osteomalacia, of other causes of osteoporosis as bone mastocytosis, or the classification of renal osteodystrophy. Bone biopsies are required in clinical trials to evaluate the safety and mechanism of action of new therapeutic agents and were applied to anti-osteoporotic agents such as bisphosphonates and denosumab, an anti-RANKL, which induces a marked reduction of the bone turnover with a consequent elongation of the mineralization period. In contrast, an increased bone turnover with an extension of the formation site is observed with teriparatide. Romosozumab, an anti-sclerostin, has a dual effect with an early increased formation and reduced resorption. Bone histomorphometric studies allow us to understand the mechanism of coupling between formation and resorption and to evaluate the respective role of bone modeling and remodeling. The adaptation of new image analysis techniques will help bone biopsy analysis in the future.
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Kalaria T, Fenn J, Sanders A, Yates A, Duff C, Ashby H, Mohammed P, Ford C, Gama R. The Diagnosis of Normocalcaemic Hyperparathyroidism is Strikingly Dissimilar Using Different Commercial Laboratory Assays. Horm Metab Res 2022; 54:429-434. [PMID: 35835142 DOI: 10.1055/a-1856-4900] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We assessed the impact of intact parathyroid hormone (iPTH) and adjusted calcium analyses on Abbott, Roche and Siemens analytical platforms in the diagnosis of normocalcaemic primary hyperparathyroidism (NCPHPT). These assays are used by over 85% of clinical laboratories in the UK. Over five months, consecutive serum samples from outpatients with NCPHPT in the laboratory with Abbott assays were identified, aliquoted and stored at -80°C. Frozen aliquots were transported monthly to the other two laboratories. After thawing, samples were mixed and analysed immediately for calcium, albumin and iPTH in the laboratories with Abbott, Roche and Siemens analytical platforms. Adjusted calcium was calculated using the equation used in the respective laboratory. Diagnostic concordance of iPTH and adjusted calcium were assessed using manufacturer-provided assay-specific reference intervals and the pathology harmony reference interval respectively. Fifty-five patients with NCPHPT were identified using Abbott assays. Of these, 16 (29.1%) and 11 (20.0%) had NCPHPT, 9 (16.4%) and 13 (23.6%) had hypercalcaemic primary hyperparathyroidism, and 30 (54.6%) and 31 (56.4%) patients had normal results when analysed in laboratories with Roche and Siemens assays, respectively. The diagnosis of NCPHPT was strikingly different depending on the commercial assay used. There is a pressing need for iPTH assay harmonisation and robust reference intervals. Reference intervals may become invalid if an assay drifts, as exemplified by adjusted calcium in this study.
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Affiliation(s)
- Tejas Kalaria
- Clinical Biochemistry, New Cross Hospital, Black Country Pathology Services, Wolverhampton, United Kingdom of Great Britain and Northern Ireland
| | - Jonathan Fenn
- Clinical Biochemistry, New Cross Hospital, Black Country Pathology Services, Wolverhampton, United Kingdom of Great Britain and Northern Ireland
| | - Anna Sanders
- Clinical Biochemistry, Russells Hall Hospital, Black Country Pathology Services, Dudley, United Kingdom of Great Britain and Northern Ireland
| | - Alexandra Yates
- Clinical Biochemistry, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom of Great Britain and Northern Ireland
| | - Christopher Duff
- Clinical Biochemistry, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom of Great Britain and Northern Ireland
- School of Primary, Community & Social Care, Faculty of Medicine & Health Sciences, Keele University, Stoke-on-Trent, United Kingdom of Great Britain and Northern Ireland
| | - Helen Ashby
- Clinical Biochemistry, Russells Hall Hospital, Black Country Pathology Services, Dudley, United Kingdom of Great Britain and Northern Ireland
| | - Pervaz Mohammed
- Clinical Biochemistry, Russells Hall Hospital, Black Country Pathology Services, Dudley, United Kingdom of Great Britain and Northern Ireland
| | - Clare Ford
- Clinical Biochemistry, New Cross Hospital, Black Country Pathology Services, Wolverhampton, United Kingdom of Great Britain and Northern Ireland
| | - Rousseau Gama
- Clinical Biochemistry, New Cross Hospital, Black Country Pathology Services, Wolverhampton, United Kingdom of Great Britain and Northern Ireland
- School of Medicine and Clinical Practice, University of Wolverhampton, Wolverhampton, United Kingdom of Great Britain and Northern Ireland
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Yahyavi SK, Holt R, Juel Mortensen L, Petersen JH, Jørgensen N, Juul A, Blomberg Jensen M. Effect of a single-dose denosumab on semen quality in infertile men (the FITMI study): study protocol for a randomized controlled trial. Trials 2022; 23:525. [PMID: 35733213 PMCID: PMC9214471 DOI: 10.1186/s13063-022-06478-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 06/11/2022] [Indexed: 11/25/2022] Open
Abstract
Background Infertility is a common problem globally and impaired semen quality is responsible for up to 40% of all cases. Almost all infertile couples are treated with either insemination or assisted reproductive techniques (ARTs) independent of the etiology of infertility because no medical treatment exists. Denosumab is an antibody that blocks RANKL signaling and inhibition of testicular RANKL signaling has been suggested to improve semen quality in a pilot study. This RCT aims to assess whether treatment with denosumab can improve spermatogenesis in infertile men selected by serum AMH as a positive predictive biomarker. This paper describes the design of the study. Methods/design FITMI is a sponsor-investigator-initiated, double-blinded, placebo-controlled 1:1, single-center, randomized clinical trial. Subjects will be randomized to receive either a single-dose denosumab 60 mg subcutaneous injection or placebo. The study will be carried out at the Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen. The primary outcome of the study is defined as the difference in sperm concentration (millions pr. mL) one spermatogenesis (80 days) after inclusion. Discussion We describe a protocol for a planned RCT aimed at evaluating whether treatment with denosumab can improve the semen quality in infertile men selected by using serum AMH as a positive predictive biomarker. The results will provide evidence crucial for future treatment in a patient group where there is a huge unmet need. Trial registration Clinical Trials.gov NCT05212337. Registered on 14 January 2022. EudraCT 2021–003,451-42. Registered on 23 June 2021. Ethical committee H-21040145. Registered on 23 December 2021. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-022-06478-4.
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Affiliation(s)
- Sam Kafai Yahyavi
- Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
| | - Rune Holt
- Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
| | - Li Juel Mortensen
- Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jørgen Holm Petersen
- International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.,Section of Biostatistics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Jørgensen
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Anders Juul
- Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Martin Blomberg Jensen
- Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. .,Division of Bone and Mineral Research, HSDM/HMS, Harvard University, Boston, USA.
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16
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Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease. Nutrients 2022; 14:nu14102124. [PMID: 35631265 PMCID: PMC9144546 DOI: 10.3390/nu14102124] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 11/17/2022] Open
Abstract
Alkaline phosphatase (ALP) is an evolutionary conserved enzyme and widely used biomarker in clinical practice. Tissue-nonspecific alkaline phosphatase (TNALP) is one of four human isozymes that are expressed as distinct TNALP isoforms after posttranslational modifications, mainly in bone, liver, and kidney tissues. Beyond the well-known effects on bone mineralization, the bone ALP (BALP) isoforms (B/I, B1, B1x, and B2) are also involved in the pathogenesis of ectopic calcification. This narrative review summarizes the recent clinical investigations and mechanisms that link ALP and BALP to inflammation, metabolic syndrome, vascular calcification, endothelial dysfunction, fibrosis, cardiovascular disease, and mortality. The association between ALP, vitamin K, bone metabolism, and fracture risk in patients with chronic kidney disease (CKD) is also discussed. Recent advances in different pharmacological strategies are highlighted, with the potential to modulate the expression of ALP directly and indirectly in CKD–mineral and bone disorder (CKD-MBD), e.g., epigenetic modulation, phosphate binders, calcimimetics, vitamin D, and other anti-fracture treatments. We conclude that the significant evidence for ALP as a pathogenic factor and risk marker in CKD-MBD supports the inclusion of concrete treatment targets for ALP in clinical guidelines. While a target value below 120 U/L is associated with improved survival, further experimental and clinical research should explore interventional strategies with optimal risk–benefit profiles. The future holds great promise for novel drug therapies modulating ALP.
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17
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Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjaer T, Formenti AM, Björnsdottir S, Schalin-Jäntti C, Belaya Z, Gibb F, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen E, Makay Ö, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith Z, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes N, Marcocci C, Kamenický P. European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders. Eur J Endocrinol 2022; 186:R33-R63. [PMID: 34863037 PMCID: PMC8789028 DOI: 10.1530/eje-21-1044] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/03/2021] [Indexed: 11/17/2022]
Abstract
This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.
