BRIEF REPORT

Fracture risk assessment and osteoporosistreatment disparities in 3,970 Japanese patientswith rheumatoid arthritis

Takefumi Furuya & Takayuki Hosoi & Seiji Saito &

Eisuke Inoue & Atsuo Taniguchi & Shigeki Momohara &

Hisashi Yamanaka

Received: 18 December 2010 /Revised: 28 March 2011 /Accepted: 1 April 2011 /Published online: 13 April 2011# Clinical Rheumatology 2011

Abstract The aims of this study are to determine theproportion of patients at high risk for major osteoporoticand hip fractures in a Japanese cohort with rheumatoidarthritis (RA) and to determine if a care gap exists for high-risk patients. The Fracture Risk Assessment Tool (FRAX®)was administered to 3,970 Japanese patients with RAenrolled in the Institute of Rheumatology RheumatoidArthritis cohort study with (n=276) and without (n=3,694) the use of bone mineral density (BMD) measure-ment. The study population had a mean age of 62 years andwas 84% female. Among the 1,522 patients ≥65 years ofage, 661 (43%) and 1,304 (86%) were at high risk for amajor osteoporotic fracture (10-year probability >20%) andhip fracture (>3%), respectively. Among patients at highrisk for a major osteoporotic fracture (n=723), only 453(63%) and 320 (44%) reported taking any osteoporosismedications and bisphosphonates, respectively. Amongfemale patients with BMD measurements (n=262), the10-year risk of a major osteoporotic fracture calculated withBMD was significantly higher than in those without BMDmeasurements (P<0.001). The FRAX identified a substan-tial proportion of elderly Japanese RA patients with a highrisk of fractures. A substantial gap exists between fracture

risk and osteoporosis treatment in Japanese RA patients, aspreviously reported for patients of other ethnicities. Inaddition, the gap may be underestimated when BMDmeasurements are not involved in the fracture riskassessment.

Keywords Bone mineral density . Fracture . FRAX® .

Japanese . Osteoporosis . Rheumatoid arthritis

Introduction

Patients with rheumatoid arthritis (RA) have an increasedrisk of hip [1–3] and osteoporotic [2, 3] fractures comparedwith controls. Previously, utilizing data from our observa-tional study of RA in Japan (IORRA, Institute ofRheumatology Rheumatoid Arthritis), we reported theclinical risk factors for fracture and the existence ofundertreatment of osteoporosis in Japanese patients withRA [4–9].

The World Health Organization Fracture Risk AssessmentTool (FRAX®) has been developed to estimate a 10-yearabsolute risk of sustaining a hip fracture and other majorosteoporotic fractures (clinical spine, forearm, hip, or shoulderfracture). The FRAX calculation tool is available on theinternet (http://www.shef.ac.uk/FRAX). The tool identifiespatients as being at low (<10%), moderate (10–20%), or high(>20%) risk of fracture using validated clinical risk factorswith or without the use of bone mineral density (BMD)measurement at the femoral neck. The FRAX has been usedin the osteoporosis guidelines put forth by the NationalOsteoporosis Foundation (NOF) [10] and in recent recom-mendations for glucocorticoid-induced osteoporosis by theAmerican College of Rheumatology (ACR) [11].

T. Furuya (*) : S. Saito : E. Inoue :A. Taniguchi :S. Momohara :H. YamanakaInstitute of Rheumatology, Tokyo Women’s Medical University,10–22 Kawada-cho, Shinjuku-ku,Tokyo 162–0054, Japane-mail: furuyat@ior.twmu.ac.jp

T. HosoiDepartment of Clinical Research and Development,National Center for Geriatrics and Gerontology,35 Gengo, Morioka-machi,Obu, Aichi 474–8511, Japan

Clin Rheumatol (2011) 30:1105–1111DOI 10.1007/s10067-011-1748-8

Among the general population, the FRAX appears to bea useful tool not only in European countries [12], but alsoin Japan [13] and Latin America [14]. Among patients withRA, limited data exist in the literature concerning fracturerisk assessment using FRAX, although results in Canadianpatients with inflammatory arthritis [15] and in AfricanAmerican patients with RA [16] were recently reported.Recent studies show the existence of a care gap betweenfracture risk and osteoporosis treatment [15, 17].

