H. Pylori is related to osteoporosis but only in premenopausal female: a cross-sectional study

Helicobacter pylori (H. pylori), a gram-negative, spiral-shaped microaerophilic bacterium, has been shown to be an important pathogen in gastrointestinal diseases [1]. Approximately 50% of the world population has been affected by H. pylori, and approximately 800 million Chinese individuals are affected by this disease. It may cause chronic inflammation of the gastric mucosa, which may lead to chronic atrophic gastritis, peptic ulcer diseases, and gastric cancer [2, 3]. Moreover, the latest reports have described the investigation of the extra-gastrointestinal effects of H. pylori, including metabolic syndrome [4], fatty liver [5], and rheumatic and skin diseases [6]. These parenteral diseases associated with H. pylori infection seriously affect the patient’s general condition and cause a series of complications.

Osteoporosis is an asymptomatic disease characterized by a decreased density of normally mineralized bone that usually occurs in elderly persons. It has been reported that approximately 2 million men and 8 million women over the age of 50 in the United States have been diagnosed with osteoporosis, with an estimated 34 million suffering from osteopenia [7]. In the development of osteoporosis, there is often a long latent period before the appearance of the main clinical manifestation: pathologic fractures. Moreover, the most prevalent sequelae of osteoporosis are compression fractures of the vertebral bodies and fractures of the ribs, proximal femurs, humeri, and distal radiuses, which could have a significant impact on the quality of life of elderly individuals. Therefore, the prevention and early detection of osteoporosis is particularly important for the elderly population.

A majority of studies support the idea that at any given age, women have a higher risk of fracture than men [8]. However, men tend to have worse outcomes after fracture than women: they are twice as likely to die after a hip fracture than women [9]. Moreover, sex-related factors remain unclear. Therefore, exploring the differences in factors influencing osteoporosis in males and females will be helpful to explore the pathogenesis of osteoporosis and early prevention of its occurrence and development.

There are some well-established risk factors for the emergence of osteoporosis, such as age, sex, body mass index, and alcohol consumption [10]. Recent articles have focused on H. pylori and osteoporosis. Different researchers have proposed different theories, including but not limited to, inflammation induced by H. pylori infection [11] and malabsorption of nutrients [12, 13]. However, there is still a lack of systematic data analyses on the relationship between H. pylori and osteoporosis. The association between osteoporosis and H. pylori has been studied by many Japanese scientists and remains controversial. In addition, there are still some deficiencies in existing research. Few studies have focused on the correlation between H. pylori and osteoporosis in Chinese premenopausal females. The sample sizes have been insufficient, there is a lack of investigations on the influence of sex, and there is a lack of sufficient serum markers. The aim of this study was to investigate the relationship between H. pylori and osteoporosis and to identify potential influencing factors.

The baseline characteristics of the participants are shown in Table 1. The mean age was 54.53 ± 0.238 years, 167 (73.2%) were male, and 76 (26.8%) were female. Among the study population, 40 (17.5%) had osteoporosis, 77 (33.8%) had osteopenia, and 111 (48.7%) had normal BMDs. The mean ages of the osteoporosis, osteopenia and normal groups were 53.43 ± 2.836, 54.53 ± 3.589 and 53.98 ± 3.205, respectively. There were no significant differences in age among the participants in the osteoporosis, osteopenia and normal BMD groups. Fifty percent of the males had normal BMDs, 34.7% of the males had osteopenia, and 15.0% of the males had osteoporosis. In addition, 44.3% of the females had normal BMDs, 31.1% of the females had osteopenia, and 24.6% of the females had osteoporosis. There was no significant difference in sex distribution among these three groups.

Among all the study participants, 35.5% had H. pylori infections, and 64.5% did not have H. pylori infections. Table 1 shows that CA724 (t = 2.265, P = 0.025) was significantly different between the study participants with H. pylori infection and those without H. pylori infection, and there were no significant differences between the H. pylori infection status and the BMD status groups.

