Advertisement

Digestive Diseases and Sciences

, Volume 64, Issue 10, pp 2736–2739 | Cite as

Bone of Contention: Helicobacter pylori and Osteoporosis—Is There an Association?

  • Konstantinos PapamichaelEmail author
  • Garyfallia Papaioannou
  • Marcy A. Cheifetz
  • Adam S. Cheifetz
Current Clinical Controversies

Abstract

Helicobacter pylori (H. pylori) infection is a common disease that can cause chronic gastritis, peptic ulcers, and gastric cancer. Nevertheless, due to its ability to elicit a systemic inflammatory response, it has also been related to several extra-gastric manifestations including endocrine disorders, such as autoimmune thyroid diseases, diabetes mellitus, dyslipidemia, and obesity. H. pylori infection has also been linked to osteoporosis, although currently available data are equivocal. This brief review will focus on the possible association between H. pylori infection and osteoporosis, a silent disease characterized by decreased bone mass that can increase the occurrence of fractures, disability, and mortality.

Keywords

Helicobacter pylori Osteoporosis Endocrine Fracture Bone 

Introduction

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that can cause chronic gastritis, peptic ulcer disease, and gastric malignancies [1]. Yet, H. pylori infection has also been linked to several extra-digestive conditions, including endocrine disorders, probably due to the induction of a chronic systemic inflammatory response characterized by an increase in pro-inflammatory cytokines [2, 3]. One of the most important extra-gastric manifestations possibly associated with H. pylori infection is osteoporosis, a silent endocrine disease characterized by decreased bone mass that can increase the risk of fractures, disability, and mortality. Although osteoporosis is most often considered a disease of postmenopausal women, it also affects males, significantly increasing the risk of fragility fractures, especially in individuals older than 50 years [4, 5]. There are four potential mechanisms that could underlie a relationship between H. pylori infection and osteoporosis. First, H. pylori can increase the release of the pro-inflammatory cytokines tumor necrosis factor, interleukin (IL)-1, and IL-6, all of which activate osteoclast differentiation, ultimately increasing bone resorption and decreasing bone mass [2, 6, 7]. However, a study from Huang et al. refutes the concept that systemic inflammation is associated with osteoporosis suggesting that H. pylori infection has something besides inflammation that may cause osteoporosis [8]. Chronic H. pylori infection may cause gastric mucosal atrophy and consequently reduce acid secretion that in turn inhibits calcium absorption and thereby has the potential to adversely affect bone mass [9]. Similarly, the chronic use of proton pump inhibitors (PPIs) for treatment or prophylaxis for gastroduodenal mucosal injury has been correlated with decreased bone mineral density (BMD) and bone fractures [10]. Finally, another potential mechanism regarding osteoporosis in men could be a reduction in the systemic levels of estrogens, which, in turn, may increase bone resorption by CagA + H. pylori strains [11].

This brief review will focus on the clinical data regarding the relationship between H. pylori infection and osteoporosis.

Helicobacter Pylori and Osteoporosis

The current literature regarding the potential associations between H. pylori and osteoporosis is summarized in Table 1 [9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. Several studies have demonstrated that H. pylori infection is an independent risk factor for osteoporosis [18, 21, 23] or decreased BMD [22, 24]. Another study showed that H. pylori was associated with a significant decrease in mean lumbar BMD (1.190 vs. 1.219 g/cm2; p = 0.006), which was greatest among men who were ≥ 50 years old (1.193 vs. 1.233 g/cm2; p = 0.006), although no significant association was observed in the BMDs of the total femur or femoral neck [19]. Moreover, Figura et al. [11] showed that infection by CagA + H. pylori strains was more prevalent in men with osteoporosis compared to the general population, reporting increased urinary cross-laps and bone turnover. Finally, using data from Taiwan’s National Health Insurance Research Database, Shih et al. [26] reported that early compared to late eradication may reduce the influence of H. pylori infection on osteoporosis in the long term (follow-up period > 5 years). This may be explained by the observation that cytokine gene expression is significantly decreased and mucosal atrophy of the stomach is markedly improved after H. pylori eradication [27, 28]. Conversely, other studies have not supported such an association between H. pylori infection and osteoporosis or decreased BMD [9, 12, 13, 14, 15, 16, 17, 25]. For example, Kalantarhormozi et al. [12] found that H. pylori IgG seropositivity did not predict the risk of lumbar osteoporosis after nearly 6 years of follow-up. More recently, a cross-sectional study regarding 268 healthy men showed that decreased bone density was not associated with H. pylori infection and H. pylori-associated gastric mucosal atrophy or estradiol level [25]. A systematic review and meta-analysis of 1321 adults who had no other causes of osteoporosis or pathological bone disease at baseline showed no significant association between H. pylori infection and osteoporosis, with a pooled odds ratio (OR) = 1.49 [95% confidence interval (CI): 0.88–2.55; p = 0.14; I2 = 52%) [29]. Nevertheless, this involved only five studies (four cross-sectional and one prospective cohort study), performed in East Asian countries (Japan, South Korea, and Taiwan), and included only postmenopausal women, with the exception of one study by Asaoka et al. [21] On the other hand, a very recent systematic review and meta-analysis of 21 case–control studies including 9655 participants showed that H. pylori infection was associated with osteoporosis (OR: 1.39, 95%CI: 1.13–1.71), although the decrease in bone mineral density in H. pylori-positive patients was not significant when compared with H. pylori-negative controls, probably due to the sample size. However, as the authors also state, the results of the meta-analysis should be interpreted with caution due to the number and quality of studies included and obvious heterogeneity. Moreover, causality cannot be established as in these observational studies the chronological order between H. pylori infection and osteoporosis cannot be confirmed [30].
Table 1

