Table of Contents

    Topic review

    Helicobacter pylori and Osteoporotic Fractures

    Subjects: Others
    View times: 52
    Contributors: Leon Fisher Alexander Fisher
    Submitted by: Leon Fisher

    Definition

    Osteoporosis (OP) and osteoporotic fractures (OFs) are common multifactorial and heterogenic disorders of increasing incidence. Helicobacter pylori (H.p.) colonizes the stomach approximately in half of the world’s population, causes gastroduodenal diseases and is prevalent in numerous extra-digestive diseases known to be associated with OP/OF. The studies regarding relationship between H.p. infection (HPI) and OP/OFs are inconsistent. The current review summarizes the relevant literature on the potential role of HPI in OP, falls and OFs and highlights the reasons for controversies in the publications. In the first section, after a brief overview of HPI biological features, we analyze the studies evaluating the association of HPI and bone status. The second part includes data on the prevalence of OP/OFs in HPI-induced gastroduodenal diseases (peptic ulcer, chronic/atrophic gastritis, and cancer) and the effects of acid-suppressive drugs. In the next section, we discuss the possible contribution of HPI-associated extra-digestive diseases and medications to OP/OF, focusing on conditions affecting both bone homeostasis and predisposing to falls. In the last section, we describe clinical implications of accumulated data on HPI as a co-factor of OP/OF and present a feasible 5-step algorithm for OP/OF risk assessment and management in regard to HPI, emphasizing the importance of an integrative (but differentiated) holistic approach. Increased awareness about the consequences of HPI linked to OP/OF can aid early detection and management. Further research on HPI – OP/OF relationship is needed to close current knowledge gaps and improve clinical management of both OP/OF and HPI-related disorders.

    1. Introduction

    Both Helicobacter pylori (H.p.) infection (HPI) and osteoporotic fractures (OFs) constitute major challenges for public health systems globally due to huge clinical and economic burdens. Accumulating evidence suggests that in health and disease stomach and gut directly and indirectly via multiple neurohormonal pathways regulate the musculoskeletal and other systems by controlling appetite, food intake, absorption of nutrients and energy balance [1][2][3][4][5][6][7]. These physiological relationships (including the gut/stomach–bone axis) may be affected by HPI. HPI is associated with numerous diseases in and outside the stomach, many of which have the potential to influence bone and muscle status, predispose to falls and, consequently, contribute to OFs. As H.p. colonizes the human stomach in over 50% of the world’s population [8][9][10][11] and HPI frequently coexists with OP/OF, deeper understanding the relationships among HPI-related diseases, the skeleton and falls becomes highly important; it may help to improve the preventive and therapeutic strategies for OFs. However, only a small number of studies have examined the association between HPI and bone status and the results have been controversial [12][13][14]. Although conventional wisdom suggests that in clinical practice the two main components of OFs—OP and falls—need to be integrated and viewed under complementary angles, the possible contribution of HPI-associated diseases to falls has not been addressed in the literature systematically.

    2. HPI-Induced Upper Gut Diseases and Osteoporotic Fractures

    2.1. Peptic Ulcer Disease

    HPI is responsible for 95% of duodenal ulcers and 85% of gastric ulcers which usually arise at the junction of the antral and corpus mucosa. At least eight studies showed that PUD is an independent risk factor (RF) for OF [15][16][17][18][19][20][21][22]. History of PUD has been found to be associated with an increased risk of osteoporotic thoracic vertebral fracture in a large population sample of Finnish men (n = 30,000) but not in the women [16]. In a Polish study of 240 females [17], women with PUD (n = 143, mean age 60.3 years) not using hormone replacement therapy (HRT) had lower BMD in all studied regions as compared to controls without PUD (n = 120, mean age 58.4 years); moreover, among HRT users, the BMD in lumbar vertebrae and Ward’s triangle was also significantly lower in women with PUD, whereas calcium intake was similar in both groups. Two reports from USA demonstrated an association between PUD and periprosthetic fractures after total hip replacement (n = 14,065; hazard ratio (HR) 1.5, 95% CI 1.1–2.2) [19] and total knee arthroplasty (n = 17,633; HR 1.87, 95% CI 1.28–2.75) [18]. In the Japanese study (n = 200, 105 women), multivariate analysis revealed that PUD (OR 4.98; 95% CI 1.51–16.45), along with HPI (OR 5.33; 95% CI 1.73–16.42) as well as common RFs (age, female gender, BMI), was independently related to OP [15]. A population-based study from Taiwan [20], which included 27,132 patients (aged ≥18 years) diagnosed with PUD and 27,132 randomly selected subjects (age- and gender-matched) without PUD, found that the OP risk (adjusted for covariates) was 1.85 times greater in the PUD group (13.99 vs. 5.80 per 1000 person-years). The highest risk was observed one year after PUD diagnosis (HR 63.4, 95% CI 28.2–142.7); use of a PPI significantly increased the OP risk (HR 1.17, 95% CI 1.03–1.34). Consistent with these data are results from two most recent large South Korean studies [21][22]. In the first prospective study (n = 10,030), PUD patients demonstrated a significantly higher OP risk (men: HR 1.72, 95% CI 1.02–2.92; women: HR 1.62, 95% CI 1.20–2.18); OP developed in 29.9% women and 11.1% men with PUD vs. 16.5% and 4.8% in controls, respectively [21]. The second report [22], based on analysis of 50,002 patients with PUD and equal number of controls matched by age, gender, past medical history, income and residence region, found increased risk of OP in PUD regardless of gender (adjusted HR 1.36, 95% CI 1.33–1.40). In contrast, a retrospective cross-sectional study from China (n = 867, with PUD 351 patient) reported that PUD was significantly associated with decreased BMD only in univariate analysis (OR 1.37, 95% CI 1.03–1.82) [23]. Lastly, in a cohort of patients operated for PUD between 1956 and 1985 (pre-HPI era) and followed for 30 years, the risk of OF was significantly (and independently of surgical procedure type) increased showing a standardized incidence ratio of 2.5 for the proximal femur, 4.7 for vertebra and 2.2 for the distal forearm [24].

    Although these reports, as any observational study, cannot indicate causality, the relationship between PUD and fragility fractures is suggested. It appears that PUD may approximately double the risk of OP/OF.

    2.2. Chronic/Atrophic Gastritis

    It is well established that HPI is responsible for the majority (>90%) of chronic/atrophic gastritis [25][26] and plays an important role in the initiation of autoimmune atrophic gastritis [26][27][28]; the latter occurs in 2% of the general population with a higher prevalence in older (>60 years) females [29]. CagA+ H.p., especially the East-Asian type, compared to the CagA− type induces more severe gastritis and mucosal atrophy and is more closely associated with gastric cancer [30]. Simultaneous presence of the CagA and other virulence factors (VacA, Helicobacter cysteine-rich protein C and the chaperonin Gro) increases the risk of chronic atrophic gastritis (a precursor lesion to gastric cancer) 18-fold [31].

    Two publications by a Brazilian group reported that in postmenopausal women neither HPI, no atrophic chronic gastritis were associated with BMD or OP [32][33]. No association between HPI-induced chronic gastritis and OP was also observed in an Iranian study [34]. In contrast, a Norwegian study [35] found that, in patients with chronic atrophic gastritis, compared to sex- and age-matched controls, bone formation markers (OC, sclerostin, OPG and OPG/RANKL ratio) were lower and the incidence of OP was higher (the latter abnormality only in males). In older Korean women, presence of atrophic gastritis was significantly linked to OP after adjusting for seven variables including age, BMI, metabolic and lifestyle variables (OR 1.89, 95% CI 1.15–3.11) [36]. Similarly, Japanese men with HPI-induced atrophic gastritis (defined by serum pepsinogen I and pepsinogen II levels) demonstrated an increased risk of low trabecular bone density (OR 1.83, 95% CI 1.04–3.2) [37]. In a small Norwegian study (n = 17 patients, 41 controls), subjects with chronic atrophic gastritis, compared to controls, have: decreased circulating levels of OC (bone formation marker), sclerostin (an inhibitor of bone formation), osteoprotegerin (OPG) and OPG/RANKL ratio; unaffected levels of P1NP (bone formation marker) and bCTX (bone resorption marker); and (in males only) lower lumbar BMD and increased frequency of osteopenia and OP. No difference in bone quality assessed by microidentation was found [35]. These features were interpreted as suggestive of decreased bone formation and higher bone resorption in patients with chronic atrophic gastritis. A study from Germany reported that OP development was associated with gastritis/duodenitis (OR 1.14; p = 0.045) and PPI use [38]. A retrospective cohort study of Korean premenopausal women in their 40s (n = 983) who had undergone a 48-month follow-up assessment of BMD of L1–4 showed that atrophic gastritis (diagnosed by gastroduodenoscopy) was significantly associated with bone loss (adjusted for confounding factors); patients with persistent atrophic gastritis exhibited a greater decrease in BMD and the prolonged duration of the disease correlated positively with the amount of BMD reduction [39]. Atrophic gastritis and CagA seropositivity were associated with lower hemoglobin levels, and anemia was 2.6-times (in women) and 1.5-times (in men) more common among persons with atrophic gastritis [40]. Severe hypochlorhydria or achlorhydria were found in 44% of patients with idiopathic iron deficient anemia and in 1.8% among healthy controls [41].

