Chronic inflammation may cause endothelial dysfunction and atherosclerosis, resulting in subsequent erectile dysfunction (ED). We examined the relationship between chronic osteomyelitis, which is a chronic inflammatory disease, and ED. A retrospective cohort study was conducted using data from the National Health Insurance Research Database. After excluding patients <40 years of age, 677 male patients newly diagnosed with chronic osteomyelitis (COM) from 1 January 2000 to 31 December 2011 were identified for the study. The non-osteomyelitis comparison cohort consisted of 2706 male participants. The incidence of ED was 2.66-fold higher in the COM cohort than in the non-osteomyelitis cohort (4.01 vs 1.51 per 10 000 person-years). After adjusting for age and comorbidities of coronary heart disease, hypertension, hyperlipidemia, depression, stroke, diabetes, peripheral vascular disease, chronic kidney disease, chronic obstructive pulmonary disease and asthma, the patients with COM had a 2.82-fold risk of ED (95% confidence interval=1.44–5.56). The incidence of ED increased with that of comorbidities in both cohorts. The highest hazard ratio was in patients between 40 and 59 years of age who had COM. Our data showed, for the first time, that COM is a possible risk factor for the development of ED.
Erectile dysfunction (ED) is becoming an increasingly widespread problem because of the aging of the world population.1 The prevalence of ED varies but is ∼2 to 9% in men >40 years old, 5 to 60% in men between 40 and 70 years old and 10 to 71% in men <70 years old.2 ED is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse.3 ED can be classified into organic, psychogenic or mixed types. The etiology of organic ED includes abnormalities of endocrine function, penile vasculature and nervous systems.4, 5 Chronic low-grade systemic inflammation and subsequent endothelial dysfunction is suspected to be a causative factor in the development of ED.6
Osteomyelitis is an inflammatory bone disease caused by a pyogenic organism infection.7 It can be identified as acute or chronic according to the disease onset, either within 2 weeks or a few months after infection or injury, respectively.7 The most common microorganisms isolated from patients with chronic osteomyelitis are Staphyllococcus epidermidis, S. aureus, Pseudomonas aeruginosa, Serratia marcescens and Escherichia coli.8 Chronic osteomyelitis (COM) is characterized by infected dead bone tissue caused by sclerosis and avascular necrosis.9 The infected foci are covered by an avascular envelope that is composed of thickened periosteum, scarred muscle and subcutaneous tissue.9 COM may be exacerbated intermittently for years and is difficult to eradicate because of the ineffectiveness of antibiotics.9
Lin et al.10 conducted a cohort study by using the National Health Insurance Research Database (NHIRD) and found that increased proinflammatory cytokines in patients with COM might contribute to the development of type 2 diabetes mellitus.11 The authors suggested that chronic inflammation in patients with COM may be a possible cause for the increased risk of developing type 2 diabetes mellitus.10, 12 Because COM and ED are both chronic inflammatory diseases, we considered the possible association between COM and the development of ED.
A population-based study was conducted using data from the NHIRD to determine whether ED and COM are correlated. Because the case numbers of pure psychogenic ED is so small that statistical analysis is difficult, this study would focus on organic ED.13
Materials and methods
The compulsory and universal National Health Insurance (NHI) system was implemented in Taiwan in March 1995. More than 99% of Taiwan residents are enrolled in the NHI program, and >98% of the nationwide hospitals are contracted with the NHI program (http://www.nhi.gov.tw/english/index.aspx). The NHIRD is a nationwide database of reimbursement claims data of the NHI program and is maintained by the National Health Research Institutes. The Longitudinal Health Insurance Database 2000 (LHID 2000) comprises a random sample of one million Taiwan residents from the longitudinally linked data from 1996 to 2011 available in the NHIRD. For the protection of personal information, the data identifications were scrambled by the Bureau of NHI before the data were released for public use. Diagnoses of diseases were coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). This study was approved to fulfill the condition for exemption by the institutional review board of China Medical University (CMUH104-REC2-115). The institutional review board also specifically waived the consent requirement.