Clinical data regarding the potential association between Helicobacter pylori infection and osteoporosis or decreased bone mineral density

Study type

Country of study origin

N

Study population

Association of Hp with osteoporosis or ↓ BMD

OR (95% CI); p value

Assessment of Hp infection

Ref.

Cross-sectional

Brazil

85

Women

No

N.R.

UBT/histology

[9]

Cross-sectional and prospective cohort analyses

Japan

250

Healthy postmenopausal women

No

Cross-sectional: 1.02 (0.39–2.55); p = 0.997

Prospective cohort: 0.965 (0.51–1.80); p = 0.910

Anti-Hp IgG

[12]

Cross-sectional

Brazil

50

Postmenopausal women

No

N.R.

UBT/histology

[13]

Cross-sectional

Iran

967

Men and women aged ≥ 60 years

No

0.759 (0.55–1.045)

Anti-Hp IgG

[14]

Cross-sectional

Japan

473

Healthy women

No

0.95 (0.55–1.63); p = 0.84

Anti-Hp IgG/Hp antigen in stool

[15]

Cross-sectional

China

1867

Men and women

No

N.R.

UBT

[17]

Cross-sectional

Japan

200

Men and women

Yes

5.33 (1.73–16.42); p = 0.004

UBT/Anti-Hp IgG

[18]

Cross-sectional

Korea

112

Men

Yes

N.R.

Anti-Hp IgG

[19]

Case-control

Italy

240

Osteoporotic male patients

Yes

N.R.

Anti-Hp IgG

[11]

Cross-sectional

Japan

255

Outpatients aged ≥ 50 years

Yes

3.00 (1.31–6.88); p = 0.009

UBT/Anti-Hp IgG

[21]

Cross-sectional

Japan

230

Men aged 50–60 years

Yes

1.83 (1.04–3.21); p = 0.030

Anti-Hp IgG

[22]

Cross-sectional

Taiwan

365

Women aged ≥ 65 years

Yes

2.03 (1.14–3.6); p = 0.016

UBT/histology

[23]

Cross-sectional

Taiwan

867

Men and women

Yes

1.62 (1.12–2.35); p = 0.011

Histology

[24]

Cross-sectional

Japan

268

Healthy men

No

With gastric mucosal atrophy: 0.74 (0.29–1.90); p = 0.531

Without gastric mucosal atrophy: 1.31 (0.54–3.21); p = 0.552

Anti-Hp IgG

[25]

Hp Helicobacter pylori, BMD bone mineral density, Ref reference, UBT13C-urea breath test, Ig immunoglobulin, OR odds ratio, CI confidence intervals, N.R. not reported

This discrepancy may be attributed to the differences in the study design and to methodological issues, including differences in the site of BMD measurement and whether serologic testing or histological examination was used to diagnose H. pylori infection (Table 1). Additionally, heterogeneity of the study population may also contribute, including differences in gender, age, ethnicity, education, nutrition, sunlight exposure, and risk factors for osteoporosis, such as family history of osteoporosis, smoking, alcohol consumption, low dietary calcium intake, lack of physical activity, corticosteroid use, low body weight, and gastrointestinal disorders (celiac disease, inflammatory bowel disease, and gastrectomy) [31, 32]. Another cause of contradictory results across studies is the fact that osteoporosis is a heterogeneous condition with respect to etiology, age, and gender. The independent association of H. pylori-induced inflammation and bone loss is difficult to differentiate from several other factors associated with bone loss; in particular, bone loss is expected to occur in patients with chronic inflammation. In a seropositive patient, the duration of inflammation and its contribution to the development of osteoporosis are still unclear.