    Molecular mimicry between H.p. antigens and gastric H/K-ATPase has been proposed as a mechanism responsible for the association between HPI and development of chronic atrophic autoimmune gastritis [25][28][42][43][44][45]. In 20–30% of patients with HPI, autoantibodies to the H/K-ATPase were identified. In this organ-specific autoimmune disorder, autoantibodies to gastric parietal cells (in 90% of patients) and intrinsic factor (in 70% of patients) cause gastric gland atrophy, achlorhydria and hypergastrinemia (which induces hyperplasia of the ECL cells) resulting in vitamin B12 and iron malabsorption/deficiency and leading to megaloblastic/pernicious anemia and/or iron-deficient anemia, respectively [46][47][48][49][50][51]. The disease is clinically heterogeneous and may have an asymptomatic course. An inverse correlation between H.p. density and vitamin B12 levels has been shown [52]. Low serum B12 levels affect DNA synthesis, an important factor for bone remodeling. Vitamin B12 (and other B vitamins—B2, B6 and folate—linked to homocysteine metabolism) is regarded an essential factor for bone health [23][53][54][55][56][57][58][59][60][61][62]. Vitamin B12 deficiency was reported to have an increased fracture risk: 1.7- to [63] 1.9-fold [64] for hip fracture, 1.8-fold for vertebral fracture [64] and 2.9-fold for distal forearm fracture [64]. Peripheral neuropathy, occurring in vitamin B12 deficient patients [65], undoubtedly, increases risk of falls. Reversal of severe OP associated with pernicious anemia has been demonstrated after vitamin B12 replacement combined with etidronate (an antiresorptive bisphosphonate) therapy [66]. Repletion of B12 resulted in an 80% reduction in hip fracture risk among stroke patients [56]. However, recent trials and a meta-analysis did not show a preventive effect of treatment with vitamin B12 and folic acid on fracture risk [67]. Daily supplementation with B vitamins did not affect markers of bone turnover and did not reduce fracture risk in middle-aged and older women at high risk of cardiovascular disease [68]. Interestingly, a significantly increased hip fracture risk persists years after correction the vitamin B12 deficiency, indicating the independent pathophysiological importance of chronic atrophic gastritis and achlorhydria [63]. Chronic atrophic autoimmune gastritis is associated with multiple other nutritional deficiencies, including calcium, vitamins D, C and folic acid, each of which may affect the skeletal, nervous and hematological systems [50][58][69]. In addition, autoimmune gastritis clusters with autoimmune thyroiditis and type 1 diabetes mellitus [26][28], conditions linked to OP/OF. Iron deficiency with or without anemia has also been recognized as a RF for OP/OFs in many [70][71][72][73][74][75][76][77] but not all [78][79] studies (the topic is discussed in following sections).

    Importantly, pharmacologic HPI eradication results in gradual and significant improvement in chronic atrophic gastritis [80][81][82]. On the other hand, when interpreting the studies on HPI-induced chronic/atrophic corpus gastritis, it has to be kept in mind that with progression of the severity and extension of atrophic lesions H.p. is spontaneously eradicated [44][83][84].

    In conclusion, findings in patients with HPI-induced (especially with cagA+ strains) chronic/atrophic gastritis suggest that gastric corpus structural and functional (e.g., hypoacidity, hormonal disbalance, etc.) changes and associated nutritional deficiencies may negatively affect bone metabolism, neuromuscular and a wide range of other functions predisposing to OP, falls and OFs.

    2.3. Gastric Cancer

    HPI is an important determinant of neoplastic gastric lesions classified by WHO/IARC [85] as class 1 human carcinogen for non-cardia gastric adenocarcinomas [86][87][88]. HPI increases the cancer risk 5.8–7.9-fold [86][89], and the risk is 2–3-times higher in subjects infected with cagA+ strains [87][90][91][92].

    According to most but not all studies [93][94], gastric cancer survivors who underwent gastrectomy, compared to the general population [95][96][97][98][99][100][101][102][103][104][105] or age- and sex-matched healthy controls [106][107][108][109], have significantly lower BMD, higher prevalence of osteopenia/OP (38.3% [97] to 55% [104]) and higher fracture rates (approximately 40% [97][101][106]). Bone loss (although of a lesser degree) was also reported in gastric cancer survivors after endoscopic tumor resection undertaken in early stage [103]. In South Korea, nationwide cohort study of cancer survivors who underwent gastrectomy (n = 133,179 matched to non-cancer controls, 1:1) demonstrated an increased risk of fractures (HR 1.61; 95% CI 1.53–1.70), which was higher in patients after total gastrectomy (HR 2.18; 95% CI 1.96–2.44) and adjuvant chemotherapy (HR 2.01; 95% CI 1.81–2.23); the elevated OF risk was significantly associated with anemia [109]. In a report from Japan, the adjusted hazard ratio for OF in men after gastrectomy (n = 132) was 2.55 (95% CI 1.17–5.55) and 3.56 (95% CI 1.33–9.52) in those who survived >20 years [110].

    A considerable amount of OFs after gastrectomy occurs in the early postoperative period [101][104]. Bone remodeling imbalance with disproportionately increased bone resorption [98][100], decreased BMD [111] and higher fracture rates [101] were often observed during the first postoperative year. Altered bone metabolism was reflected by increased serum concentrations of bone resorption markers (C-terminal telopeptides of type I collagen, deoxypyridinoline and pyridinoline) [100], elevated serum PTH and alkaline phosphatase (ALP) levels [98][111] and associated with vitamin D deficiency [111][112][113][114][115]. Some researchers, however, observed no changes in BMD, a slight elevation of OC and only minor increase in PTH levels after total gastrectomy [93]. The causes of OP and subsequent fractures in patients with gastric cancer are multifactorial. Malabsorption (especially of calcium, phosphate, iron, proteins, vitamins B12 and D), malnutrition, weight loss, use of certain medications (e.g., fluorouracil and cisplatin which induce apoptosis of osteoblasts and increase osteoclast activity [116][117][118], hormones, radiotherapy, comorbidities, physical inactivity, old age and smoking–all were documented as factors contributing to bone loss and OFs in gastric cancer patients [99][101][103][104][115][118][119].

    It is well established that HPI eradication reduces the incidence of gastric cancer [120][121][122][123] and favors regression of the low-grade B-cell gastric MALT [124].