The aims of our study were to determine the proportionof Japanese patients with RA in the IORRA cohort study athigh risk for both hip and major osteoporotic fracturesusing FRAX and to determine if a care gap exists in thesehigh-risk patients.

Materials and methods

IORRA is an observational cohort study of Japanese RApatients at the Institute of Rheumatology, Tokyo Women'sMedical University (Tokyo, Japan) that was begun in 2000.Details regarding the study's purpose and methodologyhave been reported previously [4–9, 18]. A total of 5,201patients with inflammatory polyarthritis were enrolled intothis 17th IORRA study in October or November 2008.Among them, 1,201 patients were excluded because theywere <40 years of age or because they did not meet the1987 classification criteria for RA developed by the ACR[19]. Among the 4,000 patients who satisfied the ACRclassification criteria for RA, we excluded 30 patientswhose RA overlapped with other diseases, includingscleroderma (n=8), psoriasis (n=6), vasculitis (n=6),mixed connective tissue disease (n=2), autoimmune hepa-titis (n=1), breast cancer (n=1), chronic renal failure (n=1),dermatomyositis (n=1), fibromyalgia (n=1), gout (n=1),polymyositis (n=1), and systemic lupus erythematosus (n=1). Thus, data from 3,970 patients with RA were analyzedin this study.

Among the 3,970 patients, 276 had their femoral neckBMD analyzed during April 2008 and March 2009. BMDs(grams per square centimeter) were measured with dualenergy X-ray absorptiometry by a Lunar Prodigy (GEHealthcare, Madison, WI) in our clinic. The FRAX wasapplied to the 17th IORRA cohort study in October orNovember 2008. Patients were invited to complete sixquestionnaires about previous fracture, parental history ofhip fracture, current smoking, glucocorticoid use, othercauses of secondary osteoporosis, and alcohol use, inaddition to regular IORRA questionnaires including age,weight, and height, as reported previously [4–9, 18]. Weused the FRAX v. 1.0 for the 3,694 patients without BMDand the FRAX v.3.1 for the 276 patents with BMD toestimate the 10-year risk of a major osteoporotic and hip

fracture specific to Japanese individuals (calculation com-pleted in August 2010). We combined the 3,694 and the276 patients into one group of 3,970 patients with bodymass index (BMI).

Statistical significance of the differences betweengroups was determined using the Wilcoxon or Kruskal–Wallis test (continuous variables) and chi-square forindependence test (counts) when appropriate. For allanalyses, the odds ratio and associated 95% confidenceintervals with a P value <0.01 were considered signifi-cant. All statistical analyses were conducted with the JMPstatistical software, version 7 (NC, USA).

Results

The characteristics of the 3,970 RA patients with BMIand the 276 RA patients with BMD are displayed inTable 1. Among the patients with BMI (n=3,970), malepatients were significantly older (P<0.0001), heavier (P<0.001), taller (P<0.001), had higher BMI, tended to besmokers (P<0.001), and consumed more alcohol (P<0.0001) than female patients. Female patients tended tohave more previous fractures (P=0.0003), a significantlyyounger age of RA onset (P<0.0001), longer RA diseasedurations (P=0.003), higher tender joint counts (P<0.001), swollen joint counts (P<0.001), visual analogscale (VAS)-pain scores (P<0.0001), VAS-general healthscores (P<0.0001), VAS-physician scores (P<0.001),disease activity score using 28 joint counts (DAS28) [20](P<0.001), and higher Japanese health assessment ques-tionnaire (J-HAQ) scores [18] (P<0.0001). Among thepatients with BMD (n=276), male patients had signifi-cantly higher body weight (P<0.0001), greater height (P<0.0001), tended to smoke (P=0.002), and had higherBMD (P=0.0004) compared with female patients.