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Affiliation(s)
- Jens Bollerslev
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Section of Specialized Endocrinology, Department of Endocrinology, Medical Clinic, Oslo University Hospital, Oslo, Norway
- Correspondence should be addressed to J Bollerslev Email
| | - Lars Rejnmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Alexandra Zahn
- Schön-Klinik Hamburg, Department of Endocrine Surgery, Hamburg, Germany
| | - Ansgar Heck
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Section of Specialized Endocrinology, Department of Endocrinology, Medical Clinic, Oslo University Hospital, Oslo, Norway
| | - Natasha M Appelman-Dijkstra
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center (LUMC), Leiden, the Netherlands
| | - Luis Cardoso
- Centro Hospitalar e Universitário de Coimbra, i3S – Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Porto, Portugal
| | - Fadil M Hannan
- Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK
| | - Filomena Cetani
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Tanja Sikjaer
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Anna Maria Formenti
- Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University, IRCCS San Raffaele Hospital, Milan, Italy
| | - Sigridur Björnsdottir
- Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
| | - Camilla Schalin-Jäntti
- Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Zhanna Belaya
- The National Medical Research Centre for Endocrinology, Moscow, Russia
| | - Fraser Gibb
- Edinburgh Centre for Endocrinology & Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Bruno Lapauw
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Karin Amrein
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Corinna Wicke
- Thyroid Center, Luzerner Kantonsspital, Luzern, Switzerland
| | - Corinna Grasemann
- Division of Rare Diseases, Department of Pediatrics, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Michael Krebs
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Eeva Ryhänen
- Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Özer Makay
- Division of Endocrine Surgery, Department of General Surgery, Ege University Hospital, Izmir, Turkey
| | - Salvatore Minisola
- Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Rome, Italy
| | - Sébastien Gaujoux
- Department of Digestive, Hepatobiliary and Endocrine Surgery, Paris Descartes University, Cochin Hospital, Paris, France
| | - Jean-Philippe Bertocchio
- Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Nephrology Department, Boulevard de l’Hôpital, Paris, France
| | - Zaki Hassan-Smith
- Department of Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Agnès Linglart
- Université de Paris Saclay, AP-HP, Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphate, Filière OSCAR, Service d’Endocrinologie et Diabète de l’Enfant, Hôpital Bicêtre Paris Saclay, Le Kremlin Bicêtre, France
| | - Elizabeth M Winter
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center (LUMC), Leiden, the Netherlands
| | - Martina Kollmann
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Hans-Georg Zmierczak
- Reference Centre for Rare Bone, Calcium and Phosphate Disorders – University Hospital Ghent, Ghent, Belgium
| | - Elena Tsourdi
- Center for Healthy Aging, Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany
| | - Stefan Pilz
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Heide Siggelkow
- Endokrinologikum Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Neil Gittoes
- Department of Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Peter Kamenický
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphate, Le Kremlin-Bicêtre, France
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Ogunwale AN, Hameed F, Valdez L, des Bordes J, Jamil M, Rianon N. Elevated parathyroid hormone levels in older women treated for osteoporosis using denosumab. Eur Geriatr Med 2021; 13:735-740. [PMID: 34586615 DOI: 10.1007/s41999-021-00567-4] [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] [Received: 05/31/2021] [Accepted: 09/23/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE Primary care physicians (PCPs) often struggle with elevated serum intact parathyroid hormone (iPTH) in osteoporotic patients on antiresorptive treatment, specifically, denosumab. As iPTH and calcium levels need to be within normal ranges to receive the next dose of denosumab, continuously high serum iPTH may necessitate additional tests to rule out pathological causes. We aimed to determine factors associated with iPTH elevation in a cohort of postmenopausal women receiving osteoporosis treatment. METHOD A cross-sectional analysis of electronic medical records of patients 50 years and older who visited a geriatric osteoporosis clinic between October 1, 2014 and December 31, 2019, was conducted. We divided patients into 3 categories: not currently on treatment, on bisphosphonates or on denosumab. Percentage change in iPTH levels from baseline to 1 year follow-up was the outcome measure. Other variables used are age, body mass index, chronic co-morbidities, 25OH-vitamin D, calcium, TSH, glomerular filtration rate and femoral neck BMD. Linear regression models were used to assess independent associations between treatment group and iPTH changes. RESULTS Mean (SD) age of 173 participants in our study was 78 (± 10) years, and 71% were Caucasian. At follow-up, mean percent change of iPTH was 13.47 ± 62.76, 30.35 ± 61.17, and 39.60 ± 35.51 in the "no treatment", "bisphosphonate" and "denosumab" groups, respectively. Age was a predictor of elevated percent change of iPTH in the denosumab group. CONCLUSION Increasing age is associated with iPTH elevations in osteoporotic patients on denosumab. In the absence of any pathology, continuation of denosumab may be safe in lowering fracture risk. However, a larger study may be required to confirm this.
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Affiliation(s)
- Abayomi N Ogunwale
- Department of Family and Community Medicine, The University of Texas McGovern Medical School, 6431 Fannin St, Suite JJL324, Houston, TX, 77030, USA
| | - Fariha Hameed
- Department of Family and Community Medicine, The University of Texas McGovern Medical School, 6431 Fannin St, Suite JJL324, Houston, TX, 77030, USA
| | - Luis Valdez
- Department of Family and Community Medicine, The University of Texas McGovern Medical School, 6431 Fannin St, Suite JJL324, Houston, TX, 77030, USA
| | - Jude des Bordes
- Department of Family and Community Medicine, The University of Texas McGovern Medical School, 6431 Fannin St, Suite JJL324, Houston, TX, 77030, USA
| | - Maryam Jamil
- The University of Texas School of Public Health, Houston, TX, USA
| | - Nahid Rianon
- Department of Family and Community Medicine, The University of Texas McGovern Medical School, 6431 Fannin St, Suite JJL324, Houston, TX, 77030, USA.
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19
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Cianciolo G, Tondolo F, Barbuto S, Iacovella F, Zavatta G, Altieri P, Grandinetti V, Comai G, Cozzolino M, La Manna G. Denosumab-Induced Hypocalcemia and Hyperparathyroidism in de novo Kidney Transplant Recipients. Am J Nephrol 2021; 52:611-619. [PMID: 34518468 DOI: 10.1159/000518363] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/03/2021] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Denosumab represents a realistic treatment option to increase bone mineral density in kidney transplant recipients (KTRs). It is still unknown how and at what extent posttransplantation bone disease and graft function influence the effects of denosumab on mineral metabolism indexes. In this study, we analyze risk factors of hypocalcemia and parathyroid hormone (PTH) increase after denosumab administration in eighteen de novo KTRs and its management before and after this treatment. METHODS We conducted a monocentric, observational, prospective study on de novo KTRs. All KTRs enrolled received a single 60 mg subcutaneous dose of denosumab every 6 months. Before kidney transplantation, no patients were treated with calcio-mimetic. After kidney transplantation and before antiresorptive therapy, no patients were treated with calcio-mimetic drugs and/or vitamin D receptor agonists, while all patients received nutritional vitamin D supplementation (from 1,000 IU to 1,500 IU daily). RESULTS Hypocalcemia was related to the degree of lumbar osteoporosis (p = 0.047); the increase in the PTH level was correlated to baseline bone turnover markers (bone alkaline phosphatase, serum osteocalcin, and β-C-terminal telopeptide), the 25 OH status, and eGFR. The introduction of calcitriol, after the PTH increase, in addition to cholecalciferol was necessary to ensure an adequate control of serum calcium and PTH during a follow-up of 15 months. Following the treatment with denosumab, it was observed an improvement of areal bone mineral density both at lumbar and femoral sites with a mean percentual increase of 1.74% and 0.25%, respectively. CONCLUSIONS Denosumab is an effective treatment for bone disease in KTRs. In our study, the increase in PTH is not a transient event but prolonged throughout the follow-up period and requires continuous supplementation therapy with calcitriol.
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Affiliation(s)
- Giuseppe Cianciolo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy,
| | - Francesco Tondolo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Simona Barbuto
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Francesca Iacovella
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Guido Zavatta
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Department of Medical and Surgical Sciences (DIMEC), Università Alma Mater Studiorum di Bologna, Bologna, Italy
| | - Paola Altieri
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Department of Medical and Surgical Sciences (DIMEC), Università Alma Mater Studiorum di Bologna, Bologna, Italy
| | - Valeria Grandinetti
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Giorgia Comai
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
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20
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Мокрышева НГ, Еремкина АК, Мирная СС, Крупинова ЮА, Воронкова ИА, Ким ИВ, Бельцевич ДГ, Кузнецов НС, Пигарова ЕА, Рожинская ЛЯ, Дегтярев МВ, Егшатян ЛВ, Румянцев ПО, Андреева ЕН, Анциферов МБ, Маркина НВ, Крюкова ИВ, Каронова ТЛ, Лукьянов СВ, Слепцов ИВ, Чагай НБ, Мельниченко ГА, Дедов ИИ. [The clinical practice guidelines for primary hyperparathyroidism, short version]. PROBLEMY ENDOKRINOLOGII 2021; 67:94-124. [PMID: 34533017 PMCID: PMC9753843 DOI: 10.14341/probl12801] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022]
Abstract
Primary hyperparathyroidism (PHPT) is an endocrine disorder of parathyroid glands characterized by excessive secretion of parathyroid hormone (PTH) with an upper normal or elevated blood calcium level. Classical PHPT refers to a symptomatic, multi-system disorder, wich can lead to a significant decrease in the quality of life, disability of patients, and even an increased risk of premature death. Hypercalcemia and the catabolic effect of PTH on various cells are considered as the main pathogenetic mechanisms of the PHPT associated complications. In the last two decades, there has been an increase in the incidence of PHPT, mainly due to the mild forms of the disease, primarily due to the routine calcium screening in North America, Western Europe and, Asia. High prevalence of the disease, as well as the variety of clinical manifestations, cause the attention of different specialists - physicians, rheumatologists, urologists, nephrologists, cardiologists and other doctors. This review cover the main issues of Russian guidelines for the management of PHPT, approved in 2020, including laboratory and instrumental methods, differential diagnosis, surgical and conservative approach, short-term and long-term follow-up. This guidelines also include the recommendations for special groups of patients with hereditary forms of PHPT, parathyroid carcinoma, PHPT during pregnancy.