    2.4. Gastroesophageal Reflux Disease (GERD)

    HPI does not influence the function of the lower esophageal sphincter, the motility of the esophagus and the esophageal acid exposure. HPI might protect the distal esophagus (possibly an evolutionary adaptation [9]) by causing atrophy of the fundal gastric glands and hypochlorhydria, especially in subjects with cagA+, vacA+ strains and pro-inflammatory genotypes (IL-1β and IL-1RN) [125][126][127][128][129][130]. Many studies, as would be expected, reported an inverse association between HPI-induced corpus gastritis and GERD, its severity, prevalence of Barrett’s esophagus (BO) and esophageal adenocarcinoma [9][38][131][132][133][134][135][136][137][138][139]. The strongest relationship was observed in East Asian populations [130][138]. A meta-analysis of 72 studies (84,717 patients with BO and 390,749 controls) found that HPI reduces the risk of BO by 32% (OR 0.68, 95% CI 0.58–0.79) [138]. Six meta-analyses on association of HPI and esophageal adenocarcinoma indicated an inverse relationship [139], whereas a recent meta-analysis (35 studies including 345,886 patients) did not find such association, except the Middle East data [140]. Other researchers concluded that presence of HPI might aggravate GERD [141], or, at least, is not “protective” against GERD, as the incidence of GERD and its sequelae in patients with HPI is higher than that after eradication of the infection [142][143], HPI eradication improves GERD symptoms and esophagitis [144][145][146][147][148] and does not increase the risk of BO [149][150][151]. Meta-analyses on effect of eradication HPI produced, however, inconsistent results [130]: a significantly higher risk of developing de novo GERD was demonstrated in Asian studies [152], but not in Western ones [153][154][155]. In a recent retrospective large cohort study from US (n = 36,803 patients with HPI), rates of esophageal and proximal gastric cancers 5, 10 and 15 years after treatment/eradication of HPI were low—0.15%, 0.26% and 0.34%, respectively [156]. In the interpretation of the data on the relationship between HPI and GERD the type and location of HPI-induced gastritis should be taken into account. As the level of gastric acid secretion is the main pathophysiological factor in GERD, chronic atrophic corpus gastritis causing hypo-/achlorhydria may exert a “protective” effect, while antrum gastritis with hyperchlorhydria can play an opposite role, and, not unexpectedly, HPI eradication may differently affect outcomes.

    Several studies reported an association between GERD and vertebral fractures or kyphosis [157][158][159]. The most recent publications, however, did not confirm that GERD and decreased BMD are linked [23], neither that the incidence of OFs is higher among subjects with BO [160] (Kumar S 2017). As in the total population, older age, female gender and a higher comorbidity index were the independent risk factors for OFs in patients with BO. In the BO cohort, PPI therapy even prolonged and in high-doses, was not associated with increased fracture risk (HR 0.89; 95% CI 0.12–6.55), although a predisposition (numerically but non-significantly) for osteoporotic hip and vertebral fractures was observed [160].

    The Maastricht IV/Florence Consensus Report on the management of HPI acknowledges that GERD is less common amongst those who are infected, but concludes that eradication of H.p. does not influence the severity of GERD [161]. In patients with GERD, according to Italian guidelines [162] and other recommendations [148], HPI can be eradicated.

    3. Conclusions

    In this study, we attempt to illuminate the existing clinical information on links between HPI and OP/OFs and, the complexity and interdependence of HPI–host interactions. The available evidence indicates that diseases and disorders induced by HPI (especially with virulent strains (cagA+) may contribute directly and indirectly to the development and progression of OP, falls and OFs. Despite remaining gaps in knowledge (the underlying mechanisms have not been definitely proven), there is considerable amount of data to suggest that predictive, preventive and therapeutic strategies for OP/OFs should assume HPI-related pathologies as potential pathophysiological co-factors and concentrate on individualized management of their effects on both bone health and falls. In patients with HPI-associated diseases and disorders bone status and risk for falls and fractures should be assessed, whereas in individuals with risk or presence of OP/OF the HPI status needs to be investigated and appropriate treatment prescribed. A five-step algorithm to provide guidance on assessment of the possible contribution of HPI to OP/OF is presented; its clinical effectiveness needs to be validated. Further well-designed prospective studies are warranted to provide a deeper understanding of the HPI–OP/OFs axis and develop personalized preventive and curative therapies.

