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Fitzpatrick D, Laird E, Ward M, Hoey L, Hughes CF, Strain JJ, Cunningham C, Healy M, Molloy AM, McNulty H, Lannon R, McCarroll K. Secondary hyperparathyroidism: Predictors and relationship with vitamin D status, bone turnover markers and bone mineral density. Bone 2024; 184:117108. [PMID: 38642819 DOI: 10.1016/j.bone.2024.117108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 04/15/2024] [Accepted: 04/17/2024] [Indexed: 04/22/2024]
Abstract
INTRODUCTION Secondary hyperparathyroidism (SHPT) has adverse implications for bone health but is relatively understudied. In this study we examine the prevalence and determinants of SHPT and describe the relationship of SHPT with bone turnover markers and bone mineral density (BMD) in older Irish adults. METHOD Eligible participants (n = 4139) were identified from the Trinity-Ulster-Department of Agriculture (TUDA) study, a cohort of Irish adults aged ≥60 years. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 ml/min and serum calcium >2.5 mmol/l to remove hyperparathyroidism due to advanced chronic kidney disease (CKD) and primary hyperparathyroidism respectively. The relationship between SHPT and bone turnover markers and BMD (measured by densitometry) was examined in a subsample (n = 1488). Vitamin D deficiency was defined as 25-hydroxyvitamin D [25 (OH)D] <30 nmol/l. RESULTS Participants had a mean age of 73.6 ± 7.9 years, 65.1 % were female and 19.4 % were found to be vitamin D deficient. The prevalence of SHPT decreased as vitamin D increased, from 30.6 % in those deficient to 9.8 % in those with 25(OH)D ≥ 50 nmol/l and increased with declining kidney function. In non‑calcium supplement users, principal determinants of SHPT were vitamin D deficiency (OR 4.18, CI 3.05-5.73, p < 0.001), eGFR 30-44 ml/min (OR 3.69, CI 2.44-5.57, p < 0.001), loop diuretic use (OR 3.52, CI 2.59-4.79, p < 0.001) and to a lesser extent body mass index (p = 0.001), eGFR 45-59 ml/min (p < 0.001) and 25(OH)D level 30-49 nmol/l (p = 0.002). Similar findings were observed in calcium supplement users, though proton pump inhibitors were also associated with SHPT (OR 1.55, CI 1.08-2.22, p = 0.018) while vitamin D 30-49 nmol/l was not. In participants with SHPT versus those without, bone turnover markers were higher: bone alkaline phosphatase (p = 0.017) and tartrate-resistant acid phosphatase (p = 0.033), whilst there was lower BMD at the neck of femur (0.880 vs. 0.903 g/cm2, p = 0.033) and total hip (0.968 vs. 0.995 g/cm2, P = 0.017). DISCUSSION The results show that up to one in six older Irish adults had SHPT and this was associated with lower BMD and higher concentrations of bone turnover markers. Both vitamin D deficiency and 25(OH)D level 30-49 nmol/l were important predictors of SHPT. Loop diuretics and PPIs may also increase the risk of SHPT, and their use may need to be carefully considered in this population. Further studies examining the potential impact of these factors on bone health in similar populations to our study sample are warranted.
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Affiliation(s)
- Donal Fitzpatrick
- Mercer's Institute for Research on Ageing, St James's Hospital, Dublin, Ireland; School of Medicine, Trinity College, Dublin, Ireland.
| | - Eamon Laird
- Department of Health & Nutritional Sciences, Atlantic Technological University Sligo, Ireland
| | - Mary Ward
- Nutrition Innovation Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland, United Kingdom of Great Britain and Northern Ireland
| | - Leane Hoey
- Nutrition Innovation Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland, United Kingdom of Great Britain and Northern Ireland
| | - Catherine F Hughes
- Nutrition Innovation Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland, United Kingdom of Great Britain and Northern Ireland
| | - J J Strain
- Nutrition Innovation Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland, United Kingdom of Great Britain and Northern Ireland
| | - Conal Cunningham
- Mercer's Institute for Research on Ageing, St James's Hospital, Dublin, Ireland
| | - Martin Healy
- Department of Biochemistry, St James's Hospital, Dublin, Ireland
| | - Anne M Molloy
- School of Medicine, Trinity College, Dublin, Ireland
| | - Helene McNulty
- Nutrition Innovation Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland, United Kingdom of Great Britain and Northern Ireland
| | - Rosaleen Lannon
- Mercer's Institute for Research on Ageing, St James's Hospital, Dublin, Ireland; School of Medicine, Trinity College, Dublin, Ireland
| | - Kevin McCarroll
- Mercer's Institute for Research on Ageing, St James's Hospital, Dublin, Ireland; School of Medicine, Trinity College, Dublin, Ireland
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Smaoui H, Chtourou L, Jallouli D, Jemaa SB, Karaa I, Boudabbous M, Moalla M, Gdoura H, Mnif L, Amouri A, Akrout R, Ayadi F, Baklouti S, Tahri N. Effect of long-term proton pump inhibitors on phosphocalcium metabolism and bone mineral density. Future Sci OA 2024; 10:FSO977. [PMID: 38841182 PMCID: PMC11152587 DOI: 10.2144/fsoa-2023-0198] [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: 09/15/2023] [Accepted: 02/14/2024] [Indexed: 06/07/2024] Open
Abstract
Aim: Although Proton pump inhibitors (PPIs) are well-tolerated, their long-term use may be associated with decreased bone mass. Methods: This is a case-control study including patients treated with PPIs (>1 year) and control subjects who have not received PPIs treatment. Results: A total of 90 patients and 90 matched controls were included. PPIs use was associated with hypocalcemia and hypomagnesemia. Vitamin D3 deficiency and hyperparathyroidism were associated with PPIs use. Long-term PPIs use was significantly associated with decreased bone density. Risk factors of decreased bone mineral density (BMD) included age >50 years, menopause, lack of sun exposure, double PPIs dose, daily intake, post-meal intake and association with a mucoprotective agent. Conclusion: Our results highlight the risk of decreased BMD in patients on long-term PPIs treatment.
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Affiliation(s)
- Hend Smaoui
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Lassaad Chtourou
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Dana Jallouli
- Laboratory of Biochemistry, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Samar Ben Jemaa
- Department of Rhumatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Iheb Karaa
- Laboratory of Biochemistry, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Mouna Boudabbous
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Manel Moalla
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Hela Gdoura
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Leila Mnif
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Ali Amouri
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Rim Akrout
- Department of Rhumatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Fatma Ayadi
- Laboratory of Biochemistry, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Sofien Baklouti
- Department of Rhumatology, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Nabil Tahri
- Department of Gastroenterology & Hepatology, Hedi Chaker University Hospital, Sfax, Tunisia
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Changes in bone turnover markers in adolescents with gastroesophageal reflux disease treated with lansoprazole. Acta Gastroenterol Belg 2022; 85:565-571. [PMID: 36566365 DOI: 10.51821/85.4.10906] [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] [Indexed: 12/26/2022]
Abstract
Background Proton pump inhibitors (PPIs) have been suggested to lead to bone resorption, while the effects of PPIs on the bone mineral metabolism in children has received only limited attention in literature to date. The present study investigates whether lansoprazole alters bone turnover markers in adolescents with gastroesophageal reflux disease (GERD). Patients and methods Included in the study were adolescents aged 16-18 with GERD and a healthy volunteers group. The GERD patient group was treated with lansoprazole 30 mg once daily for eight weeks. The serum calcium, phosphorus, magnesium, alkaline phosphatase (ALP), parathormone (PTH), 25 (OH) vitamin D, osteocalcin and urinary calcium, creatinine, deoxypyridinoline (DPD), collagen type-1 crosslinked C-telopeptide (CTX) and collagen type-1 crosslinked N-telopeptide (NTX) of both groups were studied before and after the end of the treatment. Results A comparison of the 30 patients with GERD and the 30 volunteers revealed no significant difference in the serum calcium, phosphorus, magnesium, ALP, urinary calcium/creatinine ratio, 25 (OH) vitamin D and PTH levels measured before and after the lansoprazole treatment, while the osteocalcin, DPD, CTX and NTX values were found to be higher after treatment when compared to those at pre- treatment. Conclusions The results of this study reveal that eight weeks of treatment with 30 mg lansoprazole daily increased the bone turnover markers of CTX, NTX, DPD and osteocalcin in adolescents aged 16-18.