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Affiliation(s)
- Н. Г. Мокрышева
- Национальный медицинский исследовательский центр эндокринологии
| | - А. К. Еремкина
- Национальный медицинский исследовательский центр эндокринологии
| | | | - Ю. А. Крупинова
- Национальный медицинский исследовательский центр эндокринологии
| | - И. А. Воронкова
- Национальный медицинский исследовательский центр эндокринологии
| | - И. В. Ким
- Национальный медицинский исследовательский центр эндокринологии
| | - Д. Г. Бельцевич
- Национальный медицинский исследовательский центр эндокринологии
| | - Н. С. Кузнецов
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. А. Пигарова
- Национальный медицинский исследовательский центр эндокринологии
| | - Л. Я. Рожинская
- Национальный медицинский исследовательский центр эндокринологии
| | - М. В. Дегтярев
- Национальный медицинский исследовательский центр эндокринологии
| | - Л. В. Егшатян
- Национальный медицинский исследовательский центр эндокринологии
| | | | - Е. Н. Андреева
- Национальный медицинский исследовательский центр эндокринологии
| | - М. Б. Анциферов
- Эндокринологический диспансер Департамента здравоохранения города Москвы
| | - Н. В. Маркина
- Эндокринологический диспансер Департамента здравоохранения города Москвы
| | - И. В. Крюкова
- Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского
| | - Т. Л. Каронова
- Национальный медицинский исследовательский центр им. В.А. Алмазова
| | | | | | - Н. Б. Чагай
- Ставропольский государственный медицинский университет
| | | | - И. И. Дедов
- Национальный медицинский исследовательский центр эндокринологии
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21
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Daga N, Joseph F. Republished: Denosumab-induced severe hypocalcaemia in a patient with vitamin D deficiency. Drug Ther Bull 2021; 59:139-143. [PMID: 33563651 DOI: 10.1136/dtb.2021.234508rep] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Natasha Daga
- Department of Endocrinology, Central Coast Local Health District, Gosford, New South Wales, Australia
| | - Flavian Joseph
- Department of Endocrinology, Central Coast Local Health District, Gosford, New South Wales, Australia
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22
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Marocco C, Zimatore G, Mocini E, Fornari R, Iolascon G, Gallotta MC, Bimonte VM, Baldari C, Lenzi A, Migliaccio S. Efficacy of Denosumab Therapy Following Treatment with Bisphosphonates in Women with Osteoporosis: A Cohort Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18041728. [PMID: 33579002 PMCID: PMC7916792 DOI: 10.3390/ijerph18041728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 01/02/2023]
Abstract
Denosumab is a human monoclonal antibody that neutralizes RANKL, a cytokine able to interact with the RANK receptor on preosteoclasts and osteoclasts, decreasing their recruitment and differentiation, leading to a decreased bone resorption. The aim of this observational real-life study was to analyze adherence to denosumab therapy and assess its efficacy in increasing bone mineral density (BMD) and modulating biochemical skeletal markers following previous treatments with bisphosphonates in a group of post-menopausal women with osteoporosis. Women were recruited in the specialized center from March 2012 to September 2019. Biochemical markers were recorded at baseline and every six months prior to subsequent drug injection. Dual X-ray absorptiometry was requested at baseline and after 18/24 months. Comparing BMD at baseline and after denosumab therapy in naive patients and in those previously treated with bisphosphonates, a positive therapeutic effect was observed in both groups. The results of our real-life study demonstrate, as expected, that BMD values significantly increased upon denosumab treatment. Interestingly, denosumab showed an increased efficacy in patients previously treated with bisphosphonates. Moreover, biochemical markers data indicate that osteoporotic patients, without other concomitant unstable health conditions, could be evaluated once a year, decreasing the number of specialistic center access.
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Affiliation(s)
- Chiara Marocco
- Department of Movement, Human and Health Sciences, Health Sciences Section, University Foro Italico of Rome, 00135 Rome, Italy; (C.M.); (V.M.B.)
| | - Giovanna Zimatore
- Department of Movement, Human and Health Sciences, Health Sciences Section, University Foro Italico of Rome, 00135 Rome, Italy; (C.M.); (V.M.B.)
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy;
- IMM-CNR, Institute for Microelectronics and Microsystems, 40129 Bologna, Italy
- Correspondence: (G.Z.); (S.M.)
| | - Edoardo Mocini
- Department of Experimental Medicine, Medical Pathophysiology, Endocrinology and Nutrition Section, University Sapienza of Rome, 00185 Rome, Italy; (E.M.); (R.F.); (A.L.)
| | - Rachele Fornari
- Department of Experimental Medicine, Medical Pathophysiology, Endocrinology and Nutrition Section, University Sapienza of Rome, 00185 Rome, Italy; (E.M.); (R.F.); (A.L.)
| | - Giovanni Iolascon
- Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy;
| | - Maria Chiara Gallotta
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy;
| | - Viviana Maria Bimonte
- Department of Movement, Human and Health Sciences, Health Sciences Section, University Foro Italico of Rome, 00135 Rome, Italy; (C.M.); (V.M.B.)
| | - Carlo Baldari
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy;
| | - Andrea Lenzi
- Department of Experimental Medicine, Medical Pathophysiology, Endocrinology and Nutrition Section, University Sapienza of Rome, 00185 Rome, Italy; (E.M.); (R.F.); (A.L.)
| | - Silvia Migliaccio
- Department of Movement, Human and Health Sciences, Health Sciences Section, University Foro Italico of Rome, 00135 Rome, Italy; (C.M.); (V.M.B.)
- Correspondence: (G.Z.); (S.M.)
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23
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Miyaoka D, Imanishi Y, Kato E, Toi N, Nagata Y, Kurajoh M, Yamada S, Inaba M, Emoto M. Effects of denosumab as compared with parathyroidectomy regarding calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism. Endocrine 2020; 69:642-649. [PMID: 32621048 DOI: 10.1007/s12020-020-02401-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/24/2020] [Indexed: 01/22/2023]
Abstract
PURPOSE To evaluate the effects of denosumab (Dmb) on calcium, renal, and bone involvement in osteoporotic patients with primary hyperparathyroidism (PHPT) and compare with those who underwent a parathyroidectomy (PTX) procedure. METHODS This retrospective, longitudinal study included patients treated with Dmb (60 mg) once every 6 months (n = 19) and those who successfully underwent a PTX procedure (n = 19) corrected calcium (cCa), eGFR, bone mineral density (BMD) in the lumbar spine (LS), total hip (TH), and femoral neck (FN) and LS-trabecular bone score (TBS) changes at 1 year after beginning Dmb or undergoing PTX were measured. RESULTS Dmb group had older age, and showed milder disease activity and lower eGFR as compared with PTX group. In PTX group, cCa and eGFR were significantly decreased following surgery, while those were stable in Dmb group. There were significant increases in LS, TH, and FN-BMD in both Dmb (LS: 6.0 ± 0.8%, TH: 3.7 ± 1.0%, FN: 4.3 ± 1.5%) and PTX (LS: 11.2 ± 1.5%, TH: 7.5 ± 1.5%, FN: 7.9 ± 2.1%) groups. In Dmb group, LS-TBS was significantly improved by 3.0 ± 1.0%, while TBS change in PTX group approached significance (2.8 ± 1.5%). Percent change in TH-BMD was significantly correlated with baseline tartrate-resistant acid phosphatase-5b (TRACP-5b) in both groups. CONCLUSIONS Dmb treatment not only increased BMD, dependent on bone turnover status, the same as PTX, but also improved LS-TBS. In addition, it did not decrease the level of eGFR, whereas PTX did. These results suggest that Dmb treatment help in the clinical management of osteoporotic patients with PHPT who do not undergo surgery as alternative to PTX.