    The entry is from 10.3390/jcm9103253

    References

    1. Karsenty, G.; Ferron, M. The contribution of bone to whole-organism physiology. Nat. Cell Biol. 2012, 481, 314–320.
    2. Kitay, A.M.; Geibel, J.P. Stomach and Bone. Adv. Exp. Med. Biol. 2017, 1033, 97–131.
    3. Suchacki, K.J.; Roberts, F.; Lovdel, A.; Farquharson, C.; Morton, N.M.; Macrae, V.E.; Cawthorn, W.P.; Morton, N.M.; Cawthorn, W. Skeletal energy homeostasis: A paradigm of endocrine discovery. J. Endocrinol. 2017, 234, R67–R79.
    4. Ramsey, W.; Isales, C.M. Intestinal Incretins and the Regulation of Bone Physiology. Adv. Exp. Med. Biol. 2017, 1033, 13–33.
    5. Schiellerup, S.P.; Skov-Jeppesen, K.; Windeløv, J.A.; Svane, M.S.; Holst, J.J.; Hartmann, B.; Rosenkilde, M. Gut Hormones and Their Effect on Bone Metabolism. Potential Drug Therapies in Future Osteoporosis Treatment. Front. Endocrinol. 2019, 10, 75.
    6. Guntur, A.R.; Rosen, C.J. Bone as an Endocrine Organ. Endocr. Pract. 2012, 18, 758–762.
    7. Wong, I.P.; Baldock, P.A.; Herzog, H. Gastrointestinal peptides and bone health. Curr. Opin. Endocrinol. Diabetes Obes. 2010, 17, 44–50.
    8. Blaser, M.J.; Atherton, J.C. Helicobacter pylori persistence: Biology and disease. J. Clin. Investig. 2004, 113, 321–333.
    9. Atherton, J.C.; Blaser, M.J. Coadaptation of Helicobacter pylori and humans: Ancient history, modern implications. J. Clin. Investig. 2009, 119, 2475–2487.
    10. Hooi, J.K.; Lai, W.Y.; Ng, W.K.; Suen, M.M.; Underwood, F.E.; Tanyingoh, D.; Malfertheiner, P.; Graham, D.Y.; Wong, V.W.; Wu, J.C.; et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017, 153, 420–429.
    11. Franceschi, F.; Tortora, A.; Gasbarrini, G.; Gasbarrini, A. Helicobacter pyloriand Extragastric Diseases. Helicobacter 2014, 19, 52–58.
    12. Upala, S.; Sanguankeo, A.; Wijarnpreecha, K.; Jaruvongvanich, V. Association between Helicobacter pylori infection and osteoporosis: A systematic review and meta-analysis. J. Bone Miner. Metab. 2015, 34, 482–483.
    13. Papamichael, K.; Papaioannou, G.; Cheifetz, M.A.; Cheifetz, A.S. Bone of Contention: Helicobacter pylori and Osteoporosis-Is There an Association? Dig. Dis. Sci. 2019, 64, 2736–2739.
    14. Wang, T.; Li, X.; Zhang, Q.; Ge, B.; Zhang, J.; Yu, L.; Cai, T.; Zhang, Y.; Xiong, H. Relationship betweenHelicobacter pyloriinfection and osteoporosis: A systematic review and meta-analysis. BMJ Open 2019, 9, e027356.
    15. Asaoka, D.; Nagahara, A.; Hojo, M.; Sasaki, H.; Shimada, Y.; Yoshizawa, T.; Osada, T.; Watanabe, S. The Relationship between H. pyloriInfection and Osteoporosis in Japan. Gastroenterol. Res. Pract. 2014, 2014, 340765.
    16. Santavirta, S.; Konttinen, Y.T.; Heliövaara, M.; Knekt, P.; Lüthje, P.; Aromaa, A. Determinants of osteoporotic thoracic vertebral fracture. Acta Orthop. Scand. 1992, 63, 198–202.
    17. Sawicki, A.; Regula, A.; Godwod, K.; Debinski, A. Peptic ulcer disease and calcium intake as risk factors of osteoporosis in women. Osteoporos. Int. 2003, 14, 983–986.
    18. Singh, J.A.; Lewallen, D.G. Association of peptic ulcer disease and pulmonary disease with risk of periprosthetic fracture after primary total knee arthroplasty. Arthritis Rheum. 2011, 63, 1471–1476.
    19. Singh, J.A.; Lewallen, D.G. Peptic ulcer disease and heart disease are associated with periprosthetic fractures after total hip replacement. Acta Orthop. 2012, 83, 353–359.
    20. Wu, C.-H.; Tung, Y.-C.; Chaiter, Y.; Lu, Y.-Y.; Su, Y.-F.; Tsai, T.-H.; Kuo, K.-L.; Lin, C.-L. Increased Risk of Osteoporosis in Patients With Peptic Ulcer Disease. Medcine 2016, 95, e3309.
    21. Yoon, P.H.; An, S.J.; Jeong, S.-H.; Yang, Y.-J.; Hong, Y.-P. Association between Peptic Ulcer Disease and Osteoporosis: The Population-Based Longitudinal Cohort Study in Korea. Int. J. Environ. Res. Public Health 2019, 16, 2777.
    22. Choi, H.G.; Rhim, C.C.; Yoon, J.Y.; Park, B.J.; Min, C.Y.; Lee, S.W. Increased risk of osteoporosis in patients with peptic ulcer: A follow-up study using a national sample cohort. Arch. Osteoporos. 2019, 14, 105.
    23. Pan, B.-L.; Huang, C.-F.; Chuah, S.-K.; Chiang, J.-C.; Loke, S.-S. Relationship between Helicobacter pylori infection and bone mineral density: A retrospective cross-sectional study. BMC Gastroenterol. 2018, 18, 54.
    24. Melton, L.J.; Crowson, C.S.; Khosla, S.; O’Fallon, W.M. Fracture risk after surgery for peptic ulcer disease: A population-based cohort study. Bone 1999, 25, 61–67.
    25. Jeffery, P.L.; McGuckin, M.A.; Linden, S.K. Endocrine impact of Helicobacter pylori: Focus on ghrelin and ghrelin o-acyltransferase. World J. Gastroenterol. 2011, 17, 1249–1260.
    26. Massironi, S.; Cavalcoli, F.; Rossi, R.E.; Conte, D.; Spampatti, M.P.; Ciafardini, C.; Verga, U.; Beck-Peccoz, P.; Peracchi, M. Chronic autoimmune atrophic gastritis associated with primary hyperparathyroidism: A transversal prospective study. Eur. J. Endocrinol. 2013, 168, 755–761.
    27. Lahner, E.; Annibale, B. Pernicious anemia: New insights from a gastroenterological point of view. World J. Gastroenterol. 2009, 15, 5121–5128.
    28. Toh, B.-H.; Kyaw, T.; Taylor, R.; Pollock, W.; Schlumberger, W. Parietal cell antibody identified by ELISA is superior to immunofluorescence, rises with age and is associated with intrinsic factor antibody. Autoimmunity 2012, 45, 527–532.
    29. Tozzoli, R.; Kodermaz, G.; Perosa, A.R.; Tampoia, M.; Zucano, A.; Antico, A.; Bizzaro, N. Autoantibodies to parietal cells as predictors of atrophic body gastritis: A five-year prospective study in patients with autoimmune thyroid diseases. Autoimmun. Rev. 2010, 10, 80–83.
    30. Abe, T.; Kodama, M.; Murakami, K.; Matsunari, O.; Mizukami, K.; Inoue, K.; Uchida, M.; Okimoto, T.; Fujioka, T.; Uchida, T.; et al. Impact of Helicobacter pylori CagA diversity on gastric mucosal damage: An immunohistochemical study of East-Asian-type CagA. J. Gastroenterol. Hepatol. 2011, 26, 688–693.
    31. Sonnenberg, A.; Lash, R.H.; Genta, R.M. A National Study of Helicobactor pylori Infection in Gastric Biopsy Specimens. Gastroenterology 2010, 139, 1894–1901.e2.
    32. Kakehasi, A.M.; Mendes, C.M.C.; Coelho, L.G.V.; Castro, L.P.; Barbosa, A.J.A. The presence of Helicobacter Pylori in postmenopausal women is not a factor to the decrease of bone mineral density. Arq. Gastroenterol. 2007, 44, 266–270.
    33. Kakehasi, A.M.; Rodrigues, C.B.; Carvalho, A.V.; Barbosa, A.J.A. Chronic Gastritis and Bone Mineral Density in Women. Dig. Dis. Sci. 2008, 54, 819–824.
    34. Heidari, B. Helicobacter pylori infection and osteoporosis in elderly patients. Casp. J. Intern. Med. 2015, 6, 48–50.
    35. Aasarød, K.M.; Mosti, M.P.; Stunes, A. (Astrid); Reseland, J.E.; Basso, T.; Syversen, U.; Fossmark, R. Impaired skeletal health in patients with chronic atrophic gastritis. Scand. J. Gastroenterol. 2016, 51, 774–781.
    36. Kim, H.W.; Kim, Y.-H.; Han, K.; Nam, G.E.; Kim, G.S.; Han, B.-D.; Lee, A.; Ahn, J.Y.; Ko, B.J. Atrophic Gastritis: A Related Factor for Osteoporosis in Elderly Women. PLoS ONE 2014, 9, e101852.
