Proton Pump Inhibitors and Fracture Risk: A Review of Current Evidence and Mechanisms Involved

Thong, Benjamin Ka Seng; Soelaiman, Ima Nirwana; Chin, Kok‐Yong

doi:10.3390/ijerph16091571

Cited by 104 publications

(99 citation statements)

References 106 publications

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“…However, we did not observe a dose-response relationship between risk of HFx and dose of PPI used. This is in contrast to other studies [11][12][13][14][15] , which demonstrated an association between dosage of www.nature.com/scientificreports/ PPI and HFx was dose-dependent. This difference might be explained by the use of different statistical analysis methods or the susceptibility of T2DM patients to HFx 5 .…”

Section: Discussioncontrasting

confidence: 99%

“…Patients with T2DM have an increased risk of fracture due to falls related to nervous and vascular disease 25,27 as well as changes in the microarchitecture that decrease bone strength and quality 28,29 . The effects of bone structure due to use of PPIs may be linked to malabsorption of calcium, hypergastrinemia, hypochlorhydria, hyperparathyroidism, and regulation of bone cells 15,30 . Previous studies have suggested that use of PPIs leads to increased gastric pH, and prolonged hypochlorhydria may reduce calcium ionization and affect intestinal absorption 15,31,32 .…”

Section: Discussionmentioning

confidence: 99%

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Proton pump inhibitor use and risk of hip fracture in patients with type 2 diabetes

Chou

Jiang

et al. 2020

Sci Rep

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Type 2 diabetes mellitus (T2DM) is associated with a high rate of comorbidity, including osteoporosis and peptic ulcers. Proton pump inhibitors (PPIs) are a group of acid-suppressing drugs commonly used for treating peptic ulcers. However, observational studies have reported an association between PPI therapy and osteoporotic fractures. This study investigated the association between PPI use and hip fracture (HFx) among patients with T2DM. We conducted this population-based propensity-matched retrospective cohort study using the National Health Insurance Research Database in Taiwan. Patients newly diagnosed with T2DM between 2000 and 2008 were identified. After excluding those who previously used PPIs or suffered HFx, 398,885 patients were recruited (44,341 PPI users; 354,544 nonusers). HFx risk data from 2000 to 2013 were collected to calculate the cumulative rate of HFx in these two groups. Sensitivity analyses were conducted to evaluate the effects of PPI dose. After propensity score matching of 1:4, 44,431 and 177,364 patients were assigned to the PPI user and non-user groups, respectively. PPI user group showed an increased risk of HFx with an adjusted hazard ratio of 1.41 (95% CI 1.29-1.54) without dose-response relationship. Thus, there is an increased risk of HFx in patients with T2DM receiving long-term PPI treatment. Type 2 diabetes mellitus (T2DM) is a common metabolic disease worldwide. In Taiwan, diabetes is one of the 10 leading causes of death. The global prevalence of diabetes mellitus has more than doubled in the past 30 years 1. Common comorbidities of T2DM include osteoporosis 2-5 , peptic ulcer 6-8 , heart and blood vessel disease, diabetic neuropathy, diabetic retinopathy, liver cirrhosis, and delayed wound healing 9. The risk of osteoporosis and associated fragility fracture is increased 1.2-fold in patients with T2DM 5. Among associated fragility fractures, hip fracture (HFx) is one of the most serious, with a 1-year mortality rate ranging from 2.4% in Japan to 34.8% in Hungary 10. Previous studies have shown a higher incidence of perforated peptic ulcer disease and related mortality rates in patients with T2DM compared with those in patients without the disease 6-8. Proton pump inhibitors (PPIs) are a group of acid-suppressing drugs commonly used in the treatment of peptic ulcers. However, several studies have reported an association between treatment with PPIs and risk of fractures, especially HFx 11-15. Although most of these studies report a higher risk of fractures in patients with high-dose and long-term use of PPIs 11,12,16,17 , the association and mechanisms involved remain controversial. The literature lacks information about risk of HFx in patients with T2DM receiving PPI treatment. The present study was a population-based cohort study using data from the National Health Insurance Research Database (NHIRD) at the National Health Research Institutes (NHRI) in Taiwan to elucidate the association between use of PPIs and risk of HFx among patients with T2DM.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proton pump inhibitor use and risk of hip fracture in patients with type 2 diabetes

Chou

Jiang

et al. 2020

Sci Rep

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“…Another clinical significance lies in the association with lower calcium levels, which potentially points to an increased risk of developing osteoporosis. Long-term PPI use has indeed been associated with decreased bone mineral density and increased risk of fractures [36]. Because many patients use PPIs without evidence based indication [37][38][39], we believe that reevaluation of treatment indication in KTR on chronic PPI therapy might be of benefit.…”

