Establishing the Association Between Osteoporosis and Peptic Ulcer Disease: A Systematic Review

Osteoporosis is one of the most common metabolic bone diseases. Many studies were conducted to find the association between peptic ulcer disease (PUD), Helicobacter pylori infection, proton-pump inhibitor (PPI) use, and increased risk for fracture, but results remain ambiguous. We performed this systematic review to understand the association between PUD and osteoporosis. We comprehensively searched relevant articles on April 19, 2022, by exploring different databases including PubMed, PubMed Central (PMC), and Medline using relevant keywords. After applying inclusion and exclusion criteria and undergoing quality assessment, we retained 25 studies published in and after 2015. For our systematic review, we included a total of 5,600,636 participants. The studies included in our review demonstrated a significant association between PUD, H. pylori infection, and the risk of osteoporosis. Long-term PPI use was also found to be a risk factor for osteoporosis. Malabsorption of nutrients, increase in inflammatory cytokines, and alterations in hormone status were found to be the notable factors behind the association. Early management of H. pylori infection and cautious use of long-term PPIs may protect against osteoporosis. Further randomized controlled trials (RCTs) are necessary to establish a causal relationship.


Introduction And Background
Osteoporosis, also known as the "silent disease", is one of the most common metabolic bone diseases characterized by reduced bone mineral density (BMD), impaired bone strength, increased bone fragility, and increased susceptibility to fractures, especially in hip and spine [1,2]. Osteoporosis has become a considerable health concern for individuals and societies [3]. The disability, morbidity, and mortality caused by osteoporosis impose a significant burden on affected individuals, their families, and the health care system [4]. Therefore, the potential burden of osteoporosis should be mitigated by identifying the risk factors and the population at risk of this disease [2].
Peptic ulcer disease (PUD) develops when the gastrointestinal protective mechanisms, such as bicarbonate and mucus secretion, are overwhelmed by the detrimental effects of gastric acid and pepsin [5]. The risk factors for PUD include Helicobacter pylori infection, nonsteroidal anti-inflammatory (NSAID) use, aspirin use, tobacco smoking, and a low level of physical activity [6]. PUD presents with ulcers along the stomach or duodenal lining, causing burning pain. It may result in complications such as ulcer perforation and internal hemorrhage [7].
Proton-pump inhibitor (PPI), one of the widely used drug classes in the world, is used for PUD management as well as for H. pylori eradication regimens [8,9]. PPIs are also one of the most commonly used off-label drugs, with 25%-70% of total prescriptions having no appropriate indication [10]. Despite excellent efficacy and trivial short-term side effects, rising concerns regarding long-term adverse effects of PPI use such as the risk of osteoporosis-related fracture, vitamin B12 deficiency, renal injury, Clostridium difficile infection, community-acquired pneumonia, and dementia is emerging [11]. Several studies have demonstrated a significant positive association between PUD, long-term PPI use, and increased incidence of osteoporotic fracture risk [2,[12][13][14][15][16][17][18][19]. Therefore, this systematic review aims to explore the association between osteoporosis and PUD and understand the different mechanisms by which osteoporosis emerges as a complication of PUD.

Methods
We conducted this systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [20]. A comprehensive literature search of electronic databases, including PubMed, PubMed Central (PMC), and Medline, was conducted on April 19, 2022. We searched for relevant studies using generic keywords "osteoporosis" AND "peptic ulcer" and identified 227 studies. The relevant terms of Medical Subject Headings (MeSH) were used in combination, and we got 73,687 studies. We also reviewed the reference section of the retrieved articles for additional relevant studies that were possibly missed in the initial search and obtained 21 articles. After applying inclusion and exclusion criteria and screening the articles by title, abstract, and full text, 25 reports were available for quality assessment, after which all the studies were retained.

Inclusion Criteria
We included articles published in English between 2015 and 2022 involving human participants and articles in full-text format. Meta-analyses, systematic reviews, RCT, cohort studies, case-control studies, and traditional reviews were included.

Exclusion Criteria
Gray literature, case reports, case series, animal studies, overlapping studies, studies not written in English, studies with inaccessible full text, and studies published before 2015 were excluded.

Results
We identified a total of 73,914 articles through search strategy and 21 articles from other sources identified mainly by reviewing the reference section of the retrieved articles. A total of 25 articles were kept after screening by title, abstract, and full text. After setting a 60% benchmark for quality assessment, all 25 studies were retained. We used the following quality assessment tools: Cochrane risk-of-bias tool (RoB 2) for RCT, Assessment of Multiple Systematic Reviews (AMSTAR) appraisal tool for systematic review and metaanalysis, Newcastle Ottawa Scale for observational studies (case-control and cohort studies), and Scale for the Assessment of Narrative Review Articles (SANRA) for traditional reviews. In our systematic review, a total of 5,600,636 participants were included. We identified one RCT, two meta-analyses, two systematic reviews and meta-analyses, 10 cohort studies, two case-control studies, and eight traditional reviews. Figure  1 shows the PRISMA flowchart.