    37. Mizuno, S.; Matsui, D.; Watanabe, I.; Ozaki, E.; Kuriyama, N.; Watanabe, Y. Serologically Determined Gastric Mucosal Condition Is a Predictive Factor for Osteoporosis in Japanese Men. Dig. Dis. Sci. 2015, 60, 2063–2069.
    38. Jacob, L.; Hadji, P.; Kostev, K. The use of proton pump inhibitors is positively associated with osteoporosis in postmenopausal women in Germany. Climacteric 2016, 19, 478–481.
    39. Kim, A.-S.; Ko, H.-J. Atrophic Gastritis as a Risk Factor for Bone Loss in Premenopausal Women in Their 40s: A Retrospective Cohort Study. Calcif. Tissue Int. 2018, 104, 34–41.
    40. Muhsen, K.; Sinnreich, R.; Beer-Davidson, G.; Nassar, H.; Cohen, D.; Kark, J.D. Sero-prevalence of Helicobacter pylori CagA immunoglobulin G antibody, serum pepsinogens and haemoglobin levels in adults. Sci. Rep. 2018, 8, 17616.
    41. Betesh, A.L.; Ana, C.A.S.; Cole, J.A.; Fordtran, J.S. Is achlorhydria a cause of iron deficiency anemia? Am. J. Clin. Nutr. 2015, 102, 9–19.
    42. Amedei, A.; Bergman, M.P.; Appelmelk, B.J.; Azzurri, A.; Benagiano, M.; Tamburini, C.; Van Der Zee, R.; Telford, J.L.; Vandenbroucke-Grauls, C.M.J.E.; D’Elios, M.M.; et al. Molecular Mimicry between Helicobacter pylori Antigens and H+,K+–Adenosine Triphosphatase in Human Gastric Autoimmunity. J. Exp. Med. 2003, 198, 1147–1156.
    43. Berman, A.G.; Organ, J.M.; Allen, M.R.; Wallace, J. Muscle contraction induces osteogenic levels of cortical bone strain despite muscle weakness in a mouse model of Osteogenesis Imperfecta. Bone 2020, 132, 115061.
    44. Weck, M.N.; Gao, L.; Brenner, H. Helicobacter pylori Infection and Chronic Atrophic Gastritis. Epidemiology 2009, 20, 569–574.
    45. Veijola, L.; Oksanen, A.M.; Sipponen, P.I.; Rautelin, H.I.K. Association of autoimmune type atrophic corpus gastritis with Helicobacter pylori infection. World J. Gastroenterol. 2010, 16, 83–88.
    46. Demiroğlu, H.; Dündar, S. Pernicious anaemia patients should be screened for iron deficiency during follow up. N. Z. Med. J. 1997, 110, 147–148.
    47. Dickey, W. Iron deficiency, gastric atrophy and Helicobacter pylori. Dig. Liver Dis. 2002, 34, 313–315.
    48. Hershko, C.; Ronson, A.; Souroujon, M.; Maschler, I.; Heyd, J.; Patz, J. Variable hematologic presentation of autoimmune gastritis: Age-related progression from iron deficiency to cobalamin depletion. Blood 2006, 107, 1673–1679.
    49. Hershko, C.; Patz, J.; Ronson, A. The anemia of achylia gastrica revisited. Blood Cells Mol. Dis. 2007, 39, 178–183.
    50. Cavalcoli, F.; Zilli, A.; Conte, D.; Massironi, S. Micronutrient deficiencies in patients with chronic atrophic autoimmune gastritis: A review. World J. Gastroenterol. 2017, 23, 563–572.
    51. Çağdaş, K.; Soykan, I. Utility of a laboratory score in the prediction of gastric emptying in autoimmune gastritis patients. Acta Clin. Belg. 2017, 73, 75–79.
    52. Çağdaş, K.; Soykan, I. Polyautoimmunity in autoimmune gastritis. Eur. J. Intern. Med. 2016, 31, 79–83.
    53. Carmel, R. Cobalamin, the stomach, and aging. Am. J. Clin. Nutr. 1997, 66, 750–759.
    54. Kim, G.; Kim, C.-H.; Park, J.; Lee, K.-U.; Park, C. Effects of vitamin B12 on cell proliferation and cellular alkaline phosphatase activity in human bone marrow stromal osteoprogenitor cells and UMR106 osteoblastic cells. Metabolism 1996, 45, 1443–1446.
    55. Tucker, K.L.; Hannan, M.T.; Qiao, N.; Jacques, P.F.; Selhub, J.; Cupples, L.A.; Kiel, D.P. Low plasma vitamin B12 is associated with lower BMD: The Framingham Osteoporosis Study. J. Bone Miner. Res. 2005, 20, 152–158.
    56. Sato, Y.; Honda, Y.; Iwamoto, J.; Kanoko, T.; Satoh, K. Effect of Folate and Mecobalamin on Hip Fractures in Patients with Stroke. JAMA 2005, 293, 1082–1088.
    57. McLean, R.R.; Jacques, P.F.; Selhub, J.; Fredman, L.; Tucker, K.L.; Samelson, E.J.; Kiel, D.P.; Cupples, L.A.; Hannan, M.T. Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women. J. Clin. Endocrinol. Metab. 2008, 93, 2206–2212.
    58. Swart, K.M.; Van Schoor, N.M.; Lips, P. Vitamin B12, Folic Acid, and Bone. Curr. Osteoporos. Rep. 2013, 11, 213–218.
    59. Lewerin, C.; Nilsson-Ehle, H.; Jacobsson, S.; Johansson, H.; Sundh, V.; Karlsson, M.K.; Ljunggren, O.; Lorentzon, M.; Kanis, J.; Lerner, U.H.; et al. Low holotranscobalamin and cobalamins predict incident fractures in elderly men: The MrOS Sweden. Osteoporos. Int. 2013, 25, 131–140.
    60. Dai, Z.; Koh, W.-P. B-Vitamins and Bone Health–A Review of the Current Evidence. Nutrients 2015, 7, 3322–3346.
    61. Saito, M.; Marumo, K. The Effects of Homocysteine on the Skeleton. Curr. Osteoporos. Rep. 2018, 16, 554–560.
    62. Su, Y.; Elshorbagy, A.; Turner, C.; Refsum, H.; Chan, R.; Kwok, T.C.Y. Circulating amino acids are associated with bone mineral density decline and ten-year major osteoporotic fracture risk in older community-dwelling adults. Bone 2019, 129, 115082.
    63. Merriman, N.A.; Putt, M.E.; Metz, D.C.; Yang, Y.-X. Hip Fracture Risk in Patients with a Diagnosis of Pernicious Anemia. Gastroenterology 2010, 138, 1330–1337.
    64. Goerss, J.B.; Kim, C.H.; Atkinson, E.J.; Eastell, R.; O’Fallon, W.M.; Melton, L.J. Risk of fractures in patients with pernicious anemia. J. Bone Miner. Res. 2009, 7, 573–579.
    65. Yang, G.-T.; Zhao, H.-Y.; Kong, Y.; Sun, N.-N.; Dong, A.-Q. Correlation between serum vitamin B12 level and peripheral neuropathy in atrophic gastritis. World J. Gastroenterol. 2018, 24, 1343–1352.
    66. Melton, M.E.; Kochman, M.L. Reversal of severe osteoporosis with vitamin B12 and etidronate therapy in a patient with pernicious anemia. Metabolism 1994, 43, 468–469.
    67. Lopez, M.G.; Baron, J.A.; Omsland, T.K.; Søgaard, A.J.; Meyer, H.E. Homocysteine-Lowering Treatment and the Risk of Fracture: Secondary Analysis of a Randomized Controlled Trial and an Updated Meta-Analysis. JBMR Plus 2018, 2, 295–303.
    68. Stone, K.L.; Lui, L.-Y.; Christen, W.G.; Troen, A.M.; Bauer, D.C.; Kado, D.; Schambach, C.; Cummings, S.R.; Manson, J.E. Effect of Combination Folic Acid, Vitamin B6, and Vitamin B12Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial. J. Bone Miner. Res. 2017, 32, 2331–2338.
    69. Massironi, S.; Cavalcoli, F.; Zilli, A.; Del Gobbo, A.; Ciafardini, C.; Bernasconi, S.; Felicetta, I.; Conte, D.; Peracchi, M. Relevance of vitamin D deficiency in patients with chronic autoimmune atrophic gastritis: A prospective study. BMC Gastroenterol. 2018, 18, 172.
    70. Cesari, M.; Pahor, M.; Lauretani, F.; Penninx, B.W.H.J.; Bartali, B.; Russo, R.; Cherubini, A.; Woodman, R.; Bandinelli, S.; Guralnik, J.M.; et al. Bone density and hemoglobin levels in older persons: Results from the InCHIANTI study. Osteoporos. Int. 2004, 16, 691–699.
    71. Laudisio, A.; Marzetti, E.; Pagano, F.; Bernabei, R.; Zuccalà, G. Haemoglobin levels are associated with bone mineral density in the elderly: A population-based study. Clin. Rheumatol. 2008, 28, 145–151.
