Table 1.
Characteristics of included reviews.
| Study | Objective | Databases searched | Included Study designs | Number of studies | Country of included studies | Year of included studies | Population | Outcomes of concern | Risk of bias tool used | Overall risk of bias | Publication bias |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Aggarwal 2019 (Aggarwal et al., 2019) | To consolidate the available data on drug induced bone disorders | PubMed, Medline, Embase (July 2019) | Prospective and Nested case-control | NA | NA | NA | NA | Risk of fracture, hip fracture | NA | NA | NA |
| Aghaloo 2019 (Aghaloo et al., 2019) | To evaluate the effect of systemic disorders, other diseases, and drugs on implant osseointegration | PubMed upto July 2018 | Case control, prospective, retrospective studies | 2 (for PPI) | NA | 2001–2017 | General | Implant survival rate | NA | NA | NA |
| Aleraij 2020 (Aleraij et al., 2020) | To evaluate the association between the use of PPIs and changes in bone mineral density | PubMed/MEDLINE, EMBASE, Cochrane, CINAHL Up to March 2019 | Prospective and retrospective cohort studies | 10 | USA, the Republic of Kosovo, Canada, China, Turkey and South Korea | 2008–2018 | General | Mean annualized percent change in BMD, Mean difference in BMD | NOS | Not reported | NA |
| Cai 2015 (Cai et al., 2015) | To assess the relationship between use of antacid drugs and fracture risk | PubMed and Embase | Nested case control, case control, cohort | 18 | UK, USA, Spain, Canada, Netherlands, Europe, Sweden, Taiwan, Denmark | 1997–2014 | General | Hip fracture, any fracture, Spine fracture, wrist fracture | NA | NA | No publication bias |
| Chappuis 2018 (Chappuis et al., 2018) | To investigate the association between the intake of medications that may affect bone metabolism and implant outcomes | PubMed, MEDLINE (OVID), EMBASE (OVID), Cochrane Library, Web of Science, and SciVerse (Elsevier) up to May 2017 | Retrospective cohort studies | 2 | Canada, Sweden | 2017 | Adults wearing implant-supported prostheses | Implant Failure | STROBE and NOS | Low risk of bias, Studies scored 8 and 9 on NOS | NA |
| Da Maia 2022 (da Maia et al., 2022) | To assess whether there is a relationship between the use of PPIs and fractures in menopausal women | PubMed, Scopus, and Science Direct, 12 April 2021 | Observational prospective cohort studies | 5 | USA, Sweden, Germany, France, Australia | 2009–2014 | Menopausal women | Fractures | NOS | Overall NOS score 8–9, low risk of bias | NA |
| Eom 2011 (Eom et al., 2011) | To investigate the association between the use of PPIs or H2RAs and fracture risk | MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 | Case-control, nested case-control, cohort | 10 (PPI) | USA, UK, Canada, Denmark, France, Taiwan, Netherlands | 2006–2011 (for PPI) | General | Any Fractures, Hip fracture, spine fracture, wrist fracture | NOS | moderate to high | No publication bias detected (Egger, p = 0.45) |
| Fan 2017 (Fan et al., 2017) | To evaluate the association between PPI use and risk of osteoporosis | PubMed, EMBASE and Web of Knowledge from inception up to March 2017. | Case-control, prospective studies | 27 | China, Germany, Taiwan, Australia, UK, USA, Korea, Denmark, Spain, Canada, Europe, Netherlands | 2006–2016 | General patient population | Osteoporosis, any Fracture, Hip fracture, Spine fracture | NOS | Moderate to high | No publication bias detected |
| Heidelbaugh2009 (Heidelbaugh et al., 2009) | To summarize adverse risks associated with long-term use of PPIs in the treatment of upper gastrointestinal disorders | MEDLINE (1966–2008) | Nested case-control, Case-control, Retrospective matched cohort | 3 | UK, Canada, Denmark | 2006 and 2008 | General Practice database from UK, Community based from Denmark and Canada | Bone fracture | NA | NA | NA |
