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Osteoporotic fractures in rheumatoid arthritis patients in Argentina: a matched retrospective cohort study

Osteoporotic fractures in rheumatoid arthritis patients in Argentina: a matched retrospective... Background: To compare the incidence of osteoporotic fractures in patients with rheumatoid arthritis (RA) with matched controls from a university hospital. Methods: Consecutive RA patients (n = 100) were matched (age and sex) with controls (1:2). The follow-up period began at the index date, defined as the date of diagnosis for RA patients and the date of the first medical claim at the Health Management Organization (HMO) for non-RA patients. Fracture incidence rates per 1000 persons-years (PY) for distinct types of fractures were calculated. Multivariate cox regression analysis was performed to identify factors associated with fractures. Results: One hundred RA patients were followed for a total of 975.1 patients-years and 200 controls for 1485.7 patients-years. No difference was found in the overall fracture incidence rate per 1000 PY between RA and controls (19.5, 95% CI 12.7–28.6 vs 12.1, 95% CI 7.7–18.7, p = 0.07). In the Cox regression analysis, only age (HR 1.06, 95% CI 1.02–1.11, p = 0.006) and history of a prior fracture (HR 9.85, 95% CI 2.97–32.64, p < 0.001) were associated with fractures after the index date. The stratified analysis of the fractures by location showed that only the vertebral fractures were more frequent in RA patients compared with controls (12.9 per 1000 PY, 95% CI 8.9–25.8, vs. 3.4, 95% CI 1.4–8.1, respectively, p = 0.01). Conclusion: Patients with RA didn’t show an overall increased risk of osteoporotic fractures compared with matched controls, but vertebral fractures were more frequently observed in patients with RA. Keywords: Rheumatoid arthritis, Incidence, Osteoporosis, Fragility fractures, Glucocorticoids Introduction OP is a very prevalent condition that affects over 200 Osteoporosis (OP) is a systemic skeletal disease charac- million people worldwide and causes an important eco- terized by decreased bone strength with a consequent nomic and health burden. The principal risk factors for increase in bone fragility and susceptibility to fracture OP are sex and age, and it is estimated to affect 50% of due to low bone mass and microarchitecture alterations women and 20% of men over 50 years [5]. The incidence that generate a reduction of bone resistance to torsion of hip fractures in Argentina for women over 50 years is and compression [1–3]. These fractures, known as fragil- 276.5 per 100,000 person-years, and 114.7 every 100,000 ity fractures, are bone cracks caused by a low-energy person-years for men [4, 6–8]. The LAVOS study (Latin trauma (i.e. falling from a standing height) that should American Study of Vertebral Osteoporosis) showed an not be able to break a healthy bone [4]. estimated vertebral fractures’ prevalence of 16.2% [9]. Fragility fractures can be underdiagnosed because they are frequently non-symptomatic and consequently, not * Correspondence: florpierini@gmail.com registered [6–8, 10, 11]. Rheumatology Unit, Internal Medicine Department, Hospital Italiano de Buenos Aires, Perón 4190, 1181 Buenos Aires, Argentina © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Pierini et al. Advances in Rheumatology (2021) 61:21 Page 2 of 7 On the other hand, Rheumatoid Arthritis is the most We reviewed each patient’s electronic medical records frequent inflammatory arthritis in the adult population, and recorded demographic information (sex and age), affecting between 0.3 and 1% of the population in clinical data (comorbidities, weight, body mass index, Argentina [12, 13]. It is an important risk factor for current or past smoking, type and location of fracture), osteoporosis and osteoporotic fractures [4] since it af- laboratory results (positivity for anti-citrullinated peptide fects bone structure in a multifactorial fashion, including antibody and/or rheumatoid factor, erythrosedimenta- chronic inflammation [14], immobility, use of corticoste- tion rate, ultrasensitive c reactive protein at the time of roids (GC), vitamin D deficiency, and augmented fall risk diagnosis), images (annual bone densitometry) and treat- [15]. Nevertheless, the relative weight of each of these ment data (chronic use of corticosteroid, use of another factors is still unknown [16, 17]. Current data suggests immunosuppressant, treatment for osteoporosis and that the pro-inflammatory cytokines (TNF-α, IL-1, IL-6, osteopenia). We defined low-dose of GC as a 2.5–7.5 and IL-17) enhance the expression of RANKL (Receptor mg/day of prednisone or equivalent dose and prolonged Activator of NF-kβ Ligand), leading to increased osteo- corticosteroid use as equal or more than 3 months of clast differentiation, and thereafter producing bone re- use. sorption [14, 15, 18]. Fractures were evaluated by using X-rays, Computer- Several recently published studies show the impact of ized Tomography, and Nuclear Magnetic Resonance, corticosteroids on bone mineral density (BMD) in patients many of which were ordered by other specialists for with RA. Cheng T. et al. found that those patients with many other clinical reasons. All images that allowed to RA who received low doses of GC had a lower BMD at see the bones were carefully reviewed looking for frac- the spine (L1–4), a higher rate of fractures, and a signifi- tures. Vertebral morphology of fractures was evaluated cantly higher risk of fractures after 10 years compared to by Genant Classification [25]. patients with RA who did not receive treatment with GC The primary outcome was the incidence rate of all [19]. There is scarce literature in Latin America regarding new fragility fractures after the index date, defined as the incidence of osteoporotic fractures in patients with bone cracks caused by a low-energy trauma [26]; and RA. Moreover, the numerous advances in recent years for the secondary outcomes were incidence rates of each site the treatment of RA may have changed the OP epidemi- fragility fractures (ribs, proximal extremity of the femur/ ology in these patients. Our objective was to compare the hip, pelvis, vertebra, humerus, distal extremity of the ra- incidence of fragility fractures in rheumatoid arthritis pa- dius and ulna). We excluded fractures produced by high tients diagnosed after the year 2000 with matched controls impact trauma and fractures in sites that are not men- from a University hospital-based health management tioned above. organization (HMO) [13, 20–23]. Statistical analysis Descriptive statistics were performed. Categorical vari- Materials and methods ables were expressed as percentages with their corre- Data source and study population sponding 95% confidence intervals (95% CI). Continuous We performed a retrospective cohort study on patients variables were expressed as means and medians, accord- enrolled in a HMO in Buenos Aires City, Argentina. We ing to their distribution, with their corresponding stand- included 100 consecutive incident RA patients diagnosed ard deviations (SD) or interquartile ranges (IQR). at our rheumatology unit between 01/01/2000 and 31/ Categorical variables were compared using a chi-square 12/2015, that fulfilled ACR/EULAR 2010 criteria [24], test or Fisher’s test, and continuous variables using Stu- and 200 controls (1:2) matched by age at diagnosis of dent’s t-test or Mann’s Whitney test. RA and by sex. The incidence rates for all fractures and for each type We excluded all patients who suffered fragility frac- of fragility fracture (vertebral, radius and femur) were tures prior to the diagnosis of RA, or regarding controls, calculated, both for patients with rheumatoid arthritis before the date of diagnosis of RA of their matched pa- and controls, and the rate ratio between both groups tient (Index Date). Patients who were affiliated to the was reported. The analysis was done at fracture level HMO for under a year were also excluded to avoid pos- and not at patient level (each patient could have had sible prevalent cases that might have been affiliated to more than one fracture after the index date). the