Table 2 describes the FRAX-estimated 10-year majorosteoporotic and hip fracture risk, stratified by gender andage. For major osteoporotic fracture risk, the FRAXclassified most men with RA as being at low or moderaterisk until they reached age 75 or older. The FRAX effectivelyrisk-stratified women ages 55–74 across a wide distributionof fracture risk; in contrast, almost all women ≥75 years ofage with RA were identified as having a major osteoporoticfracture risk >20%. For hip fracture risk, the FRAXeffectively risk-stratified men ages 65–74 across a widedistribution of fracture risk; in contrast, all men ≥75 yearswith RA were identified as having hip fracture risk >3%(considered high risk by NOF guidelines [10]). The FRAXclassified most women with RA as being at high risk of hipfracture after they reached age 65 or older.

Table 3 shows the estimated 10-year risk of a majorosteoporotic fracture and the characteristics of the patients.

1106 Clin Rheumatol (2011) 30:1105–1111

Among both men and women with RA, age, BMI, dailyprednisolone dose, duration of RA, erythrocyte sedimentationrate (ESR), VAS-pain scores, VAS-general health scores,DAS28, and J-HAQ scores were significantly different (P<0.01) among the three fracture risk groups. Among the malepatients, use of glucocorticoids (P<0.0001), any osteoporosismedication (P=0.002), and bisphosphonates (P=0.003) weresignificantly different between the low and moderate riskgroups. Among women with RA, serum CRP levels (P<0.0001), VAS-physician (P=0.0002), tender joint counts (P=0.002), and use of glucocorticoids, any osteoporosis medica-tion, and bisphosphonates were significantly different amongthe three fracture risk groups (P<0.0001). Among patients at

high risk for a major osteoporotic fracture (n=723), only 453(63%) and 320 (44%) reported taking any osteoporosismedications and taking bisphosphonates, respectively.

Table 4 shows the 10-year risk of a hip and majorosteoporotic fracture with and without BMD in patientswith femoral neck BMD (n=276). Among the women (n=262), the 10-year risk of a major osteoporotic fracturecalculated with BMD was significantly higher than in thosewithout BMD (P<0.0001) although the 10-year risk of ahip fracture was not significantly different between patientswith and without BMD. Among the men, there were nosignificant differences in the FRAX-estimated fracture riskbetween patients with and without BMD.

Table 1 Characteristics of Japanese patients with rheumatoid arthritis (n=3,970)

Variables Men with BMI(n=641)

Women with BMI(n=3,329)

Men with BMD(n=14)

Women with BMD(n=262)

Fracture-related risk factors

Age, years 62.9 (10.1) 61.3 (10.0) 66.1 (12.7) 63.2 (8.9)

Weight, kg 64.3 (10.1) 50.7 (7.9) 63.9 (8.7) 50.7 (7.6)

Height, cm 167.2 (6.4) 154.9 (5.9) 167.3 (5.7) 154.5 (5.3)

Body mass index, kg/m2 22.9 (3.1) 21.1 (3.1) 22.8 (3.1) 21.2 (3.0)

Previous fracture 10 (1.6%) 146 (4.4%) 0 19 (7.3%)

Fracture in the last 6 months 5/630 (0.8%) 64/3,251 (2.0%) 0 9/257 (3.5%)

Parent fractured hip 37 (5.8%) 244 (7.3%) 1 (7.1%) 24 (9.2%)

Current smoker 178 (27.8%) 281 (8.4%) 5 (35.7%) 16 (6.1%)

Glucocorticoid use 293 (45.7%) 1,580 (47.5%) 11 (78.6%) 138 (51.5%)

Daily PSL dose, mg/day 2.1 (3.2) 1.9 (2.6) 5.0 (3.7) 2.5 (3.7)

Alcohol ≥3 units/day 168 (26.2%) 152 (4.6%) 3 (21.4%) 7 (2.7%)

Secondary osteoporosis 8 (1.2%) 67 (2.0%) 0 8 (3.1%)

Femoral neck BMDa – – 0.8 (0.1) 0.7 (0.1)

RA disease characteristics

Age of onset 50.4 (12.0) 47.5 (11.8) 55.9 (13.9) 48.4 (12.4)

