The Relationship of Health-Related Quality of Life to Prevalent and Incident Vertebral Fractures in Postmenopausal Women With Osteoporosis

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1 ARTHRITIS & RHEUMATISM Vol. 44, No. 11, November 2001, pp , American College of Rheumatology Published by Wiley-Liss, Inc. The Relationship of Health-Related Quality of Life to Prevalent and Incident Vertebral Fractures in Postmenopausal Women With Osteoporosis Results From the Multiple Outcomes of Raloxifene Evaluation Study Stuart L. Silverman, 1 Michael E. Minshall, 2 Wei Shen, 2 Kristine D. Harper, 2 and Sunny Xie, 2 on behalf of the Health-Related Quality of Life Subgroup of the Multiple Outcomes of Raloxifene Evaluation Study Objective. To examine the effect of both prevalent and incident vertebral fractures on health-related quality of life (HRQOL) in postmenopausal women with osteoporosis and to characterize the effect of prevalent vertebral fractures on HRQOL with respect to number, location, severity, and adjacency. Methods. Participants were a subset of women (n 1,395, mean age 68.5 years) from the Multiple Outcomes of Raloxifene Evaluation trial who had low bone mineral density and/or prevalent vertebral fractures. Vertebral fractures were measured by radiography at baseline, 2 years, and 3 years. HRQOL was assessed using the Osteoporosis Assessment Questionnaire (), a validated disease-targeted instrument, at baseline and annually for 3 years. Funding for the Health-Related Quality of Life portion of the Multiple Outcomes of Raloxifene Evaluation study was provided by Eli Lilly and Company. 1 Stuart L. Silverman, MD: Cedars-Sinai Medical Center, Greater Los Angeles VA Health System, University of California, Los Angeles, and the OMC Clinical Research Center, Los Angeles, California; 2 Michael E. Minshall, MPH, Wei Shen, PhD, Kristine D. Harper, MD, MBA, Sunny Xie, MS: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana. Other members of the Health-Related Quality of Life Subgroup of the Multiple Outcomes of Raloxifene Evaluation Study are as follows: Paul Lips, MD, Anna Oleksik, MD (Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands), John A. Kanis, MD (University of Sheffield Medical School, Sheffield, UK), and Alison Dawson, MRPharmS (Eli Lilly and Company, London, UK). Address correspondence and reprint requests to Stuart L. Silverman, MD, The OMC Clinical Research Center, 8641 Wilshire Boulevard, Suite 310, Beverly Hills, CA stuarts@ omcresearch.org. Submitted for publication September 11, 2000; accepted in revised form July 6, Results. Both prevalent and incident radiographic vertebral fractures were associated with decreased HRQOL. At baseline, women with a prevalent vertebral fracture had significantly lower scores on physical function, emotional status, clinical symptoms, and overall HRQOL compared with women without a prevalent fracture (all P < 0.01). HRQOL scores were lower with each subsequent fracture. The effect of prevalent vertebral fracture was dependent on the location within the spine and was strongest in the lumbar region (L1 L4). Incident vertebral fractures significantly decreased scores on physical function, emotional status, clinical symptoms, and overall HRQOL (all P < 0.001). Conclusion. Our findings demonstrate the importance of treating postmenopausal women who have prevalent vertebral fractures to prevent further decreases in HRQOL associated with subsequent incident vertebral fracture. Osteoporosis is a major public health problem worldwide, affecting more than 75 million people in Europe, the US, and Japan alone (1). Postmenopausal women with osteoporosis have low bone mass and are at increased risk of fragility fractures. Vertebral fracture is one of the most commonly occurring osteoporotic fractures. Vertebral fractures and deformities result in back pain, limitations in physical functioning, and psychosocial impairment in postmenopausal women with osteoporosis (2 13). Crosssectional studies of older community-based women have shown an association between prevalent vertebral frac- 2611

2 2612 SILVERMAN ET AL tures and back pain or disability (5 7). Prospective data from the Study of Osteoporotic Fractures (12) showed that new vertebral fractures, even if not recognized clinically, are associated with substantial increases in back pain and disability. However, according to recent estimates, only about one-third of vertebral fractures come to medical attention (2). Vertebral fractures and deformities may also have significant impact on health-related quality of life (HRQOL). HRQOL represents a multial concept that defines a person s health status in terms of specific s, such as physical, social, emotional, and functional well-being (14). Assessment of HRQOL plays an increasingly important role in evaluating the burden of osteoporosis on a patient s daily life. HRQOL is often used as an outcome measure that complements bone mineral density (BMD) and vertebral fractures in osteoporosis intervention studies. Over the last several years, the number of HRQOL disease-targeted instruments for use in osteoporosis has expanded dramatically (6,15 21). The Multiple Outcomes of Raloxifene Evaluation (MORE) study is the first large intervention trial to perform prospective HRQOL assessments over a 3-year period (22). The primary objective of the MORE study was to examine the long-term effects of raloxifene (Evista; Eli Lilly, Indianapolis, IN) on the skeleton in postmenopausal women with osteoporosis. One of the secondary objectives of the MORE trial was to assess the impact of raloxifene on HRQOL in women with osteoporosis and prevalent vertebral fractures. Two disease-targeted instruments, the Osteoporosis Assessment Questionnaire () and the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO), were used in the MORE trial to assess HRQOL. Both the and the QUALEFFO are validated instruments showing adequate psychometric properties and appropriateness for use in clinical trials. The main purpose of this study was to examine the effect of both prevalent and incident vertebral fractures on HRQOL using data collected from a subset of women participating in the MORE trial. Results using the QUALEFFO to examine the effect of prevalent fracture have been reported elsewhere (23). We hypothesized that increased numbers of prevalent vertebral fractures would be associated with decreased HRQOL, adjacent or more severe vertebral fractures would be associated with greater decreases in HRQOL, there would be an association between the location of the prevalent vertebral fracture and decreased HRQOL based on the location of the fracture within the spine, and incident vertebral fractures would be associated with decreased HRQOL. SUBJECTS AND METHODS Study population. Participants in the MORE study included 7,705 postmenopausal women, ages 80 years, at 180 centers in 25 countries. Women who had osteoporosis, as defined by low BMD or radiographically apparent vertebral fractures, were enrolled into 2 study groups and then randomly assigned to 1 of 3 treatment groups: placebo, 60 mg of raloxifene, or 120 mg of raloxifene. Study group 1 included those whose femoral neck or lumbar spine BMD T score was at least 2.5 SD below the mean in healthy young adults. Study group 2 included women who had low BMD and 1 moderate or severe vertebral fracture, low BMD and 2 mild vertebral fractures, or at least 2 moderate vertebral fractures regardless of BMD (22). A mild vertebral fracture corresponded to a 20 25% reduction in height of the vertebral body, and a moderate vertebral fracture corresponded to a 25 40% reduction from expected vertebral height (22). The was administered to women in 4 Englishspeaking countries (Australia, Canada, New Zealand, and the US). In 1994, when the study was designed, no validated translations of the were available in other languages. A total of 1,395 postmenopausal women from the 4 Englishspeaking countries participated in the assessment at baseline. Of these 1,395 women, 190 were enrolled from study group 1 (low BMD only). These 190 women comprised a convenience sample representing all patients enrolled from 5 centers. These 190 women had an assessment performed at baseline only. The remaining 1,205 postmenopausal women represented all women from the 4 English-speaking countries who were enrolled in study group 2 (low BMD and fracture) at baseline. In the incident fracture assessment, we enrolled only the 1,205 women from study group 2. These women had an assessment at baseline and annually for 3 years (see Figure 1). Vertebral fracture measurements. Radiographs of the lumbar and thoracic spine were obtained at baseline, 2 years, and 3 years, and were examined at the quality assurance center (Osteoporosis and Arthritis Research Center, University of California, San Francisco). Women were seen every 6 months over the 3 years of the MORE study. If symptoms of vertebral fracture were reported at an interim visit, women also underwent radiography to confirm the presence of a vertebral fracture. All vertebral fractures were assessed at the central quality assurance center. To establish eligibility for study group 2, baseline radiographs were scored using a semiquantitative scale for each vertebra (T4 L4) (24). The scores were as follows: 0 no fracture, 1.0 mild, 2.0 moderate, and 3.0 severe vertebral fracture(s). After 3 years, a radiologist scored the baseline and end point radiographs using the same semiquantitative scale. An incident fracture during the study was defined as a change in score of at least 1.0. If a fracture was observed at baseline or at the end point, a second radiologist using semiquantitative methods determined whether a fracture was

3 HRQOL OF PREVALENT AND INCIDENT VERTEBRAL FRACTURES 2613 Figure 1. Population of women who were included in the analyses of associations between vertebral fractures and health-related quality of life (HRQOL; assessed by the Osteoporosis Assessment Questionnaire []). present for each vertebra and performed quantitative morphometry (with an incident fracture defined as a decrease in anterior, mid-, or posterior height of at least 20% and 4 mm). Vertebral fractures were scored when confirmed by at least 2 of the 3 types of determinations from 2 independent semiquantitative readings and 1 quantitative assessment. HRQOL measurements. (version 2.0) is a validated, self-administered HRQOL instrument consisting of 67 questions (see Appendix A, which is available at the Arthritis & Rheumatism World Wide Web site: arthritisrheum.org). The includes 49 questions grouped into 14 domains (reflecting 4 composite s), 6 individual questions (general health, overall HRQOL, change in HRQOL over the last year, and residential status), and 12 domain weighting questions; subjects respond according to a 5-point Likert scale. The domain-weighting questions were not used in this analysis. The can be scored by domain or by the 4 composite s (physical function, emotional status, symptoms, and social interaction) determined through previous factor analysis (16). The physical function includes 6 domains: walking/bending, standing/sitting, dressing/reaching, household/self-care, transfers, and usual work. The emotional status includes 4 domains: fear of falling, level of tension, body image, and independence. The symptoms includes 2 domains: back pain and fatigue. The social interaction includes 2 domains: social activity and support of family and friends. For the remainder of this report, we will refer only to the 4 composite s and to the single question on overall HRQOL, and not to the 14 individual domains. The full psychometric validation of has been published elsewhere (16). Statistical analysis. Scores for each domain and were created according to the published scoring algorithm (16). Missing values in a domain were imputed only if at least one-half of the questions within the same domain were answered. If so, the missing value was replaced with the mean of the non-missing values within the same domain. The completeness of the is summarized as follows: 92% of the questionnaires were answered completely, 5% had only 1 missing answer, and 3% had 1 missing answer. Missing data for each question ranged from 0.4% to 2.1%. To allow for comparability, the 4 scores and the single question on overall HRQOL score were transformed into a range of Higher scores indicate better HRQOL; lower scores indicate worse HRQOL. The analyses of prevalent vertebral fractures were based on cross-sectional data obtained at baseline. The association between numbers of prevalent vertebral fractures and HRQOL was evaluated using a multiple linear regression model that included the scores as the dependent variable and number of vertebral fractures as an explanatory variable. Likewise, the associations between fracture location, fracture severity, and presence of adjacent fractures (that is, 1 vertebra above or below) and HRQOL were evaluated using a similar multiple regression model. In the analysis of fracture location, women were divided into 3 groups as follows: no fracture, thoracic (T4 T12) fracture only, and lumbar (L1 L4) fracture only. Women with fractures in both the lumbar and thoracic spine regions were excluded from this analysis. In addition, a stepwise regression analysis was performed to identify fracture locations that had the strongest association with HRQOL. The analysis of adjacent fractures included only women with 2 vertebral fractures. The analyses of incident vertebral fractures were based on longitudinal data obtained at baseline and followup. Subtracting the baseline score from the score at the study end point (3-year visit or discontinuation) created an change score for each of the 4 s and the single question on overall HRQOL. We examined the effect of incident fractures by using a multiple regression model with the change scores as the dependent variable and the presence of incident fractures as an explanatory variable. The percentages of women with a significant change in scores, as defined by a change of 1 SD from the baseline scores of the entire cohort were compared between the incident fracture group and the no incident fracture group by use of a Cochran-Mantel-Haenszel general association test (25).

4 2614 SILVERMAN ET AL Table 1. Study population demographics and clinical profile* Factor Group 1 (n 190) Group 2 (n 1,205) Overall (n 1,395) Age, mean SD Body mass index, mean SD Years postmenopause, mean SD Current smoker, no. (%) 16 (8.4) 146 (12.1) 162 (11.6) 3 alcoholic drinks/week, no. (%) 44 (23.2) 243 (20.2) 287 (20.6) Racial origin, no. (%) White 184 (96.8) 1,154 (95.8) 1,338 (95.9) Other 6 (3.2) 51 (4.2) 57 (4.1) Country of origin, no. (%) United States 190 (100.0) 1,008 (83.7) 1,198 (85.9) Canada 0 (0.0) 114 (9.5) 114 (8.2) Australia 0 (0.0) 62 (5.1) 62 (4.4) New Zealand 0 (0.0) 21 (1.7) 21 (1.5) Prevalent vertebral fracture, no. (%) 12 (6.3) 1,012 (84.0) 1,024 (73.4) History of nonvertebral fracture, no. (%) 57 (30.0) 541 (44.9) 598 (42.9) History of arthritis-related comorbidity, no. (%) 90 (47.4) 624 (51.8) 714 (51.2) Concomitant medications, no. (%) (34.2) 368 (30.5) 433 (31.0) (48.9) 663 (55.0) 756 (54.2) (16.8) 174 (14.4) 206 (14.8) Bone mineral density T score, mean SD Lumbar spine Hip * Health-related quality of life (HRQOL) data were collected at baseline for the entire population (study groups 1 and 2) and at followup for study group 2 only. The differences between study groups 1 and 2 were statistically significant (P 0.05) for the following factors: age, number of years postmenopause, country of origin, prevalent vertebral fracture, history of nonvertebral fracture, and lumbar spine and hip bone mineral density. To control for potential confounding, all analyses for both prevalent and incident vertebral fractures were adjusted for age, country of origin, body mass index, smoking status, alcohol consumption, presence of arthritis-related comorbidity, history of nonvertebral fractures, and number of concomitant medications used, all of which were collected on case report forms as part of the MORE study. In addition, the analyses of incident vertebral fractures were also adjusted for baseline scores. All differences were tested at a 2-sided significance level of All statistical analyses were performed using SAS software version 6.08 (SAS Institute, Cary, NC). RESULTS The demographic and clinical characteristics of all participants in the substudy of the MORE trial are shown in Table 1. The 1,395 women were predominantly Caucasian (96%) with a mean age of 68.5 years. As expected, women in study group 1 were younger and had higher spine and hip BMD scores. As a result of a retrospective review of radiographs at 3 years performed by the quality assurance center staff and some entry criterion violations, it was found that 16% (n 193) of the women in study group 2 did not have prevalent vertebral fractures at baseline, but 6% (n 12) of the women in study group 1 did have prevalent vertebral fractures at baseline. Therefore, the initial classification into group 1 and group 2 was not maintained when examining the association between prevalent vertebral fracture and HRQOL. Similarly, 16% of the women in the incident fracture study did not have prevalent fracture at baseline. Of the 1,205 women from study group 2 who were followed up longitudinally, 1,106 (92%) completed the at the study end point, and 1,058 (88%) completed both fracture (radiograph) and assessments at the study end point. We report herein the findings for each of the 4 composite s of physical function, emotional status, symptoms, and social interaction, along with the single question on overall HRQOL. Association of prevalent vertebral fractures with HRQOL. The presence of 1 prevalent vertebral fracture, as compared with women without prevalent vertebral fractures, was associated with lower scores on the 3 composite s of physical function, emotional status, and symptoms (reflecting increased symptoms), along with overall HRQOL (all P 0.01), but not with

5 HRQOL OF PREVALENT AND INCIDENT VERTEBRAL FRACTURES 2615 Table 2. Association between prevalent vertebral fractures and HRQOL* No fracture (n 371) 1 fracture (n 1,024) P Physical function Emotional status Symptoms Social interaction Overall HRQOL * All analyses were adjusted for age, country of origin, body mass index, smoking status, alcohol consumption, history of arthritis-related comorbidity, history of nonvertebral fractures, and number of concomitant medications used. Values are the mean SD score. HRQOL health-related quality of life; Osteoporosis Assessment Questionnaire. social interaction (see Table 2). HRQOL scores were also lower for each additional fracture within these 3 composite s (Table 3). Using a linear trend analysis, the number of prevalent vertebral fractures was associated with lower scores on physical function, emotional status, symptoms, and overall HRQOL (all P 0.001). Women with only 1 prevalent fracture had statistically significantly lower HRQOL scores on physical function and symptoms (both P 0.05). A threshold (e.g., larger drop in HRQOL scores) at 3 prevalent vertebral fractures was observed when we compared the group with 2 fractures (n 250) with the group with 3 fractures (n 102). Significant differences were observed between the 2 groups in the s of physical function (P 0.001), emotional status (P 0.005), symptoms (P 0.001), and overall HRQOL (P 0.041), but not for social interaction. The data from Table 3 are presented graphically in Figure 2. Of the 1,395 women in the substudy of the MORE trial, 632 had thoracic fractures only, and 171 had lumbar fractures only. Table 4 shows the mean SD scores for women with no fracture, thoracic fracture only, and lumbar fracture only. HRQOL scores on only the symptom composite were significantly lower (P 0.006) in women with fractures of the thoracic spine only compared with women without vertebral fracture. HRQOL scores on physical function (P 0.001), emotional status (P 0.015), and symptoms (P 0.001) were significantly lower in women with vertebral fractures of the lumbar spine only compared with women without vertebral fracture. HRQOL scores were lower in women with lumbar fractures only compared with women with thoracic fractures only as the physical function approached statistical significance (P 0.055). Through stepwise regression analyses, the 5 vertebral fracture locations with the greatest negative association with HRQOL were identified as T11, T12, L1, L2, and L3. In multiple regression analyses, the severity of vertebral fractures, as defined by the radiographic score using semiquantitative analysis, was not independently associated with HRQOL. However, severity was associated with age and the number of prevalent vertebral fractures. Women with a larger number of prevalent vertebral fractures were more likely to have severe fractures. Among the 435 women with 2 prevalent vertebral fractures at baseline, 252 had adjacent fractures, as defined by a vertebral fracture with a concomitant vertebral fracture at a vertebra immediately above or below. In general, the women without adjacent vertebral fractures had better HRQOL scores than those with at least 1 pair of adjacent vertebral fractures (P values ranged from to 0.10). However, after adjusting for differences in the number of prevalent vertebral fractures, adjacent fractures had no additional negative effect on HRQOL scores. Association of incident vertebral fractures with HRQOL. Of the 1,205 women from study group 2, 1,058 had followup radiographs and assessments. Table 3. Association between the number of prevalent vertebral fractures and HRQOL* No. of prevalent vertebral fractures P 0 (n 371) 1 (n 559) 2 (n 250) 3 (n 102) 4 (n 113) Trend 0 vs. 1 fracture 2 vs. 3 fractures Physical function Emotional status Symptoms Social interaction Overall HRQOL * All analyses were adjusted for age, country of origin, body mass index, smoking status, alcohol consumption, presence of arthritis-related comorbidity, history of nonvertebral fracture, and number of concomitant medications used. Values are the mean SD score. HRQOL health-related quality of life; Osteoporosis Assessment Questionnaire.

6 2616 SILVERMAN ET AL Figure 2. Number of prevalent vertebral fractures and progressive decreases in health-related quality of life (HRQOL; assessed by the Osteoporosis Assessment Questionnaire []). All P for linear trend for each / overall HRQOL. For subjects with 0 to 1 fracture, P 0.05 for physical function and emotional status. Of these 1,058 women, 157 (14.8%) developed at least 1 incident vertebral fracture during the 3-year study period. Of the 157 women who had an incident vertebral fracture during the study, 151 had at least 1 prevalent vertebral fracture at baseline. Table 5 shows the effect of an incident vertebral fracture on HRQOL. Women with incident vertebral fractures had a greater loss in HRQOL (excluding social interaction) from baseline to study end point compared with women without incident vertebral fractures. There were statistically significant differences in the mean change from baseline to study end point between the 2 groups in physical function, emotional status, symptoms, and overall HRQOL (all P 0.001), but not social interaction. Defining a significant loss in HRQOL (e.g., 20%) as a change of 1 SD of the value for the entire cohort at baseline, women with incident vertebral fractures had a higher percentage of significant HRQOL loss compared with women without incident vertebral fractures (Table 6). There were statistically significant differences in the percentage of women with significant loss in HRQOL between these 2 groups in physical function, symptoms, and overall HRQOL (all P 0.05), but not emotional status or social interaction. There were no statistically significant HRQOL Table 4. Association between the location of prevalent vertebral fractures and HRQOL* No fractures (n 371) Thoracic fracture only (n 632) Lumbar fracture only (n 171) Thoracic vs. none P Lumbar vs. none Lumbar vs. thoracic Physical function Emotional status Symptoms Social interaction Overall HRQOL * Women with both thoracic and lumbar fractures (n 221) were excluded from this analysis. All analyses were adjusted for the number of prevalent vertebral fractures, age, country of origin, body mass index, smoking status, alcohol consumption, presence of arthritis-related comorbidity, history of nonvertebral fracture, and number of concomitant medications used. Values are the mean SD score. HRQOL health-related quality of life; Osteoporosis Assessment Questionnaire.

7 HRQOL OF PREVALENT AND INCIDENT VERTEBRAL FRACTURES 2617 Table 5. Association between incident vertebral fractures and mean change in HRQOL* No incident vertebral fracture (n 901) 1 incident vertebral fracture (n 157) P Physical function Emotional status Symptoms Social interaction Overall HRQOL * Only women from study group 2 (n 1,205) were eligible for assessment of health-related quality of life (HRQOL; by use of the Osteoporosis Assessment Questionnaire []) during the 3-year treatment period. Of those, 1,058 women completed both the fracture (radiographic) and assessments. All analyses were adjusted for age, country of origin, body mass index, smoking status, alcohol consumption, presence of arthritis-related comorbidity, history of nonvertebral fracture, baseline scores, and number of concomitant medications used. Values are the mean SD change from baseline to study end point. differences between the 3 treatment groups with respect to the effect of an incident fracture. In other words, if a subject experienced an incident vertebral fracture, her HRQOL diminished, regardless of treatment group. DISCUSSION Our study confirms that prevalent vertebral fractures are likely to be associated with lower HRQOL scores. Physical function, emotional status, symptoms, and overall HRQOL were significantly and negatively associated with prevalent vertebral fractures. There was no negative association between social function and prevalent vertebral fractures in this subset of the MORE study population. The lack of effect of prevalent vertebral fractures on social interaction may relate to the sensitivity of the instrument, or it may reflect the design of the social interaction, which measures social activity and support from family and friends, such that it may not be adversely affected by vertebral fractures. Our study suggests that the association between prevalent vertebral fracture and reduced HRQOL is dependent on the number of vertebral fractures. A reduction in HRQOL, reaching statistical significance, emerged with a single prevalent vertebral fracture, but was greater with 3 fractures. The association between prevalent vertebral fractures and reduced HRQOL, as measured by the physical function, was dependent on their location within the spine, with greater HRQOL decreases observed with lumbar than with thoracic fractures. Prevalent lumbar fractures may result in changes to the mechanical curve of the lumbar spine, changing the normal lordotic curve and resulting in difficulties with sitting (2). Our results with the were similar to those reported by Oleksik (23) with the QUALEFFO, showing an association between prevalent vertebral fracture and decreased HRQOL as measured by the s of physical functioning, emotional status, symptoms, and overall HRQOL. However, the results also differed, in that there was no significant association with the of social interaction using the. This may be explained by differences between the 2 questionnaires, since the questions in the social interaction of the QUALEFFO have a greater weighting on physical functioning than do the questions in the. Previous cross-sectional studies (5,6) had suggested that for women with prevalent vertebral fractures, the severity of fracture and the presence of adjacent fractures within the spine might negatively influence HRQOL. In contrast, we found that these 2 factors had no additional negative effect on HRQOL. In our study population, fracture severity and presence of adjacent fractures were highly associated with the number of vertebral fractures. When we statistically adjusted for the number of fractures, there were no differences between women with or without adjacent vertebral fractures. Similarly, when we statistically adjusted for the number of fractures, there were no differences between women based on fracture severity. Table 6. Association between incident vertebral fractures and proportion of women with a significant loss in HRQOL* No incident vertebral fracture (n 901) 1 incident vertebral fracture (n 157) P Physical function Emotional status Symptoms Social interaction Overall HRQOL * Only women from study group 2 (n 1,205) were eligible for assessment of health-related quality of life (HRQOL; by the Osteoporosis Assessment Questionnaire []) during the 3-year treatment period. Of those, 1,058 women completed both the fracture (radiographic) and assessments. All analyses were adjusted for age, country of origin, body mass index, smoking status, alcohol consumption, presence of arthritis-related comorbidity, history of nonvertebral fractures, baseline scores, and number of concomitant medications used. Values are the percentage of women who experienced a significant loss in HRQOL, defined as a drop of 1 SD from baseline to study end point.

8 2618 SILVERMAN ET AL Our study confirms that incident vertebral fracture is associated with lower HRQOL scores. Physical function, emotional status, symptoms, and overall HRQOL were significantly and negatively associated with incident vertebral fracture. More women with incident vertebral fracture suffered a significant loss in physical function, symptoms, and overall HRQOL. There was no significant association between social interaction and incident vertebral fracture in this MORE substudy population with. This observation is even more poignant given the fact that 151 of the 157 women with incident vertebral fracture in the study had at least 1 prevalent vertebral fracture at baseline, suggesting a sustained loss in HRQOL with new vertebral fractures. Our study showed a 5-point decrease in the domains of physical functioning and overall HRQOL. Such a 5-point change on a standardized scale of has been equated by Brook et al (26) as being equivalent to a diagnosis of hypertension, and thereby clinically meaningful. A 10-point change on a scale was considered to be equivalent to the effect of having chronic mild osteoarthritis. Even though raloxifene decreased the risk of new vertebral fracture by 30% in the entire population of the MORE study, there were no differences between the treatment groups and placebo. Only a small number of women in our study had an incident fracture (15%), a few of which had significant changes in HRQOL, thereby making it more difficult to attain statistical significance for any differences observed (see Table 6). The MORE study was the first large prospective international clinical trial in which HRQOL data were routinely collected on a large sample of postmenopausal women by use of a validated osteoporosis-targeted questionnaire. Previous studies on the effect of vertebral fracture on HRQOL, such as that by Cook et al (20) or Leidig et al (4) (n 100 and n 70 subjects, respectively), used smaller sample sizes or failed to use a validated osteoporosis-targeted HRQOL instrument. Therefore, the MORE study may be the first published study with a large enough sample size to detect changes in HRQOL across a population in which a validated osteoporosis-targeted HRQOL instrument was routinely used. Our study demonstrates that disease-targeted measures, such as the, appear to be sensitive to changes in HRQOL with incident vertebral fracture and may be able to discriminate between women with increasing numbers of prevalent vertebral fractures. Our study shows compelling evidence of an association between vertebral fractures and lower HRQOL scores in postmenopausal women. However, one must be cautious in drawing a causal relationship. The observed association of reduced HRQOL for women with vertebral fractures may be related to other confounding factors. It is well known that HRQOL in older populations is generally affected by many conditions, including comorbidity, lifestyle, socioeconomic conditions, and other risk factors. In all our analyses, we statistically adjusted for age, country of origin, body mass index, smoking status, alcohol consumption, presence of arthritis-related comorbidity (e.g., joint disorder), history of nonvertebral fractures, and number of concomitant medications used. However, other comorbid conditions, such as cardiovascular disease, diabetes, and other chronic illnesses, were not explicitly controlled for in these analyses, nor did we control for socioeconomic status. We studied predominantly white women, a group known to be at high risk for postmenopausal osteoporosis. Our results may not apply to men or to other ethnic groups. The participants in this study were a subset of the MORE study population, and they may differ considerably in their perception of HRQOL compared with the general population. We could not determine precisely when the incident fracture occurred within the 3-year study period; this limits our ability to examine the relationship between acute incident vertebral fracture and acute HRQOL outcomes. In conclusion, our findings demonstrate that both prevalent and incident vertebral fractures were associated with decreases in HRQOL, with the exception of social interaction. Increasing numbers of prevalent vertebral fractures were associated with progressive decreases in HRQOL. Prevalent vertebral fractures that are lower in the spinal column (e.g., lumbar vertebra) have a more profoundly negative impact on HRQOL than prevalent vertebral fractures higher in the spinal column (e.g., thoracic vertebra). Incident vertebral fractures seem to have an incrementally significant and negative impact on HRQOL that is detectable for patients with prevalent vertebral fractures at baseline. Patients with prevalent vertebral fracture have an increased risk of subsequent vertebral fractures. Our findings show that these patients may be at risk for further decreases in HRQOL with incident vertebral fractures.

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