The present study showed that patients with RA aged over 50 years had significantly lower total hip BMD as compared with age- and sex-matched healthy controls, but there were no significant differences in BMD in the L1-4 spine and femoral neck between the 2 groups. Similar to female counterparts, the overall frequency of osteoporosis at either the spine or the hip in male patients with RA was 2.1 times higher than that in controls. This finding suggests that appropriate management for osteoporosis in patients with RA is crucial not only for postmenopausal women but also for men aged 50 years and over. In addition, low BMI and moderate-to-high disease activity measured by DAS28-ESR were independent risk factors for the presence of osteoporosis in male patients with RA. Of interest, higher anti-CCP titer was significantly associated with reduced L1-4 BMD after adjusting for confounding factors. These findings indicate that beyond traditional risk factors, inflammatory status and RA-associated autoimmunity were important determinants for generalized bone loss in male patients with RA. Therefore, careful monitoring for the development of systemic bone loss should be considered for male patients with RA with lower BMI, higher disease activity, or higher anti-CCP antibody titer.
The major finding of our study was that frequency of osteoporosis, defined as T-scores ≤ −2.5, in male patients with RA aged over 50 years was 22.4%, approximately 2 times higher than that of healthy individuals (10.5%). Similar to our results, Haugeberg et al and Nolla et al reported that the prevalence of osteoporosis, defined using T-scores ≤ −2.5, in male patients with RA was 23% and 21%, respectively, in at least 1 of the evaluated sites, although no comparison with healthy controls was performed. The prevalence of osteoporosis in female patients with RA ranged from 11.5% to 22.1% [4,5,29,30] and 2 times higher that of controls in previous studies.[4,5] Thus, unlike general population studies showing that osteoporosis and subsequent fragility fracture are less frequent in men as compared with women,[8,14] our data and previous reports suggest that the frequency of osteoporosis in male patients with RA may be no less than that of female patients with RA. Thus, we assume that osteoporosis may also be an important clinical concern for the management of both male and female patients with RA. Although multifactorial factors such as inflammation, GCs use and functional disability can contribute to bone loss in RA patients, the role of gender in osteoporosis in RA has not been extensively studied. Thus, further researches to investigate distinctive features between male and female osteoporosis in RA patients are obviously needed.
In addition to the overall frequency, osteoporosis in RA has several distinctive clinical features compared with osteoporosis in general population. RA patients have lower bone formation marker such as serum osteocalcin and higher bone resorption markers such as crosslinked N-telopeptidases of type 1 collagen than general population, which may be due to inflammatory status in RA. In addition, unlike non-RA subject, bone loss in peripheral arthritis (periarticular osteopenia) characterized by the trabecular size loss is another feature in RA patients, which correlates with systemic osteoporosis in this population.
Using an appropriate reference database is important for measurement of the T-score in investigating the frequency of osteoporosis. Unlike the diagnosis of osteoporosis in women, there is no consensus regarding appropriate reference data in the assessment of T-scores in male patients. Use of female reference data when calculating T-score in men is supported by the by the WHO, Scientific Advisory Council of Osteoporosis Canada, National Osteoporosis Guideline Group, and International Society for Clinical Densitometry, whereas the Endocrine Society recommends use of male reference data. In the present study, South Korean female reference data provided by the manufacturers were used for calculating T-scores in male patients with RA and healthy patients of the same ethnicity. The same method was also applied in the Osteoporotic Fractures in Men Study, a representative study of male osteoporosis.
Total hip BMD in male patients with RA was significantly lower than that of healthy controls in our study, whereas there was no significant difference in spine BMD between patients with RA and controls. Similar results have been reported in both male and female patients with RA in previous studies.[4,5,35,36] Thus, unlike postmenopausal osteoporosis, marked bone loss in the total hip but relatively preserved axial bone mass may be an clinical feature of osteoporosis in “RA” patients rather than “male” patients. This notion was also pointed out by Vosse and de Vlam. As the proportion of cortical bone in the total hip is higher than that of the spine, it is assumed that cortical bone loss may be more susceptible to RA-specific risk factors, such as inflammation and autoimmunity, compared with trabecular bone loss. This hypothesis may be supported by evidence that high disease activity or high titer of RA antibodies is associated with localized cortical bone erosion, but the underlying mechanisms of RA-associated inflammation directly leading to bone loss in the hip remains elusive.