    72. Chen, Z.; Thomson, C.A.; Aickin, M.; Nicholas, J.S.; Van Wyck, D.; Lewis, C.E.; Cauley, J.A.; Bassford, T. Short list of Women’s Health Initiative Investigators The relationship between incidence of fractures and anemia in older multiethnic women. J. Am. Geriatr. Soc. 2010, 58, 2337–2344.
    73. Korkmaz, U.; Korkmaz, N.; Yazıcı, S.; Erkan, M.; Baki, A.E.; Yazici, M.; Özhan, H.; Ataoglu, S.; Yazici, S. Anemia as a risk factor for low bone mineral density in postmenopausal Turkish women. Eur. J. Intern. Med. 2012, 23, 154–158.
    74. Rutten, E.P.; Franssen, F.M.E.; Spruit, M.A.; Wouters, E.F.M. Anemia is associated with bone mineral density in chronic obstructive pulmonary disease. Copd J. Chronic Obs. Pulm. Dis. 2012, 10, 286–292.
    75. Oh, Y.H.; Moon, J.H.; Cho, B. Association between Hemoglobin Level and Bone Mineral Density in Korean Adults. J. Bone Metab. 2017, 24, 161–173.
    76. Valderrábano, R.J.; Lee, J.; Lui, L.-Y.; Hoffman, A.R.; Cummings, S.R.; Orwoll, E.S.; Wu, J.Y.; Osteoporotic Fractures in Men (MrOS) Study Research Group. Older Men with Anemia Have Increased Fracture Risk Independent of Bone Mineral Density. J. Clin. Endocrinol. Metab. 2017, 102, 2199–2206.
    77. Chuang, M.-H.; Chuang, T.-L.; Koo, M.; Wang, Y.-F. Low Hemoglobin Is Associated with Low Bone Mineral Density and High Risk of Bone Fracture in Male Adults: A Retrospective Medical Record Review Study. Am. J. Men’s Health 2019, 13, 1557988319850378.
    78. Valderrábano, R.J.; Wu, J.Y. Bone and blood interactions in human health and disease. Bone 2019, 119, 65–70.
    79. Lu, M.; Liu, Y.; Shao, M.; Tesfaye, G.C.; Yang, S. Associations of Iron Intake, Serum Iron and Serum Ferritin with Bone Mineral Density in Women: The National Health and Nutrition Examination Survey, 2005–2010. Calcif. Tissue Int. 2019, 106, 232–238.
    80. Ohkusa, T.; Fujiki, K.; Takashimizu, I.; Kumagai, J.; Tanizawa, T.; Eishi, Y.; Yokoyama, T.; Watanabe, M. Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated. Ann. Intern. Med. 2001, 134, 380–386.
    81. Ito, M.; Haruma, K.; Kamada, T.; Mihara, M.; Kim, S.; Kitadai, Y.; Sumii, M.; Tanaka, S.; Yoshihara, M.; Chayama, K. Helicobacter pylori eradication therapy improves atrophic gastritis and intestinal metaplasia: A 5-year prospective study of patients with atrophic gastritis. Aliment. Pharm. 2002, 16, 1449–1456.
    82. Hwang, Y.J.; Kim, N.; Lee, H.S.; Lee, J.B.; Choi, Y.J.; Yoon, H.; Shin, C.M.; Park, Y.S.; Lee, D.H. Reversibility of atrophic gastritis and intestinal metaplasia after Helicobacter pylori eradication—A prospective study for up to 10 years. Aliment. Pharm. 2018, 47, 380–390.
    83. Sierra, R.; Une, C.; Ramírez, V.; Alpízar-Alpízar, W.; González, I.M.; Ramírez, J.A.; De Mascarel, A.; Cuenca, P.; Perez, G.I.P.; Mégraud, F. Relation of atrophic gastritis with Helicobacter pylori-CagA+ and interleukin-1 gene polymorphisms. World J. Gastroenterol. 2008, 14, 6481–6487.
    84. Gao, L.; Weck, M.N.; Nieters, A.; Brenner, H. Inverse association between a pro-inflammatory genetic profile and Helicobacter pylori seropositivity among patients with chronic atrophic gastritis: Enhanced elimination of the infection during disease progression? Eur. J. Cancer 2009, 45, 2860–2866.
    85. IAR. Schistosomes, Liver Flukes and Helicobacter pylori; International Agency for Research on Cancer: Lyon, France, 1994; Volume 61, pp. 1–241.
    86. Kamangar, F.; Dawsey, S.M.; Blaser, M.J.; Perez-Perez, G.I.; Pietinen, P.; Newschaffer, C.J.; Abnet, C.C.; Albanes, D.; Virtamo, J.; Taylor, P.R. Opposing Risks of Gastric Cardia and Noncardia Gastric Adenocarcinomas Associated with Helicobacter pylori Seropositivity. J. Natl. Cancer Inst. 2006, 98, 1445–1452.
    87. Amieva, M.; Peek, R.M. Pathobiology of Helicobacter pylori–Induced Gastric Cancer. Gastroenterology 2016, 150, 64–78.
    88. Bakhti, S.Z.; Latifi-Navid, S.; Safaralizadeh, R. Helicobacter pylori-related risk predictors of gastric cancer: The latest models, challenges, and future prospects. Cancer Med. 2020, 9, 4808–4822.
    89. Vohlonen, I.; Pukkala, E.; Malila, N.; Härkönen, M.; Hakama, M.; Koistinen, V.; Sipponen, P. Risk of gastric cancer in Helicobacter pylori infection in a 15-year follow-up. Scand. J. Gastroenterol. 2016, 51, 1159–1164.
    90. Nomura, A.M.Y.; Lee, J.; Stemmermann, G.N.; Nomura, R.Y.; Perez, G.I.P.; Blaser, M.J. Helicobacter pyloriCagA Seropositivity and Gastric Carcinoma Risk in a Japanese American Population. J. Infect. Dis. 2002, 186, 1138–1144.
    91. Kusters, J.G.; van Vliet, A.H.; Kuipers, E.J. Pathogenesis of Helicobacter pylori infection. Clin. Microbiol Rev. 2006, 19, 449–490.
    92. Park, J.Y.; Forman, D.; Waskito, L.A.; Yamaoka, Y.; Crabtree, J.E. Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer. Toxins 2018, 10, 163.
    93. Liedman, B.; Henningsson, A.; Mellström, D.; Lundell, L. Changes in Bone Metabolism and Body Composition After Total Gastrectomy. Dig. Dis. Sci. 2000, 45, 819–824.
    94. Lai, S.-W.; Kuo, Y.-H.; Lai, S.-W. Increased risk of osteoporotic fractures in patients with gastric cancer and post-gastrectomy. Bone 2020, 132, 115185.
    95. Zittel, T.T.; Zeeb, B.; Maier, G.W.; Kaiser, G.W.; Zwirner, M.; Liebich, H.; Starlinger, M.; Becker, H.D. High prevalence of bone disorders after gastrectomy. Am. J. Surg. 1997, 174, 431–438.
    96. Kanis, J.; Johnell, O.; Gullberg, B.; Allander, E.; Elffors, L.; Ranstam, J.; Dequeker, J.; Dilsen, G.; Gennari, C.; Vaz, A.L.; et al. Risk Factors for Hip Fracture in Men from Southern Europe: The MEDOS Study. Osteoporos. Int. 1999, 9, 45–54.
    97. Lim, J.S.; Kim, S.B.; Bang, H.Y.; Cheon, G.J.; Lee, J.I. High prevalence of osteoporosis in patients with gastric adenocarcinoma following gastrectomy. World J. Gastroenterol. 2007, 13, 6492–6497.
    98. Baek, K.H.; Jeon, H.M.; Lee, S.S.; Lim, D.-J.; Oh, K.W.; Lee, W.-Y.; Rhee, E.-J.; Han, J.H.; Cha, B.Y.; Lee, K.W.; et al. Short-term changes in bone and mineral metabolism following gastrectomy in gastric cancer patients. Bone 2008, 42, 61–67.
    99. Lim, J.S.; Lee, J.-I. Prevalence, Pathophysiology, Screening and Management of Osteoporosis in Gastric Cancer Patients. J. Gastric Cancer 2011, 11, 7–15.
    100. Krupski, W.; Tatara, M.R.; Bury, P.; Szabelska, A.; Charuta, A.; Maciejewski, R.; Wallner, G.; Dabrowski, A. Negative Effects of Total Gastrectomy on Bone Tissue Metabolism and Volumetric Bone Mineral Density (vBMD) of Lumbar Spine in 1-Year Study in Men. Medcine 2016, 95, e2817.
    101. Oh, H.J.; Lim, C.-H.; Yoon, B.-H.; Yoon, S.B.; Baeg, M.K.; Kim, W.C.; Choi, M.-G.; Park, J.M.; Choi, M.-G.; Yoo, H.M.; et al. Fracture after gastrectomy for gastric cancer: A long-term follow-up observational study. Eur. J. Cancer 2017, 72, 28–36.
    102. Yoo, S.H.; Lee, J.A.; Kang, S.Y.; Kim, Y.S.; Sunwoo, S.; Kim, B.S.; Yook, J.-H. Risk of osteoporosis after gastrectomy in long-term gastric cancer survivors. Gastric Cancer 2017, 21, 720–727.
