The Association of Methotrexate, Sulfasalazine, and Hydroxychloroquine Use With Fracture in Postmenopausal Women With Rheumatoid Arthritis: Findings From the Women's Health Initiative

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ABSTRACT

This study was conducted to evaluate the extent to which disease‐modifying antirheumatic medications (DMARDs) used as part of a triple therapy for the treatment of rheumatoid arthritis (RA) including methotrexate, sulfasalazine, and hydroxychloroquine are associated with fractures in postmenopausal women with RA. Incident fractures following use of methotrexate, sulfasalazine, and/or hydroxychloroquine in postmenopausal women with RA in the Women's Health Initiative were estimated by Cox proportional hazards using hazard ratios (HRs) and 95% CIs after consideration of potential confounders. There were 1201 women with RA enrolled in the Women's Health Initiative included in these analyses, of which 74% were white, 17% were black, and 9% were of other or unknown race/ethnicity. Of the women with RA, 421 (35%) had not used methotrexate, sulfasalazine, or hydroxychloroquine, whereas 519 (43%) women had used methotrexate, 83 (7%) sulfasalazine, and 363 (30%) hydroxychloroquine alone or in combination at some time during study follow‐up. Over a median length of 6.46 years of follow‐up, in multivariable adjusted models, no statistically significant association was found between methotrexate (HR, 1.1; 95% CI, 0.8–1.6), sulfasalazine (HR, 0.6; 95% CI, 0.2–1.5), or hydroxychloroquine (HR, 1.0; 95% CI, 0.7–1.5) use and incident fractures or between combination therapy with methotrexate and sulfasalazine or methotrexate and hydroxychloroquine use (HR, 0.9; 95% CI, 0.5–1.6) and incident fractures. In conclusion, postmenopausal women with RA receiving any component of triple therapy should not be expected to have any substantial reduction in fracture risk from use of these DMARDs. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group.

SR Johnson, M Henderson, C Furberg … (1998)

The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components--dietary modification (DM) or hormone replacement therapy (HRT)--of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.

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FRAX™ and the assessment of fracture probability in men and women from the UK

J Kanis, O. Johnell, Thomas A. Odén … (2008)

Summary A fracture risk assessment tool (FRAX™) is developed based on the use of clinical risk factors with or without bone mineral density tests applied to the UK. Introduction The aim of this study was to apply an assessment tool for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density (BMD). The clinical risk factors, identified from previous meta-analyses, comprised body mass index (BMI, as a continuous variable), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking, and alcohol intake 3 or more units daily. Methods Four models were constructed to compute fracture probabilities based on the epidemiology of fracture in the UK. The models comprised the ten-year probability of hip fracture, with and without femoral neck BMD, and the ten-year probability of a major osteoporotic fracture, with and without BMD. For each model fracture and death hazards were computed as continuous functions. Results Each clinical risk factor contributed to fracture probability. In the absence of BMD, hip fracture probability in women with a fixed BMI (25 kg/m2) ranged from 0.2% at the age of 50 years for women without CRF’s to 22% at the age of 80 years with a parental history of hip fracture (approximately 100-fold range). In men, the probabilities were lower, as was the range (0.1 to 11% in the examples above). For a major osteoporotic fracture the probabilities ranged from 3.5% to 31% in women, and from 2.8% to 15% in men in the example above. The presence of one or more risk factors increased probabilities in an incremental manner. The differences in probabilities between men and women were comparable at any given T-score and age, except in the elderly where probabilities were higher in women than in men due to the higher mortality of the latter. Conclusion The models provide a framework which enhances the assessment of fracture risk in both men and women by the integration of clinical risk factors alone and/or in combination with BMD.

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Measurement characteristics of the Women's Health Initiative food frequency questionnaire.