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Gul M, Dundar S, Bozoglan A, Ozcan EC, Tekin S, Yildirim TT, Karasu N, Bingul MB. Evaluation of the effects of the systemic proton pump inhibitor-omeprazole on periimplant bone regeneration and osseointegration: An experimental study. J Oral Biol Craniofac Res 2022; 12:381-384. [PMID: 35592026 PMCID: PMC9111997 DOI: 10.1016/j.jobcr.2022.04.006] [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: 12/26/2020] [Accepted: 04/17/2022] [Indexed: 12/12/2022] Open
Abstract
Objective Investigations of the effects of proton pump inhibitors (PPIs) on bone healing have revealed that they affect bone regeneration negatively. The exact mechanism by which this adverse effect on bone tissue is not known. The aim of this study is to biomechanic and biochemical investigation of the effects of the PPIs on guided periimplant bone regeneration. Material & methods Spraque dawley rats were divided controls (n = 8): there is no treatment during 8 week experimental period, PPI- Dosage 1 (n = 8) and Dosage 2 (n = 8): 5 mg/kg and 10 mg/kg omeprazol applied 3 times in a week with oral gavage during 8 weeks respectfully. Bone defects created half of the implant length circumferencial after implant insertion and defects filled with bone grafts. After experimental period the rats sacrified and implants with surrounding bone tissues were removed to reverse torque analysis (Newton), blood samples collected to biochemical analysis (glucose, AST, ALT, ALP, urea, creatinin, calcium, P). Results Biomechanic reverse torque values did not revealed any statistical differences between the groups (P > 0,05). Conclusion According the biomechanical and biochemical parameters PPIs does not effect the periimplant guided bone regeneration.
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Affiliation(s)
- Mehmet Gul
- Sanliurfa Harran University, Department of Periodontology, Faculty of Dentistry, Sanliurfa, Turkiye
| | - Serkan Dundar
- Firat University, Department of Periodontology, Faculty of Dentistry, Elazig, Turkiye
| | - Alihan Bozoglan
- Firat University, Department of Periodontology, Faculty of Dentistry, Elazig, Turkiye
| | - Erhan Cahit Ozcan
- Firat University, Department of Esthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, Elazig, Turkiye
| | - Samet Tekin
- Firat University, Department of Protetic Dentistry, Faculty of Dentistry, Elazig, Turkiye
| | - Tuba Talo Yildirim
- Firat University, Department of Periodontology, Faculty of Dentistry, Elazig, Turkiye
| | - Necmettin Karasu
- Afyonkarahisar Health Sciences University, Department of Esthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, Afyonkarahisar, Turkiye
| | - Muhammet Bahattin Bingul
- Sanliurfa Harran University, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Sanliurfa, Turkiye
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How Do Drugs Affect the Skeleton? Implications for Forensic Anthropology. BIOLOGY 2022; 11:biology11040524. [PMID: 35453723 PMCID: PMC9030599 DOI: 10.3390/biology11040524] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/21/2022] [Accepted: 03/18/2022] [Indexed: 01/10/2023]
Abstract
Simple Summary Forensic anthropologists analyze human remains to assist in the identification of the deceased, predominantly by assessing age-at-death, sex, stature, ancestry and any unique identifying features. Whilst methods have been established to create this biological profile of the skeleton, these may be influenced by a number of factors. This paper, for the first time, provides an overview from a reading of the clinical and pharmacological literature to explore whether the intake of drugs can affect the skeleton and whether these may have implications for forensic anthropology casework. In effect, drugs such as tobacco, heroin, and prescription medications can alter bone mineral density, can increase the risk of fractures, destroy bone and changes to the dentition. By considering how drugs can affect the skeleton, forensic anthropologists can be aware of this when attempting to identify the deceased. Abstract Forensic anthropologists rely on a number of parameters when analyzing human skeletal remains to assist in the identification of the deceased, predominantly age-at-death, sex, stature, ancestry or population affinity, and any unique identifying features. During the examination of human remains, it is important to be aware that the skeletal features considered when applying anthropological methods may be influenced and modified by a number of factors, and particular to this article, prescription drugs (including medical and non-medical use) and other commonly used drugs. In view of this, this paper aims to review the medical, clinical and pharmacological literature to enable an assessment of those drug groups that as side effects have the potential to have an adverse effect on the skeleton, and explore whether or not they can influence the estimation of age-at-death, sex and other indicators of the biological profile. Moreover, it may be that the observation of certain alterations or inconsistencies in the skeleton may relate to the use of drugs or medication, and this in turn may help narrow down the list of missing persons to which a set of human remains could belong. The information gathered from the clinical and medical literature has been extracted with a forensic anthropological perspective and provides an awareness on how several drugs, such as opioids, cocaine, corticosteroids, non-steroidal anti-inflammatory drugs, alcohol, tobacco and others have notable effects on bone. Through different mechanisms, drugs can alter bone mineral density, causing osteopenia, osteoporosis, increase the risk of fractures, osteonecrosis, and oral changes. Not much has been written on the influence of drugs on the skeleton from the forensic anthropological practitioner perspective; and this review, in spite of its limitations and the requirement of further research, aims to investigate the current knowledge of the possible effects of both prescription and recreational drugs on bones, contributing to providing a better awareness in forensic anthropological practice and assisting in the identification process of the deceased.
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Abtahi S, Driessen JHM, Burden AM, Souverein PC, van den Bergh JP, van Staa TP, Boonen A, de Vries F. Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis 2021; 80:423-431. [PMID: 33310727 DOI: 10.1136/annrheumdis-2020-218758] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/12/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs and PPIs and the risk of osteoporotic fractures among patients with RA. METHODS This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral GCs and PPIs was stratified by the most recent prescription as current use (<6 months), recent use (7-12 months) and past use (>1 year); average daily and cumulative dose; and duration of use. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, statistically adjusted for lifestyle parameters, comorbidities and comedications. RESULTS Among 12 351 patients with RA (mean age of 68 years, 69% women), 1411 osteoporotic fractures occurred. Concomitant current use of oral GCs and PPIs was associated with a 1.6-fold increased risk of osteoporotic fractures compared with non-use (adjusted HR: 1.60, 95% CI: 1.35 to 1.89). This was statistically different from a 1.2-fold increased osteoporotic fracture risk associated with oral GC or PPI use alone. Most individual fracture sites were significantly associated with concomitant use of oral GCs and PPIs. Among concomitant users, fracture risk did not increase with higher daily dose or duration of PPI use. CONCLUSIONS There was an interaction in the risk of osteoporotic fractures with concomitant use of oral GCs and PPIs. Fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs.
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Affiliation(s)
- Shahab Abtahi
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Johanna H M Driessen
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
- NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Andrea M Burden
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH-Zurich, Zurich, Switzerland
| | - Patrick C Souverein
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Joop P van den Bergh
- Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre, Maastricht, The Netherlands
- Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
- Department of Internal Medicine, VieCuri Medical Centre, Venlo, The Netherlands
| | - Tjeerd P van Staa
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
- Centre for Health Informatics, Division of Informatics, Imaging and Data Science, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Annelies Boonen
- Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre, Maastricht, The Netherlands
- Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
| | - Frank de Vries
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
- MRC Epidemiology Lifecourse Unit, Southampton General Hospital, Southampton, UK
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Proton Pump Inhibitors, But Not H2-receptor Antagonists, Are Associated With Incident Fractures Among Kidney Transplant Recipients. Transplantation 2021; 104:2609-2615. [PMID: 32058466 DOI: 10.1097/tp.0000000000003178] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Fractures are a common and burdensome problem among kidney transplant recipients (KTRs). Proton pump inhibitors (PPIs) are frequently used after kidney transplantation and have been associated with increased fracture risk in the general population. This study aimed to determine whether PPI use is associated with incidence of major fractures in KTRs. METHODS Using the Wisconsin Allograft Recipient Database, we identified 155 KTRs with a major fracture that occurred at least 12 months after transplantation. Controls were selected using incidence-density sampling. Use of PPIs and histamine 2-receptor antagonists (H2RA) during the year before the index date were identified. RESULTS A total of 155 cases were matched to 685 controls. Within 1 year before the index date, 68% of cases and 52% of controls used a PPI, and 16% of cases and 11% of controls used an H2RA. PPI use was associated with higher incidence of major fractures in unadjusted analysis (odds ratio [OR], 2.4; 95% CI, 1.6-3.5) and in adjusted analyses controlling for demographic and transplant-related covariates and use of corticosteroids, bisphosphonates, vitamin D and calcium supplements (OR, 1.9; 95% CI, 1.2-3.1). H2RA use was not associated with incidence of major fractures in adjusted analyses (OR, 1.0; 95% CI, 0.5-1.8). The associations between PPI use and fractures remained similar in analyses limited to spine and hip fractures. CONCLUSIONS Use of PPIs, but not H2RAs, is associated with a higher risk of major fractures among KTRs. Clinicians should individualize PPI use in KTRs, evaluating the risks and benefits of prescribing and continuing PPIs in KTRs.