Discussion
PUD is one of the most common upper gastrointestinal diseases and is found to have a significant association with the development of osteoporosis [2,7,12,15].

Peptic Ulcer Disease: The Pathophysiology
PUD is caused mainly by H. pylori infection, NSAID use, tobacco use, alcohol use, and low physical activity. PUD is characterized by gastric or duodenal ulcers along the mucosal lining [6,7]. H. pylori infection is a bacterial infection acquired during childhood via fecal-oral transmission, persists for life unless eradicated by treatment, and is responsible for 95% of duodenal ulcers and 85% of gastric ulcers [21]. In the stomach, H. pylori infection results in many pathophysiologic events including gastric acid neutralization, damage in the mucus layer, increase in proinflammatory interleukins (IL-1β, IL-6, IL-8, IL-17), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), C-reactive protein (CRP), and anti-inflammatory (IL-4 and IL-10) cytokines. Also, H. pylori infection can lead to enhanced production of reactive oxygen species resulting in cell damage and changes in gastric structure and function, causing alterations in hormone production and secretion of acid and pepsin. In particular, H. pylori infection with virulent strains like CagA positive (positive for cytotoxin-associated gene A), which is associated with an enhanced inflammatory response, plays a critical role in the development of PUD [21,22].
PPIs, used for PUD management and H. pylori eradication, suppress gastric acid secretion by irreversibly inhibiting the gastric H + K + -ATPase pump on the parietal cells and have a very long duration of action with a gastric acid suppression effect that can last up to one week [8,23]. Hypochlorhydria/achlorhydria caused by PPI and H. pylori infection can result in chronic hypergastrinemia and malabsorption of nutrients like calcium (Ca), magnesium (Mg), iron (Fe), and vitamin B12 [23][24][25]. Thus, PUD caused by H. pylori infection is associated with a proinflammatory and hypochlorhydric/achlorhydric state which can result in malabsorption of nutrients and hormonal imbalance.

Osteoporosis: A Complication of PUD
Several studies have demonstrated a significant positive association between osteoporosis and PUD [2,[12][13][14][15][16][17][18][19]. However, one study yielded a conflicting result regarding the association [26]. A cohort study by Wu et al. reported that the risk of osteoporosis was 1.85 times higher in PUD group when compared to non-PUD group (13.99 vs 5.80 per 1,000 person-years, respectively), with a significantly (p < 0.001) higher incidence and a faster development of osteoporosis in PUD group (3.6 years) when compared to non-PUD group (6.4 years) [2]. A similar association was reported by Choi [12]. Also, the PUD group had an adjusted hazard ratio (HR) of 1.36 (95% confidence interval [CI] = 1.33 to 1.40) for osteoporosis [12]. Similarly, a cohort study done in Korea by Yoon et al. concluded that the risk of developing osteoporosis was greater in both men (HR = 1.72, 95% CI = 1.02 to 2.92) and women (HR = 1.62, 95% CI = 1.20 to 2.18) in the PUD cohort when compared to those in the control group [15]. A higher incidence rate per 1,000 person-years was reported in men (20.5%) and women (68.5%) who had PUD than in men (11.2%) and women (42.3%) with no PUD [15].
The relation between H. pylori infection and osteoporosis was discussed by Shih et al., who reported a higher risk of osteoporosis development in the early H. pylori treatment group (HR = 1.52, 95% CI = 1.23 to 1.89) and late H. pylori treatment group (HR = 1.69, 95% CI = 1.39 to 2.05) compared to the control group [13]. Also, both the early and late cohorts exhibited a higher risk of developing osteoporosis (HR = 1.69, 95% CI = 1.32 to 2.16 and HR = 1.72, 95% CI = 1.38 to 2.14, respectively) when followed up for less than five years. However, when the follow-up period was beyond five years, a higher incidence of osteoporosis was demonstrated only by the late eradication cohort (HR = 1.62, 95% CI = 1.06 to 2.47) owing to their chronic H. pylori exposure [13]. Thus, early eradication of H. pylori infection decreases the incidence of osteoporosis.
The medication used to treat H. pylori infection may be another cause of osteoporosis [13]. Based on available data, the US Food and Drug Administration (FDA) issued a drug safety warning in 2011 stating that patients who received PPI for a year or more and/or those who received high doses of prescription PPIs are at increased risk for hip, wrist, and spine fractures [27]. The association between PPI use and the occurrence of osteoporosis was revealed in a study by Wu [2]. This observation was replicated in an RCT by Jo et al., who identified that when elderly patients took PPI for more than eight weeks, their bone parameters were significantly altered due to osteoclast action enhanced by PPI use, exposing them to a higher risk of fracture [14]. A comparable observation was noted in a case-control study by Park et al. in which the cumulative use of PPI was associated with an increased risk of osteoporotic fracture (p-value for trend < 0.001) and the cumulative PPI use for more than one year had a higher osteoporotic fracture risk than that of others (odds ratio (OR) = 1.42, 95% CI = 1.32 to 1.52) [16]. Also, when compared to histamine-2 receptor antagonist (H2RA) users, PPI users had a higher odds ratio (OR) of osteoporotic fracture (OR = 1.11, 95% CI = 1.08 to 1.13), and regular PPI users for one year had a higher risk of osteoporotic fracture than H2RA users (OR = 1.37, 95% CI = 1.26 to 1.50) [16].  [26]. Thus, while H. pylori infection causing PUD may lead to osteoporosis, the medication used for PUD management may also play an important role in osteoporosis. Therefore, cautious use of PPI is warranted, especially in a high-risk population, to prevent the occurrence of osteoporotic fracture. Table  2 summarizes the findings of the studies mentioned above.