This was a population-based retrospective cohort study. Male patients aged ⩾40 years who were newly diagnosed with COM between 1 January 2000 and 31 December 2011 in the LHID 2000 were identified as the osteomyelitis cohort for this study. The index date was defined as the date of diagnosis for COM. For each case, 4 comparison participants without osteomyelitis were selected as the non-osteomyelitis cohort; they were frequency matched for age (in 5-year bands) and index year. For both cohorts, people who had a history of ED before the index date, who were aged <40 years and who had incomplete demographic information were excluded.
Outcome measurement and comorbidities
The outcome of interest in this study was the development of ED. All participants were followed from the index date to the date of ED occurrence, withdrawal from the NHI program or the end of 2011. The comorbidities that were considered as conventional risk factors before the index date included coronary heart disease (CHD), hyperlipidemia, depression, hypertension, stroke, diabetes, peripheral vascular disease, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD) and asthma.
The proportionate distributions of sociodemographic characteristics and comorbidities between the cohorts with and without COM were compared using the χ2 test. The age- and comorbidity-specific incidence of ED per 10 000 person-years of follow-up for each cohort were calculated. To investigate the risk of developing ED associated with COM, univariate and multivariate Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) of ED developing in patients with COM compared with the non-osteomyelitis cohort. The multivariable model, which was adjusted for comorbidities of CHD, hypertension, hyperlipidemia, depression, stroke, diabetes, peripheral vascular disease, CKD, COPD and asthma, revealed a significant difference in Table 1. The Kaplan–Meier method with the log-rank test was used to compare the cumulative incidence curves of ED occurrence between the two cohorts. All statistical analyses were performed using the SAS statistical package (Version 9.2 for Windows; SAS Institute, Cary, NC, USA). The statistical significance was set at α=0.05.
This study identified 677 male patients who were newly diagnosed with COM from 2000 to 2011 and 2706 male participants for the non-osteomyelitis comparison cohort (Table 1). In both cohorts, most cases (38.1%) were 40 to 59 years of age. The two cohorts had mean ages of 60.8 (s.d.=12.6) and 60.4 (s.d.=12.6) years, respectively. Compared with the non-osteomyelitis comparison cohort, patients who had COM were more likely to have CHD (27.5% vs 18.7%, P<0.001), hypertension (55.5% vs 37.6%, P<0.001), hyperlipidemia (26.0% vs 22.0%, P<0.001), depression (6.35% vs 3.47%, P<0.001), stroke (12.4% vs 6.13%, P<0.001), diabetes (28.5% vs 11.2%, P<0.001), peripheral vascular disease (8.57% vs 3.22%, P<0.001), CKD (18.9% vs 8.61%, P<0.001) and COPD (21.3% vs 15.7%, P=0.001). The mean follow-up time was 5.15 (s.d.=3.64) and 5.89 (s.d.=3.77) years for the COM cohort and the non-osteomyelitis cohort, respectively (data not shown). Overall, the incidence of ED was 2.66-fold higher in the COM cohort than in the non-osteomyelitis cohort (4.01 vs 1.51 per 10 000 person-years; Table 2). After adjusting for ages and comorbidities of CHD, hypertension, hyperlipidemia, depression, stroke, diabetes, peripheral vascular disease, CKD, COPD and asthma, patients with COM compared with patients without COM had a 2.82-fold risk of ED (95% confidence interval (CI)=1.44–5.56). The age-specific COM cohort and non-osteomyelitis cohort showed that the crude HR was highest in adults aged 40 to 59 years (crude HR=3.24, 95% CIs=2.37–4.43), with an adjusted HR of 3.12 (95% CI=1.18–8.23). The incidence of ED increased with that of comorbidities in both cohorts. Table 3 illustrates the joint effect of comorbidities and COM on ED. Compared with patients without osteomyelitis and depression, patients with osteomyelitis and depression had a significantly increased risk of ED (adjusted HR=11.4, 95% CI=3.35–38.5). The joint effect of hyperlipidemia (adjusted HR=10.3, 95% CI=4.24–25.2), peripheral vascular disease (adjusted HR=5.61, 95% CI=1.28–24.6), COPD (adjusted HR=4.82, 95% CI=1.58–14.7), hypertension (adjusted HR=4.32, 95% CI=1.81–10.3) and CHD (adjusted HR=4.28, 95% CI=1.38–13.3) were also associated with the increased risk of ED. After 12 years of follow-up, the Kaplan–Meier survival analysis showed that patients with COM had a significantly higher cumulative incidence (2.25%) of developing ED than the non-osteomyelitis cohort (P<0.001, Figure 1).
