Rheumatology Advance Access published May 9, 2014

Transcription

1 Concise report Rheumatology Advance Access published May 9, 2014 RHEUMATOLOGY 258 doi: /rheumatology/keu178 Serum 25-hydroxyvitamin D and the risk of knee and hip osteoarthritis leading to hospitalization: a cohort study of 5274 Finns Sanna Konstari 1, Leena Kaila-Kangas 2, Tuija Jääskeläinen 3, Markku Heliövaara 3, Harri Rissanen 3, Jukka Marniemi 4, Paul Knekt 3, Jari Arokoski 5,6 and Jaro Karppinen 1,2 Abstract Objective. The aim of this study was to investigate whether low levels of serum 25-hydroxyvitamin D [25(OH)D] predicts the development of knee or hip OA. Methods. The cohort consisted of 5274 participants in a national health examination survey who had no knee or hip OA at baseline. Information about the incidence of OA was drawn from the National Health Care Register. During the follow-up of 10 years ( person-years), 127 subjects developed incident, physician-diagnosed OA in the knee and 45 in the hip joint. The information on covariates, including age, sex, education, BMI, work load, leisure time physical activity, smoking history, knee or hip complaint during the past month and previous injuries, was gathered at baseline. Serum 25(OH)D concentrations were determined from baseline serum samples. Results. After adjustment for age and gender, serum 25(OH)D showed statistically significant associations with known risk factors for OA except injuries. In the fully adjusted model, low serum 25(OH)D concentration did not predict increased incidence of knee and hip OA. Conclusion. The results do not support the hypothesis that low levels of serum 25(OH)D contribute to the development of knee or hip OA. Key words: knee joint, hip joint, osteoarthritis, serum vitamin D, cohort study, risk factors. Introduction OA is a disease affecting the joints that is characterized by an imbalance between the degenerative and regenerative processes, leading to overall degeneration. Degenerative 1 Medical Research Center Oulu, Department of Physical and Rehabilitation Medicine, Oulu University Hospital and University of Oulu, Oulu, 2 Centre of Expertise for Health and Work Ability, Finnish Institute of Occupational Health, Oulu and Helsinki, 3 Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, Helsinki, 4 Department of Chronic Disease Prevention, Population Studies Unit, National Institute for Health and Welfare, Turku, 5 Department of Physical and Rehabilitation Medicine, Kuopio University Hospital and 6 Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. Submitted 13 November 2013; revised version accepted 11 March Correspondence to: Sanna Konstari, Medical Research Center Oulu, Department of Physical and Rehabilitation Medicine, University of Oulu, Box 5000, Oulu, Finland. sanna.konstari@student.oulu.fi processes lead to a loss of articular cartilage volume. Bone changes are also considered to be an important aetiological element in the pathogenesis of OA [1]. It has been hypothesized that the development or progression of OA is affected by vitamin D status [1]. There are, however, only a few studies pertaining to the relationship between low serum 25-hydroxyvitamin D [25(OH)D] levels and the development or progression of OA. Longitudinal studies have observed an increased risk of knee OA progression in association with low serum 25(OH)D levels [2, 3] and an increased risk of incident hip joint space narrowing in association with low baseline serum 25(OH)D levels [4]. However, in a recent study consisting of two longitudinal cohorts, serum 25(OH)D levels did not predict joint space narrowing or loss of cartilage volume of the knee [5]. In our previous longitudinal study, serum 25(OH)D did not predict the development of knee or hip OA diagnosed at a clinical examination [6]. In the current study we aimed CLINICAL SCIENCE! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com 1

2 Sanna Konstari et al. to evaluate in another Finnish population-based sample whether serum 25(OH)D predicts incident knee or hip OA leading to hospitalization. Materials and methods Study population The present study is based on the Health 2000 Survey, which was carried out in Finland between September 2000 and March 2001 [7]. The nationally representative population sample was formed using a two-stage stratified cluster sampling method of the adult population 5 30 years of age living in mainland Finland. The sample frame was regionally stratified according to the five university hospital regions. In the first stage of sampling, 80 health care districts were sampled as a cluster. In the second stage, a random sample of individuals from each of the 80 health care districts (8028 men and women) was drawn from a nationwide population register. Written informed consent was obtained from all the participants. The study was approved by the Ethical Committee for Research in Epidemiology and Public Health at the Hospital District of Helsinki and Uusimaa in Finland. Of the sample, 80% participated in the comprehensive health examination. A total of 2454 men and 2820 women who were free from knee and hip OA, based on disease history, symptoms and a standardized clinical examination, and whose serum 25(OH)D concentrations were determined, were included