Section: Discussionmentioning

confidence: 97%

Proton-Pump Inhibitors and Hypomagnesaemia in Kidney Transplant Recipients

Douwes

Gomes-Neto

Schutten

et al. 2019

JCM

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Proton-pump inhibitors (PPIs) are commonly used after kidney transplantation and there is rarely an incentive to discontinue treatment. In the general population, PPI use has been associated with hypomagnesaemia. We aimed to investigate whether PPI use is associated with plasma magnesium, 24-h urinary magnesium excretion and hypomagnesaemia, in kidney transplant recipients (KTR). Plasma magnesium and 24-h urinary magnesium excretion were measured in 686 stable outpatient KTR with a functioning allograft for ≥1 year from the TransplantLines Food and Nutrition Biobank and Cohort-Study (NCT02811835). PPIs were used by 389 KTR (56.6%). In multivariable linear regression analyses, PPI use was associated with lower plasma magnesium (β: −0.02, P = 0.02) and lower 24-h urinary magnesium excretion (β: −0.82, P < 0.001). Moreover, PPI users had a higher risk of hypomagnesaemia (plasma magnesium <0.70 mmol/L), compared with non-users (Odds Ratio (OR): 2.12; 95% confidence interval (CI) 1.43–3.15, P < 0.001). This risk tended to be highest among KTR taking high PPI dosages (>20 mg omeprazole Eq/day) and was independent of adjustment for potential confounders (OR: 2.46; 95% CI 1.32–4.57, P < 0.005). No interaction was observed between PPI use and the use of loop diuretics, thiazide diuretics, tacrolimus, or diabetes (Pinteraction > 0.05). These results demonstrate that PPI use is independently associated with lower magnesium status and hypomagnesaemia in KTR. The concomitant decrease in urinary magnesium excretion indicates that this likely is the consequence of reduced intestinal magnesium absorption. Based on these results, it might be of benefit to monitor magnesium status periodically in KTR on chronic PPI therapy.

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“…Moreover, the effect of PPIs on the BMD is usually reversible (Corley et al, 2010). Current studies claimed that hypochlorite due to PPI is the cause of bone fractures as hypohydrochloria and high gastrin levels reduced the mineral absorption and thereby producing a defect in the bone remodelling (Thong et al, 2019). Some authors claimed that PPIs directly altered bone regeneration and osseointegration (Mester et al, 2019).…”

Section: 879mentioning

confidence: 99%

Proton Pump Inhibitors Adversely Induce Selective Changes in the Bone Mineral Density Detected by Dual-Energy X-ray Absorptiometry in Postmenopausal Women

Saleh

Al-Nimer

2020

ijrps

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Dual-energy X-ray absorptiometry (DEXA) is a universal tool that can detect bone loss and diagnose osteoporosis. Long term of using certain drugs contributed to the etiopathology of bone loss. Proton pump inhibitors (PPIs) users are at risk of developing osteoporosis. This study aimed to prove the selectivity of PPIs in inducing bone loss in postmenopausal women by determining the T-score of the axial spine and femur bone. A total number of 215 menopausal women were recruited from a Teaching hospital and private clinics from August 2018 to November 2019. The participants were grouped into Group I, n=150 (had no PPIs treatment) and Group II, n=65 (had treatment with PPIs). All the participants were subjected to DEXA investigation. Group II patients showed significantly lower T-score of the femur bone, while Group I patients showed a significantly lower T-score of lumbar vertebrae. The percentage of Group II patients had a T-score – 2.5 in femur ward bone is 35.4%, while the percentage of Group I patients had a T score -2.5 in the lumbar-3 vertebrae is 35.3%. Moreover, PPIs users showed an acceleration of bone loss despite the age, duration of menopause, body mass index, and waist-to-height ratio. We conclude that PPIs users are at risk of developing bone mass loss in the femur more than in the lumbar vertebrae

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Proton Pump Inhibitors and Fracture Risk: A Review of Current Evidence and Mechanisms Involved

Cited by 104 publications

References 106 publications

Proton pump inhibitor use and risk of hip fracture in patients with type 2 diabetes

Proton pump inhibitor use and risk of hip fracture in patients with type 2 diabetes

Proton-Pump Inhibitors and Hypomagnesaemia in Kidney Transplant Recipients

Proton Pump Inhibitors Adversely Induce Selective Changes in the Bone Mineral Density Detected by Dual-Energy X-ray Absorptiometry in Postmenopausal Women

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