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Byberg L, Warensjö Lemming E. Milk Consumption for the Prevention of Fragility Fractures. Nutrients 2020; 12:E2720. [PMID: 32899514 PMCID: PMC7551481 DOI: 10.3390/nu12092720] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 12/17/2022] Open
Abstract
Results indicating that a high milk intake is associated with both higher and lower risks of fragility fractures, or that indicate no association, can all be presented in the same meta-analysis, depending on how it is performed. In this narrative review, we discuss the available studies examining milk intake in relation to fragility fractures, highlight potential problems with meta-analyses of such studies, and discuss potential mechanisms and biases underlying the different results. We conclude that studies examining milk and dairy intakes in relation to fragility fracture risk need to study the different milk products separately. Meta-analyses should consider the doses in the individual studies. Additional studies in populations with a large range of intake of fermented milk are warranted.
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Affiliation(s)
- Liisa Byberg
- Department of Surgical Sciences, Orthopaedics, Uppsala University, SE-751 85 Uppsala, Sweden;
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Min YW, Lee YC, Kim K, Ryu S, Hong KS, Jeon HH, Kim YS, Park JH, Son HJ, Rhee PL. Proton pump inhibitor use is associated with hip fracture development: a nationwide population-based cohort study. Korean J Intern Med 2020; 35:1084-1093. [PMID: 31671930 PMCID: PMC7487306 DOI: 10.3904/kjim.2018.331] [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: 09/10/2018] [Accepted: 11/13/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS Effect of proton pump inhibitor (PPI) use on the risk of hip fracture is controversial. This study aimed to clarify the association between PPI use and hip fracture risk using a large cohort. METHODS This study recruited participants from the nationwide cohort (n = 1,025,340). After exclusion of participants who had hip fractures or were aged less than 40 years during the baseline period (2002 to 2004), 371,806 participants were followed to 2013. Participants prescribed PPIs for more than 90 days during baseline period were defined as users. Fracture cases were defined when participants were hospitalized with claims of a hip fracture. RESULTS During 4,159,343 person-years of follow-up, fractures developed more often in PPI users than in nonusers (relative risk [RR], 1.787; 95% confidence interval [CI], 1.260 to 2.534; p = 0.002). The results persisted after adjusting for age, sex, and many drugs relevant to osteoporosis or influential in bone health. Furthermore, fracture risk associated with PPI use increased with duration of use (p trend < 0.001). The fully adjusted RRs of hip fracture development were 1.350 (95% CI, 1.203 to 1.515) for 1- to 90-day users, 1.487 (95% CI, 0.957 to 2.311) for 91- to 180-day users, and 1.771 (95% CI, 0.931 to 3.368) for > 180-day users. The positive association between PPI use and fracture was also confirmed in a subgroup with health screening data where further adjustment for body mass index, smoking status, alcohol consumption, and physical activity was available (adjusted RR, 2.025; 95% CI, 1.151 to 3.564, p = 0.014). CONCLUSION PPI use is associated with hip fracture development.
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Affiliation(s)
- Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yeong Chan Lee
- Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea
| | - Kyunga Kim
- Department of Digital Health, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea
- Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Seungho Ryu
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea
- Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung Sub Hong
- Department of Gastroenterology, Mediplex Sejong Hospital, Incheon, Korea
| | - Han Ho Jeon
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Ilsan, Korea
| | - Yong Sung Kim
- Department of Gastroenterology, Wonkwang Digestive Disease Research Institute, Wonkwang University Sanbon Hospital, Gunpo, Korea
| | - Jong Heon Park
- Big Data Steering Department, National Health Insurance Service, Wonju, Korea
| | - Hee Jung Son
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Hee Jung Son, M.D. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3409, Fax: +82-2-3410-6983, E-mail:
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Correspondence to Poong-Lyul Rhee, M.D. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3409, Fax: +82-2-3410-6983, E-mail:
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The Clinical Characteristics of Fractures in Pediatric Patients Exposed to Proton Pump Inhibitors. J Pediatr Gastroenterol Nutr 2020; 70:815-819. [PMID: 32443038 DOI: 10.1097/mpg.0000000000002690] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES There are increasing concerns regarding proton pump inhibitor (PPI) use and the risk of fractures in adults. Few studies have evaluated this risk among pediatric patients. This study examined fractures and fracture location among pediatric patients exposed to PPI compared with those without documented exposure. STUDY DESIGN Encounters for patients 6 months to 15.5 years were identified between July 1, 2011 to December 31, 2015 in the Pediatric Hospital Information System database. Exclusion criteria was applied for chronic illnesses, conditions or medications predisposing to fracture. Encounters were classified as PPI encounters if a charge for PPI was documented. PPI encounters were propensity matched to non-PPI encounters. Following initial encounter, patients were evaluated over a 2-year period for hospitalizations resulting from fracture. RESULTS There was a statistically significant higher rate of fractures among the PPI-exposed group (1.4% vs 1.2%, P = 0.019). Adjusting for remaining differences in sex, race, encounter type, payer, and resource intensity after matching, the difference remained statistically significant (P = 0.017) with an adjusted odds ratio (95% CI) of 1.2 (1.0--1.4). Upper extremity was the most common location for fracture; however, the PPI cohort was more likely to suffer from lower extremity, rib, and spinal fractures (P = 0.01). CONCLUSIONS This study suggests an increased risk of fracture among pediatric patients taking PPI. Among patients hospitalized with a fracture, those with PPI exposure had a higher rate of lower extremity, rib, and spine fractures compared with controls. This appeared to be a class effect not related to individual PPI agent.
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Hoff M, Skovlund E, Skurtveit S, Meyer HE, Langhammer A, Søgaard AJ, Syversen U, Forsmo S, Abrahamsen B, Schei B. Proton pump inhibitors and fracture risk. The HUNT study, Norway. Osteoporos Int 2020; 31:109-118. [PMID: 31741023 DOI: 10.1007/s00198-019-05206-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 10/22/2019] [Indexed: 12/16/2022]
Abstract
UNLABELLED Proton pump inhibitors (PPIs) have been linked to increased risk of fracture; the data have, however, been diverging. We did not find any increased risk of fractures among users of PPIs in a Norwegian population of 15,017 women and 13,241 men aged 50-85 years with detailed information about lifestyle and comorbidity. INTRODUCTION Proton pump inhibitors (PPIs) are widely prescribed and have been linked to increased risk of fracture. METHODS We used data from the Nord-Trøndelag Health Study (HUNT3), The Fracture registry in Nord-Trøndelag, and the Norwegian Prescription Database, including 15,017 women and 13,241 men aged 50-85 years. The study population was followed from the date of participating in HUNT3 (2006-2008) until the date of first fracture (forearm or hip), death, or end of study (31 December 2012). The Cox proportional hazards model with time-dependent exposure to PPIs was applied, and each individual was considered as unexposed until the first prescriptions was filled. To be included, the prescription of PPIs should minimum be equivalent to 90 defined daily doses (DDD) in the period. Individuals were defined as exposed until 6 months after end of drug supply. RESULTS The proportion of women and men using PPIs was 17.9% and 15.5%, respectively. During a median of 5.2 years follow-up, 266 women and 134 men had a first hip fracture and 662 women and 127 men, a first forearm fracture. The combined rate/1000 patient-years for forearm and hip fractures in women was 49.2 for users of PPIs compared with 64.1 among non-users; for men 18.6 and 19.8, respectively. The hazard ratios with 95% confidence interval for the first forearm or hip fracture among users of PPIs in the age-adjusted analysis were 0.82 (0.67-1.01) for women and 1.05 (0.72-1.52) for men. Adjusting for age, use of anti-osteoporotic drugs, and FRAX, the HR declined to 0.80 (0.65-0.98) in women and 1.00 (0.69-1.45) in men. CONCLUSIONS Use of PPIs was not associated with an increased risk of fractures.
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Affiliation(s)
- M Hoff
- Department of Public Health and Nursing, Norwegian University of Science and Technology, PB 8905, 7491, Trondheim, Norway.