in the present cohort study with a record linkage to the National Health Care Register (HCR). Health examination The implementation of the Health 2000 Survey, described in detail elsewhere [7, 8], involved a home interview followed by a comprehensive health examination with an interview on joint symptoms, self-administered questionnaires, anthropometric measurements, fasting blood samples and a standardized clinical examination by physicians who applied pre-set diagnostic criteria [6, 8]. The health examinations started on 11 September 2000 and ended on 2 March The baseline diagnoses of knee and hip OA and traumatic injuries were assessed on a standardized clinical examination. Specially trained physicians performed the physical examinations according to detailed written instructions with uniform diagnostic criteria. The examination included estimations of tenderness and limitations in the range of motion of the hip and knee joints. The final diagnosis of knee and hip OA was made on the basis of disease history, symptoms and clinical findings. The clinical examination and criteria of knee and hip OA have been described in detail elsewhere [6 10]. Fasting blood samples were taken and stored at 70 C. For the purposes of the present study, the time span (days) from summertime was computed as the difference between the actual day of the blood draw and 31 August, which is considered to be the last summer month in Finland. After this date, the amount of vitamin D synthesized in the skin due to sun exposure is generally diminished. Serum 25(OH)D was determined by radioimmunoassay (RIA; Diasorin, Stillwater, MN, USA) between January 2001 and November The interassay coefficient of variation for 25(OH)D concentration measurements was 7.80% at a mean level of 47.3 nmol/l. The laboratory where analyses were carried out participated in an external quality control programme run by Labquality Ltd (Helsinki, Finland). At the home interview, the level of formal education was determined and, for the present study, classified into three categories based on the number of years of education. History of physical workload was assessed by inquiring how many years the subjects had been exposed in their current or past jobs to heavy physical work involving lifting, carrying or pushing loads >20 kg on average at least 10 times per working day. The information was classified as follows: (i) 0 years, (ii) 1 12 years, (iii) years or (iv) >24 years [11]. Smoking history was categorized as never smokers, ex-smokers and current smokers. Information on leisure time physical activity was elicited with a self-administered questionnaire and categorized as (i) little or irregular leisure time physical activity or (ii) regular fitness training at least 3 h/week or regular competitive sports training several times per week. Difficulties in walking or limping during the past month due to a knee or hip disorder or complaint were determined with a standardized interview on musculoskeletal symptoms [7]. Weight and height were measured in the health examination in light clothing without shoes and BMI (kg/m 2 ) was calculated. Hospital discharge records The follow-up information about the incidence of OA was drawn from the National HCR data. The patients discharged from hospital with a diagnosis of hip or knee OA were identified using International Classification of Diseases, 10th revision (ICD-10), codes M16 and M17. The follow-up period started from the baseline examination and continued until the first hospitalization for knee or hip OA, death or the end of 2010, whichever came first. The procedures to identify cases with knee or hip OA were independent of each other. Statistical analysis Cross-sectional associations between baseline characteristics, including the known risk factors for OA and serum 25(OH)D, were analysed with a generalized linear model. This analysis comprised all the participants in the health examination. First those who had hip or knee OA at baseline were excluded. Then the Cox proportional hazards model was used to estimate the strength of association between quartiles of serum 25(OH)D and the risk of developing knee or hip OA. Age, gender, BMI, history of physical workload, education, smoking, leisure time physical activity, time elapsed from 31 August, injuries and difficulty in walking due to a disorder or complaint in knees or hips were entered as potential confounding 2

3 Serum vitamin D level in relation to the incidence of knee and hip osteoarthritis and effect-modifying factors. The factors were selected from those available on the basis of a priori assumptions of determinants of serum 25(OH)D [12] and OA, of which BMI, physical workload and injuries are major risk factors for OA [9 11, 13, 14]. Adjusted relative risks with 95% CIs were estimated. Serum 25(OH)D was categorized into quartiles. The P-value for trend was calculated by assigning the subjects the median value of each category and including this as a continuous variable in the model. All analyses were performed using SAS for Windows, version 9.1 (SAS Institute, Cary, NC, USA). Results Distributions of baseline characteristics and their crosssectional associations with serum 25(OH)D are shown in Table 1. After adjustment for age and