Osteoporosis is a systemic skeletal disease characterized by a relatively low bone mineral density (BMD) and increased susceptibility to fracture.¹⁾ There is an increasing incidence of osteoporosis-related fractures and the related mortality rate, as a high proportion of the global population is affected by osteoporosis.^2,3,4) Although this disease historically has been considered more common among women, it has been reported recently that the prevalence of osteoporosis and fractures among men has increased, owing to their increasing life expectancy and the growing population of elderly men.⁵⁾ Almost 20% of men who are ≥50 years old have osteoporosis,⁶⁾ and femoral fracture-related deaths are more common among men than among women.⁷⁾ During their lifetime, 25% of men are likely to experience an osteoporosis-related fracture,⁸⁾ and therefore premature death and disability due to osteoporosis are recognized as important public health concerns.⁵⁾

There are two main types of osteoporosis: primary and secondary. The cause of primary osteoporosis is unknown (idiopathic osteoporosis), while that of secondary osteoporosis is relatively well understood. Approximately 40% of osteoporosis cases in men are classified as primary osteoporosis.^7,9) Therefore, the majority of male osteoporosis cases have at least one (occasionally more than one) secondary cause, and it is important to identify the risk factors associated with secondary osteoporosis, thereby facilitating the interventions needed for prevention. Known risk factors associated with osteoporosis include race, a family history of osteoporosis, age of menarche, smoking, alcohol consumption, low dietary calcium intake, lack of physical activity, various medications, various endocrine disorders, and low body weight.^1,10) Moreover, inflammatory bowel disease, celiac disease, and gastrectomy also are known risk factors of osteoporosis.¹¹⁾

Helicobacter pylori (H. pylori) infection causes chronic gastritis by inducing a localized and systematic inflammatory response that may increase the concentrations of tumor necrosis factor-α, interleukin-1, and interleukin-6, which are known to affect BMD.^12,13,14) However, few studies have assessed the relationship between H. pylori infection and BMD, especially in men.^{15,16,17,18,19)} In this study, we confined our analysis to men because the effect of estrogen on BMD is very strong compared to H. pylori. Therefore, the aim of the present study was to verify whether H. pylori infection is a risk factor for osteoporosis, by analyzing the relationship between H. pylori infection and BMD in Korean men.

In the present study, we analyzed the difference in BMD according to H. pylori infection status, and observed that H. pylori infection could negatively affect BMD. This effect was enhanced among men who were ≥50 years old, compared to that among younger men. The reason for this finding may be related to the long-term exposure to inflammation caused by H. pylori infection. Therefore, we believe that monitoring for (and if necessary, eradicating) H. pylori infection may be warranted in this high-risk group.

The hypothesis that H. pylori infection can induce localized and systemic inflammation, thereby increasing the production of inflammatory cytokines such as tumor necrosis factor-α, interleukin-1, and interleukin-6 (which are known to affect BMD) has been reported in previous studies.^{12,13,14,22,23)} Another study investigated the possibility that H. pylori infection might increase the risk of osteoporosis (due to altered bone metabolism) in a group of male subjects with osteoporosis. The authors examined serum antibodies to H. pylori and the cytotoxin-associated gene A (CagA) protein among 80 osteoporotic men and 160 controls, and found that infections with CagA-positive H. pylori strains were more prevalent among men with osteoporosis. Therefore, infection with H. pylori strains expressing CagA may be a risk factor for osteoporosis in men.¹⁶⁾ Another study of 50 Western women (>49 years old) who were >5 years after menopause examined the degree of atrophy of the gastric mucosa and prevalence of H. pylori infection using endoscopic biopsy. However, the authors concluded that the association between H. pylori infection and osteoporosis was not statistically significant.¹⁸⁾ It is also possible that H. pylori infected subjects, due to digestive symptoms, are more likely to take proton pump inhibitors, which in turn can affect BMD.^24,25)

In the present study, a reduction in the mean lumbar BMD was observed among the H. pylori-positive group. This finding supports the hypothesis that H. pylori infection may affect BMD. According to previous studies, the average annual reduction in lumbar spine BMD among men without existing osteoarthritis is approximately 0.001 to 0.006 g/cm².^26,27,28) Given this relatively small average annual reduction, the mean difference of 0.029 g/cm² that we observed between the H. pylori-positive and negative groups may be of significant clinical relevance. Interestingly, the reduction in lumbar spine BMD was greatest among subjects who were ≥50 years old, which may indicate that chronic infection is associated with a greater reduction in BMD.

However, unlike BMD at the lumbar spine, BMD at the femoral neck and total femur was not associated with H. pylori infection status. These differences might be due to the differences in the composition and characteristics of the lumbar spine and femur. Trabecular bone accounts for 70% to 100% of the lumbar spine, whereas cortical bone accounts for approximately 75% of the femur neck and 50% of the femoral diaphysis, with trabecular bone accounting for 100% of Ward's triangle.²⁹⁾ Thus, the lumbar vertebrae and femur may differ in their speed of progression and features of osteoporosis, as previous studies have reported that the risk factors for osteoporosis might be different at two sites.^30,31,32) Therefore, we recommend that future studies focus on the mechanism through which H. pylori affects BMD reduction in different parts of the body.

The present study has several limitations. First, a causal relationship cannot be established, as this study was based on cross-sectional data. Second, this study did not consider dietary calcium intake and serum 25-(OH) vitamin D concentrations, which might affect BMD. Third, the study population was selected from voluntary health check-up participants, which do not represent the general Korean population. Fourth, H. pylori infection was evaluated using serologic testing, rather than histological examination. However, a positive serologic result for H. pylori may indicate past infection, rather than a current infection, and therefore long-standing effects must be evaluated. Unfortunately, using biopsy to detect H. pylori infection in our clinic would likely lead to the selection of patients with gastritis or ulcers, thereby creating a selection bias in our analysis. Thus, evaluating the correlation between H. pylori infection status and BMD using serological testing could reduce this bias, and we believe this is one of the advantages of the present study.

In conclusion, we observed that H. pylori infection was significantly associated with a decrease in BMD at the lumbar spine after adjusting for bone-related factors that might affect BMD. Given the statistical power generated by the large study population, these results might facilitate the development of clinical interventions for screening, assessment, and management of male osteoporosis. We recommend that further prospective studies evaluate the causal relationship between H. pylori infection and decreased BMD among a large patient population.