- Department of Rheumatology, St Olavs Hospital, Trondheim, Norway.
| | - E Skovlund
- Department of Public Health and Nursing, Norwegian University of Science and Technology, PB 8905, 7491, Trondheim, Norway
- Norwegian Institute of Public Health, Oslo, Norway
| | - S Skurtveit
- Norwegian Institute of Public Health, Oslo, Norway
- Norwegian Centre for Addiction Research, University of Oslo, Oslo, Norway
| | - H E Meyer
- Norwegian Institute of Public Health, Oslo, Norway
- Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
| | - A Langhammer
- Department of Public Health and Nursing, Norwegian University of Science and Technology, PB 8905, 7491, Trondheim, Norway
| | - A J Søgaard
- Norwegian Institute of Public Health, Oslo, Norway
| | - U Syversen
- Department of Endocrinology, St. Olavs Hospital, Trondheim, Norway
- Department of Clinical and and Molecular Medicine, NTNU, Trondheim, Norway
| | - S Forsmo
- Department of Public Health and Nursing, Norwegian University of Science and Technology, PB 8905, 7491, Trondheim, Norway
| | - B Abrahamsen
- Department of Medicine, Holbæk Hospital, Holbæk, Denmark
- Odense Patient Data Explorative Network, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - B Schei
- Department of Public Health and Nursing, Norwegian University of Science and Technology, PB 8905, 7491, Trondheim, Norway
- Department of Gynecology, St Olavs Hospital, Trondheim, Norway
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Saad FA. Novel insights into the complex architecture of osteoporosis molecular genetics. Ann N Y Acad Sci 2019; 1462:37-52. [PMID: 31556133 DOI: 10.1111/nyas.14231] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/22/2019] [Accepted: 08/14/2019] [Indexed: 12/19/2022]
Abstract
Osteoporosis is a prevalent osteodegenerative disease and silent killer linked to a decrease in bone mass and decline of bone microarchitecture, due to impaired bone matrix mineralization, raising the risk of fracture. Nevertheless, the process of bone matrix mineralization is still an unsolved mystery. Osteoporosis is a polygenic disorder associated with genetic and environmental risk factors; however, the majority of genes associated with osteoporosis remain largely unknown. Several signaling pathways regulate bone mass; therefore, dysregulation of a single signaling pathway leads to metabolic bone disease owing to high or low bone mass. Parathyroid hormone, core-binding factor α-1 (Cbfa1), Wnt/β-catenin, the receptor activator of the nuclear factor kappa-B (NF-κB) ligand (RANKL), myostatin, and osteogenic exercise signaling pathways play pivotal roles in the regulation of bone mass. The myostatin signaling pathway increases bone resorption by activating the RANKL signaling pathway, whereas osteogenic exercise inhibits myostatin and sclerostin while inducing irisin that consequentially activates the Cbfa1 and Wnt/β-catenin bone formation pathways. The aims of this review are to summarize what is known about osteoporosis-related signaling pathways; define the role of these pathways in osteoporosis drug discovery; focus light on the link between bone, muscle, pancreas, and adipose integrative physiology and osteoporosis; and underline the emerging role of osteogenic exercise in the prevention of, and care for, osteoporosis, obesity, and diabetes.
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Affiliation(s)
- Fawzy Ali Saad
- Department of Orthopaedic Surgery, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts
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Miranda-Bautista J, Verdejo C, Díaz-Redondo A, Bretón I, Bellón JM, Pérez-Valderas MD, Caballero-Marcos A, de Dios-Lascuevas M, González-Río E, García-Sánchez C, Marín-Jiménez I, Bañares R, Menchén L. Metabolic bone disease in patients diagnosed with inflammatory bowel disease from Spain. Therap Adv Gastroenterol 2019; 12:1756284819862152. [PMID: 31391867 PMCID: PMC6669853 DOI: 10.1177/1756284819862152] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 06/13/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The objective of this study was to analyse the prevalence of metabolic bone disease (MBD) in a cohort of Southern European patients with inflammatory bowel disease (IBD) and to identify associated risk factors in this population. METHODS We conducted a retrospective, both cross-sectional and longitudinal study of MBD, assessed by dual energy X-ray absorptiometry (DXA), among patients diagnosed with IBD and previously recognized risk factors for this complication from two referral Spanish institutions. RESULTS A total of 612 patients (58.6% diagnosed with Crohn's disease) were included. Mean (SD) age was 44.9 (14.7) years; 71.7% of patients received at least one tapered dosage of corticosteroids before first DXA. MBD and osteoporosis were diagnosed in 66.4% and 21.4% of patients, respectively. At baseline, male gender, menopause and ulcerative colitis were found as independent risks factors for osteoporosis, whereas age, more than three IBD-related hospitalizations and previous steroid treatment were found as independent risks factors for MBD. A total of 261 patients had at least a second DXA and were included in the longitudinal study; median follow up was 56.4 months. Logistic regression model identified menopause, ulcerative colitis and baseline lumbar DXA T-score value, but not steroid treatment, as risk factors for worsening ⩾1 SD in follow-up DXA T-score. According to guidelines, all patients under treatment with corticosteroids received calcium and vitamin D supplements. CONCLUSION MBD is a frequent complication in south-European IBD patients. Routine evaluation of bone density when risk factors are present, as well as calcium plus D vitamin prophylaxis in patients under corticosteroid treatment should be recommended.
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Affiliation(s)
- José Miranda-Bautista
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria, Madrid, Spain
| | | | - Alicia Díaz-Redondo
- Servicio de Medicina Preventiva, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Irene Bretón
- Sección de Nutrición Clínica, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - José M. Bellón
- Unidad de Estadística, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - María Dolores Pérez-Valderas
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria, Gregorio Marañón, Madrid, Spain
| | - Aránzazu Caballero-Marcos
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria, Gregorio Marañón, Madrid, Spain
| | - Marta de Dios-Lascuevas
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria, Gregorio Marañón, Madrid, Spain
| | - Elena González-Río
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria, Gregorio Marañón, Madrid, Spain
| | - Cristina García-Sánchez
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria, Gregorio Marañón, Madrid, Spain
| | - Ignacio Marín-Jiménez
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria, Gregorio Marañón, Madrid, Spain
| | - Rafael Bañares
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón - Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain,Departamento de Medicina, Universidad Complutense de Madrid, Spain
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Altay MA, Sindel A, Özalp Ö, Yıldırımyan N, Kocabalkan B. Proton pump inhibitor intake negatively affects the osseointegration of dental implants: a retrospective study. J Korean Assoc Oral Maxillofac Surg 2019; 45:135-140. [PMID: 31334101 PMCID: PMC6620305 DOI: 10.5125/jkaoms.2019.45.3.135] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/05/2018] [Accepted: 08/08/2018] [Indexed: 12/14/2022] Open
Abstract
Objectives This study sought to investigate the association between the systemic intake of proton pump inhibitors (PPI) and the early failure of dental implants. Materials and Methods A retrospective cohort study involving 1,918 dental implants in 592 patients (69 implants in 24 PPI users and 1,849 implants in 568 nonusers, respectively) was conducted. The effect of PPI intake on the osseointegration of dental implants was evaluated using patient- and implant-level models. Results Among 24 PPI users, two patients experienced implant failure, one of whom had three and the other of whom had one failed implant, respectively. Thus, the rate of failure for this population was 8.3%. Separately, 11 nonusers each experienced one implant failure, and the failure rate for these patients was 1.9%. Fisher's exact test revealed statistically significant differences between PPI users and nonusers at the implant level (P=0.002) but failed to show any significance at the patient level (P=0.094). The odds of implant failure were 4.60 times greater among PPI users versus nonusers. Dental implants that were placed in patients using PPIs were found to be 4.30 times more likely to fail prior to loading. Conclusion The findings of this study suggest that PPI intake may be associated with an increased risk of early dental implant failure.
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Affiliation(s)
- Mehmet Ali Altay
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Akdeniz University, Antalya, Turkey
| | - Alper Sindel
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Akdeniz University, Antalya, Turkey
| | - Öznur Özalp
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Akdeniz University, Antalya, Turkey
| | - Nelli Yıldırımyan
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Akdeniz University, Antalya, Turkey
| | - Burak Kocabalkan
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Akdeniz University, Antalya, Turkey
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Thong BKS, Ima-Nirwana S, Chin KY. Proton Pump Inhibitors and Fracture Risk: A Review of Current Evidence and Mechanisms Involved. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:E1571. [PMID: 31060319 PMCID: PMC6540255 DOI: 10.3390/ijerph16091571] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/25/2019] [Accepted: 04/30/2019] [Indexed: 12/11/2022]
Abstract
The number of patients with gastroesophageal problems taking proton pump inhibitors (PPIs) is increasing. Several studies suggested a possible association between PPIs and fracture risk, especially hip fractures, but the relationship remains contentious. This review aimed to investigate the longitudinal studies published in the last five years on the relationship between PPIs and fracture risk. The mechanism underlying this relationship was also explored. Overall, PPIs were positively associated with elevated fracture risk in multiple studies (n = 14), although some studies reported no significant relationship (n = 4). Increased gastrin production and hypochlorhydria are the two main mechanisms that affect bone remodeling, mineral absorption, and muscle strength, contributing to increased fracture risk among PPI users. As a conclusion, there is a potential relationship between PPIs and fracture risks. Therefore, patients on long-term PPI treatment should pay attention to bone health status and consider prophylaxis to decrease fracture risk.
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Affiliation(s)
- Benjamin Ka Seng Thong
- Department of Pharmacology, Universiti Kebangsaan Malaysia Medical Centre, Cheras 56000, Malaysia.
| | - Soelaiman Ima-Nirwana
- Department of Pharmacology, Universiti Kebangsaan Malaysia Medical Centre, Cheras 56000, Malaysia.
| | - Kok-Yong Chin
- Department of Pharmacology, Universiti Kebangsaan Malaysia Medical Centre, Cheras 56000, Malaysia.