HMO with the disease (RA or fractures). We then performed a multivariate logistic regression The follow-up period began at the index date, defined analysis, evaluating possible factors associated with frac- as the date of RA diagnosis for cases and the date of the tures (RA diagnosis, treatment with biologic DMARDs, first medical claim at the HMO for the non-RA patients. sex, age, prior fracture after the index date, prolonged Subjects were followed until they voluntarily left the corticosteroid use – equal or more than 3 months-, HMO, death, or the end of study (05/01/2018). osteoporosis diagnosis, osteoporosis treatment). Pierini et al. Advances in Rheumatology (2021) 61:21 Page 3 of 7 Results 18.9–37.6) of controls, p = 0.21, according to The Inter- Patient’s demographic and clinical characteristics national Society for Clinical Densitometry (ISCD) [27] One hundred patients with RA and 200 age and sex- and WHO criteria [28]. There was no statistically signifi- matched controls were included. RA patients were cant difference in the use of antiresortive treatment be- followed for a total of 975.1 patients-years (PY) and con- tween patients with RA (24, 95% CI 16.6–33.4) and trols for 1485.7 patients-years. As shown in Tables 1, controls (15, 95% CI 10.7–20.7) (p = 0.06). 78% were female in both groups and the mean age at index date was 62 years. The median duration of follow- Fractures incidence rates up was 9.5 years (IQR 5.9–13.4) for the RA group and The 100 RA patients contributed with a total of 975.1 7.4 years (IQR 2.4–12.3) for the control group. patients/years, and showed a global fracture incidence Regarding the RA patients, 97.9% (95% CI 92.0–99.5) rate of 19.5/1000 PY (95% CI 12.7–28.6) with 25 frac- were seropositive for Rheumatoid Factor and/or Anti tures occurring in 16 patients. The control group con- Citrullinated Peptide Antibodies (ACPA), 94% (95% CI tributed with a total of 1485.7 patients/years, and 87.1–97.3) were treated with conventional Disease- presented a fracture incidence rate of 12.1/1000 PY (95% Modifying Antirheumatic Drugs (DMARDs), and 20% CI 7.7–18.7), with 23 fractures in 15 patients. The (95% CI 13.2–29.1) with biologic DMARDs. Sixty-nine between-group difference is non-significant (p = 0.07). percent of the patients with RA (69.0%, CI 0.59–77.3) When analyzing each type of fracture, only the verte- used GC at some time of their disease vs. 5 patients in bral fractures were more frequently found in RA patients the control group (2.5%, CI 1.0–5.9), being this differ- compared with controls (12.9 per 1000 PY, 95% CI 8.9– ence statistically significant (p < 0.001). In the same line, 25.8, versus 3.4, 95% CI 1.4–8.1, p = 0.01, respectively) there was a statistically significant difference between (Table 2). The remaining incidence rates for other site groups (p < 0.001) for the prolonged use of GC, showing fractures were similar across groups (Table 2). that 63 RA patients were exposed to prolonged GC (63.0%, CI 53.1–71.9) (p < 0.001) vs. 4 controls (2.0%, CI Cox regression analysis association between fracture and 0.7–5.2). other factors At least one Bone Mineral Density test was performed After adjusting for RA diagnosis, treatment with biologic during follow-up in 74 of the RA patients (74, 95% CI DMARDs, sex, age, history of prior fracture after the 64.4–81.7) and in 88 of controls (44, 95% CI 37.2–50.9), index date, prolonged corticosteroid use, osteoporosis p < 0.001. Osteoporosis was diagnosed by BMD in diagnosis and treatment for osteoporosis, we found that 36.5% (95% CI 26.2–48.1) of RA patients and 27.3% (CI age (HR 1.06, 95% CI 1.02–1.11, p = 0.006) and a Table 1 Patient characteristics RA patients Controls p (n = 100) (n = 200) Age at index date, years, mean (SD) 62.1 (12.9) 62.4 (13.9) 0.87 Female, n (%, 95 CI) 78 (78, 68.7–85.1) 156 (78, 71.7–83.2) 1 Follow up, years, median (IQR) 9.5 (5.9–13.4) 7.4 (IQR 2.4–12.3) < 0.001 Seropositive Rheumatoid Factor and/or ACPA, n (%, 95 CI) 97,7 (97,7, 92.0–99.5) Use DMARDs, n (%, 95 CI) 94 (94, 87.1–97.3) Use biologic DMARDs, n (%, 95 CI) 20 (20, 13.2–29.1) BMI < 20, n (%, 95 CI) 5 (5.3, 2.2–12.1) 1 (0.6, 0.1–4.3) 0.02 Ever Smoker, n (%, 95 CI) 33 (33, 24.4–42.9) 31 (15.6, 11.1–21.3) 0.001 Menopause age, years, median (IQR) 47.8 (40.7–51) 48.4 (44.6–51.4) 0.27 Age at first Bone Mineral Densitometry, years, median (IQR) 62.7 (54.4–74.8) 67.0 (58.9–75.5) 0.09 Osteopenia at first densitometry, n (%, 95 CI) 21 (28.4, 19.2–39.8) 31 (35.6, 26.2–46.3) 0.33 Osteoporosis at first densitometry, n (%, 95 CI) 23 (31.3, 21.5–42.6) 22 (25, 16.9–35.2) 0.39 Osteoporosis at any densitometry, n (%, 95 CI) 27 (36.5, 26.2–48.1) 24 (27.3, 18.9–37.6) 0.21 Anti-resorptives use ever, n (% 95 CI) 24 (24.0%, 16.6–33.4) 30 (15.0%, 10.7–20.7) 0.06 Corticosteroid use ever, n (%, 95 CI) 69 (69.0, 59.2–77.3) 5 (2.5, 1.0–5.9) < 0.001 Prednisone use > = 20 mg/day ever, n (%, 95 CI) 5 (5.0, 2.1–11.5) 1 (0.5, 0.1–3.5) 0.01 Corticosteroid use > = 3 months, n (%, 95 CI) 63 (63.0, 53.1–71.9) 4 (2.0, 0.7–5.2) < 0.001 Pierini et al. Advances in Rheumatology (2021) 61:21 Page 4 of 7 Table 2 Incidence rates of distinct types of fractures RA patients Controls P (n = 100) (n = 200) value Number of Patient/ Incidence rate per 1000 Number of Patient/ Incidence rate per 1000 fractures years persons/years (95% CI) fractures years persons/years (95% CI) All fractures 24 1230.76 19.5 (12.7–28.6) 23 1900.82 12.1 (7.7–18.7) 0.07 Vertebral 9 697.67 12.9 (8.9–25.8) 5 1470.58 3.4 (1.4–8.1) 0.01 fractures Radius 5 675.67 7.4 (3.6–14.9) 4 851.06 4.7 (2.3–9.8) 0.21 fracture Ulna 1 1000 1.0 (0.1–7.1) 1 1428.57 0.7 (0.1–4.7) 0.39 fracture Humerus 1 1000 1.0 (0.1–7.1) 5 1219.51 4.1 (1.8–8.9) 0.09 fracture Rib fracture 0 0 0 1 1428.57 0.7 (0.1–4.7) 0.30 Hip fracture 5 793.65 6.3 (2.8–13.4) 5 1470.58 3.4 (1.4–8.0) 0.16 Pelvis 2 625 3.2 (0.9–9.4) 2 1428.57 1.4 (0.3–5.3) 0.19 fracture previous fracture (after index date) (HR 9.85, 95% CI relationship between RA and fragility fractures [17, 19, 2.97–32.64, p < 0.001) were the only variables independ- 32–35]. A possible explanation for the discordance be- ently associated with fragility fractures. Neither RA diag- tween our results and many of the previous studies in nosis (HR 0.86, 95% CI 0.24–3.07, p = 0.81) nor a patients with RA is that we included patients diagnosed prolonged use (> 3 months) of low dose corticosteroids with RA after the year 2000, when several new and more (HR 1.57, 95% CI 0.39–6.23, p = 0.52) were associated effective treatment options – Biologic DMARDs – were with increased fracture risk. developed, and when the “treat to target” strategy was When analyzing vertebral fractures separately in a incorporated to daily practice, leading to better control multivariate cox regression analysis (adjusting for age, of RA activity and consequently, lowering the need for RA diagnosis, gender, and a prior fracture), the use of corticosteroids [36]. Although conventional DMARDs low dose corticosteroids for more than 3 months was diminish the activity of pro-inflammatory cytokines, it is not associated in these patients with an increased verte- reported that biological DMARDs have a better protect- bral fracture risk (HR 3.43, 95% CI 0.74–15.82, p = 0.11). ive effect on the bone [37] by suppressing inflammation [38], and hence, they might protect the bone from frac- Discussion tures. Only 20% of this cohort of RA patients were in Osteoporosis risk in RA patients is influenced by both treatment with biologic DMARDs, so we couldn’t dem- general background factors (such as female gender, body onstrate a protective effect regarding fractures, perhaps mass index, age) and RA specific factors (ACPAs positiv- due to the low number of cases. ity, disease activity, immobility, systemic inflammation, In line with this, a recent meta-analysis suggested that and treatments) [29]. Additionally, the GIOTTO study there might be a change in fracture risk trends as a re- reported that RA patients received sub-optimal preven- sult of the change in therapeutic strategies in RA and tion of BMD loss [30]. earlier control of inflammation [33]. Since sex, age, and having had a prior fragility fracture Vertebral fractures