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Affiliation(s)
- Daichi Miyaoka
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | - Yasuo Imanishi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Eiko Kato
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norikazu Toi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuki Nagata
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masafumi Kurajoh
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shinsuke Yamada
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaaki Inaba
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masanori Emoto
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
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24
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Daga N, Joseph F. Denosumab-induced severe hypocalcaemia in a patient with vitamin D deficiency. BMJ Case Rep 2020; 13:13/8/e234508. [PMID: 32847872 DOI: 10.1136/bcr-2020-234508] [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] [Indexed: 11/04/2022] Open
Abstract
Postmenopausal women are at increased risk of osteoporosis. Osteoporotic fractures carry an increased risk of morbidity and mortality. Denosumab is a monoclonal antibody widely used for the treatment of osteoporosis by inhibiting osteoclast-induced bone resorption. Hypocalcaemia is a known side-effect of denosumab treatment. The majority of such cases have been described in patients with underlying metastatic cancer or chronic kidney disease. We present a patient who developed severe hypocalcaemia after administration of denosumab in the context of severe vitamin D deficiency and a normal kidney function. The management was further complicated by hypophosphatemia. Following replacement of vitamin D, the patient's calcium and phosphate levels stabilised. The patient required intensive care monitoring for replacement of electrolytes. This case report emphasises the importance of screening and ongoing monitoring of risk factors for iatrogenic hypocalcaemia with denosumab treatment.
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Affiliation(s)
- Natasha Daga
- Department of Endocrinology, Central Coast Local Health District, Gosford, New South Wales, Australia
| | - Flavian Joseph
- Department of Endocrinology, Central Coast Local Health District, Gosford, New South Wales, Australia
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25
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Jang SM, Anam S, Pringle T, Lahren P, Infante S. Contrasting PTH Response of Denosumab Use in Dialysis Patients: A Report of 2 Cases. PHARMACY 2020; 8:E59. [PMID: 32244607 PMCID: PMC7355881 DOI: 10.3390/pharmacy8020059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/29/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
A common complication of end-stage renal disease (ESRD) is mineral and bone disorder. Yet, many anti-osteoporotic drugs are contraindicated in ESRD patients. Denosumab, a monoclonal antibody, does not require renal dose adjustment. However, its use is uncertain due to a lack of safety and efficacy of data in this population. Two hemodialysis patient cases of contrasting responses in parathyroid hormone (PTH) after denosumab administration were observed. Patient 1, a 62-years-old male received denosumab 60 mg at Day 0. His calcium decreased from 8.8 mg/dL to 6.8 mg/dL on Day 30. The PTH level increased from 265 pg/mL to 372 pg/mL after 30 days. Calcium and PTH levels approached normal range after increasing doses of vitamin D/calcium supplements, and calcitriol. Patient 2, a 72-years-old male on hemodialysis also received denosumab 60 mg on Day 0. His baseline calcium and PTH were 9.2 mg/dL and 420 pg/mL, respectively. On Day 30, his calcium level decreased (6.8 mg/dL) but, PTH level drastically increased (>5,000 pg/mL). Denosumab commonly causes hypocalcemia and hyperparathyroidism since it inhibits osteoclast activation, reduces calcium release from bone and increases PTH levels as a compensatory mechanism. With a wait-and-watch approach, Patient 2's levels approached the normal range (calcium 9.6 mg/dL and PTH 274 pg/mL at Day 90).
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Affiliation(s)
- Soo Min Jang
- Department of Pharmacy Practice, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA;
- Loma Linda University Kidney Center, Loma Linda, CA 92354, USA; (T.P.); (P.L.)
| | | | - Tara Pringle
- Loma Linda University Kidney Center, Loma Linda, CA 92354, USA; (T.P.); (P.L.)
| | - Paul Lahren
- Loma Linda University Kidney Center, Loma Linda, CA 92354, USA; (T.P.); (P.L.)
| | - Sergio Infante
- Loma Linda University Kidney Center, Loma Linda, CA 92354, USA; (T.P.); (P.L.)
- Department of Internal Medicine Nephrology Division, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
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26
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Fraser TR, Flogaitis I, Moore AE, Hampson G. The effect of previous treatment with bisphosphonate and renal impairment on the response to denosumab in osteoporosis: a 'real-life' study. J Endocrinol Invest 2020; 43:469-475. [PMID: 31664706 PMCID: PMC7067751 DOI: 10.1007/s40618-019-01131-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 10/14/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE To investigate changes in bone mineral density (BMD) following denosumab after previous bisphosphonate therapy and the impact of chronic kidney disease (CKD) on response. METHODS A retrospective study of 134 patients (11 M, 123 F) aged [mean (SD)] 72 [11] years on denosumab was undertaken. Ninety-five patients had previously been on oral and 28 on iv bisphosphonate. Lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD were measured before treatment and at 2.7 [1.2] years. GFR was < 35 ml/min in 24 patients (18%). Ninety-four (18 M, 76 F) patients aged 71 [11] years transitioning to zoledronate were also studied. RESULTS BMD improved following denosumab [mean (SEM) % change LS: 6.0 (0.62) p < 0.001, TH: 2.28 (0.64) p < 0.001, FN: 1.9 (0.77) p = 0.045]. Changes at the TH and FN were lower in patients with GFR < 35 ml/min (Group B) compared to those with GFR > 35 ml/min (Group A) [% change TH; Group A: 2.9 (0.72), Group B: - 0.84 (1.28), p = 0.015, FN; Group A: 2.76 (0.86), Group B: - 1.47 (1.53), p = 0.025]. % change in BMD at the FN and PTH were negatively associated (r = - 0.25, p = 0.013). BMD changes were not different at 12-18 months between patients on denosumab compared to zoledronate [% change at LS: denosumab: 3.97% (0.85), zoledronate: 2.6% (0.5), p = 0.19 TH: denosumab: 0.97% (0.58), zoledronate: 0.92% (0.6), p = 0.95). CONCLUSION Denosumab increases BMD following previous bisphosphonate treatment and is comparable to zoledronate. Lower response seen at the hip in CKD is related to PTH concentrations.
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Affiliation(s)
- T R Fraser
- Department of Chemical Pathology and Metabolic Medicine, St Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK
- Osteoporosis Unit, Guy's Hospital, London, SE1 9RT, UK
| | - I Flogaitis
- Department of Chemical Pathology and Metabolic Medicine, St Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK
- Osteoporosis Unit, Guy's Hospital, London, SE1 9RT, UK
| | - A E Moore
- Osteoporosis Unit, Guy's Hospital, London, SE1 9RT, UK
| | - G Hampson
- Department of Chemical Pathology and Metabolic Medicine, St Thomas' Hospital, Lambeth Palace Road, London, SE1 7EH, UK.
- Metabolic Bone Clinic, Department of Rheumatology, Guy's Hospital, London, UK.
- Osteoporosis Unit, Guy's Hospital, London, SE1 9RT, UK.
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27
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Tsvetov G, Amitai O, Shochat T, Shimon I, Akirov A, Diker-Cohen T. Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low? Osteoporos Int 2020; 31:655-665. [PMID: 31838550 DOI: 10.1007/s00198-019-05261-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 12/05/2019] [Indexed: 02/08/2023]
Abstract
UNLABELLED Hypocalcemia was reported at low rates (0.05-1.7%) in denosumab-treated postmenopausal women with osteoporosis. This real-life study shows a 7.4% rate of denosumab-induced hypocalcemia in community-dwelling osteoporotic men and women. Pretreatment serum calcium and creatinine levels are major predictors for this complication. Serum-calcium monitoring may help to identify and prevent severe hypocalcemia. PURPOSE RCTs have reported a 0.05-1.7% rate of hypocalcemia in denosumab-treated postmenopausal women with osteoporosis, but long-term real-life data are lacking. We assessed the rate of hypocalcemia in osteoporotic community-dwelling patients treated with denosumab. METHODS A retrospective analysis was conducted based on medical records (2010-2018) from a large HMO. An albumin-adjusted serum calcium concentration lower than 8.5 mg/dL was defined as hypocalcemia. RESULTS We included 2005 patients (93% women, mean age 76 ± 9 years). Hypocalcemia developed during treatment in 149 patients (7.4%; 1% less than 8 mg/dL): in 66 after 0.5-1 years; 48 after 1-2 years; 35 after > 2 years. On comparison of the hypocalcemic and normocalcemic patients, the strongest predictors of hypocalcemia were pretreatment levels of albumin-adjusted serum calcium (9.1 ± 0.4 vs. 9.4 ± 0.5 mg/dL, respectively; p < 0.05) and creatinine (0.9 ± 0.5 vs. 0.8 ± 0.3 mg/dL, respectively; p < 0.05). The hypocalcemia rate increased in parallel to a decrease in eGFR (p = 0.032 for the difference between eGFR ranges). Baseline calcium level ≤ 9.31 mg/dL predicted hypocalcemia with a sensitivity of 77% and specificity of 56%. A model of (- 2)*calcium + creatinine predicted hypocalcemia (3.7% when lower and 17.1% when higher than - 17.4). Gender, age, 25-hydroxyvitamin-D, parathyroid hormone, alkaline phosphatase, and whether denosumab was given as first or advanced line of osteoporotic therapy had no predictive value. CONCLUSION Real-life rates of denosumab-induced hypocalcemia are higher than previously reported. Hypocalcemia might develop after each dose of denosumab in ongoing treatment. Adequate calcium and vitamin D supplementation are needed. Serum calcium monitoring is advised in high-risk patients for early detection of severe hypocalcemia.
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Affiliation(s)
- G Tsvetov
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - O Amitai
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Clalit Healthcare Services, Petah-Tikva, Israel
| | - T Shochat
- Statistical Consulting Unit, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petah Tikva, Israel
| | - I Shimon
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - A Akirov
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - T Diker-Cohen
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petah Tikva, Israel.