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Hansen KE, Nieves JW, Nudurupati S, Metz DC, Perez MC. Dexlansoprazole and Esomeprazole Do Not Affect Bone Homeostasis in Healthy Postmenopausal Women. Gastroenterology 2019; 156:926-934.e6. [PMID: 30445008 DOI: 10.1053/j.gastro.2018.11.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Epidemiological studies have associated proton pump inhibitor (PPI) therapy with osteoporotic fractures, but it is not clear if PPIs directly cause osteoporosis. We evaluated the effect of dexlansoprazole and esomeprazole on bone turnover, bone mineral density (BMD), true fractional calcium absorption (TFCA), serum and urine levels of minerals, and levels of parathyroid hormone (PTH) in healthy postmenopausal women. METHODS We performed a prospective, multicenter, double-blind study of 115 healthy, postmenopausal women (45 to 75 years of age) from November 4, 2010, through August 7, 2014. Women were randomly assigned to groups given dexlansoprazole (60 mg), esomeprazole (40 mg), or placebo daily for 26 weeks. We measured plasma levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at 0 (baseline), 13, and 26 weeks. Primary outcomes were percent change in P1NP and CTX between weeks 0 and 26. We also measured changes in serum and urine levels of mineral, BMD, PTH (all subjects), and TFCA (n = 30). RESULTS Between baseline and week 26, there were no significant within-group differences in markers of bone turnover; there was a nonsignificant increase in CTX levels in the dexlansoprazole group (0.12 ng/mL). The esomeprazole and dexlansoprazole groups had significantly increased levels of P1NP (18.2% and 19.2%, respectively) and CTX (22.0% and 27.4%, respectively) at week 26 compared with the placebo group, although these values remained within normal ranges. There were no statistically significant differences between groups in serum or urine levels of minerals, BMD, or PTH at week 26. PPI therapy did not reduce TFCA. CONCLUSIONS In a prospective study of postmenopausal women, we found significant increases in markers of bone turnover in women given PPI therapy compared with women given placebo, but levels remained within the normal reference range. We found no significant differences among groups in changes in BMD, PTH, serum or urine levels of minerals, or TFCA. Our findings indicate that 26 weeks of treatment with a PPI has no clinically meaningful effects on bone homeostasis. Clinicaltrials.gov no: NCT01216293.
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Affiliation(s)
- Karen E Hansen
- School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
| | - Jeri W Nieves
- Mailman School of Public Health, Columbia University, New York, New York
| | - Sai Nudurupati
- Takeda Development Center Americas, Inc., Deerfield, Illinois
| | - David C Metz
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Poly TN, Islam MM, Yang HC, Wu CC, Li YCJ. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int 2019; 30:103-114. [PMID: 30539272 DOI: 10.1007/s00198-018-4788-y] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/17/2018] [Accepted: 11/19/2018] [Indexed: 02/07/2023]
Abstract
UNLABELLED We performed a meta-analysis of relevant studies to quantify the magnitude of the association between proton pump inhibitors (PPIs) and risk of hip fracture. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14-1.28, p < 0.0001). These results could be taken into consideration with caution, and patients should also be concerned about the inappropriate use of PPIs. INTRODUCTION Proton pump inhibitors (PPIs) are generally considered as first-line medicine with great safety profile, commonly prescribed for gastroesophageal reflux disease (GERD) and peptic ulcer disease. However, several epidemiological studies documented that long-term use of PPIs may be associated with an increased risk of hip fracture. Although, the optimal magnitude of the hip fracture risk is still undetermined. We, therefore, performed a meta-analysis of relevant studies to quantify the magnitude of the association between PPIs and risk of hip fracture. METHODS We collected relevant articles using MEDLINE, EMBASE, Google Scholar, and Web of Science from January 1, 1990, to March 31, 2018. We included only the large (n ≥ 500) observational studies with a follow-up duration of at least one year in which the hip fracture patients were identified by a standard procedure. Two of the authors extracted data from each included study independently according to a standardized protocol. RESULTS A total of 24 observational studies with 2,103,800 participants (319,568 hip fracture patients) met all the eligibility criteria. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14-1.28, p < 0.0001). An increased association was also observed in both low and medium doses of PPI taken and hip fracture risk (RR 1.17, 95% CI 1.05-1.29, p = 0.002; RR 1.28, 95% CI 1.14-1.44, p < 0.0001), but it appeared to be even greater among the patients with higher dose (RR 1.30, 95% CI 1.20-1.40, p < 0.0001). Moreover, the overall pooled risk ratios were 1.20 (95% CI 1.15-1.25, p < 0.0001) and 1.24 (95% CI 1.10-1.40, p < 0.0001) for the patients with short- and long-term PPI therapy, respectively, compared with PPI non-users. CONCLUSION Our results suggest that PPI use is significantly associated with an increased risk of hip fracture development, which is not observed in H2RA exposure. Physicians should, therefore, exercise caution when considering a long-term PPI treatment to their patients who already have an elevated risk of hip fracture. In addition, patients should be concerned about the inappropriate use of PPIs; if necessary, then, they should continue to receive it with a clear indication.
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Affiliation(s)
- T N Poly
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
- International Center for Health Information Technology (ICHIT), Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
| | - M M Islam
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
- International Center for Health Information Technology (ICHIT), Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
| | - H-C Yang
- International Center for Health Information Technology (ICHIT), Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
| | - C C Wu
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
- International Center for Health Information Technology (ICHIT), Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
| | - Y-C J Li
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan.
- International Center for Health Information Technology (ICHIT), Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan.
- Department of Dermatology, Wan Fang Hospital, Taipei, Taiwan.
- TMU Research Center of Cancer Translational Medicine, Taipei, Taiwan.
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Bardou M, Fortinsky KJ, Chapelle N, Luu M, Barkun A. An update on the latest chemical therapies for reflux esophagitis in children. Expert Opin Pharmacother 2018; 20:231-239. [DOI: 10.1080/14656566.2018.1549224] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Marc Bardou
- Centre d’Investigations Cliniques CIC1432, CHU de Dijon, Dijon Cedex, France
- Gastroenterology Department, CHU de Dijon, Dijon Cedex, France
| | - Kyle J. Fortinsky
- Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
| | | | - Maxime Luu
- Centre d’Investigations Cliniques CIC1432, CHU de Dijon, Dijon Cedex, France
| | - Alan Barkun
- Gastroenterology department, McGill University Health Centre, Montréal, Québec, Canada
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Osteoporosis in patients with intestinal insufficiency and intestinal failure: Prevalence and clinical risk factors. Clin Nutr 2018; 37:1654-1660. [DOI: 10.1016/j.clnu.2017.07.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 07/20/2017] [Accepted: 07/30/2017] [Indexed: 02/07/2023]
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Thompson W, Black C, Welch V, Farrell B, Bjerre LM, Tugwell P. Patient Values and Preferences Surrounding Proton Pump Inhibitor Use: A Scoping Review. THE PATIENT 2018; 11:17-28. [PMID: 28608038 DOI: 10.1007/s40271-017-0258-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) treat various upper gastrointestinal (GI) diseases. Around 50% of patients may remain on PPIs long-term without ongoing need. Eligible patients should be offered the choice of continuing their PPI or trying to reduce/stop their PPI (deprescribing), a choice dependent on values and preferences. OBJECTIVES Our objective was to systematically scope the available evidence on patient values and preferences surrounding continued PPI treatment and/or the decision to try a reduction in their PPI. We searched the MEDLINE, Embase, and Cochrane Library databases and the grey literature as of 9 August 2016 for studies of any design examining patient values and preferences toward PPI treatment and/or deprescribing. We included patients aged ≥18 years taking PPIs for upper GI diseases. RESULTS We located 12 eligible studies (seven surveys, four qualitative studies, one randomized controlled trial). One study only examined values and preferences towards reducing PPI use, five studies looked only at PPI treatment (initiation/continuation), four studies assessed both PPI treatment and reduction, and two studies evaluated PPI treatment and switching (to alternative PPIs). Patients value symptom control highly and worry about symptoms returning if the PPI is reduced. They are encouraged to consider reducing their PPI if a clinician provides advice and education. All five studies that examined reducing PPI use suggest patients should understand the rationale for considering continuation versus deprescribing of PPIs and should know what to expect from deprescribing. Patients are encouraged by knowing they can return to their previous dose if necessary. Our results were limited by the small sizes of studies and the heterogeneous populations. CONCLUSION Patients are willing to discuss the option of continuing PPI use or trying to reduce their PPI; however, a range of attitudes exist. The results suggest that reducing a PPI is a preference-sensitive decision. Therefore, patient attitudes should be elicited and incorporated into shared decision making surrounding the decision to continue or try deprescribing a PPI, and structured tools will be helpful to encourage this.
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Affiliation(s)
- Wade Thompson
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada.