| Hussain 2018 (Hussain et al., 2018) | Tor explore the association of PPI use and risk of hip fracture | MEDLINE via PubMed and Cochrane central | Cohort, Case control and nested case-control | 17 | USA, UK, Canada, Taiwan, Spain, Netherlands | 2006 to 2017 | Patients with PPI exposure | Hip fracture | NOS | Medium to high quality | NA |
| Islam 2018 (Islam et al., 2018) | To quantify the associations as presented in the literature and to also provide this information to healthcare professionals and patients about PPIs potentially adverse effects | Medline (PubMed), Embase, and the Cochrane Library (July 2016) | Case-control, cohort, and cross-sectional | 43 (12 studies on Hip fracture) | USA, UK, Spain, Taiwan, Korea, Netherlands | General | Hip fracture | Modified NOS | NA | NA | |
| Kwok 2011 (Kwok et al., 2011) | To perform a meta-analysis of fractures in patients taking PPIs and H2RAs | MEDLINE and Embase September 2010 | Case-control, prospective and retrospective cohort | 12 | USA, UK, Netherlands, Europe, Canada | 1997–2010 | General | Spine fracture, hip fracture, overall fracture | Cochrane Adverse Effects Methods Group | Unclear and low risk of biases | NA |
| Li 2021 (Li et al., 2021) | To evaluate the risk of fracture with PPIs and H2RAs use in children and young adults | PubMed, EMBASE database, Cochrane Library, and Web of Science (May 2021) | Retrospective cohort, cohort, case control | 6 | Sweden, Israel, UK, USA | 2015–2020 | Children and young adults | Risk of fracture | NOS | High | No publication bias detected |
| Liu 2019 (Liu et al., 2019) | To determine the link between PPI use and fractures, osteoporosis, and BMD loss | PubMed, EMBASE and the Cochrane Library from inception up to May 2018 | Case-control, Cohort and cross-sectional studies | 32 | USA, Canada, UK, France, Denmark, Netherland, Iran | 2006–2018 | General | Fracture/Osteoporosis/ Bone mineral loss | NOS | All studies scored moderate to high score for NOS | No publication bias detected for hip, any fracture, and osteoporosis (p = 0.54, 0.39, 0.07), Spine fracture showed publication bias (p = 0.03) |
| Mortensen 2020 (Mortensen et al., 2020) | To assess the impact of various classes of medications on the risk of fragility hip fracture | EMBASE, PubMed, Web of Science, and Cochrane Central and clinicaltrials.gov in September 2017. | NA | 38 | Denmark, USA, Norway, Netherlands, UK, Taiwan, Ireland, France, Greece, Canada, Austria, Germany | 1981 to 2017, | General | Hip fractures | NOS | High quality | No publication bias detected, Begg and Mazumdar test for rank correlation (p = 0.35) |
| Nassar 2018 (Nassar and Richter, 2018) | To evaluate the relation-ship between PPI use and fracture incidence | PubMed, Embase, and Google Scholar, Feb 2018 | Prospective or retrospective observational studies | 33 | NA | 2006–2017 | General and patient population | Fracture risk, Change in BMD | NA | NA | No publication bias detected. Begg's test (p = 0.15) |
| Ngamruengphong 2011 (Ngamruengphong et al., 2011) | To evaluate an association between the use of PPI and risks for fracture | MEDLINE, EMBASE, and Cochrane Up to Aug 2010 | Cohort and Case-control studies | 10 | UK, Denmark, USA, Netherlands, Canada, Europe | 2006–2010 | Men and women aged >50 years, Men and women aged >43 years, Men and women aged >18 years, Men and women aged 50–79 years, Post-menopausal women | Hip fracture, Spine, wrist, Any fracture | Validity criteria suggested by Loke et al. (9) and Levine (10) | Overall Low-moderate Risk of bias, only one study had high bias | NA |
| Poly 2019 (Poly et al., 2019) | To gauge precisely the nature and magnitude of the association between PPIs and hip fracture risk | PubMed, EMBASE, Scopus, Google Scholar, and Web of Science (January 1990 and March 2018) | Cohort and case-control studies | 24 | USA, UK, Taiwan, Denmark, Korea, Netherlands, Canada, Finaland | 2006 to 2018 | Adults (aged 18 years or greater) | Development of hip fracture | NOS | Moderate to high | Egger’s regression test of the funnel asymmetry showed no observed significantpublication bias (p value = 0.75). |