Risk factors for osteoporosis and low BMD in male patients with RA were analyzed in the present study. First, increased disease activity was an independent risk factor for osteoporosis in our data, similar to a previous study by Dao et al. However, as 50% of RA patients were in remission (39.5%) or low disease activity (10.5%), relationship between disease activity and generalized bone loss in RA in our data needed to be interpreted cautiously. As TNF-α, a key proinflammatory cytokine in RA, can stimulate osteoclastogenesis via receptor activator of nuclear factor kappa B ligand activation, leading to systemic bone loss, it is obvious that inflammation is a considerable contributing factor for osteoporosis in RA. However, bone loss in chronic inflammatory diseases such as RA must be a multifactorial affair and changes in energy balance, calcium metabolism, and hormonal pathways during inflammatory process can also cause low bone mass. Thus, we assumed that disease activity is necessary but not sufficient for development of bone loss in RA. Second, anti-CCP antibody titer inversely correlated with spine BMD in male patients with RA and a significant inverse association between anti-citrullinated protein antibody (ACPA) titer and BMD in patients with RA was observed in previous studies.[40,41] The effect of ACPA on inducing osteoclasts activation, even in the absence of inflammation in RA, was also reported and the binding of ACPAs to citrullinated vimentin in the surface of monocyte/macrophage lineage induces differentiation of these cells into osteoclasts, which supports the effect of ACPA on bone loss in RA. Third, cumulative GC dose did not show a significant association with osteoporosis or BMD in male patients with RA in our study. For female patients with RA, a significant association between GC use and osteoporosis was found in some previous studies,[4,36] but others reported no association.[29,43] As GC use is a major cause of osteoporosis and fragility fracture, the lack of association between cumulative GC dose and reduced BMD in our study is somewhat unexpected. The small sample size and imprecise data collection regarding cumulative dose due to the retrospective design may have led to a lack of power to detect a correlation between GCs and bone loss in our study. Third, lower BMI, which is considered a traditional risk factor for osteoporosis, was also significantly linked with generalized bone loss in male patients with RA. Lastly, DMARD therapy, such as methotrexate and hydroxychloroquine, did not affect the rate of osteoporosis in patients with RA. Of interest, Mok et al reported the protective role of hydroxychloroquine against osteoporosis in patients with systemic lupus erythematosus, but this effect was not found in our study. Further longitudinal studies are needed to confirm the effect of DMARDs on systemic bone loss in RA.
The present study has several limitations. First, the main limitation of the present study is the small sample size leading to low statistical power. As our study was conducted in a single center and RA is more common in female patients than male patients, it is difficult to collect a substantial number of male patients with RA. In particular, although male RA patients had significantly higher overall frequency of osteoporosis at either site compared with controls, there were no differences in the frequency of osteoporosis at the spine or hip between these 2 groups in our study. In addition, because no healthy subjects had hip osteoporosis, the direct comparison of hip osteoporosis between RA patients and controls may not be reasonable in our study. This result may be due to a small sample size and further larger studies are needed. Second, our study participants may not necessarily be representative of all South Korean male patients with RA. The cost of DEXA examination in South Korea is approximately $100 (US dollars) and male patients with RA can receive reimbursement for DEXA from the National Health Insurance Service in South Korean government if age 70 years or older. Thus, male patients with RA aged from 50 to 69 years could be reluctant to check their BMD due to cost, which may cause selection bias in our data based on real clinical practice. Third, we only evaluated T-scores of study participants based on female reference data. Further studies are needed to compare T-scores of male patients with RA according to male and female reference data. Lastly, due to retrospective study design, we could not fully collect information about the functional status in RA patients, which is important for analysis of the risk factors for osteoporosis.
In conclusion, male patients with RA had a 2.1 times higher risk for osteoporosis as compared with healthy controls. Low BMI (BMI ≤ 22 kg/m2) and moderate-to-high disease activity (DAS28-ESR > 3.2) were independent risk factors for the presence of osteoporosis in male patients with RA. Thus, similar to their female counterparts, special attention may also be needed to detect and treat osteoporosis in male patients with RA, especially those with low BMI and higher disease activity. Despite significant advances in the understanding of male osteoporosis in recent years, little work has been done on epidemiology, etiology, and optimal treatment of osteoporosis in male patients with RA. The present study sheds light on the importance of the increased risk of osteoporosis in male patients with RA, but further research is needed to confirm our findings due to limitations of our data, such as the small sample size.
We specially thank the late Professor Sung-Il Kim who devoted himself to education, research, and patient care in the Division of Rheumatology, Department of Internal medicine, Pusan National University School of Medicine (1963–2011).
Conceptualization: Dong Hyun Sohn, Seung-Geun Lee.
Data curation: Ji-Heh Park, Jung Hee Koh, Keunyoung Kim, Seung-Geun Lee.
Formal analysis: Seong-Min Kweon, Dong Hyun Sohn, Keunyoung Kim, Seung-Geun Lee.
Funding acquisition: Dong Hyun Sohn
Investigation: Seong-Min Kweon, Dong Hyun Sohn, Ji-Heh Park, Jung Hee Koh, Eun-Kyoung Park, Keunyoung Kim, Seung-Geun Lee.
Methodology: Seong-Min Kweon, Jung Hee Koh, Han-Na Lee, Keunyoung Kim, Seung-Geun Lee.
Project administration: Seung-Geun Lee.
Resources: Seung-Geun Lee.
Software: Seung-Geun Lee.
Supervision: Geun-Tae Kim, Seung-Geun Lee.
Validation: Dong Hyun Sohn, Seung-Geun Lee.
Writing – original draft: Seong-Min Kweon, Dong Hyun Sohn, Seung-Geun Lee.
Writing – review & editing: Yunkyung Kim, Geun-Tae Kim, Seung-Geun Lee.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
bone density; inflammation; male; osteoporosis; rheumatoid arthritis