Disease duration, years 12.6 (9.7) 13.8 (9.4) 10.1 (8.8) 14.5 (10.1)

RF, IU/ml 150.7 (253.8) 123.0 (287.7) 247.3 (334.4) 132.4 (245.5)

RF positive, >20 IU 436/618 (70.6%) 2,346/3,203 (73.2%) 11/12 (91.7%) 181/257 (70.4%)

Tender joint count, 0–28 1.1 (2.0) 1.5 (2.3) 1.5 (2.9) 1.3 (2.4)

Swollen joint count, 0–28 0.9 (1.7) 1.3 (2.4) 2.8 (3.2) 1.4 (2.4)

ESR, mm/hour 24.7 (21.2) 33.2 (22.6) 24.9 (15.4) 35.1 (22.9)

CRP, mg/100 ml 0.8 (1.2) 0.7 (1.3) 1.2 (1.6) 0.6 (1.2)

VAS-pain, 0–10 cm 2.2 (2.3) 2.6 (2.5) 2.7 (1.9) 2.7 (2.5)

VAS-general health, 0–10 cm 2.4 (2.3) 2.8 (2.4) 2.8 (2.1) 3.0 (2.5)

VAS-physician, 0–10 cm 1.2 (1.4) 1.5 (1.5) 1.8 (1.3) 1.4 (1.4)

DAS28 2.8 (1.1) 3.3 (1.1) 3.3 (1.4) 3.4 (1.0)

J-HAQ score 0.4 (0.6) 0.8 (0.8) 0.5 (0.6) 0.8 (0.8)

Methotrexate use 410 (64.0%) 2,300 (69.1%) 11 (78.6%) 179 (68.3%)

Values are expressed as means (standard deviation) or number of participants (percent) in the category listed

BMI body mass index, BMD bone mineral density, PSL prednisolone, RA rheumatoid arthritis, RF rheumatoid factor, ESR erythrocytesedimentation rate, CRP C-reactive protein, VAS visual analog scale, DAS disease activity score, J-HAQ Japanese health assessment questionnairea During April 2008 to March 2009

Clin Rheumatol (2011) 30:1105–1111 1107

Discussion

Among 3,970 Japanese patients with RA, most femalepatients >75 years of age and more than one third of thefemale patients aged 65 to 74 years were at high risk for amajor osteoporotic fracture (>20%), and the majority of thepatients (86%) ≥65 years of age had a high risk of hipfractures (>3%) (Table 2). The NOF guidelines recommendosteoporosis treatment for those patients [10]. The FRAXtool appears useful for assessing risk and identifying high-risk persons in need of additional evaluation in Japanesepatients with RA, as previously reported for Canadian (n=238) patients with inflammatory arthritis [15] and AfricanAmerican (n=328) patients with RA [16]. Although RApatients are reported to have a significantly higher risk ofhip fracture compared with controls [1–3], previous reportsdid not evaluate [15] or show [16] the dataset of hip

fracture risk evaluated with the FRAX in RA patients. Ourdata and other studies [1–3] suggest that RA patients have ahigh risk of hip fractures as well as osteoporotic fractures,and fracture risk categories using both FRAX-estimatedclinical osteoporotic and hip fracture risks may be neededto reduce hip fractures in RA patients.

Although 723 (18%) of the patients in our cohort belongto the high-risk group for a major osteoporotic fracture,only 453 (63%) and 320 (44%) reported taking anyosteoporosis medications and bisphosphonates, respectively(Table 3). Bisphosphonates have been proven effective inJapanese patients with RA [5] and osteoporosis [21]. A caregap appears to exist between fracture risk and osteoporosistreatment in Japanese RA patients, as reported in Canadianpatients with inflammatory arthritis [15]. Practicing rheu-matologists should recognize the undertreatment of osteo-porosis among patients with RA.