were the only type of fragility frac- are well-known risk factors for fragility fractures [16, 31, tures that were more frequent in RA patients than in the 32], we matched RA patients with controls by sex and age, general population in our study. On the multivariate lo- and excluded any patient who had fragility fractures prior gistic regression analysis, the only independently associ- to the index date. ated variables were age and history of previous fractures. Our study shows a similar incidence rate of fragility Unfortunately, we could not analyze factors such as fractures in RA patients compared with a recent system- BMD in all patients and functional disability which atic review and meta-analyses 19.5 (95% CI 12.7–28.6) vs could be associated with fractures. The possibility of 15.31 (95% CI 10.43–22.47) per 1000 persons/years [33]. finding differences between groups in the rate of osteo- We did not find an overall increased incidence of fra- porosis might have been hampered by the statistically gility fractures in RA patients compared to the general significant difference of BMD tests performed (77% vs. population. We acknowledge that our data differs from 44%, p < 0.001), explained by the increased awareness of most previous studies, which suggested a causal the risk in RA patients and the fact that most of the Pierini et al. Advances in Rheumatology (2021) 61:21 Page 5 of 7 controls did not have indication for screening of and women per 1000 persons/year), within the range of osteoporosis. lower values. Remarkably, 35% of the patients with RA diagnosed This study has several limitations. Due to the retro- with osteoporosis by BMD test and 45% of controls were spective nature of the study, we lacked information on not under antiresortive treatment. Although we cannot some possible risk factors for osteoporosis, such as func- rule out that it might respond to the retrospective nature tional disability, malabsorption, vitamin D levels, supple- of this study and under-registration of the treatment, we mentation with vitamin D or calcium, and RA disease believe that it might reflect real life up to some extent activity. We were also unable to stratify patients accord- and the fact that patients diagnosed with OP often go ing to FRAX and to properly register the RA disease ac- undertreated until they have a fragility fracture. tivity and its relationship with fracture risk. Although steroids use is associated with loss of tra- On the other hand, some strengths should be listed. becular bone, the main component of vertebrae, we did First, our HMO offers comprehensive health and med- not find an association between vertebral fractures and ical services to approximately 140,000 outpatients on prolonged use of low-dose corticosteroids. We don’t two central hospitals and 24 peripheral centers, and is have a certain explanation for this, but we believe that broadly representative of the population from Buenos although more than half of RA patients (63, 95% CI Aires city [13]. Second, all included patients fulfill strict 53.1–71.9, Table 1) were on corticosteroids for more classification criteria, and were compared with 2 than 3 months, doses were in general low, and only 5% matched controls. Third, only patients with incident (95% CI 2.1–11.5, Table 1) of patients have ever received diagnosis of RA were included and only incident frac- prednisone doses greater than 20 mg/d and low doses tures were considered. Finally, we included all types of may not have had an impact on fractures risk. fragility fractures in the analysis. Since less than half of Our finding on vertebral fractures is in opposition to vertebral fractures are symptomatic, we performed a re- the study by Kim D. et al. [17], where they found an in- vision of all the dorsal and lumbar spine x-rays, elimin- creased risk on RA patients with longer duration and a ating the possibility of under-diagnosis of asymptomatic higher dose of oral corticosteroids. fractures. Despite radius is also mostly composed of trabecular bone, we did not find a higher incidence rate of fractures Conclusions in patients with RA compared with controls. In this cohort of RA patients with diagnosis after the Regarding the incidence of fragility fractures in con- year 2000, no overall increased risk of fractures was trols, we found an incidence rate for hip fractures of 3.4 found in comparison with matched controls, but an in- (95% CI 1.4–8.0) per 1000 persons/years. This result is creased incidence of vertebral fractures in these patients similar to previous studies reported in Argentina, such versus matched controls was found. as the study by A. Wittich et al. in Tucumán [6] with an Acknowledgements incidence rate of 2.76 and 1.14 per 1000 persons/years Not applicable. for women and men respectively; the study by M. Moro- sano et al. in Rosario with 2.9 per 1000 persons/years Authors’ contributions FP, MB and VS performed the examination of the patients’ data in medical [7]; and the study by A. Bagur et al. in La Plata with 3.79 records and were a major contribution in writing the manuscript. MS, JR and and 1.01 per 1000 persons/year for women and men re- ERS analyzed and interpreted the patient data statistically. All authors read spectively [8]. Regarding the incidence rate of vertebral and approved the final manuscript. fractures in controls, our cohort shows an incidence of Authors’ information 3.4 per 1000 persons/years (95% CI 1.4–8.0), but we Not applicable. didn’t find any another study in Argentina or Latin America to compare with. Recently, a worldwide study Funding by Ballane, G. et al. [39], reported higher age- Not applicable. standardized incidence rates of vertebral fractures in Availability of data and materials South Korea (5,44 and 15,75 for men and women per The datasets used and/or analyzed during the current study are available 1000 persons/year), USA (7,07 and 10,83 for men and from the corresponding author on reasonable request. women per 1000 persons/year) and Hong Kong (2,02 y Declarations 7,64 for men and women per 1000 persons/year); and the lowest incidence for the UK (0,48 and 0,84 for Ethics approval and consent to participate women and men per 1000 persons/year). The incidence This study was carried out in accordance with the Good Clinical Practice (GCP) guidelines, defined in the International Conference on Harmonization rate for vertebral fractures reported in our study was (ICH), and in accordance with the ethical principles detailed in the European similar to Germany (0.87 and 2.05 for men and women Union Directive 2001/20 (EC) and the federal of the United States Code (Title per 1000 persons/year) and Italy (2.11 and 2.49 for men 21, Part 50 (21CFR50). The study was approved by Institutional Review Board Pierini et al. Advances in Rheumatology (2021) 61:21 Page 6 of 7 (IRB00010193, protocol #3518). Since this is a retrospective study, formal oral glucocorticoid therapy. Arthritis Rheum. 2003;48(11):3224–9. https://doi. consent is not required. org/10.1002/art.11283. 17. Kim SY, Schneeweiss S, Liu J, Daniel GW, Chang C-L, Garneau K, et al. Risk of osteoporotic fracture in a large population-based cohort of patients with Consent for publication rheumatoid arthritis. Arthritis Res Ther. 2010;12(4):R154. https://doi.org/10.11 Not applicable. 86/ar3107. 18. Lane NE, Pressman AR, Star VL, Cummings SR, Nevitt MC. Rheumatoid Competing interests arthritis and bone mineral density in elderly women. J Bone Miner Res. - Pierini M.D.; Brom M.D.; Scaglioni M.D.; Scolnik M.D. and Rosa M.D. declare 2009;10(2):257–63. https://doi.org/10.1002/jbmr.5650100212. no conflicts of interest. 19. Cheng T-T, Lai H-M, Yu S-F, Chiu W-C, Hsu C-Y, Chen J-F, et al. The impact - Soriano M.D.: has received in the past speaker’s honorarium from AbbVie, of low-dose glucocorticoids on disease activity, bone mineral density, Novartis, Bristol MS, Novartis, Eli Lilly, Genzyme, Pfizer, Amgen, and Roche. He fragility fractures, and 10-year probability of fractures in patients with is on the advisory board for Novartis, AbbVie, Pfizer, Eli Lilly, Sanofi, Sandoz, rheumatoid arthritis. J Investig Med. 2018;66(6):1004–7. https://doi.org/1 Amgen. He has received grant from Roche, Novartis, AbbVie, Glaxo Smith 0.1136/jim-2018-000723. Kline. 