This study demonstrated that patients with COM had a higher risk of ED, even after adjusting for comorbidities (crude HR=2.66, adjusted HR=2.83). The highest HR was in patients with COM aged between 40 and 59 years.
Patients with COM had a higher prevalence of comorbidities, including CHD, hypertension, hyperlipidemia, depression, stroke, diabetes, CKD and COPD. These comorbidities are known to be risk factors for the development of ED;14, 15, 16, 17, 18, 19, 20, 21 this is compatible with our findings that patients with comorbidities had a higher incidence of ED.
The bacterial surface antigen, such as lipopolysaccharide and staphylococcal surface-associated proteins, would activate immune response and increased release of several cytokines (interleukin-1, interleukin-6, tumor necrosis factor-α and -β). These cytokines could cause osteolysis and result in COM. The infected dead bones will result in subsequent chronic inflammation.22, 23 Patients with COM had an increased risk of ischemic stroke and CHD that are closely related to endothelial dysfunction and atherosclerosis caused by chronic inflammation.24, 25 Endothelial dysfunction caused by chronic inflammation is demonstrated in several disorders, such as rheumatoid arthritis,26 psoriasis27 and periodontitis.28 The primary mechanism of ED is also endothelial dysfunction and subsequent reduced nitric oxide production in the penile arterial system.29 Chronic inflammation caused by COM may impair endothelial cell function and result in the development of ED.
In our study, the highest HR of ED incidence was in patients with COM aged 40 to 59 years but not the older ones. The incidence of ED increased in normal aging process.2 As shown in Table 2, the incidence of ED is higher in patients without COM aged 60 to 79 years than 40 to 59 years. However, higher incidence of ED was found in patients with COM aged 40 to 59 years. This finding suggests that COM may increase the incidence of ED in younger patients. This effect would be obscure in older patients because of already high incidence of ED in this group. This finding also supports our hypothesis that COM may be a risk factor of ED.
This study had several limitations. First, information on smoking and alcohol consumption are not available in the Taiwan NHIRD; hence, we could not examine their impact on the risk of ED in patients with COM. Therefore, we added several smoking-related diseases, including COPD, CHD and stroke, in our analysis to minimize the influence from smoking. Second, cohort studies have a lower methodological quality than that of randomized clinical trials because cohort studies are subject to biases related to the adjustment of confounders. Unknown or unmeasured confounders might have influence our findings despite the adequate control of confounding factors. Third, because the diagnoses documented in NHI claims have not undergone scientific verification and are primarily intended for administrative billing purposes, they may not represent accurate diagnoses.
The results showed, for the first time, that patients with COM have an increased risk of ED. Comorbidities including CHD, hypertension, hyperlipidemia, depression, stroke, diabetes, peripheral vascular disease and CKD further increase this risk. However, additional population-based studies are warranted to confirm our findings.
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This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM10501010037); NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039 -005); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan, and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. No additional external funding was received for this study.
Conception and design: Hsin-Yi Wang, Chih-Hao Chao and Chia-Hung Kao. Administrative support: Chia-Hung Kao. Data collection and assembly, data analysis and interpretation, manuscript writing and final approval of manuscript: all authors. The guarantor of the paper Chia-Hung Kao assumes responsibility for the integrity of the work as a whole.
The authors declare no conflict of interest.
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Wang, HY., Chao, CH., Lin, CL. et al. Increased subsequent risk of erectile dysfunction among middle and old age males with chronic osteomyelitis: a nationwide population-based cohort study. Int J Impot Res 28, 143–147 (2016). https://doi.org/10.1038/ijir.2016.17