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Department of Medicine A, Rabin Medical Center - Beilinson Hospital, 39 Jabotinski St., 4941492, Petah Tikva, Israel.
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28
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Lee H, Jin Y, Roh M, Tsacogianis TN, Park S, Choi NK, Kim SC. Risk of Cataract Surgery and Age-Related Macular Degeneration After Initiation of Denosumab vs Zoledronic Acid for Osteoporosis: A Multi-Database Cohort Study. Drugs Aging 2020; 37:311-320. [PMID: 32026309 DOI: 10.1007/s40266-020-00745-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND OBJECTIVE There is a relative lack of head-to-head comparisons of denosumab against other osteoporosis drugs on safety. We aimed to explore ocular outcomes in patients with osteoporosis initiating denosumab vs zoledronic acid. METHODS We conducted a cohort study using claims data (2010-15) from two large US commercial insurance databases including patients with osteoporosis who were aged 50 years or older and initiators of denosumab or zoledronic acid. The primary outcomes were (1) receipt of cataract surgery and development of (2) wet age-related macular degeneration and (3) dry age-related macular degeneration within 365 days after initiation of denosumab vs zoledronic acid. Propensity score fine stratification and weighting were used to control for potential confounding, and we calculated the incidence rate and hazard ratio for each outcome in the cohorts. The estimates from the two databases were combined with a fixed-effects model meta-analysis. RESULTS The study cohort included 50,821 denosumab and 67,471 zoledronic acid initiators. In the propensity score-weighted analysis, compared to zoledronic acid use, denosumab was associated with a modestly decreased risk of undergoing cataract surgery (hazard ratio 0.91; 95% confidence interval 0.85-0.98) but not with the risk of wet age-related macular degeneration (hazard ratio 1.29; 95% confidence interval 0.99-1.70) or dry age-related macular degeneration (hazard ratio 1.03; 95% confidence interval 0.98-1.09). CONCLUSIONS In this large population-based cohort study of 118,292 patients with osteoporosis, initiation of denosumab was associated with a modestly decreased risk of cataract surgery vs zoledronic acid. The risk of age-related macular degeneration was similar between the two drugs.
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Affiliation(s)
- Hemin Lee
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3-030, Boston, MA, 02120, USA
| | - Yinzhu Jin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3-030, Boston, MA, 02120, USA
| | - Miin Roh
- Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Theodore N Tsacogianis
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3-030, Boston, MA, 02120, USA
| | - Sangshin Park
- Graduate School of Urban Public Health, University of Seoul, Seoul, Republic of Korea
| | - Nam-Kyong Choi
- Department of Health Convergence, Ewha Women's University, Seoul, Republic of Korea
| | - Seoyoung C Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3-030, Boston, MA, 02120, USA.
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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29
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Fassio A, Adami G, Benini C, Vantaggiato E, Saag KG, Giollo A, Lippolis I, Viapiana O, Idolazzi L, Orsolini G, Rossini M, Gatti D. Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women. Bone 2019; 123:191-195. [PMID: 30910600 DOI: 10.1016/j.bone.2019.03.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/12/2019] [Accepted: 03/16/2019] [Indexed: 02/01/2023]
Abstract
PURPOSE The positive effects of denosumab (DMAb) on bone mineral density (BMD) are quickly reversible after its discontinuation. We investigated whether this rebound was associated with dysregulation of the Wnt canonical pathway and/or by the increase in the receptor-activator of nuclear factor-kappa B ligand (RANKL) serum levels. METHODS The study included patients (n = 15) with postmenopausal osteoporosis to whom DMAb was administered for 78 months and then discontinued. We collected BMD data at baseline/month 0 (M0), M60, M84 (6 months after last DMAb administration, coinciding when the next DMAb dose would typically be due), and after 3 and 12 months of follow-up (FU-M3 and FU-M12, respectively). Serum C-terminal telopeptide of type 1 collagen (CTX-I), Dickkopf-1 (Dkk-1), and sclerostin were measured at M0, M60, M84, FU-M3, and FU-M12. Serum N-terminal propeptide of type 1 procollagen (PINP) and RANKL were dosed at M60, M84, FU-M3, and FU-12. RESULTS We found a significant decrease in the T-score at all sites at FU-M12, when compared to M84 (-0.51 ± 0.91 at the lumbar spine; -0.72 ± 0.33 at the total hip; and -0.42 ± 0.27 at the femoral neck, p < 0.05). After DMAb discontinuation (M84 vs FU M12) CTX-I, PINP increased already at FU-M3 (+0.921 ± 0.482 ng/mL, +126.60 ± 30.36 ng/mL, respectively, p < 0.01), RANKL increased at FU-M12 (+0.041 ± 0.062 ng/mL, p < 0.05), while Dkk-1 and sclerostin decreased at FU-M12 (-10.90 ± 11.80 and - 13.00 ± 10.52 pmol/L, respectively, p < 0.01). No changes in BMD or any of the markers were found between M60 and M84. CONCLUSIONS RANKL serum levels progressively increased after discontinuation of long-term DMAb while Dkk-1 and sclerostin serum levels decreased. The increase in RANKL serum levels supports the hypothesis of a sudden loss of inhibition of the resting osteoclast line after DMAb clearance, with a hyperactivation of these cells. Our results suggest that the changes in serum Wnt inhibitors after DMAb suspension might represent a mere feedback response to the increased bone turnover.
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Affiliation(s)
- A Fassio
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy.
| | - G Adami
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy; Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 510 20th Street South, Faculty Office Tower 820D, Birmingham, AL 35294, USA
| | - C Benini
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - E Vantaggiato
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - K G Saag
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 510 20th Street South, Faculty Office Tower 820D, Birmingham, AL 35294, USA
| | - A Giollo
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - I Lippolis
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - O Viapiana
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - L Idolazzi
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - G Orsolini
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - M Rossini
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
| | - D Gatti
- Rheumatology Unit, University of Verona, Piazzale A. Scuro, 10, 37134 Verona, Italy
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Thongprayoon C, Acharya P, Aeddula NR, Torres-Ortiz A, Bathini T, Sharma K, Ungprasert P, Watthanasuntorn K, Suarez MLG, Salim SA, Kaewput W, Chenbhanich J, Mao MA, Cheungpasitporn W. Effects of denosumab on bone metabolism and bone mineral density in kidney transplant patients: a systematic review and meta-analysis. Arch Osteoporos 2019; 14:35. [PMID: 30852679 DOI: 10.1007/s11657-019-0587-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 03/04/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The use of immunosuppressive agents, especially glucocorticoids, are associated with increased risks of bone loss in kidney transplant patients. Denosumab, a potent antiresorptive agent, has been shown to increase bone mineral density (BMD) in patients with CKD. However, its effects on bone metabolism and BMD in kidney transplant patients remain unclear. METHODS A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through April 2018 to identify studies evaluating denosumab's effect on changes in bone metabolism and BMD from baseline to post-treatment course in kidney transplant patients. Study results were pooled and analyzed utilizing random-effects model. The protocol for this systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42018095055). RESULTS Five studies (a clinical trial and four cohort studies) with a total of 162 kidney transplant patients were identified. The majority of patients had a baseline eGFR ≥ 30 mL/min/1.73 m2. After treatment (≥ 6 to 12 months), there were significant increases in BMD with standardized mean differences (SMDs) of 3.26 (95% CI 0.88-5.64) and 1.83 (95% CI 0.43 to 3.22) for lumbar spine and femoral neck, respectively. There were also significant increases in T scores with SMDs of 0.92 (95% CI 0.58 to 1.25) and 1.14 (95% CI 0.17 to 2.10) for lumbar spine and femoral neck, respectively. After treatment, there were no significant changes in serum calcium (Ca) or parathyroid hormone (PTH) from baseline to post-treatment course (≥ 6 months) with mean differences (MDs) of 0.52 (95% CI, - 0.13 to 1.16) mmol/L and - 13.24 (95% CI, - 43.85 to 17.37) ng/L, respectively. The clinical trial data demonstrated more asymptomatic hypocalcemia in the denosumab (12 episodes in 39 patients) than in the control (1 episode in 42 patients) group. From the cohort studies, the pooled incidence of hypocalcemia following denosumab treatment was 1.7% (95% CI 0.4 to 6.6%). All reported hypocalcemic episodes were mild and asymptomatic, but the majority of patients required Ca and vitamin D supplements. CONCLUSION Among kidney transplant patients with good allograft function, denosumab effectively increases BMD and T scores in the lumbar spine and femur neck. From baseline to post-treatment, there are no differences in serum Ca and PTH. However, mild hypocalcemia can occur following denosumab treatment, requiring monitoring and titration of Ca and vitamin D supplements.