20. Pierini FS, Scolnik M, Scaglioni V, Mollerach F, Soriano ER. Incidence and prevalence of granulomatosis with polyangiitis and microscopic polyangiitis Received: 21 August 2020 Accepted: 25 March 2021 in health management organization in Argentina: a 15-year study. Clin Rheumatol. 2019;38(7):1935–40. https://doi.org/10.1007/s10067-019-04463-y. 21. Rosa J, Garrot LF, Navarta DA, Saucedo C, Scolnik M, Bedran Z, et al. References Incidence and prevalence of Polymyositis and Dermatomyositis in a health 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, Management Organization in Buenos Aires. J Clin Rheumatol. 2013;19(6): and Therapy. Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001; 303–7. https://doi.org/10.1097/RHU.0b013e3182a21ba8. 285(6):785–795. https://doi.org/10.1001/jama.285.6.785. 22. Soriano ER, Rosa J, Velozo E, Schpilberg M, Imamura PM, Diaz J, et al. 2. Assessment of fracture risk and its application to screening for Incidence and prevalence of psoriatic arthritis in Buenos Aires, Argentina: a postmenopausal osteoporosis. Report of a WHO Study Group. World Health 6-year health management organization-based study. Rheumatology. 2011; Organ Tech Rep Ser. 1994;843:1–129. 50(4):729–34. https://doi.org/10.1093/rheumatology/keq369. 3. Siris ES, Chen Y-T, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, et al. 23. Scolnik M, Marin J, Valeiras SM, Marchese MF, Talani AS, Avellaneda NL, et al. Bone mineral density thresholds for pharmacological intervention to Incidence and prevalence of lupus in Buenos Aires, Argentina: a 11-year prevent fractures. Arch Intern Med. 2004;164(10):1108–12. https://doi.org/1 health management organisation-based study. Lupus Sci Med. 2014;1(1): 0.1001/archinte.164.10.1108. e000021. https://doi.org/10.1136/lupus-2014-000021. 4. Mosquera MT, Maurel DL, Pavón S, Arregui A, Moreno C, Vázquez J. 24. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. Incidencia y factores de riesgo de la fractura de fémur proximal por 2010 rheumatoid arthritis classification criteria: an American College of osteoporosis [Incidence and risk factors in fractures of the proximal femur Rheumatology/European league against rheumatism collaborative initiative. due to osteoporosis]. Rev Panam Salud Publica. 1998;3(4):211–9. Spanish. Arthritis Rheum. 2010;62(9):2569–81. https://doi.org/10.1002/art.27584. https://doi.org/10.1590/s1020-49891998000400001. 25. Genant HK, Wu CY, van Kuijk C, Nevitt MC. Vertebral fracture assessment 5. Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, et al. The using a semiquantitative technique. J Bone Miner Res. 1993;8(9):1137–48 recent prevalence of osteoporosis and low bone mass in the United States Available from: https://pubmed.ncbi.nlm.nih.gov/8237484/. [cited 2021 Feb based on bone mineral density at the femoral neck or lumbar spine. J Bone 9]. Miner Res. 2014;29(11):2520–6. https://doi.org/10.1002/jbmr.2269. 26. Fragility fractures | International Osteoporosis Foundation [Internet]. [cited 6. Wittich A, Bagur A, Mautalen C, Cristofari A, Escobar O, Carrizo G, et al. 2021 Feb 10]. Available from: https://www.osteoporosis.foundation/health- Epidemiology of hip fracture in Tucuman. Argentina. Osteoporos Int. 2010; professionals/fragility-fractures 21(11):1803–7. https://doi.org/10.1007/s00198-009-1135-3. 27. Lewiecki EM, Gordon CM, Baim S, Leonard MB, Bishop NJ, Bianchi ML, et al. 7. Morosano M, Masoni A, Sánchez A. Incidence of hip fractures in the city of International Society for Clinical Densitometry 2007 adult and pediatric Rosario. Argentina Osteoporos Int. 2005;16(11):1339–44. https://doi.org/10.1 official positions. Bone. 2008;43(6):1115–21. https://doi.org/10.1016/j.bone.2 007/s00198-005-1839-y. 008.08.106. 8. Bagur A, Mautalen C, Rubin Z. Epidemiology of hip fractures in an urban 28. Kanis JA, Kanis JA. Assessment of fracture risk and its application to population of Central Argentina. Osteoporos Int. 1994;4(6):332–5. https://doi. screening for postmenopausal osteoporosis: Synopsis of a WHO report. org/10.1007/BF01622193. Osteoporos Int. 1994;4(6):368–81. https://doi.org/10.1007/BF01622200 [cited 9. Clark P, Cons-Molina F, Deleze M, Ragi S, Haddock L, Zanchetta JR, et al. The 2021 Feb 23]. prevalence of radiographic vertebral fractures in Latin American countries: 29. Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases the Latin American vertebral osteoporosis study (LAVOS). Osteoporos Int. and bone fragility. Osteoporosis Int. 2017;28:3301–14. 2009;20(2):275–82. https://doi.org/10.1007/s00198-008-0657-4. 30. Rossini M, Viapiana O, Vitiello M, Malavolta N, La Montagna G, Maddali 10. Harvey N, Dennison E, bone CC-P on the metabolic, 2008 undefined. Bongi S, et al. Prevalence and incidence of osteoporotic fractures in patients Epidemiology of osteoporotic fractures. books.google.com. on long-term glucocorticoid treatment for rheumatic diseases: the 11. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic glucocorticoid induced OsTeoporosis TOol (GIOTTO) study. Reumatismo. fractures. Lancet. 2002;359(9319):1761–7. https://doi.org/10.1016/S0140-673 2017;69(1):30. https://doi.org/10.4081/reumatismo.2017.922. 6(02)08657-9. 31. Akkawi I, Zmerly H. Osteoporosis: current concepts. Joints. 2018;6:122–7. 12. Scublinsky D, Venarotti H, Citera G, Messina OD, Scheines E, Rillo O, et al. 32. Kim D, Cho S-K, Park B, Jang EJ, Bae S-C, Sung Y-K. Glucocorticoids are The prevalence of rheumatoid arthritis in Argentina. JCR J Clin Rheumatol. associated with an increased risk for vertebral fracture in patients with 2010;16(7):317–21. https://doi.org/10.1097/RHU.0b013e3181f3bfdd. rheumatoid arthritis. J Rheumatol. 2018 May;45(5):612–20. https://doi.org/1 13. Di WT, Vergara F, Bertiller E, de LA Gallardo M, Gandino I, Scolnik M, et al. 0.3899/jrheum.170054. Incidence and Prevalence of Rheumatoid Arthritis in a Health Management 33. Jin S, Hsieh E, Peng L, Yu C, Wang Y, Wu C, et al. Incidence of fractures among Organization in Argentina: A 15-year Study. J Rheumatol. 2016;43(7):1306–11 patients with rheumatoid arthritis: a systematic review and meta-analysis. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27084906. [cited 2020 Osteoporos Int. 2018;29(6):1263–75. https://doi.org/10.1007/s00198-018-4473-1. Apr 16]. 34. Van Staa TP, Geusens P, Bijlsma JWJ, Leufkens HGM, Cooper C. Clinical 14. Goldring SR. Inflammatory signaling induced bone loss. Bone. 2015;80:143– assessment of the long-term risk of fracture in patients with rheumatoid 9. https://doi.org/10.1016/j.bone.2015.05.024. arthritis. Arthritis Rheum. 2006;54(10):3104–12. https://doi.org/10.1002/a 15. Heinlen L, Humphrey MB. Skeletal complications of rheumatoid arthritis. rt.22117. Osteoporos Int. 2017;28(10):2801–12. https://doi.org/10.1007/s00198-017-41 70-5. 35. Xue A-L, Wu S-Y, Jiang L, Feng A-M, Guo H-F, Zhao P. Bone fracture risk in 16. Van Staa TP, Laan RF, Barton IP, Cohen S, Reid DM, Cooper C. Bone density patients with rheumatoid arthritis. Medicine (Baltimore). 2017;96(36):e6983. threshold and other predictors of vertebral fracture in patients receiving https://doi.org/10.1097/MD.0000000000006983. Pierini et al. Advances in Rheumatology (2021) 61:21 Page 7 of 7 36. Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430): 263–9. https://doi.org/10.1016/S0140-6736(04)16676-2. 37. Killinger Z, Gajdarova L, Kuzma M, Krajcovicova A, Brazdilova K, Jackuliak P, et al. Biologic treatment in comparison to methotrexate has positive effect on trabecular bone score in rheumatoid arthritis patients: 1-year follow-up. Acta Clin Belg. 2019;74(2):121–5. https://doi.org/10.1080/17843286.2018.1 512189. Epub 2018 Aug 23. 38. Zerbini CAF, Clark P, Mendez-Sanchez L, Pereira RMR, Messina OD, Uña CR, et al. Biologic therapies and bone loss in rheumatoid arthritis. Osteoporos Int. 2017;28(2):429–46. https://doi.org/10.1007/s00198-016-3769-2. 39. Ballane G, Cauley JA, Luckey MM, El-Hajj FG. Worldwide prevalence and incidence of osteoporotic vertebral fractures. Osteoporos Int. 2017;28(5): 1531–42. https://doi.org/10.1007/s00198-017-3909-3. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Osteoporotic fractures in rheumatoid arthritis patients in Argentina: a matched retrospective cohort study