Conclusion

H. pylori infection, a common cause of chronic gastritis, peptic ulcers, and gastric cancer, may also be potentially associated with the development of osteoporosis, although data are currently equivocal, derived mostly from small cross-sectional studies. Weaknesses of the current literature include a retrospective, single-center study design (thus studies are marred by selection bias and missing data), small sample size, short follow-up time, and the lack of investigation of important independent risk factors for osteoporosis. The studies also mostly lack endoscopic assessment of the severity, duration of H. pylori infection, and measurement of systemic inflammatory markers. Ultimately, large prospective studies are required to definitively determine whether there is a causal relationship between H. pylori infection and osteoporosis and whether H. pylori eradication may reduce the development of bone loss. This information would be of high clinical importance given the significant prevalence of osteoporosis and fragility fracture worldwide, with a potentially vast impact on human health and health economics.

Notes

Author’s contribution

K.P. and G.P. wrote the manuscript; A.S.C. and M.A.C. critically revised the manuscript. All the authors reviewed and approved the final manuscript.

Compliance with Ethical Standards

Conflict of interest

A.S.C has received consulting fees from Abbvie, Janssen, Takeda Pfizer, Amag, and Arena and research support from Miraca. K.P. has received a lecture fee from Mitsubishi Tanabe Pharma. The remaining authors declare no conflict of interest.