Table 2 Prevalence of FRAX-estimated 10-year major osteoporotic and hip fracture risks by gender and age in Japanese patients with rheumatoidarthritis (n=3,970)

Age group, years Estimated 10-yearfracture risk

Men with BMI(n=641)

Women with BMI(n=3,329)

Men with BMDa

(n=14)Women with BMDa

(n=262)

Major osteoporotic fracture

40–54 <10% 141 (99) 874 (96) 3 (75)/4 (100) 32 (78)/37 (90)

10–20% 2 (1) 33 (4) 1 (25)/0 7 (17)/4 (10)

>20% 0 0 0/0 2 (5)/0

55–64 <10% 196 (91) 658 (56) 0/0 39 (39)/50 (50)

10–20% 19 (9) 463 (39) 0/0 45 (45)/39 (39)

>20% 0 62 (5) 0/0 15 (15)/10 (10)

65–74 <10% 115 (59) 9 (1) 2 (33)/2 (33) 13 (13)/1 (1)

10–20% 78 (40) 578 (61) 4 (67)/4 (67) 40 (38)/70 (67)

>20% 3 (1) 357 (38) 0/0 51 (49)/33 (32)

≥75 <10% 2 (2) 0 1 (25)/0 0/0

10–20% 75 (86) 4 (1) 3 (75)/4 (100) 3 (17)/1 (6)

>20% 10 (11) 291 (99) 0/0 15 (83)/17 (94)

Hip fracture

40–54 <3% 143 (100) 901 (99) 3 (75)/4 (100) 33 (80)/41 (100)

3–10% 0 6 (1) 1 (25)/0 7 (17)/0

>10% 0 0 0/0 1 (2)/0

55–64 <3% 206 (96) 913 (77) 0/0 62 (62)/73 (73)

3–10% 9 (4) 256 (22) 0/0 33 (33)/24 (24)

>10% 0 14 (1) 0/0 4 (4)/2 (2)

65–74 <3% 82 (42) 136 (14) 3 (50)/2 (33) 23 (22)/11 (11)

3–10% 106 (54) 584 (62) 3 (50)/4 (67) 61 (59)/75 (72)

>10% 8 (4) 224 (24) 0/0 20 (19)/18 (17)

≥75 <3% 0 0 1 (25)/0 1 (6)/0

3–10% 55 (64) 37 (13) 3 (75)/3 (75) 5 (28)/4 (22)

>10% 32 (36) 258 (87) 0/1 (25) 12 (67)/14 (78)

Values are n (%)a The left and right columns show the distribution of the fracture risk categories estimated by FRAX with and without BMD, respectively. See Table 1 fordefinitions.

1108 Clin Rheumatol (2011) 30:1105–1111

An increasing fracture risk was significantly associ-ated with glucocorticoid use, DAS28, and J-HAQ score(Table 3). These results are in agreement with a recentreport analyzing fracture risks using the FRAX inCanadian patients with inflammatory arthritis [15]. Al-though DAS28 is reported to be associated with loss ofBMD in RA patients [22], we [4–6, 8] and others [23]previously reported that fracture risks were significantlyassociated with high HAQ disability score rather thanDAS28. Thus, the effect of DAS28 on fracture risk may

be complex, and further studies are needed to drawconclusions.

We found a significant difference between the FRAXwith and without BMD calculating a major osteoporoticfracture risk in female patients with RA (Table 4). Amongthe 262 female patients with BMD, 75 patients (29%)belonged to different fracture risk categories when weestimated their fracture risk with and without BMD(Table 2). Nevertheless, the difference between the FRAXwith and without BMD appears to be marginal and may

Table 3 Ten-year risk of a major osteoporotic fracture and characteristics of patients (n=3,970)

Low risk (<10%) Moderate risk (10–20%) High risk (>20%)

Men, n=454 Women, n=1,541 Men, n=174 Women, n=1,078 Men, n=13 Women, n=710

Fracture-related risk factors

Age, years 58.8 (8.2) 53.3 (6.6) 72.8 (6.8) 64.7 (5.0) 76.7 (4.5) 73.3 (6.0)

Body mass index, kg/m2 23.3 (3.0) 21.2 (3.1) 22.0 (3.1) 21.3 (2.9) 22.0 (4.1) 20.6 (3.2)