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Abstract

Background: To compare the incidence of osteoporotic fractures in patients with rheumatoid arthritis (RA) with matched controls from a university hospital. Methods: Consecutive RA patients (n = 100) were matched (age and sex) with controls (1:2). The follow-up period began at the index date, defined as the date of diagnosis for RA patients and the date of the first medical claim at the Health Management Organization (HMO) for non-RA patients. Fracture incidence rates per 1000 persons-years (PY) for distinct types of fractures were calculated. Multivariate cox regression analysis was performed to identify factors associated with fractures. Results: One hundred RA patients were followed for a total of 975.1 patients-years and 200 controls for 1485.7 patients-years. No difference was found in the overall fracture incidence rate per 1000 PY between RA and controls (19.5, 95% CI 12.7–28.6 vs 12.1, 95% CI 7.7–18.7, p = 0.07). In the Cox regression analysis, only age (HR 1.06, 95% CI 1.02–1.11, p = 0.006) and history of a prior fracture (HR 9.85, 95% CI 2.97–32.64, p < 0.001) were associated with fractures after the index date. The stratified analysis of the fractures by location showed that only the vertebral fractures were more frequent in RA patients compared with controls (12.9 per 1000 PY, 95% CI 8.9–25.8, vs. 3.4, 95% CI 1.4–8.1, respectively, p = 0.01). Conclusion: Patients with RA didn’t show an overall increased risk of osteoporotic fractures compared with matched controls, but vertebral fractures were more frequently observed in patients with RA. Keywords: Rheumatoid arthritis, Incidence, Osteoporosis, Fragility fractures, Glucocorticoids Introduction OP is a very prevalent condition that affects over 200 Osteoporosis (OP) is a systemic skeletal disease charac- million people worldwide and causes an important eco- terized by decreased bone strength with a consequent nomic and health burden. The principal risk factors for increase in bone fragility and susceptibility to fracture OP are sex and age, and it is estimated to affect 50% of due to low bone mass and microarchitecture alterations women and 20% of men over 50 years [5]. The incidence that generate a reduction of bone resistance to torsion of hip fractures in Argentina for women over 50 years is and compression [1–3]. These fractures, known as fragil- 276.5 per 100,000 person-years, and 114.7 every 100,000 ity fractures, are bone cracks caused by a low-energy person-years for men [4, 6–8]. The LAVOS study (Latin trauma (i.e. falling from a standing height) that should American Study of Vertebral Osteoporosis) showed an not be able to break a healthy bone [4]. estimated vertebral fractures’ prevalence of 16.2% [9]. Fragility fractures can be underdiagnosed because they are frequently non-symptomatic and consequently, not * Correspondence: florpierini@gmail.com registered [6–8, 10, 11]. Rheumatology Unit, Internal Medicine Department, Hospital Italiano de Buenos Aires, Perón 4190, 1181 Buenos Aires, Argentina © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Pierini et al. Advances in Rheumatology (2021) 61:21 Page 2 of 7 On the other hand, Rheumatoid Arthritis is the most We reviewed each patient’s electronic medical records frequent inflammatory arthritis in the adult population, and recorded demographic information (sex and age), affecting between 0.3 and 1% of the population in clinical data (comorbidities, weight, body mass index, Argentina [12, 13]. It is an important risk factor for current or past smoking, type and location of fracture), osteoporosis and osteoporotic fractures [4] since it af- laboratory results (positivity for anti-citrullinated peptide fects bone structure in a multifactorial fashion, including antibody and/or rheumatoid factor, erythrosedimenta- chronic inflammation [14], immobility, use of corticoste- tion rate, ultrasensitive c reactive protein at the time of roids (GC), vitamin D deficiency, and augmented fall risk diagnosis), images (annual bone densitometry) and treat- [15]. Nevertheless, the relative weight of each of these ment data (chronic use of corticosteroid, use of another factors is still unknown [16, 17]. Current data suggests immunosuppressant, treatment for osteoporosis and that the pro-inflammatory cytokines (TNF-α, IL-1, IL-6, osteopenia). We defined low-dose of GC as a 2.5–7.5 and IL-17) enhance the expression of RANKL (Receptor mg/day of prednisone or equivalent dose and prolonged Activator of NF-kβ Ligand), leading to increased osteo- corticosteroid use as equal or more than 3 months of clast differentiation, and thereafter producing bone re- use. sorption [14, 15, 18]. Fractures were evaluated by using X-rays, Computer- Several recently published studies show the impact of ized Tomography, and Nuclear Magnetic Resonance, corticosteroids on bone mineral density (BMD) in patients many of which were ordered by other specialists for with RA. Cheng T. et al. found that those patients with many other clinical reasons. All images that allowed to RA who received low doses of GC had a lower BMD at see the bones were carefully reviewed looking for frac- the spine (L1–4), a higher rate of fractures, and a signifi- tures. Vertebral morphology of fractures was evaluated cantly higher risk of fractures after 10 years compared to by Genant Classification [25]. patients with RA who did not receive treatment with GC The primary outcome was the incidence rate of all [19]. There is scarce literature in Latin America regarding new fragility fractures after the index date, defined as the incidence of osteoporotic fractures in patients with bone cracks caused by a low-energy trauma [26]; and RA. Moreover, the numerous advances in recent years for the secondary outcomes were incidence rates of each site the treatment of RA may have changed the OP epidemi- fragility fractures (ribs, proximal extremity of the femur/ ology in these patients. Our objective was to compare the hip, pelvis, vertebra, humerus, distal extremity of the ra- incidence of fragility fractures in rheumatoid arthritis pa- dius and ulna). We excluded fractures produced by high tients diagnosed after the year 2000 with matched controls impact trauma and fractures in sites that are not men- from a University hospital-based health management tioned above. organization (HMO) [13, 20–23]. Statistical analysis Descriptive statistics were performed. Categorical vari- Materials and methods ables were expressed as percentages with their corre- Data source and study population sponding 95% confidence intervals (95% CI). Continuous We performed a retrospective cohort study on patients variables were expressed as means and medians, accord- enrolled in a HMO in Buenos Aires City, Argentina. We ing to their distribution, with their corresponding stand- included 100 consecutive incident RA patients diagnosed ard deviations (SD) or interquartile ranges (IQR). at our rheumatology unit between 01/01/2000 and 31/ Categorical variables were compared using a chi-square 12/2015, that fulfilled ACR/EULAR 2010 criteria [24], test or Fisher’s test, and continuous variables using Stu- and 200 controls (1:2) matched by age at diagnosis of dent’s t-test or Mann’s Whitney test. RA and by sex. The incidence rates for all fractures and for each type We excluded all patients who suffered fragility frac- of fragility fracture (vertebral, radius and femur) were tures prior to the diagnosis of RA, or regarding controls, calculated, both for patients with rheumatoid arthritis before the date of diagnosis of RA of their matched pa- and controls, and the rate ratio between both groups tient (Index Date). Patients who were affiliated to the was reported. The analysis was done at fracture level HMO for under a year were also excluded to avoid pos- and not at patient level (each patient could have had sible prevalent cases that might have been affiliated to more than one fracture after the index date). the HMO with the disease (RA or fractures). We then performed a multivariate logistic regression The follow-up period began at the index date, defined analysis, evaluating possible factors associated with frac- as the date of RA diagnosis for cases and the date of the tures (RA diagnosis, treatment with biologic DMARDs, first medical claim at the HMO for the non-RA patients. sex, age, prior fracture after the index date, prolonged Subjects were followed until they voluntarily left the corticosteroid use – equal or more than 3 months-, HMO, death, or the end of study (05/01/2018). osteoporosis diagnosis, osteoporosis treatment). Pierini et al. Advances in Rheumatology (2021) 61:21 Page 3 of 7 Results 18.9–37.6) of controls, p = 0.21, according to The Inter- Patient’s demographic and clinical characteristics national Society for Clinical Densitometry (ISCD) [27] One hundred patients with RA and 200 age and sex- and WHO criteria [28]. There was no statistically signifi- matched controls were included. RA patients were cant difference in the use of antiresortive treatment be- followed for a total of 975.1 patients-years (PY) and con- tween patients with RA (24, 95% CI 16.6–33.4) and trols for 1485.7 patients-years. As shown in Tables 1, controls (15, 95% CI 10.7–20.7) (p = 0.06). 