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Affiliation(s)
- Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Prakrati Acharya
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, 2500 N. State St, Jackson, MS, 39216, USA
| | - Narothama Reddy Aeddula
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine and Deaconess Health System, Evansville, IN, USA
| | - Aldo Torres-Ortiz
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, 2500 N. State St, Jackson, MS, 39216, USA
| | - Tarun Bathini
- Department of Internal Medicine, University of Arizona, Tucson, AZ, USA
| | - Konika Sharma
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | - Patompong Ungprasert
- Clinical Epidemiology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Maria Lourdes Gonzalez Suarez
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, 2500 N. State St, Jackson, MS, 39216, USA
| | - Sohail Abdul Salim
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, 2500 N. State St, Jackson, MS, 39216, USA
| | - Wisit Kaewput
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Jirat Chenbhanich
- Department of Internal Medicine, Metrowest Medical Center, Framingham, MA, USA
| | - Michael A Mao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Wisit Cheungpasitporn
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, 2500 N. State St, Jackson, MS, 39216, USA.
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Abstract
Traditional hypercalcemic primary hyperparathyroidism is a common endocrine disease. Patients with a history of nephrolithiasis or a suspected metabolic bone disease are increasingly being identified with elevated PTH concentrations in the setting of consistently normal serum and ionized calcium concentrations. In the absence of secondary causes of hyperparathyroidism, a diagnosis of normocalcemic primary hyperparathyroidism is reasonable. As most cohorts described in the literature are from referral populations, involvement of the skeleton and the kidneys is common, two traditional target organs of primary hyperparathyroidism. Data from small cohorts show patients with normocalcemic disease respond similarly to hypercalcemic primary hyperparathyroidism with regard to medical and surgical approaches. In normocalcemic patients, multiglandular disease may be more common. In this article, we review the available literature on the epidemiology, diagnosis, clinical features, medical and surgical management of this newer phenotype of primary hyperparathyroidism.
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Affiliation(s)
- Natalie E Cusano
- Division of Endocrinology, Department of Medicine, Lenox Hill Hospital, 110 East 59th St, Suite 8B, New York, NY, 10022, USA.
| | - Cristiana Cipriani
- Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
| | - John P Bilezikian
- Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physician and Surgeons, Columbia University, 630 West 168th St, New York, NY, 10032, USA.
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Thongprayoon C, Acharya P, Acharya C, Chenbhanich J, Bathini T, Boonpheng B, Sharma K, Wijarnpreecha K, Ungprasert P, Gonzalez Suarez ML, Cheungpasitporn W. Hypocalcemia and bone mineral density changes following denosumab treatment in end-stage renal disease patients: a meta-analysis of observational studies. Osteoporos Int 2018; 29:1737-1745. [PMID: 29713798 DOI: 10.1007/s00198-018-4533-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 04/11/2018] [Indexed: 02/06/2023]
Abstract
The incidence of hypocalcemia and bone mineral density (BMD) changes in end-stage renal disease (ESRD) patients on denosumab remains unclear. We performed this meta-analysis to assess the incidence of denosumab-associated hypocalcemia and effects of denosumab on BMD in ESRD patients. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through November 2017 to identify studies evaluating incidence of denosumab-associated hypocalcemia and changes in serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and BMD from baseline to post-treatment course of denosumab in ESRD patients. Study results were pooled and analyzed using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017081074). Six observational studies with a total of 84 ESRD patients were enrolled. The pooled estimated incidence of hypocalcemia during denosumab treatment was 42% (95% CI 29-55%, I2 = 0%). Hypocalcemia occurred approximately 7 to 20 days after the first dose and reached nadir of low calcium levels in the first 2 weeks up to 2 months. However, there were no significant changes in serum calcium or phosphate from baseline to post-treatment course (≥ 3 months after treatment) with mean differences [MDs] of 0.20 mg/dL (95% CI, - 0.30 to 0.69 mg/dL) and - 0.10 mg/dL (95% CI, - 0.70 to 0.49 mg/dL). There were significant reductions in ALP and PTH levels with standardized mean differences (SMDs) of - 0.65 (95% CI - 1.13 to - 0.16) and - 1.89 (95% CI - 3.44 to - 0.34), respectively. There were significant increases in T-scores with MDs of 0.39 (95% CI 0.10 to 0.69) and 0.79 (95% CI 0.60 to 0.98) for lumbar spine and femoral neck, respectively. Our study demonstrates the estimated incidence of denosumab-associated hypocalcemia in dialysis patients of 42%. From baseline to post-treatment course, although there are no differences in serum calcium and phosphate, our findings suggest significant reductions in ALP and PTH and a significant increase in BMD. Currently, denosumab should not be considered as the treatment of choice in ESRD patients until more safety and efficacy data are available.
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Affiliation(s)
- C Thongprayoon
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | - P Acharya
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Mississippi, 2500 N. State St., Jackson, MS, 39216, USA
| | - C Acharya
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Mississippi, 2500 N. State St., Jackson, MS, 39216, USA
| | - J Chenbhanich
- Department of Internal Medicine, Metrowest Medical Center, Framingham, MA, USA
| | - T Bathini
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | - B Boonpheng
- Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA
| | - K Sharma
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | - K Wijarnpreecha
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
| | - P Ungprasert
- Clinical Epidemiology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - M L Gonzalez Suarez
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Mississippi, 2500 N. State St., Jackson, MS, 39216, USA
| | - W Cheungpasitporn
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Mississippi, 2500 N. State St., Jackson, MS, 39216, USA.
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Anastasilakis AD, Polyzos SA, Makras P. THERAPY OF ENDOCRINE DISEASE: Denosumab vs bisphosphonates for the treatment of postmenopausal osteoporosis. Eur J Endocrinol 2018; 179:R31-R45. [PMID: 29691303 DOI: 10.1530/eje-18-0056] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 04/23/2018] [Indexed: 12/11/2022]
Abstract
The most widely used medications for the treatment of osteoporosis are currently bisphosphonates (BPs) and denosumab (Dmab). Both are antiresorptives, thus targeting the osteoclast and inhibiting bone resorption. Dmab achieves greater suppression of bone turnover and greater increases of bone mineral density (BMD) at all skeletal sites, both in naïve and pretreated patients. No superiority on fracture risk reduction has been documented so far. In long-term administration, BPs reach a plateau in BMD response after 2-3 years, especially at the hip, while BMD increases progressively for as long as Dmab is administered. Both BPs and Dmab are generally considered safe, although they have been correlated to rare adverse events, such as osteonecrosis of the jaw and atypical femoral fractures. Dmab should be preferred in patients with impaired renal function. BPs are embedded in the bone, from which they are slowly released during bone remodeling, therefore continuing to act for years after their discontinuation. In contrast, Dmab discontinuation fully and rapidly reverses its effects on bone markers and BMD and increases the risk for fractures; therefore, Dmab discontinuation should be discouraged, especially in previously treatment-naïve patients, regardless of the conventional fracture risk. In case of discontinuation, other treatment, mainly BPs, should immediately follow, although the optimal sequential treatment strategy is yet to be defined. Combination of teriparatide with Dmab or zoledronic acid, but not alendronate, provides increased BMD gains at all sites. In conclusion, both BPs and Dmab are safe and efficient therapeutic options although their particularities should be carefully considered in an individual basis.
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Affiliation(s)
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Polyzois Makras
- Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
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Makras P, Anastasilakis AD. Bone disease in primary hyperparathyroidism. Metabolism 2018; 80:57-65. [PMID: 29051042 DOI: 10.1016/j.metabol.2017.10.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 10/05/2017] [Accepted: 10/07/2017] [Indexed: 11/16/2022]
Abstract
Primary hyperparathyroidism (PHPT) is a disease of high bone turnover, decreased bone mineral density (BMD) especially at cortical sites, and increased risk of fractures at all skeletal sites. Early diagnosis during the last decades resulted in milder forms of bone involvement. New methods of imaging and validation such as high resolution peripheral quantitative computed tomography and trabecular bone score provide evidence of disturbed bone microarchitecture and explain further the increased risk of fractures at both cortical and trabecular skeletal sites. Parathyroidectomy has a long-term beneficial effect on the skeleton and is probably prudent to refer PHPT patients for surgery in all cases where increased bone fragility is suspected. Bisphosphonates (BPs), mainly alendronate, have been proved as reasonable choices for BMD improvement while cinacalcet has no effect on bone strength in PHPT. Combination of BPs and cinacalcet, is a valid therapeutic approach from a pathophysiological point of view at least in terms of bone health, however, an adequately powered study to prove it is lacking. Adequate dietary calcium intake and vitamin D supplementation is advised as in the general population for the skeletal integrity of PHPT patients albeit with a close monitoring of serum and urinary calcium levels.