| Srinutta 2019 (Srinutta et al., 2019) | To find out an association between PPI dose or treatment duration and the development of hypomagnesemia | MEDLINE, Scopus, Cochrane (1978 to June 2018) | Cross-sectional, case-control, cohort studies | 16 | North America = 7, Europe = 6, Asia = 3 | 2012–2018 | Patients in ambulatory settings, dialysis facilities, hospital settings | Hypomagnesemia | NHLBI | Fair to good | Not present Egger p value = 0.69 |
| Verma 2022 (Verma, 2022) | To determine the influence of PPIs on biomechanical efficiency of dental implants | PubMed, Cochrane database, EBSCO host, Web of Science and Scopus from 2010 upto Dec 2021 | RCTs | 6 | NA | 2017–2019 (human) | Patients undergoing dental implant treatment modality | Dental implant failure | Cochrane RoB | Low bias | NA |
| Vestergaard2020 (Vestergaard, 2020) | To perform systematic review of drugs inducing bone loss or associated with fracture risk | Medline | NA | 5 | NA | 2006–2019 | General | Bone loss | NA | NA | NA |
| Vinnakota 2020 (Vinnakota and Kamatham, 2020) | To find out the usage of PPIs in individuals undergoing dental implantation influence the success of an implant compared to controls | MEDLINE, Ovid and Cochrane Up to July 2019 | Retrospective cohort studies | 3 | Canada, Turkey, Sweden | 2017–2019 | Patients who underwent dental implant | Dental implant failure | NOS | Low risk of bias, good quality overall | NA |
| Yang 2022 (Yang et al., 2022) | To evaluate the risk of fracture in children and young adults exposed to ASDs | Cochrane Library, PubMed, and EMBASE (inception to December 2020) | Cohort, Nested case-control study | 6 | USA, UK, Israel, Sweden | 2015 to 2020 | Children, Young adults | Fracture risk | NOS | Four studies out of 6 scored high quality | NA |
| Ye 2011 (Ye et al., 2011) | To determine whether the association between PPIs and hip fracture exists quantitatively | PubMed and EMBASE, Cochrane up to June 2010 | Prospective and retrospective cohort studies, case-control studies | 7 | Netherlands, USA, UK, CANADA, Denmark | 2008–2011 | 18 and older, 50–79 aged, post-menopausal women | Hip fracture | STROBE | Not reported | No publication bias detected |
| Yu 2011 (Elaine et al., 2011) | To estimate the overall effect of PPI use on fracture rates | PubMed/MEDLINE, EMBASE, Web of Science, and BIOSIS Previews upto October 10, 2010 | Case-control, retrospective longitudinal cohort | 11 | USA, UK, Denmark, Europe, Netherlands, Taiwan | 2006–2010 | Adults (Predominantly postmenopausal women and older men) | Hip fracture, Any fracture, Spine fracture | NA | NA | No evidence of publication bias (Begg's test p = 0.22) |
| Zhang 2022 (Zhang et al., 2022) | To find put the impact of PPIs on Hemodialysis patient outcomes | Pubmed, Embase, Cochrane Library, and Web of Science, April 2022 | Prospective, Retrospective and cross-sectional studies | 12 | Japan, USA, Croatia, Denmark, Multicentre, Spain | 2013–2019 | Hemodialysis Patients | Fracture, Hypomagnesemia, Vascular calcification | NOS | Moderate to high | No publication bias detected |
| Zhou 2016 (Zhou et al., 2016) | To further clarify the association between PPI use and fracture risk | PubMed upto Feb 2015 | Cohort and case-control studies | 17 | UK, Denmark, Canada, USA, Europe, Sweden, Spain, Netherlands, Taiwan, Australia | 1987–2012 | General | Hip fracture, Spine and all site fracture | NOS | Good quality | No publication bias detected for any site fracture (p = 0.297), Detected for spine fracture (p = 0.038) |
Abbreviations: - ASDs - Acid Suppressing Drugs, BMD - Bone Mineral Density, H2RAs - Histamine-2 Receptor Antagonists, MEDLINE - Medical Literature Analysis and Retrieval System Online, NOS - Newcastle-Ottawa Scale, NHLBI - National Heart, Lung, and Blood Institute, PPI - Proton Pump Inhibitor, RCTs - Randomized Controlled Trials, RoB - Risk of Bias, STROBE - Strengthening The Reporting of Observational studies in Epidemiology.