gender, serum 25(OH)D showed a statistically significant association with known risk factors for OA except traumatic injury. Serum 25(OH)D concentrations were lowest in old and obese people and when longer time was elapsed from 31 August. It was lower among those who had more years of manual handling of heavy loads, fewer years of education and less leisure time physical activity, and among smokers. At baseline, subjects with diagnosed hip OA had lower serum 25(OH)D concentrations than subjects without hip OA. Knee OA at baseline was not significantly connected to serum 25(OH)D status. Difficulty in walking or limping due to discomfort or trouble in the hip, but not in the knee, during the last month was associated with lower serum 25(OH)D concentrations (Table 1). During the follow-up of person-years, 127 subjects developed incident OA in the knee and 45 in the hip joint. Low serum 25(OH)D levels did not predict the risk of knee or hip OA leading to hospitalization. Instead, higher serum 25(OH)D concentrations showed significant associations with risk. When adjusted for age and sex, the relative risks (with 95% CI) of hospitalization for knee OA in quartiles of serum 25(OH)D were 1.00, 1.31 (0.77, 2.24), 1.70 (1.03, 2.79) and 1.23 (0.72, 2.08), and for hip OA they were 1.00, 2.20 (0.75, 6.44), 2.80 (1.02, 7.70) and 2.60 (0.95, 7.17). After further adjustment for all the potential confounding factors, the relative risks did not change substantially (Table 2). None of the interaction terms of serum 25(OH)D proved statistically significant. The P-values of interactions of time from summer and serum 25(OH)D for incident knee and hip OA were 0.20 and 0.69, respectively. Discussion Our findings do not support the hypothesis that low serum 25(OH)D levels increase the risk of incident knee or hip OA, but higher serum levels predicted hospitalizations due to knee and hip OA. These results were in line with our previous findings from another population study in which serum 25(OH)D did not predict the incidence of knee or hip OA [6]. Neither of these studies support the hypothesis that high levels of 25(OH)D protect against knee and hip OA [1]. Low levels of serum 25(OH)D have been found to increase the risk of progression of radiographic knee OA [2, 3]. However, no association was found between serum 25(OH)D levels and the progression of knee OA, defined as joint space narrowing on radiography in the Framingham cohort or as a worsening cartilage score on MRI in another cohort with symptomatic knee OA patients [5]. A recent systematic review [15] found insufficient or limited evidence for the association of 25(OH)D with hand or hip OA, but moderate evidence showing that low levels of 25(OH)D were associated with increased progression of radiographic knee OA, and strong evidence for an association between 25(OH)D and cartilage loss, defined as joint space narrowing or changes in cartilage volume. We found that vitamin D level was related to the known major risk factors of OA apart from female gender and musculoskeletal injuries. Our findings also suggest that serum 25(OH)D is related to time elapsed from 31 August and difficulties in walking due to discomfort or trouble in the knee or hip. There is biological plausibility in the hypothesis that low serum 25(OH)D is related to OA since vitamin D has an important role in vascular invasion and osteoclastogenesis during endochondral bone development [16]. However, our results do not lend support for the role of vitamin D in OA. A limitation of our study is the availability of only a single measurement of serum 25(OH)D, since it could mainly reflect recent exposures at the time of assessment rather than average levels in the long term [17]. Moreover, we were unable to take into consideration co-morbidities of the study subjects that may have affected eligibility to arthroplasty. The follow-up covered OA cases admitted to a hospital, but only a portion of all patients suffering from OA are ever hospitalized. The hospitalized persons may not be representative of all people with knee or hip OA. Thus in our study, serum 25(OH)D levels may have predicted either the development of OA per se or the likelihood of hospitalization once OA occurred, or both. Furthermore, we cannot rule out that some of the subjects may have had early OA missed by the physicians at the baseline survey. The paradoxical association we found between higher serum 25(OH)D levels and OA risk should therefore be interpreted with caution. A strength of our study is that the study sample represents the Finnish population well. The participation rate was 85% of the working-age subjects, which can be considered high. The population sample is also well characterized. The questionnaires, face-to-face interviews and health examination protocols were mostly selected on the basis of standardized, generally accepted recommendations or nationally established practice [7]. The reliability and repeatability of diagnoses of knee and hip OA at baseline proved to be acceptable, and the agreement between clinical and radiological diagnoses proved to be moderate in quality control trials carried out as part of field examinations, which was also shown in the previous 3