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Affiliation(s)
- Polyzois Makras
- Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
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35
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Gifre L, Ruiz-Gaspà S, Carrasco JL, Portell E, Vidal J, Muxi A, Monegal A, Guañabens N, Peris P. Effect of recent spinal cord injury on the OPG/RANKL system and its relationship with bone loss and the response to denosumab therapy. Osteoporos Int 2017; 28:2707-2715. [PMID: 28580511 DOI: 10.1007/s00198-017-4090-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 05/11/2017] [Indexed: 10/19/2022]
Abstract
UNLABELLED There is marked bone loss after spinal cord injury (SCI); however, its pathogenesis and clinical management remain unclear. The increased circulating levels of receptor activator of nuclear factor kB ligand (RANKL) associated with bone loss shortly after SCI and the prevention of bone loss with denosumab treatment suggest a contributory role of RANKL in SCI-induced osteoporosis. INTRODUCTION Bone turnover and bone loss are markedly increased shortly after SCI. However, the pathogenesis and clinical management of this process remain unclear, especially the role of the osteoprotegerin (OPG)/RANKL system in this disorder. The aim of this study was to analyze serum levels of OPG and RANKL in bone loss associated with recent SCI and the effect of denosumab treatment on these mediators. METHODS Twenty-three males with recent complete SCI were prospectively included. Serum OPG and RANKL levels, bone turnover markers (PINP, bone ALP, CTX), and bone mineral density (BMD) were assessed at baseline, at 6 months of follow-up, prior to initiating denosumab, and 6 months after treatment. The results were compared with a healthy control group. RESULTS At baseline, SCI patients showed higher RANKL levels vs. controls which were correlated with days-since-SCI and total hip BMD loss at 6 months. OPG levels were similar to controls at baseline. After denosumab treatment, OPG showed no changes, whereas RANKL levels became undetectable in 67% of patients. Patients with undetectable RANKL during treatment showed better response in femoral BMD and bone markers vs. patients with detectable RANKL at 6 months of denosumab. Increased parathormone (PTH) levels during treatment were negatively correlated with RANKL changes. CONCLUSIONS RANKL levels are increased after SCI and related to BMD loss at the proximal femur, becoming undetectable after denosumab treatment. The effect of denosumab on preventing sublesional bone loss, especially in patients with undetectable levels during treatment, suggests a contributory role of RANKL in this process.
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Affiliation(s)
- L Gifre
- Rheumatology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Rheumatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | - J L Carrasco
- Public Health Department, University of Barcelona, Barcelona, Spain
| | - E Portell
- Guttmann Neurorehabilitation Institute, Universitat Autònoma de Barcelona, Badalona, Spain
| | - J Vidal
- Guttmann Neurorehabilitation Institute, Universitat Autònoma de Barcelona, Badalona, Spain
| | - A Muxi
- Nuclear Medicine Department, Hospital Clínic of Barcelona, Barcelona, Spain
| | - A Monegal
- Rheumatology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
| | - N Guañabens
- Rheumatology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- CIBERehd, Barcelona, Spain
| | - P Peris
- Rheumatology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
- CIBERehd, Barcelona, Spain.
- Metabolic Bone Diseases Unit, Department of Rheumatology, Hospital Clinic of Barcelona, Villarroel 170, 08036, Barcelona, Spain.
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Fountas A, Tigas S, Tsatsoulis A. Denosumab is a long-term option for the management of parathyroid carcinoma-related refractory hypercalcemia. QJM 2017; 110:53-54. [PMID: 28011856 DOI: 10.1093/qjmed/hcw206] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/09/2016] [Indexed: 11/13/2022] Open
Affiliation(s)
- A Fountas
- From the Department of Endocrinology, University Hospital of Ioannina, Ioannina, Greece
| | - S Tigas
- From the Department of Endocrinology, University Hospital of Ioannina, Ioannina, Greece
| | - A Tsatsoulis
- From the Department of Endocrinology, University Hospital of Ioannina, Ioannina, Greece
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37
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Huynh ALH, Baker ST, Stewardson AJ, Johnson DF. Denosumab-associated hypocalcaemia: incidence, severity and patient characteristics in a tertiary hospital setting. Pharmacoepidemiol Drug Saf 2016; 25:1274-1278. [PMID: 27255807 DOI: 10.1002/pds.4045] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 05/12/2016] [Accepted: 05/12/2016] [Indexed: 11/11/2022]
Abstract
PURPOSE Denosumab-associated hypocalcaemia (DAH) has been reported in patients with osteoporosis or metastatic bone disease and is associated with stages 4 and 5 chronic kidney disease (CKD, estimated glomerular filtration rate <30 mL/min/1.73m2 ). Other risk factors for hypocalcaemia have not been fully elucidated. We aimed to investigate the incidence of hypocalcaemia amongst patients receiving denosumab and to identify clinical features associated with this adverse event. METHODS Retrospective cohort study between June 2013 and June 2014 of patients administered denosumab (60/120 mg) at a tertiary hospital in Melbourne, Australia, to identify the incidence of an albumin-adjusted serum calcium concentration <2.10 mmol/L or ionized calcium <1.13 mmol/L within 6 months of treatment. Univariable and multivariable logistic regression analyses were performed to identify clinical features associated with DAH. RESULTS One hundred and fifty-five patients were administered denosumab (100 osteoporosis, 55 bone metastases). Twenty-two patients (14% [95%CI 9.1-20.7]) developed hypocalcaemia: 55% were men, and 55% had osteoporosis. Eighty-six per cent had a 25-hydroxyvitamin D concentration >50 nmol/L, and 91% were on calcium/colecalciferol supplementation. Stages 4 and 5 CKD (adjusted odd ratio [aOR] 4.71, 95%CI 1.61-13.79, p = 0.005) and male sex (aOR 4.30, 95%CI 1.69-10.96, p = 0.002) were associated with DAH. No patients were documented as having hypocalcaemic symptoms. One patient received intravenous calcium gluconate treatment. CONCLUSIONS The incidence of denosumab-associated hypocalcaemia was 14% (95%CI 9.1-20.7) within 6 months of treatment despite widespread use of appropriate calcium/colecalciferol supplementation. Stages 4 and 5 CKD and male sex were associated with subsequent hypocalcaemia. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
| | - Scott Thomas Baker
- Department of General Medicine, Austin Health, Heidelberg, Victoria, Australia.,Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | | | - Douglas Forsyth Johnson
- Department of General Medicine, Austin Health, Heidelberg, Victoria, Australia.,Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia
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Dempster DW, Zhou H, Recker RR, Brown JP, Recknor CP, Lewiecki EM, Miller PD, Rao SD, Kendler DL, Lindsay R, Krege JH, Alam J, Taylor KA, Janos B, Ruff VA. Differential Effects of Teriparatide and Denosumab on Intact PTH and Bone Formation Indices: AVA Osteoporosis Study. J Clin Endocrinol Metab 2016; 101:1353-63. [PMID: 26859106 PMCID: PMC4880160 DOI: 10.1210/jc.2015-4181] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
We compared effects of teriparatide and denosumab on PTH, bone turnover markers, and bone histomorphometry in osteoporotic postmenopausal women. The findings were inconsistent with an early indirect anabolic effect of denosumab.
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Affiliation(s)
- David W Dempster
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Hua Zhou
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Robert R Recker
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Jacques P Brown
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Christopher P Recknor
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - E Michael Lewiecki
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Paul D Miller
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Sudhaker D Rao
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - David L Kendler
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Robert Lindsay
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - John H Krege
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Jahangir Alam
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Kathleen A Taylor
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Boris Janos
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
| | - Valerie A Ruff
- Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers (C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K., J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men's Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development - Bio-Medicines (B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
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Diagnosis and Differential Diagnosis of Primary Hyperparathyroidism. Updates Surg 2016. [DOI: 10.1007/978-88-470-5758-6_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Abstract
PURPOSE OF REVIEW Normocalcemic primary hyperparathyroidism (PHPT) received special attention in the publication of the conference proceedings from the Fourth International Workshop on the Management of Asymptomatic PHPT, although much remains unknown about the disorder. RECENT FINDINGS Observational studies have found that despite maintaining normocalcemia, patients with normocalcemic PHPT have a high incidence of kidney stones and osteoporosis. Small studies focusing on the cardiovascular implications of normocalcemic PHPT have shown a possible association with hypertension and an atherogenic lipid profile, but not insulin resistance. Recent data from small cohorts show that subjects with normocalcemic PHPT respond to medical therapy and have a positive densitometric response following parathyroid surgery. SUMMARY The available evidence suggests that patients with normocalcemic PHPT develop complications of PHPT, despite having normal calcium levels. Most data come from referral populations and information regarding a mild, asymptomatic form of the disease is lacking. Future research requires a standardized approach to the diagnostic criteria of normocalcemic PHPT.
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Affiliation(s)
- Monika Pawlowska
- aDepartment of Medicine, Division of Endocrinology, University of British Columbia, Vancouver, British Columbia bDepartment of Medicine, Division of Endocrinology, Columbia University, New York, New York, USA
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Compston J. Emerging therapeutic concepts for muscle and bone preservation/building. Bone 2015; 80:150-156. [PMID: 26453503 DOI: 10.1016/j.bone.2015.04.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 03/24/2015] [Accepted: 04/07/2015] [Indexed: 01/16/2023]
Abstract
Loss of muscle or bone mass occurs with ageing, immobility and in association with a variety of systemic diseases. The interaction of these two processes is most evident in the major contribution of falls to the risk of fractures in the elderly population. Exercise and nutrition are key common physiological variables that allow for preservation or formation of greater muscle or bone mass. However, although several pharmacological approaches have the potential to benefit both muscle and bone health, for example vitamin D, selective androgen receptor modulators and ghrelin mimetics, clinical trials with appropriate primary outcomes are lacking. Conventional approaches to address muscle loss are being extended to include stem cell biology and conserved molecular mechanisms of atrophy/hypertrophy. Pharmacological interventions to reduce fracture risk are exploring new mechanisms of action, in particular the uncoupling of bone resorption and formation. Emerging key issues for clinical trial design include adequate phenotyping of patients (personalised medicine), optimisation of the physiological background (multimodal approach) and the use of meaningful and robust outcomes relevant to daily clinical practice. At present, effective treatments that combine beneficial effects on both muscle and bone are lacking, although this is an important target for the future. This review therefore considers current and developing strategies to improve muscle function and bone strength in separate sections.