R. Patterson, A R Kristal, L. Tinker … (1999)

The Women's Health Initiative (WHI) is the largest research program ever initiated in the United States with a focus on diet and health. Therefore, it is important to understand and document the measurement characteristics of the key dietary assessment instrument: the WHI food frequency questionnaire (FFQ). Data are from 113 women screened for participation in the WHI in 1995. We assessed bias and precision of the FFQ by comparing the intake of 30 nutrients estimated from the FFQ with means from four 24-hour dietary recalls and a 4-day food record. For most nutrients, means estimated by the FFQ were within 10% of the records or recalls. Precision, defined as the correlation between the FFQ and the records and recalls, was similar to other FFQs. Energy adjusted correlation coefficients ranged from 0.2 (vitamin B12) to 0.7 (magnesium) with a mean of 0.5. The correlation for percentage energy from fat (a key measure in WHI) was 0.6. Vitamin supplement use was common. For example, almost half of total vitamin E intake was obtained from supplements. Including supplemental vitamins and minerals increased micronutrient correlation coefficients, which ranged from 0.2 (thiamin) to 0.8 (vitamin E) with a mean of 0.6. The WHI FFQ produced nutrient estimate, that were similar to those obtained from short-term dietary recall and recording methods. Comparison of WHI FFQ nutrient intake measures to independent and unbiased measures, such as doubly labeled water estimates of energy expenditure, are needed to help address the validity of the FFQ in this population.

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Author and article information

Contributors

Rachel Elam:

ORCID: https://orcid.org/0000-0001-9927-6063

relam@augusta.edu

Journal

Journal ID (nlm-ta): JBMR Plus

Journal ID (iso-abbrev): JBMR Plus

Journal ID (doi): 10.1002/(ISSN)2473-4039

Journal ID (publisher-id): JBM4

Title: JBMR Plus

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Electronic): 2473-4039

Publication date (Electronic): 18 August 2020

Publication date Collection: October 2020

Volume: 4

Issue: 10 ( doiID: 10.1002/jbm4.v4.10 )

Electronic Location Identifier: e10393

Affiliations

[ ¹ ] Department of Medicine, Division of Rheumatology, J. Harold Harrison MD, Distinguished University Chair in Rheumatology Medical College of Georgia at Augusta University Augusta GA USA

[ ² ] Department of Rheumatology Charlie Norwood Veterans Affairs Medical Center Augusta GA USA

[ ³ ] Fred Hutchinson Cancer Research Center Seattle WA USA

[ ⁴ ] Department of Medicine, Division of Rheumatology Medical College of Georgia at Augusta University Augusta GA USA

[ ⁵ ] Department of Medicine, Division of General Internal Medicine and Health Services Research David Geffen School of Medicine at University of California, Los Angeles Los Angeles CA USA

[ ⁶ ] Department of Epidemiology and Environmental Health, School of Public Health and Health Professions University at Buffalo Buffalo NY USA

[ ⁷ ] Department of Preventive Medicine University of Tennessee Health Science Center Memphis TN USA

Author notes

[*] [* ]Address correspondence to: Rachel Elam, MD, ScM, Division of Rheumatology, Department of Medicine, Medical College of Georgia at Augusta University, 1467 Harper Street, HB 2030, Augusta, GA 30912. E‐mail: relam@ 123456augusta.edu

Author information

Laura Carbone https://orcid.org/0000-0003-1007-5949

Rachel Elam https://orcid.org/0000-0001-9927-6063

Carolyn Crandall https://orcid.org/0000-0001-9441-0198

Karen C Johnson https://orcid.org/0000-0002-3493-4077

Article

Publisher ID: JBM410393

DOI: 10.1002/jbm4.10393

PMC ID: 7574701

SO-VID: 9ba70ce3-40a7-4db3-9416-20ba9e8d8820

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 15 April 2020

Date revision received : 16 June 2020

Date accepted : 24 June 2020

Page count

Figures: 0, Tables: 5, Pages: 10, Words: 8302

Funding

Funded by: National Heart, Lung, and Blood Institute , open-funder-registry 10.13039/100000050;

Award ID: HHSN268201100001C

Award ID: HHSN268201100002C

Award ID: HHSN268201100003C

Award ID: HHSN268201100004C

Award ID: HHSN268201100046C

Award ID: HHSN271201100004C

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source-schema-version-number 2.0

cover-date October 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:20.10.2020

Keywords: cox proportional hazards modeling,disease modifying antirheumatic drugs,fracture risk assessment,osteoporosis,rheumatoid arthritis

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Keywords: cox proportional hazards modeling, disease modifying antirheumatic drugs, fracture risk assessment, osteoporosis, rheumatoid arthritis

The Association of Methotrexate, Sulfasalazine, and Hydroxychloroquine Use With Fracture in Postmenopausal Women With Rheumatoid Arthritis: Findings From the Women's Health Initiative

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Fracture and Structural Integrity

Most cited references 50

Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group.

FRAX™ and the assessment of fracture probability in men and women from the UK

Measurement characteristics of the Women's Health Initiative food frequency questionnaire.

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