In Table 2, we separate the study population according to sex. We found that there was a significant relationship between H. pylori infection status and bone density in females (P = 0.025) but not in males (P = 0.381).

As shown in Table 3, there was a significant association of H. pylori positivity (OR = 0.132, 95% CI 0.023–0.753, P = 0.023), BMI (OR = 28.163, 95% CI 1.647–481.545, P = 0.021), and HCY (OR = 17.218, 95% CI 1.061–279.779, P = 0.045) with osteoporosis in premenopausal females. Ca (OR = 0.060, 95% CI 0.003–1.347, P = 0.076) and TC (OR = 7.250, 95% CI 0.773–68.033, P = 0.076) had a trend, but neither was significantly associated with osteoporosis.

Meanwhile, we analysed the differences in markers between males and females, which are shown in Table 4. We found that age (P < 0.001), SP (P < 0.001), BP (P < 0.001), BMI (P < 0.001), WHR (P < 0.001), Hb (P < 0.001), platelets (P < 0.001), UA (P < 0.001), TC (P = 0.002), TG (P = 0.006), HDL-C (P < 0.001), GLU (P = 0.002), CEA (P < 0.001), Ghb (P = 0.029), iron (P < 0.001), HCY (P < 0.001), and B12 (P = 0.002) demonstrated significant differences between males and females.

The relationship between sex and markers is shown in Table 5. We found that WHR (OR = 5.783, 95% CI 1.192–28.078, P = 0.029), TG (OR = 0.201, 95% CI 0.045–0.902, P = 0.036), and BMI (OR = 0.152, 95% CI 0.034–0.688, P = 0.014) were significantly different by sex, adjusting for age as a confounder.

Osteoporosis is an important health and societal burden in elderly people, not only in females but also in males. There are numerous osteoporosis-related fracture risk factors, including age, sex, race, lifestyle and concomitant medical conditions [16]. In men, osteoporosis is underrecognized and undertreated. Only a few men are screened for osteoporosis, even after a fracture [17]. The treatment rate is much lower in males than in females [18]. Meanwhile, more men than women die every year due to hip fractures [19]. Hence, we also included men in the study population to determine the risk factors for osteoporosis.

Some studies about the influence of sex on osteoporosis remain controversial. In our study, there was a significant relationship between H. pylori and osteoporosis in premenopausal females but not in males. The reasons for the difference between males and females are as follows: First, differences in clinical outcomes of osteoporosis in men and women may be rooted in the biologic properties of bone. Barrett-Connor E holds the view that there are sex-specific differences in the number of osteoprogenitor cells and in hormone responses and regulation [20, 21]. Second, men have a greater bone size, trabecular BMD and bone area at the radius and tibia than women, even after adjusting for weight and height, which may lead to a decrease in osteoporosis and fracture [22]. Third, men undergo a slow decrease in BMD with increasing age, while women experience a profound period of rapid bone resorption, especially after entering menopause [23]. Last but not least, some studies support the idea that men are more likely to suffer from secondary disease, for example, rheumatoid arthritis, alcoholism, excessive smoking, gonadal deficiencies and others [24], which may lead to sustainable bone loss.

Unfortunately, the relationship between osteoporosis and H. pylori infection is still controversial. Some studies hold the view that there is no difference between men and women in the relationship between H. pylori and osteoporosis [25, 26]. Some studies hold the view that H. pylori is related to osteoporosis only in women. Shih-Chun Lin conducted a retrospective study including 365 women and showed that H. pylori is related to osteoporosis in females [27], while others think that there is no correlation between them in females. Daisuke Chinda conducted a study of 473 healthy women and found that H. pylori is not a significant risk factor for osteopenia [28]. In our study, we analysed the relationship between H. pylori infection and osteoporosis. We found a significant relationship between H. pylori infection status and bone density in premenopausal females but not in males. We suspect this may be due to the difference in the aetiology of osteoporosis between males and females. However, we did not find any other studies on this, and it requires more systematic research for analysis.