78% were female in both groups and the mean age at index date was 62 years. The median duration of follow- Fractures incidence rates up was 9.5 years (IQR 5.9–13.4) for the RA group and The 100 RA patients contributed with a total of 975.1 7.4 years (IQR 2.4–12.3) for the control group. patients/years, and showed a global fracture incidence Regarding the RA patients, 97.9% (95% CI 92.0–99.5) rate of 19.5/1000 PY (95% CI 12.7–28.6) with 25 frac- were seropositive for Rheumatoid Factor and/or Anti tures occurring in 16 patients. The control group con- Citrullinated Peptide Antibodies (ACPA), 94% (95% CI tributed with a total of 1485.7 patients/years, and 87.1–97.3) were treated with conventional Disease- presented a fracture incidence rate of 12.1/1000 PY (95% Modifying Antirheumatic Drugs (DMARDs), and 20% CI 7.7–18.7), with 23 fractures in 15 patients. The (95% CI 13.2–29.1) with biologic DMARDs. Sixty-nine between-group difference is non-significant (p = 0.07). percent of the patients with RA (69.0%, CI 0.59–77.3) When analyzing each type of fracture, only the verte- used GC at some time of their disease vs. 5 patients in bral fractures were more frequently found in RA patients the control group (2.5%, CI 1.0–5.9), being this differ- compared with controls (12.9 per 1000 PY, 95% CI 8.9– ence statistically significant (p < 0.001). In the same line, 25.8, versus 3.4, 95% CI 1.4–8.1, p = 0.01, respectively) there was a statistically significant difference between (Table 2). The remaining incidence rates for other site groups (p < 0.001) for the prolonged use of GC, showing fractures were similar across groups (Table 2). that 63 RA patients were exposed to prolonged GC (63.0%, CI 53.1–71.9) (p < 0.001) vs. 4 controls (2.0%, CI Cox regression analysis association between fracture and 0.7–5.2). other factors At least one Bone Mineral Density test was performed After adjusting for RA diagnosis, treatment with biologic during follow-up in 74 of the RA patients (74, 95% CI DMARDs, sex, age, history of prior fracture after the 64.4–81.7) and in 88 of controls (44, 95% CI 37.2–50.9), index date, prolonged corticosteroid use, osteoporosis p < 0.001. Osteoporosis was diagnosed by BMD in diagnosis and treatment for osteoporosis, we found that 36.5% (95% CI 26.2–48.1) of RA patients and 27.3% (CI age (HR 1.06, 95% CI 1.02–1.11, p = 0.006) and a Table 1 Patient characteristics RA patients Controls p (n = 100) (n = 200) Age at index date, years, mean (SD) 62.1 (12.9) 62.4 (13.9) 0.87 Female, n (%, 95 CI) 78 (78, 68.7–85.1) 156 (78, 71.7–83.2) 1 Follow up, years, median (IQR) 9.5 (5.9–13.4) 7.4 (IQR 2.4–12.3) < 0.001 Seropositive Rheumatoid Factor and/or ACPA, n (%, 95 CI) 97,7 (97,7, 92.0–99.5) Use DMARDs, n (%, 95 CI) 94 (94, 87.1–97.3) Use biologic DMARDs, n (%, 95 CI) 20 (20, 13.2–29.1) BMI < 20, n (%, 95 CI) 5 (5.3, 2.2–12.1) 1 (0.6, 0.1–4.3) 0.02 Ever Smoker, n (%, 95 CI) 33 (33, 24.4–42.9) 31 (15.6, 11.1–21.3) 0.001 Menopause age, years, median (IQR) 47.8 (40.7–51) 48.4 (44.6–51.4) 0.27 Age at first Bone Mineral Densitometry, years, median (IQR) 62.7 (54.4–74.8) 67.0 (58.9–75.5) 0.09 Osteopenia at first densitometry, n (%, 95 CI) 21 (28.4, 19.2–39.8) 31 (35.6, 26.2–46.3) 0.33 Osteoporosis at first densitometry, n (%, 95 CI) 23 (31.3, 21.5–42.6) 22 (25, 16.9–35.2) 0.39 Osteoporosis at any densitometry, n (%, 95 CI) 27 (36.5, 26.2–48.1) 24 (27.3, 18.9–37.6) 0.21 Anti-resorptives use ever, n (% 95 CI) 24 (24.0%, 16.6–33.4) 30 (15.0%, 10.7–20.7) 0.06 Corticosteroid use ever, n (%, 95 CI) 69 (69.0, 59.2–77.3) 5 (2.5, 1.0–5.9) < 0.001 Prednisone use > = 20 mg/day ever, n (%, 95 CI) 5 (5.0, 2.1–11.5) 1 (0.5, 0.1–3.5) 0.01 Corticosteroid use > = 3 months, n (%, 95 CI) 63 (63.0, 53.1–71.9) 4 (2.0, 0.7–5.2) < 0.001 Pierini et al. Advances in Rheumatology (2021) 61:21 Page 4 of 7 Table 2 Incidence rates of distinct types of fractures RA patients Controls P (n = 100) (n = 200) value Number of Patient/ Incidence rate per 1000 Number of Patient/ Incidence rate per 1000 fractures years persons/years (95% CI) fractures years persons/years (95% CI) All fractures 24 1230.76 19.5 (12.7–28.6) 23 1900.82 12.1 (7.7–18.7) 0.07 Vertebral 9 697.67 12.9 (8.9–25.8) 5 1470.58 3.4 (1.4–8.1) 0.01 fractures Radius 5 675.67 7.4 (3.6–14.9) 4 851.06 4.7 (2.3–9.8) 0.21 fracture Ulna 1 1000 1.0 (0.1–7.1) 1 1428.57 0.7 (0.1–4.7) 0.39 fracture Humerus 1 1000 1.0 (0.1–7.1) 5 1219.51 4.1 (1.8–8.9) 0.09 fracture Rib fracture 0 0 0 1 1428.57 0.7 (0.1–4.7) 0.30 Hip fracture 5 793.65 6.3 (2.8–13.4) 5 1470.58 3.4 (1.4–8.0) 0.16 Pelvis 2 625 3.2 (0.9–9.4) 2 1428.57 1.4 (0.3–5.3) 0.19 fracture previous fracture (after index date) (HR 9.85, 95% CI relationship between RA and fragility fractures [17, 19, 2.97–32.64, p < 0.001) were the only variables independ- 32–35]. A possible explanation for the discordance be- ently associated with fragility fractures. Neither RA diag- tween our results and many of the previous studies in nosis (HR 0.86, 95% CI 0.24–3.07, p = 0.81) nor a patients with RA is that we included patients diagnosed prolonged use (> 3 months) of low dose corticosteroids with RA after the year 2000, when several new and more (HR 1.57, 95% CI 0.39–6.23, p = 0.52) were associated effective treatment options – Biologic DMARDs – were with increased fracture risk. developed, and when the “treat to target” strategy was When analyzing vertebral fractures separately in a incorporated to daily practice, leading to better control multivariate cox regression analysis (adjusting for age, of RA activity and consequently, lowering the need for RA diagnosis, gender, and a prior fracture), the use of corticosteroids [36]. Although conventional DMARDs low dose corticosteroids for more than 3 months was diminish the activity of pro-inflammatory cytokines, it is not associated in these patients with an increased verte- reported that biological DMARDs have a better protect- bral fracture risk (HR 3.43, 95% CI 0.74–15.82, p = 0.11). ive effect on the bone [37] by suppressing inflammation [38], and hence, they might protect the bone from frac- Discussion tures. Only 20% of this cohort of RA patients were in Osteoporosis risk in RA patients is influenced by both treatment with biologic DMARDs, so we couldn’t dem- general background factors (such as female gender, body onstrate a protective effect regarding fractures, perhaps mass index, age) and RA specific factors (ACPAs positiv- due to the low number of cases. ity, disease activity, immobility, systemic inflammation, In line with this, a recent meta-analysis suggested that and treatments) [29]. Additionally, the GIOTTO study there might be a change in fracture risk trends as a re- reported that RA patients received sub-optimal preven- sult of the change in therapeutic strategies in RA and tion of BMD loss [30]. earlier control of inflammation [33]. Since sex, age, and having had a prior fragility fracture Vertebral fractures were the only type of fragility frac- are well-known risk factors for