- Bruyère Research Institute, 43 Bruyère Street, Ottawa, ON, K1N 5C8, Canada.
| | - Cody Black
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada
- Bruyère Research Institute, 43 Bruyère Street, Ottawa, ON, K1N 5C8, Canada
| | - Vivian Welch
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada
- Bruyère Research Institute, 43 Bruyère Street, Ottawa, ON, K1N 5C8, Canada
- Centre for Global Health, Ottawa, ON, Canada
| | - Barbara Farrell
- Bruyère Research Institute, 43 Bruyère Street, Ottawa, ON, K1N 5C8, Canada
- Department of Family Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Lise M Bjerre
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada
- Bruyère Research Institute, 43 Bruyère Street, Ottawa, ON, K1N 5C8, Canada
- Department of Family Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Peter Tugwell
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada
- Bruyère Research Institute, 43 Bruyère Street, Ottawa, ON, K1N 5C8, Canada
- Centre for Global Health, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Miyazaki Y, Ichimura A, Sato S, Fujii T, Oishi S, Sakai H, Takeshima H. The natural flavonoid myricetin inhibits gastric H + , K + -ATPase. Eur J Pharmacol 2018; 820:217-221. [DOI: 10.1016/j.ejphar.2017.12.042] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 12/16/2017] [Accepted: 12/19/2017] [Indexed: 01/26/2023]
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Abstract
Proton-pump inhibitors (PPIs) are the most effective therapy for the full spectrum of gastric-acid-related diseases. However, in the past decade, a steadily increasing list of complications following long-term use of PPIs has been reported. Their potent acid-suppressive action induces several structural and functional changes within the gastric mucosa, including fundic gland polyps, enterochromaffin-like cell hyperplasia and hypergastrinaemia, which can be exaggerated in the presence of Helicobacter pylori infection. As discussed in this Review, most associations of PPIs with severe adverse events are not based on sufficient evidence because of confounding factors and a lack of plausible mechanisms. Thus, a causal relationship remains unproven in most associations, and further studies are needed. Awareness of PPI-associated risks should not lead to anxiety in patients but rather should induce the physician to consider the appropriate dosing and duration of PPI therapy, including long-term monitoring strategies in selected groups of patients because of their individual comorbidities and risk factors.
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Trifan A, Stanciu C, Girleanu I, Stoica OC, Singeap AM, Maxim R, Chiriac SA, Ciobica A, Boiculese L. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. World J Gastroenterol 2017; 23:6500-6515. [PMID: 29085200 PMCID: PMC5643276 DOI: 10.3748/wjg.v23.i35.6500] [Citation(s) in RCA: 183] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 08/11/2017] [Accepted: 08/25/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI). METHODS We conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran's Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS). RESULTS Fifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002). CONCLUSION This meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.
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Affiliation(s)
- Anca Trifan
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Carol Stanciu
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, 700111 Iasi, Romania
| | - Irina Girleanu
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Oana Cristina Stoica
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Ana Maria Singeap
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Roxana Maxim
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Stefan Andrei Chiriac
- Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
| | - Alin Ciobica
- Department of Research, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, 700506 Iasi, Romania
| | - Lucian Boiculese
- Department of Preventive Medicine and Interdisciplinarity, “Grigore. T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
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Abstract
PURPOSE OF REVIEW The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY The use of PPIs is a risk factor for development of osteoporosis and osteoporotic fractures. However, as the direct pathogenesis remains unclear, specific points of intervention are lacking, other than being vigilant in regard to the indication for prescribing PPIs and to use the lowest effective dose where PPIs cannot be avoided.
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Le B, Waller JL, Radhakrishnan R, Oh SJ, Kheda MF, Nahman NS, Carbone L. Osteoporotic fractures in patients with systemic lupus erythematosus and end stage renal disease. Lupus 2017; 27:17-24. [PMID: 28530467 DOI: 10.1177/0961203317709953] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background The incidence of end stage renal disease (ESRD) in patients with systemic lupus erythematosus (SLE) is rising. However, the relationship between osteoporotic fractures and SLE in the setting of ESRD remains uninvestigated. The purpose of this study was to compare the frequency of incident osteoporotic fractures in patients with ESRD with and without SLE, to identify risk factors for fractures in patients with SLE and ESRD, and to examine the contribution of these fractures to mortality. Methods Retrospective cohort study of patients with SLE ( n = 716) and a 5% random sample of controls without SLE ( n = 4176) in the United States Renal Data System (USRDS) from years 2006-2008 enrolled in Medicare Part D. Results Fractures occurred in 10.6% ( n = 76) of patients with SLE and ESRD and 12.1% ( n = 507) of patients with ESRD without SLE ( p = 0.24). Older age (adjusted relative risk 1.02, 95% confidence interval 1.01-1.04) was associated with an increased risk for fracture in patients with SLE and ESRD. In multivariable analyses, vertebral and hip fractures more than doubled the risk for mortality. Conclusions The frequency of osteoporotic fractures in patients with SLE and ESRD is similar to the general population of patients with ESRD. Vertebral and hip fractures are significant contributors to mortality in patients with SLE and ESRD. Fracture prevention, in particular, for elderly patients with SLE and ESRD, should be considered. Summary SLE is not an independent risk factor for fractures in patients with ESRD. However, among patients with SLE and ESRD, vertebral and hip fractures are significant contributors to mortality.
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Affiliation(s)
- B Le
- 1 Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,2 Charlie Norwood VA Medical Center, Augusta, Georgia, USA
| | - J L Waller
- 3 Department of Biostatistics and Epidemiology, Augusta University, Augusta, Georgia, USA
| | - R Radhakrishnan
- 4 School of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - S J Oh
- 5 Division of Rheumatology, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - M F Kheda
- 6 Southwest Georgia Nephrology Clinic, PC, Albany, Georgia, USA
| | - N S Nahman
- 1 Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,2 Charlie Norwood VA Medical Center, Augusta, Georgia, USA.,7 Division of Nephrology, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - L Carbone
- 1 Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,2 Charlie Norwood VA Medical Center, Augusta, Georgia, USA.,5 Division of Rheumatology, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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Fukuba N, Ishihara S, Sonoyama H, Yamashita N, Aimi M, Mishima Y, Mishiro T, Tobita H, Shibagaki K, Oshima N, Moriyama I, Kawashima K, Miyake T, Ishimura N, Sato S, Kinoshita Y. Proton pump inhibitor is a risk factor for recurrence of common bile duct stones after endoscopic sphincterotomy - propensity score matching analysis. Endosc Int Open 2017; 5:E291-E296. [PMID: 28382327 PMCID: PMC5378546 DOI: 10.1055/s-0043-102936] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background and study aims Recurrence of common bile duct stones (CBDS) in patients treated with endoscopic sphincterotomy (ES) can lead to deterioration in their quality of life. Although the pathology and related factors are unclear, we speculated that proton pump inhibiter (PPI) administration increases the risk of CBDS recurrence by altering the bacterial mixture in the bile duct. Patients and methods The primary endpoint of this retrospective study was recurrence-free period. Several independent variables considered to have a relationship with CBDS recurrence including PPI use were analyzed using a COX proportional hazard model, with potential risk factors then evaluated by propensity score matching analysis. Results A total of 219 patients were analyzed, with CBDS recurrence found in 44. Analysis of variables using a COX proportional hazard model demonstrated that use of PPIs and ursodeoxycholic acid (UDCA), as well as the presence of periampullary diverticula (PD) each had a hazard ratio (HR) value greater than 1 (HR 2.2, P = 0.007; HR 2.0, P = 0.02; HR 1.9, P = 0.07; respectively). Furthermore, propensity score matching analysis revealed that the mean recurrence-free period in the oral PPI cohort was significantly shorter as compared with the non-PPI cohort (1613 vs. 2587 days, P = 0.014). In contrast, neither UDCA administration nor PD presence was found to be a significant factor in that analysis (1557 vs. 1654 days, P = 0.508; 1169 vs. 2011 days, P = 0.121; respectively). Conclusion Our results showed that oral PPI administration is a risk factor for CBDS recurrence in patients who undergo ES.