After analysing the differences between males and females, we found that there were significant differences in BMI, WHR, and TG in the study population. This study provides evidence for follow-up research on sex differences in the relationship between H. pylori and osteoporosis.

Most studies hold the view that obesity is related to osteoporosis [29]. It is generally believed that obesity may be a protective factor against bone loss and osteoporosis [30]. However, the effect of obesity remains unclear. On the one hand, obesity has traditionally been considered positive for bone because of the beneficial effect of mechanical loading [31]. On the other hand, people hold the view that BMI may harm BMD. Osteoblasts and adipocytes both stem from marrow mesenchymal stromal cells. Osteoblasts and adipocytes are in a competitive relationship, and an increase in adipocytes will inhibit osteoblasts [30]. In our study, there was a significant relationship between BMI and osteoporosis. Increased BMD levels in obese people may be associated with increased mechanical loading and strain; this is a complicated problem that cannot be generalized.

In our study, we found that H. pylori infection is associated with a decrease in bone density. The possible reasons are as follows: First, H. pylori infection may cause systemic inflammation and increase the production of tumour necrosis factor-α, interleukin-1, and interleukin-6 [11]. These cytokines are directly involved in the reduction of BMD. We found that HCY is related to osteoporosis, which supports this hypothesis. Second, osteoporosis may be related to a decrease in vitamin B12 levels [32]. Serin et al.’s study examined 145 patients without atrophy, erosions or ulcers, and they found that the histopathological scores for both antral and corpus H. pylori density and inflammation were significantly inversely associated with serum vitamin B12 levels [13]. In our study, although we did not find a significant relationship between B12 and osteoporosis, we still support the relevant theory. The absence of our results may be due to a lack of sufficient data and the influence of confounding factors. Last but not least, most patients chronically infected with H. pylori manifest pangastritis with reduced acid secretion due to bacterial virulence factors, inflammatory cytokines, and various degrees of gastric atrophy [33]. Calcium is ionized in acidic conditions and absorbed in the small bowel. Therefore, in either hypochlorhydria or achlorhydric stomachs, calcium absorption is impaired [12]. Moreover, the long-term use of acid suppressants, for example, proton pump inhibitors, may lead to osteoporosis or a decrease in BMD. Limited experimental evidence indicates that PPI may influence calcium absorption, leading to compensatory physiologic responses, including secondary hyperparathyroidism, which may cause an increase in the rate of osteoclastic bone resorption [34]. The results showed that calcium had a trend, though it was not statistically significant (P = 0.076), with osteoporosis. Our results do not support the theory that there is a correlation between Ca and osteoporosis, but it may be that Helicobacter pylori infection may cause calcium absorption damage and affect BMD. We did not analyse vitamin D levels, which could affect both bone homeostasis and the inflammatory state [35]. Although H. pylori infection causing a decrease in bone density is supported by most researchers, the effect of early eradication therapy is still insufficient. Replogle ML holds the view that early eradication therapy may eliminate chronic inflammation from H. pylori [36]. Some articles have also reported an improvement in B12 levels after complete eradication [13, 37], which requires further investigation.

Despite its relevant findings, our study had several limitations. First, because most patients cannot remember the time of HP infection accurately, we were not able to obtain the time of HP infection, so different infection times may have had an impact on the results. Second, we did not collect vitamin D data, the sample size of our data was not large enough, and the study population only included participants from Beijing Shijitan Hospital, meaning that there might have confounding factors because of differences in the distribution of hospital study populations. Further large-scale studies in the general population are needed to validate our results. Third, the study participants were all Chinese, and the findings might not be generalizable to other ethnic populations. In addition, we only found some differences between men and women but failed to further explore them.

H. pylori is associated with osteoporosis in premenopausal females. BMI and HCY are related to osteoporosis in premenopausal females. Chronic inflammation may be involved in the relationship between H. pylori and osteoporosis.