References

  1. 1.
    Huang H, Tian J, Xu X, et al. A study on the roles of Helicobacter pylori in bile reflux gastritis and gastric cancer. J BUON. 2018;23:659–664.Google Scholar
  2. 2.
    Perri F, Clemente R, Festa V, et al. A Serum tumour necrosis factor-alpha is increased in patients with Helicobacter pylori infection and CagA antibodies. Ital J Gastroenterol Hepatol. 1999;31:290–294.Google Scholar
  3. 3.
    Papamichael KX, Papaioannou G, Karga H, et al. Helicobacter pylori infection and endocrine disorders: Is there a link? World J Gastroenterol. 2009;15:2701–2707.CrossRefGoogle Scholar
  4. 4.
    Sidlauskas KM, Sutton EE, Biddle MA. Osteoporosis in men: Epidemiology and treatment with denosumab. Clin Interv Aging. 2014;9:593–601.Google Scholar
  5. 5.
    Milte R, Crotty M. Musculoskeletal health, frailty and functional decline. Best Pract Res Clin Rheumatol. 2014;28:395–410.CrossRefGoogle Scholar
  6. 6.
    Ferrari SL, Karasik D, Liu J, et al. Interactions of interleukin-6 promoter polymorphisms with dietary and lifestyle factors and their association with bone mass in men and women from the Framingham Osteoporosis Study. J Bone Miner Res. 2004;19:552–559.CrossRefGoogle Scholar
  7. 7.
    Chung HW, Seo JS, Hur SE, et al. Association of interleukin-6 promoter variant with bone mineral density in pre-menopausal women. J Hum Genet. 2003;48:243–248.CrossRefGoogle Scholar
  8. 8.
    Huang JV, Schooling CM. Inflammation and bone mineral density: A Mendelian randomization study. Sci Rep. 2017;7:8666.CrossRefGoogle Scholar
  9. 9.
    Kakehasi AM, Rodrigues CB, Carvalho AV, et al. Chronic gastritis and bone mineral density in women. Dig Dis Sci. 2009;54:819–824.CrossRefGoogle Scholar
  10. 10.
    Andersen BN, Johansen PB, Abrahamsen B. Proton pump inhibitors and osteoporosis. Curr Opin Rheumatol. 2016;28:420–425.CrossRefGoogle Scholar
  11. 11.
    Figura N, Gennari L, Merlotti D, et al. Prevalence of Helicobacter pylori infection in male patients with osteoporosis and controls. Dig Dis Sci. 2005;50:847–852.CrossRefGoogle Scholar
  12. 12.
    Kalantarhormozi MR, Assadi M, Vahdat K, et al. Chlamydia pneumoniae and Helicobacter pylori IgG seropositivities are not predictors of osteoporosis-associated bone loss: A prospective cohort study. J Bone Miner Metab. 2016;34:422–428.CrossRefGoogle Scholar
  13. 13.
    Kakehasi AM, Mendes CM, Coelho LG, et al. 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.CrossRefGoogle Scholar
  14. 14.
    Fotouk-Kiai M, Hoseini SR, Meftah N, et al. Relationship between Helicobacter pylori infection (Hp) and bone mineral density (BMD) in elderly people. Casp J Intern Med. 2015;6:62–66.Google Scholar
  15. 15.
    Chinda D, Shimoyama T, Iino C, et al. Decrease of estradiol and several lifestyle factors, but not Helicobacter pylori infection, are significant risks for osteopenia in Japanese females. Digestion. 2017;96:103–109.CrossRefGoogle Scholar
  16. 16.
    Heidari B, Muhammadi A, Javadian Y, et al. Associated factors of bone mineral density and osteoporosis in elderly males. Int J Endocrinol Metab. 2017;15:e39662.Google Scholar
  17. 17.
    Lu LJ, Hao NB, Liu JJ, et al. Correlation between Helicobacter pylori infection and metabolic abnormality in general population: A cross-sectional study. Gastroenterol Res Pract. 2018;2018:7410801.Google Scholar
  18. 18.
    Asaoka D, Nagahara A, Hojo M, et al. The relationship between H. pylori infection and osteoporosis in Japan. Gastroenterol Res Pract. 2014;2014:340765.CrossRefGoogle Scholar
  19. 19.
    Chung YH, Gwak JS, Hong SW, et al. Helicobacter pylori: A possible risk factor for bone health. Korean J Fam Med. 2015;36:239–244.CrossRefGoogle Scholar
  20. 20.
    Chen LW, Chen FP, Hsieh CW, et al. Analysis of the associations among Helicobacter pylori infection, adiponectin, leptin, and 10-year fracture risk using the fracture risk assessment tool: A cross-sectional community-based study. PLoS ONE. 2017;12:e0175365.CrossRefGoogle Scholar
  21. 21.
    Asaoka D, Nagahara A, Shimada Y, et al. Risk factors for osteoporosis in Japan: Is it associated with Helicobacter pylori? Ther Clin Risk Manag. 2015;11:381–391.CrossRefGoogle Scholar
  22. 22.
    Mizuno S, Matsui D, Watanabe I, et al. Serologically determined gastric mucosal condition is a predictive factor for osteoporosis in Japanese men. Dig Dis Sci. 2015;60:2063–2069.CrossRefGoogle Scholar
  23. 23.
    Lin SC, Koo M, Tsai KW. Association between Helicobacter pylori infection and risk of osteoporosis in elderly Taiwanese women with upper gastrointestinal diseases: A retrospective patient record review. Gastroenterol Res Pract. 2014;2014:814756.Google Scholar
  24. 24.
    Pan BL, Huang CF, Chuah SK, et al. Relationship between Helicobacter pylori infection and bone mineral density: A retrospective cross-sectional study. BMC Gastroenterol. 2018;18:54.CrossRefGoogle Scholar
  25. 25.
    Chinda D, Shimoyama T, Sawada K, et al. Lifestyle factors rather than Helicobacter pylori infection or estradiol level are associated with osteopenia in Japanese men. Am J Mens Health. 2019;13:1557988319848219.Google Scholar
  26. 26.
    Shih HM, Hsu TY, Chen CY. Analysis of patients with Helicobacter pylori infection and the subsequent risk of developing osteoporosis after eradication therapy: A nationwide population-based cohort study. PLoS ONE. 2016;11:e0162645.CrossRefGoogle Scholar
  27. 27.
    Moss S, Legon S, Davies J, Calam J. Cytokine gene expression in Helicobacter pylori associated antral gastritis. Gut. 1994;35:1567–1570.CrossRefGoogle Scholar
  28. 28.
    Rokkas T, Pistiolas D, Sechopoulos P, et al. The long-term impact of Helicobacter pylori eradication on gastric histology: A systematic review and meta-analysis. Helicobacter. 2007;12:32–38.CrossRefGoogle Scholar
  29. 29.
    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. 2016;34:482–483.CrossRefGoogle Scholar
  30. 30.
    Wang T, Li X, Zhang Q, et al. Relationship between Helicobacter pylori infection and osteoporosis: A systematic review and meta-analysis. BMJ Open. 2019;9:e027356.CrossRefGoogle Scholar
  31. 31.
    Bours SP, van Geel TA, Geusens PP, et al. Contributors to secondary osteoporosis and metabolic bone diseases in patients presenting with a clinical fracture. J Clin Endocrinol Metab. 2011;96:1360–1367.CrossRefGoogle Scholar
  32. 32.
    Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006;194:S3–S11.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.North Florida Regional Medical Center, Internal Medicine Residency Program, College of MedicineUniversity of Central FloridaGainesvilleUSA
  3. 3.Department of EndocrinologyHarvard Vanguard Medical Associates/Atrius HealthChestnut HillUSA

Personalised recommendations