    103. Noh, H.M.; Yoo, J.-H.; Jeong, J.Y.; Park, Y.S. Bone mineral density after treatment for gastric cancer. Medcine 2018, 97, e9582.
    104. Seo, G.H.; Kang, H.Y.; Choe, E.K. Osteoporosis and fracture after gastrectomy for stomach cancer. Medcine 2018, 97, e0532.
    105. Iki, M.; Fujita, Y.; Kouda, K.; Yura, A.; Tachiki, T.; Tamaki, J.; Sato, Y.; Moon, J.-S.; Hamada, M.; Kajita, E.; et al. Increased risk of osteoporotic fracture in community-dwelling elderly men 20 or more years after gastrectomy: The Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Cohort Study. Bone 2019, 127, 250–259.
    106. Inoue, K.; Shiomi, K.; Higashide, S.; Kan, N.; Nio, Y.; Tobe, T.; Shigeno, C.; Konishi, J.; Okumurat, H.; Yamamuro, T.; et al. Metabolic bone disease following gastrectomy: Assessment by dual energy X-ray absorptiometry. BJS 1992, 79, 321–324.
    107. Heiskanen, J.T.; Kröger, H.; Pääkkönen, M.; Parviainen, M.T.; Lamberg-Allardt, C.; Alhava, E. Bone mineral metabolism after total gastrectomy. Bone 2001, 28, 123–127.
    108. Jeong, S.-M.; Shin, N.W.; Lee, J.E.; Jin, S.-M.; Kim, S. Increased Risk of Osteoporosis in Gastric Cancer Survivors Compared to General Population Control: A Study with Representative Korean Population. Cancer Res. Treat. 2018, 51, 530–537.
    109. Shin, N.W.; Suh, B.; Lim, H.; Suh, Y.-S.; Choi, Y.J.; Jeong, S.-M.; Yun, J.M.; Song, S.O.; Park, Y. Increased Risk of Osteoporotic Fracture in Postgastrectomy Gastric Cancer Survivors Compared With Matched Controls: A Nationwide Cohort Study in Korea. Am. J. Gastroenterol. 2019, 114, 1735–1743.
    110. Tachiki, T.; Kouda, K.; Dongmei, N.; Tamaki, J.; Iki, M.; Kitagawa, J.; Takahira, N.; Sato, Y.; Kajita, E.; Fujita, Y.; et al. Muscle strength is associated with bone health independently of muscle mass in postmenopausal women: The Japanese population-based osteoporosis study. J. Bone Miner. Metab. 2017, 37, 53–59.
    111. Atsumi, Y.; Rino, Y.; Wada, H.; Kitani, Y.; Ozawa, Y.; Aoyama, T.; Oshima, T.; Yukawa, N.; Yoshikawa, T.; Masuda, M. Changes in bone metabolism after gastric cancer surgery in male patients: A prospective observational study. Gastric Cancer 2018, 22, 237–243.
    112. Imawari, M.; Kozawa, K.; Akanuma, Y.; Koizumi, S.; Itakura, H.; Kosaka, K. Serum 25-hydroxyvitamin D and vitamin D-binding protein levels and mineral metabolism after partial and total gastrectomy. Gastroenterology 1980, 79, 255–258.
    113. Ichikawa, C.; Takiguchi, N.; Koda, K.; Oda, K.; Suzuki, H.; Miyazaki, M. Early phase metabolic bone disorders after gastrectomy: Influence of active vitamin D treatment. Dig. Dis. Sci. 2002, 47, 1886–1890.
    114. Rino, Y.; Takanashi, Y.; Yamamoto, Y.; Inagaki, D.; Kawamoto, M.; Harada, H.; Ashida, A.; Wada, H.; Yamada, R.; Ohshima, T.; et al. Bone disorder and vitamin D after gastric cancer surgery. Hepatogastroenterology 2007, 54, 1596–1600.
    115. Climent, M.; Pera, M.; Aymar, I.; Ramón, J.M.; Grande, L.; Nogués, X. Bone health in long-term gastric cancer survivors: A prospective study of high-dose vitamin D supplementation using an easy administration scheme. J. Bone Miner. Metab. 2017, 36, 462–469.
    116. Ehrhart, N.; Eurell, J.A.C.; Tommasini, M.; Constable, P.D.; Johnson, A.L.; Feretti, A. Effect of cisplatin on bone transport osteogenesis in dogs. Am. J. Veter Res. 2002, 63, 703–711.
    117. Xian, C.J.; Cool, J.C.; Pyragius, T.; Foster, B.K. Damage and recovery of the bone growth mechanism in young rats following 5-fluorouracil acute chemotherapy. J. Cell. Biochem. 2006, 99, 1688–1704.
    118. Stava, C.J.; Jimenez, C.; Hu, M.I.; Vassilopoulou-Sellin, R. Skeletal sequelae of cancer and cancer treatment. J. Cancer Surviv. 2009, 3, 75–88.
    119. Yaprak, G.; Gemici, C.; Temizkan, S.; Ozdemir, S.; Dogan, B.C.; Seseogullari, O.O. Osteoporosis development and vertebral fractures after abdominal irradiation in patients with gastric cancer. BMC Cancer 2018, 18, 972.
    120. Lee, Y.-C.; Chiang, T.-H.; Chou, C.-K.; Tu, Y.-K.; Liao, W.-C.; Wu, M.-S.; Graham, D.Y. Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A Systematic Review and Meta-analysis. Gastroenterology 2016, 150, 1113–1124.e5.
    121. Sugano, K. (Kentaro) Effect of Helicobacter pylori eradication on the incidence of gastric cancer: A systematic review and meta-analysis. Gastric Cancer 2018, 22, 435–445.
    122. Ding, S.-Z. Global whole family based-Helicobacter pylori eradication strategy to prevent its related diseases and gastric cancer. World J. Gastroenterol. 2020, 26, 995–1004.
    123. Ford, A.C.; Yuan, Y.; Moayyedi, P. Helicobacter pylori eradication therapy to prevent gastric cancer: Systematic review and meta-analysis. Gut 2020. (Epub ahead of print).
    124. Papagiannakis, P.; Michalopoulos, C.; Papalexi, F.; Dalampoura, D.; Diamantidis, M.D. The role of Helicobacter pylori infection in hematological disorders. Eur. J. Intern. Med. 2013, 24, 685–690.
    125. Vicari, J.J.; Peek, R.M.; Falk, G.W.; Goldblum, J.R.; Easley, K.A.; Schnell, J.; Perez-Perez, G.I.; Halter, S.A.; Rice, T.W.; Blaser, M.J.; et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology 1998, 115, 50–57.
    126. Vaezi, M.F.; Falk, G.W.; Peek, R.M.; Vicari, J.J.; Goldblum, J.R.; Perez-Perez, G.I.; Rice, T.W.; Blaser, M.J.; Richter, J.E. CagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. Am. J. Gastroenterol. 2000, 95, 2206–2211.
    127. Queiroz, D.M.M.; Guerra, J.B.; Rocha, G.A.; Rocha, A.M.C.; Santos, A.; De Oliveira, A.G.; Cabral, M.M.D.A.; Nogueira, A.M.M.F.; De Oliveira, C.A. IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis. Gastroenterology 2004, 127, 73–79.
    128. Corley, D.A.; Kubo, A.; Levin, T.R.; Block, G.; Habel, L.; Rumore, G.; Quesenberry, C.; Buffler, P.; Parsonnet, J. Helicobacter pylori and gastroesophageal reflux disease: A case-control study. Helicobacter 2008, 13, 352–360.
    129. Ghoshal, U.C.; Chourasia, D. Gastroesophageal Reflux Disease and Helicobacter pylori: What May Be the Relationship? J. Neurogastroenterol. Motil. 2010, 16, 243–250.
    130. Hong, S.J.; Kim, S.W. Helicobacter pylori Infection in Gastroesophageal Reflux Disease in the Asian Countries. Gastroenterol. Res. Pract. 2015, 2015, 985249.
    131. Ye, W.; Held, M.; Lagergren, J.; Engstrand, L.; Blot, W.J.; McLaughlin, J.K.; Nyrén, O. Helicobacter pylori Infection and Gastric Atrophy: Risk of Adenocarcinoma and Squamous-Cell Carcinoma of the Esophagus and Adenocarcinoma of the Gastric Cardia. J. Natl. Cancer Inst. 2004, 96, 388–396.
    132. De Martel, C.; Llosa, A.E.; Farr, S.M.; Friedman, G.D.; Vogelman, J.H.; Orentreich, N.; Corley, D.A.; Parsonnet, J. Helicobacter pyloriInfection and the Risk of Development of Esophageal Adenocarcinoma. J. Infect. Dis. 2005, 191, 761–767.
    133. De Martel, C.; Haggerty, T.D.; Corley, A.U.; Vogelman, J.H.; Orentreich, N.; Parsonnet, J. Serum Ghrelin Levels and Risk of Subsequent Adenocarcinoma of the Esophagus. Am. J. Gastroenterol. 2007, 102, 1166–1172.
    134. Kandulski, A.; Malfertheiner, P. Helicobacter pylori and gastroesophageal reflux disease. Curr. Opin. Gastroenterol. 2014, 30, 402–407.
    135. Sugimoto, M.; Uotani, T.; Ichikawa, H.; Andoh, A.; Furuta, T. Gastroesophageal Reflux Disease in Time Covering Eradication for All Patients Infected with Helicobacter pylori in Japan. Digestion 2016, 93, 24–31.
    136. Tomasello, G.; Giordano, F.; Mazzola, M.; Jurjus, R.; Jurjus, A.; Damiani, P.; Nobile, S.; Carini, F.; Leone, A. Helicobacter pylori and Barrett’s esophagus: A protective factor or a real cause? J. Boil. Regul. Homeost. Agents 2017, 31, 9–15.
    137. Sonnenberg, A.; Turner, K.O.; Spechler, S.J.; Genta, R.M. The influence of Helicobacter pylori on the ethnic distribution of Barrett’s metaplasia. Aliment. Pharm. 2016, 45, 283–290.
    138. Eross, B.; Farkas, N.; Vincze, A.; Tinusz, B.; Szapary, L.; Garami, A.; Balasko, M.; Sarlos, P.; Czopf, L.; Alizadeh, H.; et al. Helicobacter pylori infection reduces the risk of Barrett’s esophagus: A meta-analysis and systematic review. Helicobacter 2018, 23, e12504.
    139. Polyzos, S.A.; Zeglinas, C.; Artemaki, F.; Doulberis, M.; Kazakos, E.; Katsinelos, P.; Kountouras, J. Helicobacter pylori infection and esophageal adenocarcinoma: A review and a personal view. Ann. Gastroenterol. 2017, 31, 8–13.
    140. Gao, H.; Li, L.; Zhang, C.; Tu, J.; Geng, X.; Wang, J.; Zhou, X.; Jing, J.; Pan, W.-S. Systematic Review with Meta-analysis: Association of Helicobacter pylori Infection with Esophageal Cancer. Gastroenterol. Res. Pract. 2019, 2019, 1953497.
    141. Rossi, G.; Gambi, R.; Uncini, R.; Piccinini, R.; Berardi, S.; Pengo, G.; Bassotti, G.; Cerquetella, M. Severe gastritis with double Helicobacter spp. infection associated with Barrett’s esophagus in a cheetah. Helicobacter 2014, 19, 462–464.
    142. Graham, D.Y. Helicobacter pylori is not and never was “protective” against anything, including GERD. Dig. Dis. Sci. 2003, 48, 629–630.
    143. Kountouras, J.; Chatzopoulos, D.; Zavos, C. Eradication of Helicobacter pylori might halt the progress to oesophageal adenocarcinoma in patients with gastro-oesophageal reflux disease and Barrett’s oesophagus. Med. Hypotheses 2007, 68, 1174–1175.
    144. Schwizer, W.; Thumshirn, M.; Dent, J.; Guldenschuh, I.; Menne, D.; Cathomas, G.; Fried, M. Helicobacter pylori and symptomatic relapse of gastro-oesophageal reflux disease: A randomised controlled trial. Lancet 2001, 357, 1738–1742.
    145. Moayyedi, P.; Soo, S.; Deeks, J.J.; Delaney, B.C.; Harris, A.; Innes, M.; Oakes, R.; Wilson, S.; Roalfe, A.; Bennett, C.; et al. Withdrawn: Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst. Rev. 2011, 2001, CD002096.
    146. Kountouras, J.; Zavos, C.; Chatzopoulos, D.; Romiopoulos, I.; Polyzos, S.A.; Kapetanakis, N.; Tsiaousi, E.; Vardaka, E.; Deretzi, G.; Tsarouchas, G.; et al. Letter: Is Helicobacter pylori behind Barrett’s oesophagus and colorectal neoplasms? Aliment. Pharm. 2013, 37, 837.
    147. Kountouras, J.; Zavos, C.; Polyzos, S.A.; Katsinelos, P. Helicobacter pylori infection and gastroesophageal reflux disease-Barrett’s esophagus sequence “dilemma”. Ann. Gastroenterol. 2015, 28, 153.
    148. Doulberis, M.; Kountouras, J.; Polyzos, S.A.; Tzivras, D.; Vardaka, E.; Kountouras, C.; Tzilves, D.; Kotronis, G.; Boutsikou, E.; Gialamprinou, D.; et al. Impact of Helicobacter pylori and/or Helicobacter pylori-related metabolic syndrome on gastroesophageal reflux disease—Barrett’s esophagus- esophageal adenocarcinoma sequence. Helicobacter 2018, 23, e12534.
    149. Schwizer, W.; Menne, D.; Schütze, K.; Vieth, M.; Goergens, R.; Malfertheiner, P.; Leodolter, A.; Fried, M.; Fox, M.R. The effect of Helicobacter pylori infection and eradication in patients with gastro-oesophageal reflux disease: A parallel-group, double-blind, placebo-controlled multicentre study. United Eur. Gastroenterol. J. 2013, 1, 226–235.
    150. Aghayeva, S.; Mara, K.C.; Katzka, D.A. The impact of Helicobacter pylori on the presence of Barrett’s esophagus in Azerbaijan, a high-prevalence area of infection. Dis. Esophagus 2019, 32.
    151. Doorakkers, E.; Lagergren, J.; Santoni, G.; Engstrand, L.; Brusselaers, N. Helicobacter pylori eradication treatment and the risk of Barrett’s esophagus and esophageal adenocarcinoma. Helicobacter 2020, 25, e12688.
    152. Xie, F.-J. Helicobacter pyloriinfection and esophageal cancer risk: An updated meta-analysis. World J. Gastroenterol. 2013, 19, 6098–6107.
    153. Yaghoobi, M.; Farrokhyar, F.; Yuan, Y.; Hunt, R.H. Is There an Increased Risk of GERD After Helicobacter pylori Eradication?: A Meta-Analysis. Am. J. Gastroenterol. 2010, 105, 1007–1013.
    154. Saad, A.M.; Choudhary, A.; Bechtold, M.L. Effect of Helicobacter pyloritreatment on gastroesophageal reflux disease (GERD): Meta-analysis of randomized controlled trials. Scand. J. Gastroenterol. 2012, 47, 129–135.
    155. Qian, B.; Ma, S.; Shang, L.; Qian, J.; Zhang, G. Effects of Helicobacter pylori Eradication on Gastroesophageal Reflux Disease. Helicobacter 2011, 16, 255–265.
    156. Kumar, S.; Metz, D.C.; Ginsberg, G.G.; Kaplan, D.E.; Goldberg, D.S. Oesophageal and proximal gastric adenocarcinomas are rare after detection of Helicobacter pylori infection. Aliment. Pharm. 2020, 51, 781–788.
    157. Miyakoshi, N.; Kasukawa, Y.; Sasaki, H.; Kamo, K.; Shimada, Y. Impact of spinal kyphosis on gastroesophageal reflux disease symptoms in patients with osteoporosis. Osteoporos. Int. 2008, 20, 1193–1198.
    158. Yamane, Y.; Yamaguchi, T.; Tsumori, M.; Yamauchi, M.; Yano, S.; Yamamoto, M.; Honda, C.; Kinoshita, Y.; Sugimoto, T. Elcatonin is effective for lower back pain and the symptoms of gastroesophageal reflux disease in elderly osteoporotic patients with kyphosis. Geriatr. Gerontol. Int. 2011, 11, 215–220.
    159. Sugimoto, M.; Hasegawa, T.; Nishino, M.; Sahara, S.; Uotani, T.; Ichikawa, H.; Kagami, T.; Sugimoto, K.; Yamato, Y.; Togawa, D.; et al. Improvement of gastroesophageal reflux disease in Japanese patients with spinal kyphotic deformity who underwent surgical spinal correction. Dig. Endosc. 2015, 28, 50–58.
    160. Kumar, S.; Drake, M.T.; Schleck, C.D.; Johnson, M.L.; Alexander, J.A.; Katzka, D.A.; Iyer, P.G. Incidence and predictors of osteoporotic fractures in patients with Barrett’s oesophagus: A population-based nested case-control study. Aliment. Pharm. 2017, 46, 1094–1102.
    161. Malfertheiner, P.; Mégraud, F.; O’Morain, A.C.; Atherton, J.; Axon, A.T.R.; Bazzoli, F.; Gensini, G.F.; Gisbert, J.P.; Graham, D.Y.; Rokkas, T.; et al. Management of Helicobacter pyloriinfection—The Maastricht IV/Florence Consensus Report. Gut 2012, 61, 646–664.
    162. Zagari, R.M.; Romano, M.; Ojetti, V.; Stockbrugger, R.; Gullini, S.; Annibale, B.; Farinati, F.; Ierardi, E.; Maconi, G.; Rugge, M.; et al. Guidelines for the management of Helicobacter pylori infection in Italy: The III Working Group Consensus Report 2015. Dig. Liver Dis. 2015, 47, 903–912.
    More