Study Author Year
Type of study To assess the association between PUD and osteoporosis in the Korean population.
Men and women in the PUD group had a greater risk and higher incidence of developing osteoporosis in comparison to the control group.
PUD is coupled with a higher incidence and risk of developing osteoporosis in both men and women. 6 Harding et al. [25] 2018 Cohort 4,438 To determine the association between PPI use and fracture risk.
No association was found between PPI use and non-vertebral fracture risk among light, moderate, and heavy PPI users.
PPI use was not associated with increased fracture risk. 7 Wu et al. [2] 2016 Cohort 27,132 To investigate osteoporosis risk in PUD patients of the Taiwan population.
PUD patients had a significantly higher risk, incidence, and a faster development of osteoporosis than non-PUD group. Furthermore, a significant association was found between PUD patients with PPI use and osteoporosis than PUD patients with no use of PPI.

Factors Causing Osteoporosis in PUD
Hypochlorhydric/achlorhydric conditions in PUD can result in decreased absorption of Ca, Fe, Mg, and vitamin B12 [24]. H. pylori infection may induce an inflammatory state and can also result in hormonal imbalance [25,28,29].
Malabsorption: Ca is absorbed in the small intestine in the ionized form [24]. The release of ionized Ca from insoluble Ca salts is aided by the acid-rich, low pH in the stomach. As Ca plays a crucial role in bone development and bone mineral accumulation, chronic use of gastric acid suppression drugs like PPI can lead to hypochlorhydria/achlorhydria resulting in decreased enteral absorption of Ca, contributing to osteoporosis with reduced BMD [24,30,31]. However, an RCT conducted by Jo et al. noticed that both urine deoxypyridinoline (DPD) (a bone resorption marker) and serum Ca were increased after PPI use, which portrays that PPI use directly affects bone metabolism through osteoclast action rather than by decreased intestinal Ca absorption [14]. Hence, more studies are required to ascertain the relation between PPI use and Ca absorption.
Mg levels were found to be low in patients using long-term PPI. A prospective cohort study conducted by Kieboom et al. in 2015 revealed an increased risk of hypomagnesemia with PPI use (n = 36; OR = 2.00, 95% CI = 1.36 to 2.93) with serum Mg level 0.022 mEq/L lower in PPI users (n = 724; 95% CI = -0.032 to -0.014 mEq/L) versus those with no PPI use [32]. The elevated risk with PPI use was only evident after prolonged use (range = 182 to 2,618 days; OR = 2.99, 95% CI = 1.73 to 5.15). A similar association was found with H2RA users (n = 250) revealing an increased risk of hypomagnesemia (n = 12; OR = 2.00, 95% CI = 1.08 to 3.72) compared to non-users [32]. A study in hemodialysis patients conducted by Sakaguchi et al. found a significantly (p < 0.001) increased risk of hip fracture in patients with lower serum Mg levels [33]. A one milligram/deciliter (mg/dL) increase in serum Mg level led to a 14.3% decrease (95% CI = 3.8 to 23.8; p < 0.01) in incident hip fracture risk. An increase in serum Mg level up to 4.0 mg/dL was associated with a linear decrease in fracture risk [33]. The US FDA raised a similar concern in 2011 and issued a drug safety announcement regarding the potential risk of hypomagnesemia with prolonged PPI use (over one year) [34]. The relationship between hypomagnesemia and PPI use can be explained by the effect of PPI on the proper functioning of colonic transient receptor potential melastatin-6 transporters (TRPMs). TRPM cation channels 6 and 7 regulate the active transport of Mg in the gastrointestinal tract. A more acidic pH maintained by the colonic H + K + -ATPase increases the activity of these channels. The inhibition of colonic H + K + -ATPase by PPIs leads to decreased activity of TRPM cation channels, resulting in hypomagnesemia in some patients [35,36]. Mg deficiency may have direct effects on the bone, such as decreased bone stiffness, decreased osteoblast activity, and increased osteoclast activity. The indirect effects of Mg deficiency include decreased parathyroid hormone (PTH) secretion leading to vitamin D deficiency resulting in decreased bone formation. Hypomagnesemia can also promote inflammation, which can lead to increased bone resorption [37]. Table 3 summarizes the studies discussing the effect of PPI use on serum Mg levels and fracture risk.

Study Author
Year Type of study  Vitamin B12 absorption essentially requires the acidic pH of the stomach [38]. Therefore, gastric acid inhibition by PPI may inhibit the absorption of vitamin B12 and can result in low levels of vitamin B12 [39,40]. Vitamin B12 deficiency can lead to an increase in osteoclastic activity, a decrease in osteoblastic activity, and homocysteinemia causing abnormal collagen cross-linking [11]. The deficiency of vitamin B12 can affect bone fragility through modulation of collagen cross-linking independently of areal BMD [41,42]. This increased bone fragility, along with increased fall risk in elderly patients with PPI use due to peripheral neuropathy caused by vitamin B12 deficiency, can contribute to increased fracture rates [42,43].
Inflammation: In PUD, H. pylori infection elicits a localized and systemic inflammatory response that may cause a rise in levels of several cytokines, including TNF-α, IL-1, and IL-6 [28]. Chronic inflammatory processes promote osteoclastogenesis as cytokines enhance osteoclast formation and development, stimulating bone resorption [44].
Endocrine: Regarding hormonal factors, chronic hypergastrinemia can occur as a result of hypochlorhydria/achlorhydria caused by H. pylori infection and chronic use of potent gastric antisecretory drugs like PPI [23,25]. Hypergastrinemia induced by PPI use can lead to parathyroid hyperplasia, resulting in increased PTH secretion and decreased BMD [24,45].
A decrease in total, free, and bioavailable estradiol levels was found in patients of both genders with H. pylori infection by CagA-positive strain in a study conducted by Gennari et al. [29]. The gastric parietal cells express aromatase enzyme and aid in the peripheral conversion of androgen to estrogen. The loss of gastric parietal cells due to H. pylori infection can thus lead to a decrease in the pool of estrogen, causing a potential link to bone fragility [29,46].
Ghrelin levels were significantly (p < 0.001) lower in CagA-positive patients than in CagA-negative and H. pylori-uninfected patients, both in the fasting state and after the meal, in a cohort study by Gennari et al. [29]. H. pylori infection can destroy gastric oxyntic glands that secrete ghrelin. Ghrelin, besides appetite stimulation, promotes osteoblast proliferation and differentiation. Lower ghrelin levels can decrease bone formation and increase the risk of bone fracture [29,47]. Table 4 summarizes the study findings between H. pylori infection with CagA-positive strain and the effect on estrogen and ghrelin levels.  The above studies and findings portray the primary mechanisms by which osteoporosis emerges as a complication of PUD, H. pylori infection, and PPI use. PUD and PPI use may lead to the release of proinflammatory cytokines and malabsorption of nutrients like Ca, Mg, and vitamin B12. It can also cause hormonal imbalance, including increased gastrin secretion and reduced ghrelin and circulating estrogen levels. These may lead to the development of osteoporosis. Figure 2 briefly outlines the mechanisms by which H. pylori infection and PPI use can result in an increased risk of osteoporosis and fracture.

Limitations
There were limitations to our study. Most of the studies included in this systematic review were observational studies and contained only one RCT. Therefore, the risk of potential bias is not negligible. Also, we identified articles that were published only in the English language in this systematic review.

Conclusions
In this systematic review, we tried to elucidate the link between PUD and fracture risk. From the available data, we conclude that PUD, H. pylori infection (particularly, the more virulent CagA-positive strain), and PPI use may result in osteoporosis through different mechanisms, including malabsorption of nutrients, increase in proinflammatory cytokines, and creating an endocrinal imbalance. We observed a lower incidence of osteoporosis with early H. pylori eradication therapy. Therefore, early management of H. pylori infection should be implemented for patients with a high risk for osteoporosis. Also, we noted that long-term regular use of PPI for over one year had a more adverse effect on BMD. Hence, physicians should be cautious while prescribing long-term PPIs for patients, particularly the elderly population who are at elevated risk of fracture. However, further RCTs should be conducted to establish a causal relationship between PUD and osteoporosis and to understand the underlying mechanisms.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.