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Affiliation(s)
- Nobuhiko Fukuba
- Department of Internal Medicine II, Shimane University School of Medicine, Japan,Corresponding author Nobuhiko Fukuba, MD Department of Internal Medicine IIShimane University Faculty of Medicine89-1, Enya-cho, Izumo, Shimane, Japan
| | - Shunji Ishihara
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Hiroki Sonoyama
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Noritsugu Yamashita
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Masahito Aimi
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Yoshiyuki Mishima
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Tsuyoshi Mishiro
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Hiroshi Tobita
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Koutarou Shibagaki
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Naoki Oshima
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Ichiro Moriyama
- Division of Cancer Center, Shimane University Hospital, Japan
| | - Kousaku Kawashima
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Tatsuya Miyake
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Norihisa Ishimura
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
| | - Shuichi Sato
- Division of Gastrointestinal Endoscopy, Shimane University Hospital, Japan
| | - Yoshikazu Kinoshita
- Department of Internal Medicine II, Shimane University School of Medicine, Japan
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de la Coba Ortiz C, Argüelles Arias F, Martín de Argila de Prados C, Júdez Gutiérrez J, Linares Rodríguez A, Ortega Alonso A, Rodríguez de Santiago E, Rodríguez-Téllez M, Vera Mendoza MI, Aguilera Castro L, Álvarez Sánchez Á, Andrade Bellido RJ, Bao Pérez F, Castro Fernández M, Giganto Tomé F. Proton-pump inhibitors adverse effects: a review of the evidence and position statement by the Sociedad Española de Patología Digestiva. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:207-24. [PMID: 27034082 DOI: 10.17235/reed.2016.4232/2016] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION In the last few years a significant number of papers have related the use of proton-pump inhibitors (PPIs) to potential serious adverse effects that have resulted in social unrest. OBJECTIVE The goal of this paper was to provide a literature review for the development of an institutional position statement by Sociedad Española de Patología Digestiva (SEPD) regarding the safety of long-term PPI use. MATERIAL AND METHODS A comprehensive review of the literature was performed to draw conclusions based on a critical assessment of the following: a) current PPI indications; b) vitamin B12 deficiency and neurological disorders; c) magnesium deficiency; d) bone fractures; e) enteric infection and pneumonia; f) interactions with thienopyridine derivatives; e) complications in cirrhotic patients. RESULTS Current PPI indications have remained unchanged for years now, and are well established. A general screening of vitamin B12 levels is not recommended for all patients on a PPI; however, it does seem necessary that magnesium levels be measured at therapy onset, and then monitored in subjects on other drugs that may induce hypomagnesemia. A higher risk for bone fractures is present, even though causality cannot be concluded for this association. The association between PPIs and infection with Clostridium difficile is mild to moderate, and the risk for pneumonia is low. In patients with cardiovascular risk receiving thienopyridines derivatives it is prudent to adequately consider gastrointestinal and cardiovascular risks, given the absence of definitive evidence regardin potential drug-drug interactions; if gastrointestinal risk is found to be moderate or high, effective prevention should be in place with a PPI. PPIs should be cautiously indicated in patients with decompensated cirrhosis. CONCLUSIONS PPIs are safe drugs whose benefits outweigh their potential side effects both short-term and long-term, provided their indication, dosage, and duration are appropriate.
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Affiliation(s)
| | | | | | - Javier Júdez Gutiérrez
- Departamento de Gestión del Conocimiento, Sociedad Española de Patología Digestiva SEPD, España
| | | | - Aida Ortega Alonso
- UGC Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, España
| | | | - Manuel Rodríguez-Téllez
- UGC Intercentros de Aparato Digestivo , Hospital Universitario Virgen de la Macarena (HUVM), España
| | | | | | - Ángel Álvarez Sánchez
- Servicio de Aparato Digestivo, Hospital Clínico San Carlos. Universidad Complutense de Madrid., España
| | - Raúl Jesús Andrade Bellido
- Unidad de Gestión Clinica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, España
| | | | | | - Froilán Giganto Tomé
- Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias, España
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Thompson W, Farrell B, Welch V, Tugwell P, Bjerre LM. Should I continue taking my acid reflux medication? Design of a pilot before/after study evaluating a patient decision aid. Can Pharm J (Ott) 2017; 150:19-23. [PMID: 28286589 PMCID: PMC5330419 DOI: 10.1177/1715163516679425] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
| | - Barbara Farrell
- School of Epidemiology, Public Health and Preventive Medicine (Thompson, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Bruyère Research Institute (Thompson, Farrell, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Centre for Global Health (Welch, Tugwell), University of Ottawa, Ontario
- Department of Family Medicine (Farrell, Bjerre), University of Ottawa, Ontario
- Ottawa Hospital Research Institute (Tugwell), Ottawa, Ontario
| | - Vivian Welch
- School of Epidemiology, Public Health and Preventive Medicine (Thompson, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Bruyère Research Institute (Thompson, Farrell, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Centre for Global Health (Welch, Tugwell), University of Ottawa, Ontario
- Department of Family Medicine (Farrell, Bjerre), University of Ottawa, Ontario
- Ottawa Hospital Research Institute (Tugwell), Ottawa, Ontario
| | - Peter Tugwell
- School of Epidemiology, Public Health and Preventive Medicine (Thompson, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Bruyère Research Institute (Thompson, Farrell, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Centre for Global Health (Welch, Tugwell), University of Ottawa, Ontario
- Department of Family Medicine (Farrell, Bjerre), University of Ottawa, Ontario
- Ottawa Hospital Research Institute (Tugwell), Ottawa, Ontario
| | - Lise M. Bjerre
- School of Epidemiology, Public Health and Preventive Medicine (Thompson, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Bruyère Research Institute (Thompson, Farrell, Welch, Tugwell, Bjerre), University of Ottawa, Ontario
- Centre for Global Health (Welch, Tugwell), University of Ottawa, Ontario
- Department of Family Medicine (Farrell, Bjerre), University of Ottawa, Ontario
- Ottawa Hospital Research Institute (Tugwell), Ottawa, Ontario
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Collins S, Reid G. Distant Site Effects of Ingested Prebiotics. Nutrients 2016; 8:E523. [PMID: 27571098 PMCID: PMC5037510 DOI: 10.3390/nu8090523] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/12/2016] [Accepted: 08/23/2016] [Indexed: 12/17/2022] Open
Abstract
The gut microbiome is being more widely recognized for its association with positive health outcomes, including those distant to the gastrointestinal system. This has given the ability to maintain and restore microbial homeostasis a new significance. Prebiotic compounds are appealing for this purpose as they are generally food-grade substances only degraded by microbes, such as bifidobacteria and lactobacilli, from which beneficial short-chain fatty acids are produced. Saccharides such as inulin and other fructo-oligosaccharides, galactooligosaccharides, and polydextrose have been widely used to improve gastrointestinal outcomes, but they appear to also influence distant sites. This review examined the effects of prebiotics on bone strength, neural and cognitive processes, immune functioning, skin, and serum lipid profile. The mode of action is in part affected by intestinal permeability and by fermentation products reaching target cells. As the types of prebiotics available diversify, so too will our understanding of the range of microbes able to degrade them, and the extent to which body sites can be impacted by their consumption.
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Affiliation(s)
- Stephanie Collins
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6A 5C1, Canada.
| | - Gregor Reid
- Department of Microbiology and Immunology, The University of Western Ontario, London, ON N6A 5C1, Canada.
- Centre for Human Microbiome and Probiotics, Lawson Health Research Institute, 268 Grosvenor St., London, ON N6A 4V2, Canada.
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Lei ZB. Adverse reactions and rational use of proton pump inhibitors. Shijie Huaren Xiaohua Zazhi 2016; 24:3468-3475. [DOI: 10.11569/wcjd.v24.i23.3468] [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] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors (PPIs) are a class of important drugs for treating acid related diseases, such as gastroesophageal reflux diseases (GERD), peptic ulcer, Zollinger-Ellison syndrome, and upper gastrointestinal bleeding. When combined with other drugs, PPIs can be used for the eradication of Helicobacter pylori. Short-term use of PPIs can cause allergic reactions, adverse reactions of the hematologic system, the digestive system and the nervous system and so on. Long-term use of PPIs can cause a series of new safety issues, such as increased risk of infection, vitamin B12 deficiency caused by the lack of nutrients, fractures, hypomagnesemia, occurrence or development of atrophic gastritis, interstitial nephritis, microscopic colitis, increased risk of serious skin allergy and so on. However, inappropriate use and off-label use of PPIs, and even abuse of PPIs are very common worldwide. Therefore, clinical rational use of PPIs should be emphasized among the relevant national administration departments, clinicians and pharmacists.