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Affiliation(s)
- Juliet Compston
- University of Cambridge School of Clinical Medicine, Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge UK CB2 0QQ.
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Makras P, Delaroudis S, Anastasilakis AD. Novel therapies for osteoporosis. Metabolism 2015; 64:1199-214. [PMID: 26277199 DOI: 10.1016/j.metabol.2015.07.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Revised: 07/02/2015] [Accepted: 07/06/2015] [Indexed: 12/28/2022]
Abstract
Since the identification of osteoporosis as a major health issue in aging populations and the subsequent development of the first treatment modalities for its management, considerable progress has been made in our understanding of the mechanisms controlling bone turnover and disease pathophysiology, thus enabling the pinpointing of new targets for intervention. This progress, along with advances in biotechnology, has rendered possible the development of ever more sophisticated treatments employing novel mechanisms of action. Denosumab, a monoclonal antibody against RANKL, approved for the treatment of postmenopausal and male osteoporosis, significantly and continuously increases bone mineral density (BMD) and maintains a low risk of vertebral, non-vertebral, and hip fractures for up to 8 years. Currently available combinations of estrogens with selective estrogen receptor modulators moderately increase BMD without causing the extra-skeletal adverse effects of each compound alone. The cathepsin K inhibitor odanacatib has recently been shown to decrease vertebral, non-vertebral, and hip fracture rates and is nearing approval. Romosozumab, an anti-sclerosin antibody, and abaloparatide, a PTH-related peptide analog, are at present in advanced stages of clinical evaluation, so far demonstrating efficaciousness together with a favorable safety profile. Several other agents are currently in earlier clinical and preclinical phases of development, including dickkopf-1 antagonists, activin A antagonists, β-arrestin analogs, calcilytics, and Src tyrosine kinase inhibitors.
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Affiliation(s)
- Polyzois Makras
- Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
| | - Sideris Delaroudis
- Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece
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Anastasilakis AD, Polyzos SA, Gkiomisi A, Saridakis ZG, Digkas D, Bisbinas I, Sakellariou GT, Papatheodorou A, Kokkoris P, Makras P. Denosumab versus zoledronic acid in patients previously treated with zoledronic acid. Osteoporos Int 2015; 26:2521-7. [PMID: 25990355 DOI: 10.1007/s00198-015-3174-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/12/2015] [Indexed: 01/06/2023]
Abstract
UNLABELLED Denosumab and zoledronic acid are potent antiresorptives. In this study in patients pre-treated with zoledronic acid, denosumab achieved similar increases with zoledronic acid in lumbar spine BMD despite the more prominent reduction of bone turnover markers. Denosumab reversibly reduced endogenous RANKL. INTRODUCTION We aimed to compare yearly changes in lumbar spine (LS) bone mineral density (BMD), bone turnover markers, free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and sclerostin levels between denosumab and zoledronic acid. METHODS Postmenopausal women with low bone mass previously treated with zoledronic acid for 1 year were assigned to denosumab injection (n = 32) or zoledronic acid infusion (n = 26). Procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx), sRANKL, and sclerostin levels were measured in serum samples obtained at baseline and 3, 6, and 12 months after denosumab injection or zoledronic acid infusion. LS BMD was measured at baseline and 12 months. RESULTS The mean LS increase was 4.5 and 4.4% with denosumab and zoledronic acid, respectively (p = 0.560). Denosumab caused a larger decrease in CTx at 3 months (p < 0.001) and P1NP at 3 (p < 0.001), 6 (p = 0.021), and 12 months (p = 0.042). Denosumab significantly decreased sRANKL by 87.4% at 3 months (p < 0.001). Sclerostin levels were not changed with either intervention (p = 0.162 and p = 0.214, respectively). CONCLUSIONS In patients previously treated with zoledronic acid, denosumab reduces bone turnover more than zoledronic acid, but the increases in LS BMD are comparable. Furthermore, denosumab administration results in reversible inhibition of the metabolically significant endogenous free soluble RANKL levels. Serum sclerostin is not affected by either agent.
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Affiliation(s)
- A D Anastasilakis
- Department of Endocrinology, 424 General Military Hospital, Ring Road, 564 29 N.Efkarpia, Thessaloniki, Greece.
| | - S A Polyzos
- Second Medical Clinic, Department of Medicine, Ippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - A Gkiomisi
- Department of Obstetrics and Gynaecology, 424 General Military Hospital, Thessaloniki, Greece
| | - Z G Saridakis
- Hellenic Military School of Medicine, Thessaloniki, Greece
| | - D Digkas
- Hellenic Military School of Medicine, Thessaloniki, Greece
| | - I Bisbinas
- 1st Department of Orthopaedics, 424 General Military Hospital, Thessaloniki, Greece
| | - G T Sakellariou
- Department of Rheumatology, 424 General Military Hospital, Thessaloniki, Greece
| | - A Papatheodorou
- Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
| | - P Kokkoris
- Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
| | - P Makras
- Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
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Mosali P, Bernard L, Wajed J, Mohamed Z, Ewang M, Moore A, Fogelman I, Hampson G. Vitamin D status and parathyroid hormone concentrations influence the skeletal response to zoledronate and denosumab. Calcif Tissue Int 2014; 94:553-9. [PMID: 24509506 DOI: 10.1007/s00223-014-9840-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 11/24/2013] [Indexed: 12/01/2022]
Abstract
Studies suggest that optimal vitamin D status is required for the maximal effect of antiresorptive agents. We investigated the relationship between vitamin D status, serum parathyroid hormone (PTH) concentrations, and change in bone mineral density (BMD) following iv zoledronate and denosumab. We carried out a retrospective analysis of 111 patients, mean age 70 (SD 13) years, 89 women and 22 men, prescribed zoledronate and 43 postmenopausal women treated with denosumab for osteoporosis. We measured BMD at the lumbar spine (LS) and total hip (TH), serum 25 (OH) vitamin D, PTH, and bone turnover markers (plasma CTX, P1NP) at 1 year. In patients on zoledronate, BMD increased at the LS and TH (mean LS change [SEM] = 2.6 % [0.5 %], mean TH change = 1.05 % [0.5 %], p < 0.05). A significant increase in BMD was seen at the LS only in the denosumab group (p = 0.001). Significant decreases in CTX and P1NP were observed at 12 months in both treatment groups. At baseline and at 12 months, 34 % and 23 % of the patients on zoledronate had a serum vitamin D of <50 nmol/L, respectively. The mean PTH concentration in patients with 25 (OH) vitamin D <50 nmol/L was 44 ng/L (SEM 16.6). Patients with PTH concentration <44 ng/L had significantly higher increases in TH BMD compared to those with PTH >44 ng/L (zoledronate 1.9 [0.83] vs. -0.43 [0.81], p = 0.04; denosumab 4.1 [0.054] vs. -1.7 [0.04], p = 0.004). Optimal vitamin D status and PTH concentrations improve the skeletal response to zoledronate and denosumab.
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Affiliation(s)
- P Mosali
- Department of Clinical Chemistry, St Thomas' Hospital, 5th Floor, North Wing, Lambeth Palace Road, London, SE1 7EH, UK
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Anastasilakis AD, Polyzos SA, Makras P, Gkiomisi A, Bisbinas I, Katsarou A, Filippaios A, Mantzoros CS. Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months. Osteoporos Int 2014; 25:1633-42. [PMID: 24599275 DOI: 10.1007/s00198-014-2673-x] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 02/19/2014] [Indexed: 10/25/2022]
Abstract
UNLABELLED In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months. INTRODUCTION This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass and to assess a potential effect of denosumab or teriparatide treatment for 3 months. METHODS Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤-2.0) and their age-matched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n = 50; Dmab control group, n = 25) and (b) women with more severe disease (LS or FN BMD T-score ≤-2.8) and their age-matched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n = 25; TPTD control group, n = 25). RESULTS At baseline, irisin levels were inversely correlated with age (partial coefficient (r p ) = -0.24; p = 0.009), parathyroid hormone (PTH) (r p = -0.30; p = 0.001), and creatinine (r p = -0.23; p = 0.016) in univariate analysis, and were lower in women with (n = 26; 41.6 ± 2.7 ng/dL) than without previous osteoporotic fracture(s) (n = 99; 51.0 ± 1.6 ng/dL; p = 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p = 0.04, CI -16.1 to -0.4 and p = 0.002, CI -0.3 to -0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months. CONCLUSIONS Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified.
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Affiliation(s)
- A D Anastasilakis
- Department of Endocrinology, 424 General Military Hospital, Ring Road, 564 29 N. Efkarpia, Thessaloniki, Greece,
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