fragility fractures [16, 31, tures that were more frequent in RA patients than in the 32], we matched RA patients with controls by sex and age, general population in our study. On the multivariate lo- and excluded any patient who had fragility fractures prior gistic regression analysis, the only independently associ- to the index date. ated variables were age and history of previous fractures. Our study shows a similar incidence rate of fragility Unfortunately, we could not analyze factors such as fractures in RA patients compared with a recent system- BMD in all patients and functional disability which atic review and meta-analyses 19.5 (95% CI 12.7–28.6) vs could be associated with fractures. The possibility of 15.31 (95% CI 10.43–22.47) per 1000 persons/years [33]. finding differences between groups in the rate of osteo- We did not find an overall increased incidence of fra- porosis might have been hampered by the statistically gility fractures in RA patients compared to the general significant difference of BMD tests performed (77% vs. population. We acknowledge that our data differs from 44%, p < 0.001), explained by the increased awareness of most previous studies, which suggested a causal the risk in RA patients and the fact that most of the Pierini et al. Advances in Rheumatology (2021) 61:21 Page 5 of 7 controls did not have indication for screening of and women per 1000 persons/year), within the range of osteoporosis. lower values. Remarkably, 35% of the patients with RA diagnosed This study has several limitations. Due to the retro- with osteoporosis by BMD test and 45% of controls were spective nature of the study, we lacked information on not under antiresortive treatment. Although we cannot some possible risk factors for osteoporosis, such as func- rule out that it might respond to the retrospective nature tional disability, malabsorption, vitamin D levels, supple- of this study and under-registration of the treatment, we mentation with vitamin D or calcium, and RA disease believe that it might reflect real life up to some extent activity. We were also unable to stratify patients accord- and the fact that patients diagnosed with OP often go ing to FRAX and to properly register the RA disease ac- undertreated until they have a fragility fracture. tivity and its relationship with fracture risk. Although steroids use is associated with loss of tra- On the other hand, some strengths should be listed. becular bone, the main component of vertebrae, we did First, our HMO offers comprehensive health and med- not find an association between vertebral fractures and ical services to approximately 140,000 outpatients on prolonged use of low-dose corticosteroids. We don’t two central hospitals and 24 peripheral centers, and is have a certain explanation for this, but we believe that broadly representative of the population from Buenos although more than half of RA patients (63, 95% CI Aires city [13]. Second, all included patients fulfill strict 53.1–71.9, Table 1) were on corticosteroids for more classification criteria, and were compared with 2 than 3 months, doses were in general low, and only 5% matched controls. Third, only patients with incident (95% CI 2.1–11.5, Table 1) of patients have ever received diagnosis of RA were included and only incident frac- prednisone doses greater than 20 mg/d and low doses tures were considered. Finally, we included all types of may not have had an impact on fractures risk. fragility fractures in the analysis. Since less than half of Our finding on vertebral fractures is in opposition to vertebral fractures are symptomatic, we performed a re- the study by Kim D. et al. [17], where they found an in- vision of all the dorsal and lumbar spine x-rays, elimin- creased risk on RA patients with longer duration and a ating the possibility of under-diagnosis of asymptomatic higher dose of oral corticosteroids. fractures. Despite radius is also mostly composed of trabecular bone, we did not find a higher incidence rate of fractures Conclusions in patients with RA compared with controls. In this cohort of RA patients with diagnosis after the Regarding the incidence of fragility fractures in con- year 2000, no overall increased risk of fractures was trols, we found an incidence rate for hip fractures of 3.4 found in comparison with matched controls, but an in- (95% CI 1.4–8.0) per 1000 persons/years. This result is creased incidence of vertebral fractures in these patients similar to previous studies reported in Argentina, such versus matched controls was found. as the study by A. Wittich et al. in Tucumán [6] with an Acknowledgements incidence rate of 2.76 and 1.14 per 1000 persons/years Not applicable. for women and men respectively; the study by M. Moro- sano et al. in Rosario with 2.9 per 1000 persons/years Authors’ contributions FP, MB and VS performed the examination of the patients’ data in medical [7]; and the study by A. Bagur et al. in La Plata with 3.79 records and were a major contribution in writing the manuscript. MS, JR and and 1.01 per 1000 persons/year for women and men re- ERS analyzed and interpreted the patient data statistically. All authors read spectively [8]. Regarding the incidence rate of vertebral and approved the final manuscript. fractures in controls, our cohort shows an incidence of Authors’ information 3.4 per 1000 persons/years (95% CI 1.4–8.0), but we Not applicable. didn’t find any another study in Argentina or Latin America to compare with. Recently, a worldwide study Funding by Ballane, G. et al. [39], reported higher age- Not applicable. standardized incidence rates of vertebral fractures in Availability of data and materials South Korea (5,44 and 15,75 for men and women per The datasets used and/or analyzed during the current study are available 1000 persons/year), USA (7,07 and 10,83 for men and from the corresponding author on reasonable request. women per 1000 persons/year) and Hong Kong (2,02 y Declarations 7,64 for men and women per 1000 persons/year); and the lowest incidence for the UK (0,48 and 0,84 for Ethics approval and consent to participate women and men per 1000 persons/year). The incidence This study was carried out in accordance with the Good Clinical Practice (GCP) guidelines, defined in the International Conference on Harmonization rate for vertebral fractures reported in our study was (ICH), and in accordance with the ethical principles detailed in the European similar to Germany (0.87 and 2.05 for men and women Union Directive 2001/20 (EC) and the federal of the United States Code (Title per 1000 persons/year) and Italy (2.11 and 2.49 for men 21, Part 50 (21CFR50). The study was approved by Institutional Review Board Pierini et al. Advances in Rheumatology (2021) 61:21 Page 6 of 7 (IRB00010193, protocol #3518). Since this is a retrospective study, formal oral glucocorticoid therapy. Arthritis Rheum. 2003;48(11):3224–9. https://doi. consent is not required. org/10.1002/art.11283. 17. Kim SY, Schneeweiss S, Liu J, Daniel GW, Chang C-L, Garneau K, et al. Risk of osteoporotic fracture in a large population-based cohort of patients with Consent for publication rheumatoid arthritis. Arthritis Res Ther. 2010;12(4):R154. https://doi.org/10.11 Not applicable. 86/ar3107. 18. Lane NE, Pressman AR, Star VL, Cummings SR, Nevitt MC. Rheumatoid Competing interests arthritis and bone mineral density in elderly women. J Bone Miner Res. - Pierini M.D.; Brom M.D.; Scaglioni M.D.; Scolnik M.D. and Rosa M.D. declare 2009;10(2):257–63. https://doi.org/10.1002/jbmr.5650100212. no conflicts of interest. 19. Cheng T-T, Lai H-M, Yu S-F, Chiu W-C, Hsu C-Y, Chen J-F, et al. The impact - Soriano M.D.: has received in the past speaker’s honorarium from AbbVie, of low-dose glucocorticoids on disease activity, bone mineral density, Novartis, Bristol MS, Novartis, Eli Lilly, Genzyme, Pfizer, Amgen, and Roche. He fragility fractures, and 10-year probability of fractures in patients with is on the advisory board for Novartis, AbbVie, Pfizer, Eli Lilly, Sanofi, Sandoz, rheumatoid arthritis. J Investig Med. 2018;66(6):1004–7. https://doi.org/1 Amgen. He has received grant from Roche, Novartis, AbbVie, Glaxo Smith 0.1136/jim-2018-000723. Kline. 