Previous fracture 3/446 (1%) 17/1,517 (1%) 2/71 (3%) 21/1,057 (2%) 0 26/677 (4%)

Glucocorticoid use 185 (41%) 549 (36%) 98 (56%) 555 (51%) 11 (85%) 476 (67%)

Daily PSL dose, mg/day 2.0 (3.4) 1.3 (2.2) 2.4 (2.8) 2.1 (2.7) 3.8 (2.8) 2.9 (3.0)

Any osteoporosis medication use 47 (10%) 317 (21%) 34 (20%) 476 (44%) 6 (46%) 447 (63%)

Bisphosphonate use 35 (8%) 205 (13%) 27 (16%) 337 (31%) 4 (31%) 316 (45%)

Active vitamin D3 use 16 (4%) 125 (8%) 12 (7%) 173 (16%) 3 (23%) 159 (22%)

RA-related factors

Disease duration, year 11.0 (8.0) 11.4 (3.1) 15.7 (11.7) 15.2 (9.4) 23.6 (14.4) 16.8 (10.6)

ESR, mm/hr 21.5 (19.4) 28.3 (19.3) 31.3 (23.4) 35.3 (23.2) 38.0 (24.9) 40.8 (25.8)

CRP, mg/100 mL 0.7 (1.1) 0.5 (1.0) 0.9 (1.5) 0.7 (0.5) 1.2 (1.5) 0.9 (1.6)

RF positive 298/435 (69%) 1,096/1,497 (73%) 127/171 (74%) 771/1,035 (74%) 11/12 (92%) 480/674 (71%)

Swollen joint countsa 1.1 (2.0) 1.5 (2.4) 1.2 (2.0) 1.5 (2.3) 1.7 (1.8) 1.5 (2.4)

Tender joint countsa 0.8 (1.7) 1.2 (2.3) 0.9 (1.5) 1.2 (2.3) 1.0 (1.0) 1.6 (2.8)

VAS-painb 2.1 (2.2) 2.4 (2.3) 2.2 (2.4) 2.6 (2.5) 4.8 (2.6) 3.2 (2.7)

VAS-general healthb 2.3 (2.2) 2.5 (2.7) 2.6 (2.4) 2.8 (2.5) 5.4 (2.4) 3.5 (2.6)

VAS-physicianb 1.2 (1.4) 1.4 (1.4) 1.4 (1.3) 1.5 (1.5) 2.4 (1.8) 1.7 (1.6)

DAS28 2.7 (1.1) 3.2 (1.0) 3.1 (1.1) 3.3 (1.1) 3.8 (0.8) 3.6 (1.1)

J-HAQ score 0.3 (0.5) 0.6 (0.6) 0.5 (0.7) 0.8 (0.8) 1.4 (0.8) 1.2 (0.9)

Methotrexate use 304 (67%) 1,127 (73%) 100 (57%) 736 (68%) 6 (46%) 437 (62%)

Values are n (%) or average (SD). See Table 1 for definitionsa 0–28 jointsb 0–10 cm

Fracture type Clinical risk factors alone Clinical risk factors incombination with BMD

P value

Major osteoporotic fracture (%)

Men (n=14) 10.9 (5.2) 10.8 (4.6) NS

Women (n=262) 15.4 (10.7) 17.2 (11.9) <0.0001

Hip fracture (%)

Men (n=14) 5.0 (4.0) 4.3 (3.6) NS

Women (n=262) 5.7 (7.3) 6.0 (7.6) NS

Table 4 FRAX-estimated10-year major osteoporotic andhip fracture risks using clinicalrisk factors alone and incombination with femur neckBMD (n=276)

Values are expressed as means(standard deviation)

NS not significant

Clin Rheumatol (2011) 30:1105–1111 1109

represent a selection bias, since physicians refer those atincreased risk for osteoporosis for BMD measurement. Wedid not find any significant differences between estimatedfracture risk with and without BMD in males, although thenumber of men was relatively low compared with thenumber of women (Table 4). Our results suggest thatmeasuring BMD may be necessary in women but not inmen when we estimate fracture risk using FRAX inJapanese RA patients.