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Al Subaie A, Emami E, Tamimi I, Laurenti M, Eimar H, Abdallah MN, Tamimi F. Systemic administration of omeprazole interferes with bone healing and implant osseointegration: an in vivo study on rat tibiae. J Clin Periodontol 2016; 43:193-203. [DOI: 10.1111/jcpe.12506] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Ahmed Al Subaie
- Faculty of Dentistry; McGill University; Montreal QC Canada
- College of Dentistry; University of Dammam; Dammam Saudi Arabia
| | - Elham Emami
- Faculty of Dentistry; University of Montreal; Montreal QC Canada
| | | | - Marco Laurenti
- Faculty of Dentistry; McGill University; Montreal QC Canada
| | - Hazem Eimar
- Faculty of Dentistry; McGill University; Montreal QC Canada
| | | | - Faleh Tamimi
- Faculty of Dentistry; McGill University; Montreal QC Canada
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Hinson AM, Wilkerson BM, Rothman-Fitts I, Riggs AT, Stack BC, Bodenner DL. Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults. J Am Geriatr Soc 2015; 63:2070-3. [PMID: 26415604 DOI: 10.1111/jgs.13661] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To measure the effect of proton pump inhibitors (PPIs), with and without concurrent bisphosphonates, on parathyroid hormone (PTH), vitamin D, and calcium. DESIGN Retrospective chart review of individuals 60 years and older. Subjects with reduced renal function (creatinine >1.3 mg/dL) and low vitamin D (<30 ng/mL) were excluded. SETTING Academic geriatric outpatient center in southern midwest. PARTICIPANTS Individuals aged 60 and older with concurrent calcium, PTH, vitamin D, and creatinine laboratory measurements (N = 80) meeting labeled criteria. MEASUREMENTS Serum calcium, PTH, vitamin D, and creatinine. RESULTS Chronic PPI exposure was associated with statistically significantly higher PTH (65.5 vs 30.3 pg/mL, P < .001; normal range 10-55 pg/mL) and lower calcium (9.1 vs 9.4 mg/dL, P = .02; normal range 8.5-10.5 mg/dL) than no PPI exposure. Chronic PPI exposure with concurrent BP therapy was associated with statistically significantly higher PTH (65.2 vs 43.4 pg/mL, P = .05) and lower calcium (9.2 vs 9.6 mg/dL, P = .04) than BP therapy only. CONCLUSION Based on the present study, chronic PPI exposure in elderly adults is associated with mild hyperparathyroidism regardless of concurrent oral BP administration.
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Affiliation(s)
- Andrew M Hinson
- Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.,Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Bekka M Wilkerson
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Ivy Rothman-Fitts
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Ann T Riggs
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Brendan C Stack
- Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Donald L Bodenner
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice. PLoS One 2015; 10:e0138881. [PMID: 26397986 PMCID: PMC4580428 DOI: 10.1371/journal.pone.0138881] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 09/04/2015] [Indexed: 12/26/2022] Open
Abstract
Background Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH. Methods Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR. Results Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake. Conclusions This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies.
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Veronese N, Bano G, Bertozzo G, Granziera S, Solmi M, Manzato E, Sergi G, Cohen AT, Correll CU. Vitamin K antagonists' use and fracture risk: results from a systematic review and meta-analysis. J Thromb Haemost 2015; 13:1665-75. [PMID: 26179400 DOI: 10.1111/jth.13052] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 06/28/2015] [Indexed: 01/02/2023]
Abstract
BACKGROUND Although vitamin K antagonists (VKAs) lower serum values of bone deposition markers, the link with osteoporosis and fractures remains controversial. OBJECTIVES To assess whether the use of VKAs is associated with an increased prevalence and/or incidence of osteoporosis, fractures, or lower bone mineral density (BMD) values. METHODS We conducted a systematic PubMed and EMBASE literature search until August 31, 2014, and a meta-analysis of cross-sectional and longitudinal studies investigating fractures and BMD, comparing patients treated with VKAs and healthy controls (HCs) or with patients with medical illness (medical controls, MCs). Standardized mean differences ± 95% and confidence intervals (CIs) were calculated for BMD, and risk ratios (RRs) were calculated for prevalent and incident fractures. RESULTS Of 4597 initial hits, 21 studies were eligible, including 79 663 individuals treated with VKAs vs. 597,348 controls. Compared with HCs, VKA-treated individuals showed significantly higher fracture risk in cross-sectional (three studies; RR = 1.24; 95% CI: 1.12-1.39, P < 0.0001) and longitudinal studies (seven studies; RR = 1.09; 95% CI: 1.01-1.18, P = 0.03) and more incident hip fractures (four studies; RR = 1.17; 95% CI: 1.05-1.31, P = 0.003). Analyzing studies that matched VKA participants with HCs (four studies), both these findings in longitudinal studies became non-significant. Notably, the VKA and MC group had similar BMD values at all investigated sites. Compared with HCs, a single study showed significantly lower spine T-scores in the VKA-treated group (standardized mean difference = - 0.45; 95% CI: - 0.75, - 0.14, P = 0.004). CONCLUSION VKAs neither increased prospectively-assessed fracture risk compared with MCs when matching eliminated confounding factors nor reduced BMD beyond effects of medical illness. Future studies, using careful matching and/or adequate MC groups, are needed to further clarify the short- and long-term effects of VKAs on bone health.
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Affiliation(s)
- N Veronese
- Department of Medicine, Geriatrics Section, University of Padova, Padova, Italy
| | - G Bano
- Department of Medicine, Geriatrics Section, University of Padova, Padova, Italy
| | - G Bertozzo
- Department of Medicine, Geriatrics Section, University of Padova, Padova, Italy
| | - S Granziera
- Department of Medicine, Geriatrics Section, University of Padova, Padova, Italy
| | - M Solmi
- Department of Neurosciences, University of Padova, Padova, Italy
| | - E Manzato
- Department of Medicine, Geriatrics Section, University of Padova, Padova, Italy
- National Research Council, Aging Branch, Institute of Neuroscience, Padova, Italy
| | - G Sergi
- Department of Medicine, Geriatrics Section, University of Padova, Padova, Italy
| | - A T Cohen
- Department of Hematological Medicine, Guys and St. Thomas' NHS Foundation Trust, London, UK
| | - C U Correll
- Psychiatry Research, The Zucker Hillside Hospital, North Shore - Long Island Jewish Health System, Glen Oaks, NY, USA
- Hofstra North Shore LIJ School of Medicine, Hempstead, NY, USA
- The Feinstein Institute for Medical Research, Manhasset, NY, USA
- Albert Einstein College of Medicine, Bronx, NY, USA
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Takebayashi K, Inukai T. Effect of proton pump inhibitors on glycemic control in patients with diabetes. World J Diabetes 2015; 6:1122-1131. [PMID: 26322158 PMCID: PMC4549663 DOI: 10.4239/wjd.v6.i10.1122] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 07/06/2015] [Accepted: 07/27/2015] [Indexed: 02/05/2023] Open
Abstract
Gastrin is a linear peptide hormone which is secreted mostly in the stomach pyloric antrum G cells. Although the main role of this hormone is the promotion of the secretion of gastric acid from the stomach parietal cells, gastrin can also behave as a growth factor and stimulate gastric cell proliferation. It is also reported that gastrin promotes β cell neogenesis in the pancreatic ductal complex, modest pancreatic β cell replication, and improvement of glucose tolerance in animal models, in which the remodeling of pancreatic tissues is promoted. These findings suggest the possibility that gastrin has the potential to promote an increase of β cell mass in pancreas, and therefore that gastrin may improve glucose tolerance. Proton pump inhibitors (PPIs) are wildly used clinically for the therapy of gastro-esophageal reflex disease, gastritis due to excess stomach acid, and gastric ulcers. PPIs indirectly elevate serum gastrin levels via a negative feedback effect. Recent evidence has revealed the beneficial effect of PPIs on glycemic control especially in patients with type 2 diabetes mellitus (T2DM), probably via the elevation of the levels of serum gastrin, although the detailed mechanism remains unclear. In addition, the beneficial effects of a combination therapy of gastrin or a PPI with a glucagon-like peptide-1 receptor agonist on glycemic control in animal models have been demonstrated. Although PPIs may be possible candidates for a new approach in the therapy of diabetes, a prospective, long-term, randomized, double-blind, placebo-controlled study is needed to establish the effect of PPIs on glycemic control in a large number of patients with T2DM.
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Fortinsky KJ, Bardou M, Barkun AN. Role of Medical Therapy for Nonvariceal Upper Gastrointestinal Bleeding. Gastrointest Endosc Clin N Am 2015; 25:463-78. [PMID: 26142032 DOI: 10.1016/j.giec.2015.02.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Nonvariceal upper gastrointestinal bleeding (UGIB) is a major cause of morbidity and mortality worldwide. Mortality from UGIB has remained 5-10% over the past decade. This article presents current evidence-based recommendations for the medical management of UGIB. Preendoscopic management includes initial resuscitation, risk stratification, appropriate use of blood products, and consideration of nasogastric tube insertion, erythromycin, and proton pump inhibitor therapy. The use of postendoscopic intravenous proton pump inhibitors is strongly recommended for certain patient populations. Postendoscopic management also includes the diagnosis and treatment of Helicobacter pylori, appropriate use of proton pump inhibitors and iron replacement therapy.
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Affiliation(s)
- Kyle J Fortinsky
- Department of Medicine, Toronto General Hospital, University of Toronto, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Marc Bardou
- Gastroenterology Department & Centre d'Investigations Clinique CIC1432, CHU de Dijon, 14 rue Gaffarel BP77908, Dijon, Cedex 21079, France.
| | - Alan N Barkun
- Gastroenterology Department, McGill University Health Centre, Montreal General Hospital Site, Room D7-346, 1650 Cedar Avenue, Montréal, Québec H3G 1A4, Canada
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Bardou M, Fortinsky KJ. Safety of medication options for treating pediatric esophagitis. Expert Opin Drug Saf 2015; 14:1087-96. [DOI: 10.1517/14740338.2015.1040389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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