20. Pierini FS, Scolnik M, Scaglioni V, Mollerach F, Soriano ER. Incidence and prevalence of granulomatosis with polyangiitis and microscopic polyangiitis Received: 21 August 2020 Accepted: 25 March 2021 in health management organization in Argentina: a 15-year study. Clin Rheumatol. 2019;38(7):1935–40. https://doi.org/10.1007/s10067-019-04463-y. 21. Rosa J, Garrot LF, Navarta DA, Saucedo C, Scolnik M, Bedran Z, et al. References Incidence and prevalence of Polymyositis and Dermatomyositis in a health 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, Management Organization in Buenos Aires. J Clin Rheumatol. 2013;19(6): and Therapy. Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001; 303–7. https://doi.org/10.1097/RHU.0b013e3182a21ba8. 285(6):785–795. https://doi.org/10.1001/jama.285.6.785. 22. Soriano ER, Rosa J, Velozo E, Schpilberg M, Imamura PM, Diaz J, et al. 2. Assessment of fracture risk and its application to screening for Incidence and prevalence of psoriatic arthritis in Buenos Aires, Argentina: a postmenopausal osteoporosis. Report of a WHO Study Group. World Health 6-year health management organization-based study. Rheumatology. 2011; Organ Tech Rep Ser. 1994;843:1–129. 50(4):729–34. https://doi.org/10.1093/rheumatology/keq369. 3. Siris ES, Chen Y-T, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, et al. 23. Scolnik M, Marin J, Valeiras SM, Marchese MF, Talani AS, Avellaneda NL, et al. Bone mineral density thresholds for pharmacological intervention to Incidence and prevalence of lupus in Buenos Aires, Argentina: a 11-year prevent fractures. Arch Intern Med. 2004;164(10):1108–12. https://doi.org/1 health management organisation-based study. Lupus Sci Med. 2014;1(1): 0.1001/archinte.164.10.1108. e000021. https://doi.org/10.1136/lupus-2014-000021. 4. Mosquera MT, Maurel DL, Pavón S, Arregui A, Moreno C, Vázquez J. 24. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. Incidencia y factores de riesgo de la fractura de fémur proximal por 2010 rheumatoid arthritis classification criteria: an American College of osteoporosis [Incidence and risk factors in fractures of the proximal femur Rheumatology/European league against rheumatism collaborative initiative. due to osteoporosis]. Rev Panam Salud Publica. 1998;3(4):211–9. Spanish. Arthritis Rheum. 2010;62(9):2569–81. https://doi.org/10.1002/art.27584. https://doi.org/10.1590/s1020-49891998000400001. 25. Genant HK, Wu CY, van Kuijk C, Nevitt MC. Vertebral fracture assessment 5. Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, et al. The using a semiquantitative technique. J Bone Miner Res. 1993;8(9):1137–48 recent prevalence of osteoporosis and low bone mass in the United States Available from: https://pubmed.ncbi.nlm.nih.gov/8237484/. [cited 2021 Feb based on bone mineral density at the femoral neck or lumbar spine. J Bone 9]. Miner Res. 2014;29(11):2520–6. https://doi.org/10.1002/jbmr.2269. 26. Fragility fractures | International Osteoporosis Foundation [Internet]. [cited 6. Wittich A, Bagur A, Mautalen C, Cristofari A, Escobar O, Carrizo G, et al. 2021 Feb 10]. Available from: https://www.osteoporosis.foundation/health- Epidemiology of hip fracture in Tucuman. Argentina. Osteoporos Int. 2010; professionals/fragility-fractures 21(11):1803–7. https://doi.org/10.1007/s00198-009-1135-3. 27. Lewiecki EM, Gordon CM, Baim S, Leonard MB, Bishop NJ, Bianchi ML, et al. 7. Morosano M, Masoni A, Sánchez A. Incidence of hip fractures in the city of International Society for Clinical Densitometry 2007 adult and pediatric Rosario. Argentina Osteoporos Int. 2005;16(11):1339–44. https://doi.org/10.1 official positions. Bone. 2008;43(6):1115–21. https://doi.org/10.1016/j.bone.2 007/s00198-005-1839-y. 008.08.106. 8. Bagur A, Mautalen C, Rubin Z. Epidemiology of hip fractures in an urban 28. Kanis JA, Kanis JA. Assessment of fracture risk and its application to population of Central Argentina. Osteoporos Int. 1994;4(6):332–5. https://doi. screening for postmenopausal osteoporosis: Synopsis of a WHO report. org/10.1007/BF01622193. Osteoporos Int. 1994;4(6):368–81. https://doi.org/10.1007/BF01622200 [cited 9. Clark P, Cons-Molina F, Deleze M, Ragi S, Haddock L, Zanchetta JR, et al. The 2021 Feb 23]. prevalence of radiographic vertebral fractures in Latin American countries: 29. Briot K, Geusens P, Em Bultink I, Lems WF, Roux C. Inflammatory diseases the Latin American vertebral osteoporosis study (LAVOS). Osteoporos Int. and bone fragility. Osteoporosis Int. 2017;28:3301–14. 2009;20(2):275–82. https://doi.org/10.1007/s00198-008-0657-4. 30. Rossini M, Viapiana O, Vitiello M, Malavolta N, La Montagna G, Maddali 10. Harvey N, Dennison E, bone CC-P on the metabolic, 2008 undefined. Bongi S, et al. Prevalence and incidence of osteoporotic fractures in patients Epidemiology of osteoporotic fractures. books.google.com. on long-term glucocorticoid treatment for rheumatic diseases: the 11. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic glucocorticoid induced OsTeoporosis TOol (GIOTTO) study. Reumatismo. fractures. Lancet. 2002;359(9319):1761–7. https://doi.org/10.1016/S0140-673 2017;69(1):30. https://doi.org/10.4081/reumatismo.2017.922. 6(02)08657-9. 31. Akkawi I, Zmerly H. Osteoporosis: current concepts. Joints. 2018;6:122–7. 12. Scublinsky D, Venarotti H, Citera G, Messina OD, Scheines E, Rillo O, et al. 32. Kim D, Cho S-K, Park B, Jang EJ, Bae S-C, Sung Y-K. Glucocorticoids are The prevalence of rheumatoid arthritis in Argentina. JCR J Clin Rheumatol. associated with an increased risk for vertebral fracture in patients with 2010;16(7):317–21. https://doi.org/10.1097/RHU.0b013e3181f3bfdd. rheumatoid arthritis. J Rheumatol. 2018 May;45(5):612–20. https://doi.org/1 13. Di WT, Vergara F, Bertiller E, de LA Gallardo M, Gandino I, Scolnik M, et al. 0.3899/jrheum.170054. Incidence and Prevalence of Rheumatoid Arthritis in a Health Management 33. Jin S, Hsieh E, Peng L, Yu C, Wang Y, Wu C, et al. Incidence of fractures among Organization in Argentina: A 15-year Study. J Rheumatol. 2016;43(7):1306–11 patients with rheumatoid arthritis: a systematic review and meta-analysis. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27084906. [cited 2020 Osteoporos Int. 2018;29(6):1263–75. https://doi.org/10.1007/s00198-018-4473-1. Apr 16]. 34. Van Staa TP, Geusens P, Bijlsma JWJ, Leufkens HGM, Cooper C. Clinical 14. Goldring SR. Inflammatory signaling induced bone loss. Bone. 2015;80:143– assessment of the long-term risk of fracture in patients with rheumatoid 9. https://doi.org/10.1016/j.bone.2015.05.024. arthritis. Arthritis Rheum. 2006;54(10):3104–12. https://doi.org/10.1002/a 15. Heinlen L, Humphrey MB. Skeletal complications of rheumatoid arthritis. rt.22117. Osteoporos Int. 2017;28(10):2801–12. https://doi.org/10.1007/s00198-017-41 70-5. 35. Xue A-L, Wu S-Y, Jiang L, Feng A-M, Guo H-F, Zhao P. Bone fracture risk in 16. Van Staa TP, Laan RF, Barton IP, Cohen S, Reid DM, Cooper C. Bone density patients with rheumatoid arthritis. Medicine (Baltimore). 2017;96(36):e6983. threshold and other predictors of vertebral fracture in patients receiving https://doi.org/10.1097/MD.0000000000006983. Pierini et al. Advances in Rheumatology (2021) 61:21 Page 7 of 7 36. Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430): 263–9. https://doi.org/10.1016/S0140-6736(04)16676-2. 37. Killinger Z, Gajdarova L, Kuzma M, Krajcovicova A, Brazdilova K, Jackuliak P, et al. Biologic treatment in comparison to methotrexate has positive effect on trabecular bone score in rheumatoid arthritis patients: 1-year follow-up. Acta Clin Belg. 2019;74(2):121–5. https://doi.org/10.1080/17843286.2018.1 512189. Epub 2018 Aug 23. 38. Zerbini CAF, Clark P, Mendez-Sanchez L, Pereira RMR, Messina OD, Uña CR, et al. Biologic therapies and bone loss in rheumatoid arthritis. Osteoporos Int. 2017;28(2):429–46. https://doi.org/10.1007/s00198-016-3769-2. 39. Ballane G, Cauley JA, Luckey MM, El-Hajj FG. Worldwide prevalence and incidence of osteoporotic vertebral fractures. Osteoporos Int. 2017;28(5): 1531–42. https://doi.org/10.1007/s00198-017-3909-3. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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