Our study has some limitations. First, information aboutfractures was obtained using self-reported questionnaires,and some degree of under-reporting is likely. Second,although IORRA is a large cohort study of Japanese RApatients, it is a single institute-based study and notnecessarily representative of all Japanese RA patients.Third, the FRAX does not incorporate falls and glucocor-ticoid dose, although the increasing fracture risk groupswere significantly associated with high HAQ disabilityscore and daily prednisolone dose (Table 3) that arecorrelated to falls [7, 24] and incident fractures in RApatients [4], respectively. Fourth, we looked at FRAXscores for RA patients on bisphosphonates in this study,although FRAX was not designed for use in patients ontherapy. Finally, our study was cross sectional, andtherefore, it is not possible to determine the temporal natureof any observed associations. Thus, a future longitudinalstudy will be needed to verify the FRAX-estimated risk inJapanese RA patients.

In conclusion, Japanese elderly RA patients have a highrisk for major osteoporotic and hip fractures. The FRAXtool appears useful for assessing risk and identifying high-risk Japanese patients with RA in need of additionalevaluation. A substantial gap exists between fracture riskand osteoporosis treatment in Japanese RA patients. Thegap may be underestimated when BMD measurements arenot involved in the fracture risk assessment.

Acknowledgments We thank all members of the Institute ofRheumatology, Tokyo Women's Medical University for the successfulmanagement of the IORRA cohort and Dr. R. L. Wilder for his usefulsuggestions. The IORRA cohort was supported by nonrestrictedresearch grants from 37 pharmaceutical companies: Abbott JapanCo., Ltd.; Asahikasei Kuraray Medical Co., Ltd.; Asahikasei PharmaCorporation; Astellas Pharma Inc.; AstraZeneca K.K.; Banyu Phar-maceutical Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Daiichi FineChemical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Dainippon SumitomoPharma Co., Ltd.; Eisai Co., Ltd.; GlaxoSmithKline K.K.; JanssenPharmaceutical K.K.; Japan Tobacco Inc.; Kaken Pharmaceutical Co.,Ltd.; Kissei Pharmaceutical Co., Ltd.; Kowa Pharmaceutical Co., Ltd.;Mitsubishi Chemical Medience Corporation; Mitsubishi TanabePharma Corporation; Mundipharma K.K.; Nippon Chemiphar Co.,Ltd.; Nippon Shinyaku Co., Ltd.; Novartis Pharma K.K.; OtsukaPharmaceutical Co., Ltd.; Pfizer Japan Inc.; Sanofi-Aventis K.K.;Santen Pharmaceutical Co., Ltd.; Sanwa Kagaku Kenkyusho Co.,Ltd.; Sekisui Medical Co., Ltd.; Taisho Toyama Pharmaceutical Co.,Ltd.; Takeda Pharmaceutical Company Limited; Teijin PharmaLimited; Torii Pharmaceutical Co., Ltd.; Toyama Chemical Co.,

Ltd.; UCB Japan Co., Ltd.; Wyeth K.K.; and Zeria PharmaceuticalCo., Ltd. This work was also supported in part by a grant from theJapan Osteoporosis Society.

Disclosures HY received research grants from Chugai Pharmaceu-tical Co., Ltd.; Astellas Pharma Inc.; Wyeth; Daiichi-Sankyo; BanyuPharmaceutical Co., Ltd.; Tanabe-Mitsubishi; Abbott; Eisai; SantenPharmaceutical Co., Ltd.; Taisyo-Toyama Pharmaceutical Co., Ltd.;Takeda Pharmaceutical Co; Kissei Pharmaceutical Co., Ltd.; andJanssen Pharmaceutical K.K. HY received lecture fees from Abbott,Eisai, Takeda Pharmaceutical Co., Tanabe-Mitsubishi, Janssen Phar-maceutical K.K., Hoffmann-La Roche, and Chugai PharmaceuticalCo., Ltd. The others have no conflicts of interest.

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