4 Sanna Konstari et al. TABLE 1 Baseline characteristics and their cross-sectional associations with vitamin D status n % 25(OH)D level, mean (S.D.), nmol/l a P-value b Age, years < (16.1) (16.8) (17.8) (17.8) Sex 0.77 Men (16.9) Women (16.6) Time from summer (quartiles) c, days < (16.3) (18.3) (15.6) (15.2) BMI, kg/m 2 < < (17.7) (16.4) (15.9) > (13.9) Manual handling of loads >20 kg, years < (16.6) (17.8) (16.0) > (16.4) Education in years < (17.1) (16.4) > (16.7) Leisure time physical activity < Little or irregular physical exercise (16.7) Regular physical exercise (16.7) Smoking < Never having smoked (16.9) Ex-smoker (17.1) Smoker (15.5) Injury 0.46 No injury (16.8) Self-reported traumatic lower limb injury or an injury of the meniscus or the cruciate ligament of the knee diagnosed by a clinician (16.8) Difficulty in walking or limping due to discomfort or trouble in the hip during the last month Yes (16.4) No (16.8) Difficulty in walking or limping due to discomfort or trouble in the knee during the last month Yes (17.2) No (16.7) Baseline hip OA No (16.7) Yes (18.2) Baseline knee OA No (16.7) Yes (17.6) a Serum 25-hydroxyvitamin D [25(OH)D] concentration (nmol/l) adjusted for age (continuous variable) and sex. b P-value for heterogeneity from a linear model. c Time from 31 August until the baseline health examination. 4

5 Serum vitamin D level in relation to the incidence of knee and hip osteoarthritis TABLE 2 Risk a of hospitalization due to incident knee and hip OA according to serum vitamin D status Serum 25- hydroxyvitamin D, nmol/l, quartiles All Cases RR national health examination survey using the same diagnostic criteria and a similar protocol [6, 8, 10, 12, 14]. In conclusion, the results of the current study do not support the hypothesis that low levels of serum 25(OH)D contribute to the development of knee or hip OA. Rheumatology key messages. Serum 25(OH)D at baseline was associated with known risk factors of OA except traumatic injury.. Low 25(OH)D status does not predict increased incidence of knee or hip OA. Disclosure statement: The authors have declared no conflicts of interest. References 95% CI P-value for trend b Knee OA (0 33) (34 42) , (43 54) , (55 134) , 2.47 Hip OA (0 33) (34 42) , (43 54) , (55 134) , 7.85 Knee or hip OA (0 33) (34 42) , (43 54) , (55 134) , 2.60 a Relative risk (RR) with 95% CI adjusted for age, gender, BMI, current physical workload, education, smoking, leisure time physical activity, time of serum draw from 31 August, injuries and difficulty in walking due to discomfort or trouble in the knee or hip. b Median value of each quartile as a continuous variable. 1 Kwan Tat S, Lajeunesse D, Pelletier JP, Martel-Pelletier J. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res 2010;24: McAlindon TE, Felson DT, Zhang Y et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 1996;125: Bergink AP, Uitterlinden AG, Van Leeuwen JP et al. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: the Rotterdam Study. J Clin Rheumatol 2009;15: Lane NE, Gore LR, Cummings SR et al. Serum vitamin D levels and incident changes of radiographic hip osteoarthritis: a longitudinal study. Study of Osteoporotic Fractures Research Group. Arthritis Rheum 1999;42: Felson DT, Niu J, Clancy M et al. Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies. Arthritis Rheum 2007;56: Konstari S, Paananen M, Heliövaara M et al. Association of 25-hydroxyvitamin D with the incidence of knee and hip osteoarthritis: a 22-year follow-up study. Scand J Rheumatol 2012;41: Heistaro S, Methodology Report. The Health 2000 Survey. Helsinki, Finland: Publications of the National Public Health Institute. 8 Kaila-Kangas L, Musculoskeletal Disorders and Diseases in Finland. Helsinki, Finland: Publications of the National Public Health Institute. 9 Juhakoski R, Heliövaara M, Impivaara O et al. Risk factors for the development of hip osteoarthritis: a population-based prospective study. Rheumatology 2009; 48: Toivanen AT, Heliövaara M, Impivaara O et al. Obesity, physically demanding work and traumatic knee injury are major risk factors for knee osteoarthritis a populationbased study with a follow-up of 22 years. Rheumatology 2010;49: Kaila-Kangas L, Arokoski J, Impivaara O et al. Associations of hip osteoarthritis with history of recurrent exposure to manual handling of loads over 20 kg and work participation: a population-based study of men and women. Occup Environ Med 2011;68: Jääskeläinen T, Knekt P, Marniemi J et al. Vitamin D status is associated with sociodemographic factors, lifestyle and metabolic health. Eur J Nutr 2013;52: Blagojevic M, Jinks C, Jeffery A et al. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 2010;18: Heliövaara M, Mäkelä M, Impivaara O et al. Association of overweight, trauma and workload with coxarthrosis. A health survey of 7,217 persons. Acta Orthop Scand 1993; 64: Cao Y, Winzenberg T, Nguo K et al. Association between serum levels of 25-hydroxyvitamin D and osteoarthritis: a systematic review. Rheumatology 2013;52: St-Arnaud R, Naja RP. Vitamin D metabolism, cartilage and bone fracture repair. Mol Cell Endocrinol 2011;347: Kilkkinen A, Knekt P, Heliövaara M et al. Vitamin D status and the risk of lung cancer: a cohort study in Finland. Cancer Epidemiol Biomarkers Prev 2008;17: