Health-Related Quality of Life in Postmenopausal Women With Low BMD With or Without Prevalent Vertebral Fractures

Authors


  • Oleksik A, Dawson A, Moseley E, Cooper C, Lips P 1998 Quality of life in osteoporotic patients with or without vertebral fractures. Osteoporos Int 8(Suppl 3):14 (abstract).

  • Oleksik A, Moseley E, Dawson A, Minshall M, Lips P 1998 The impact on health-related quality of life (HRQOL) in postmenopausal women with low BMD and prevalent vertebral fractures. J Bone Miner Res 23(Suppl):S398 (abstract).

Abstract

Fractures and subsequent morbidity determine the impact of established postmenopausal osteoporosis. Health-related quality of life (HRQOL) has become an important outcome criterion in the assessment and follow-up of osteoporotic patients. As part of the baseline measurements of the Multiple Outcomes of Raloxifene Evaluation (MORE) study, HRQOL was assessed in 751 osteoporotic (bone mineral density [BMD] T score ≥ −2.5) women from Europe with or without vertebral fractures (VFX). This was done using the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO), Nottingham Health Profile (NHP) and the EQ-5D (former EuroQol). QUALEFFO contains questions in five domains: pain, physical function, social function, general health perception, and mental function. Each domain score and QUALEFFO total scores are expressed on a 100-point scale, with 0 corresponding to the best HRQOL. In comparison with patients without VFX, those with VFX were older (66.2 ± 5.9 years vs. 68.8 ± 6.3 years; p < 0.001), had higher prevalence of nonvertebral fractures (25% vs. 36%; p = 0.002), and higher QUALEFFO scores (worse HRQOL; total score, 26 ± 14 vs. 36 ± 17; p < 0.001). QUALEFFO scores increased progressively with increasing number of VFX, especially lumbar fractures (p < 0.001). Patients with a single VFX already had a significant increase in QUALEFFO scores (p < 0.05). Similar, though weaker, associations were seen for NHP and EQ-5D scores. This study confirms decreased HRQOL for patients with prevalent VFX. In osteoporotic patients, QUALEFFO scores change in relation to the number of VFX. QUALEFFO is suitable for clinical studies in patients with postmenopausal osteoporosis.

INTRODUCTION

OSTEOPOROSIS IS a systemic skeletal disease characterized by low bone mass and deterioration of bone structure with a consequent increase in bone fragility.(1) Vertebral fractures (VFX) are a common complication of osteoporosis(2–8) and are associated with back pain and functional impairment.(9–11) However, according to recent estimates, only one in three vertebral deformities comes to clinical attention.(5, 7, 8) On the other hand, pain after a VFX may last for 3 years or more.(10–13) VFX cannot be restored and may result in permanent spinal deformity. Impaired physical functioning,(14–18) immobility,(16) social isolation, lack of energy, and depression are, therefore, potential long-term consequences of VFX. All together, these factors may have an important impact on patient health-related quality of life (HRQOL).(11, 17, 19–24)

HRQOL assessment plays an increasingly important role in intervention studies for patients with osteoporosis.(25–27) HRQOL is used as an outcome measure that complements bone mineral density (BMD) measurement and the assessment of VFX incidence. During the last 20 years, several generic instruments for measuring HRQOL have been designed such as the Nottingham Health Profile (NHP),(28) Sickness Impact Profile,(29) SF-36,(30) and EQ-5D.(31)More recently, disease-specific instruments have been developed.(32–34) In 1992, the European Foundation for Osteoporosis (EFFO) initiated the development of an HRQOL instrument (quality of life questionnaire of the European Foundation for Osteoporosis [QUALEFFO]) specifically for use in clinical trials.(35) The instrument was developed and validated in seven languages.(36) QUALEFFO consists of 41 questions organized into 5 domains: back pain, physical function, social function, general health perception, and mental function. QUALEFFO was validated in a multicenter study showing adequate test-retest reliability, internal consistency, and discriminatory ability between patients with VFX and control subjects.(36)

The first clinical trial that incorporated QUALEFFO into the protocol was the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The MORE clinical trial is a large prospective study on the effect of raloxifene in postmenopausal women with low BMD with or without prevalent VFX. This article reports baseline HRQOL data from the MORE study collected in seven European countries. The main purpose was to assess the impact of prevalent VFX on HRQOL in patients with postmenopausal osteoporosis in the setting of a clinical trial. In addition, QUALEFFO was compared with two generic instruments: the NHP(37) and EQ-5D (former EuroQol).(38)

MATERIALS AND METHODS

Study population

Study subjects were 751 healthy ambulant women from seven countries in Europe (Belgium, France, Germany, The United Kingdom, Italy, The Netherlands, and Sweden) aged up to 80 years. The women were at least 2 years postmenopausal or in case of hysterectomy, had serum follicle-stimulating hormone (FSH) > 30 IU/liter and serum estradiol < 73 pmol/liter. A further inclusion criterion was low lumbar or femoral neck BMD (T score ≤ −2.5). Women with a history of either metabolic bone disease, malignancy, or recent antiosteoporotic treatment (with exception of calcium and vitamin D supplements and/or hormonal replacement up to 6 months before randomization) were excluded. Spinal deformities that impaired radiographic morphometry also were an exclusion criterion (e.g., scoliosis > 15°). All subjects gave informed consent.

Evaluation of VFX

The presence of prevalent vertebral deformity was evaluated from standardized lateral spinal radiographs using three different methods: the semiquantitative (SQ) morphometric method, the binary semiquantitative (BSQ) method, and the quantitative morphometric (QM) method.(39, 40) Before inclusion, standardized baseline spinal radiographs were assessed in an SQ way (Kiel, Germany). Vertebral deformities were assigned to anterior, central, or posterior height loss in comparison with the adjacent vertebra. Mild fractures were described as 20–25% height loss and moderate as more than 25% height loss.(39) Subsequently, in all patients with at least one VFX and in a sample of patients without VFX, two independent readings of digitized images were performed, BSQ and QM, with both baseline and follow-up displayed in order to control for false positives. A vertebra was defined as fractured when two of the three readings of the baseline X-rays agreed.(40)

HRQOL questionnaire

Three types of HRQOL questionnaires were used: a general health assessment (NHP), a preference-based instrument (EQ-5D [formerly named the EuroQol]), and a disease-targeted instrument (QUALEFFO). General health assessments allow comparison of health care interventions across multiple disease areas. Preference-based questionnaires allow the conversion of HRQOL scores into utility scores that then can be used in a cost-utility analysis. Disease-targeted questionnaires focus data collection on the physical, emotional, and psychological domains most affected by the disease under study.

Each questionnaire was administered in countries where validated and translated versions were available. NHP and QUALEFFO were administrated to patients in all seven countries. EQ-5D was given to patients in Belgium, The United Kingdom, The Netherlands, and Sweden. Each questionnaire was administered at the clinics, after screening and enrollment procedures but before randomization. Subjects completed the questionnaires after a short instruction period by a study nurse.

NHP and EQ-5D were scored according to their published user manuals.(37, 38) QUALEFFO was scored according to the following algorithm. First, the response options for each item were standardized, so that option 1 corresponded to the least impact on HRQOL and option 5 to the greatest impact. Next, if at least one-half of the items in the domain were answered, the domain scores were calculated by averaging the nonmissing scores for individual questions within a domain. Doing this, we have assumed that the mean of missing scores would be equal to the mean of the nonmissing scores (imputation). In the general health perception domain 1% of scores was imputed and in domains of pain, physical function, and mental function, 11% of scores were imputed. This percentage was higher (66%) in the social function domain where the “nonapplicable” answer option was allowed. The domain scores were then transformed linearly to a 100-point scale with 0 corresponding to the best HRQOL and 100 to the worst HRQOL. Finally, the QUALEFFO total score was calculated in two ways: as the average of transformed domain scores (total 1) or as the average of scores for all nonmissing individual questions (total 2).(36) The QUALEFFO total score 2 was calculated only if at least 50% of all items was answered. Both total scores (1 and 2) were expressed on a 100-point scale.

Statistical methods

The assessment of country differences was done in a relatively homogeneous population, for example, those with VFX. Two countries (France and Germany) were excluded from this analysis because of small sample sizes (n = 13 and 10, respectively). The differences between countries were analyzed by analysis of covariance (ANCOVA), controlling for differences in age and number of VFX. The baseline demographic data in patients without and those with VFX were compared using one-way analysis of variance (ANOVA) or χ2 test.

The assumptions of a Likert scale, necessary for application of the scoring algorithm, were examined by an analysis of convergent validity, discriminant validity, and internal consistency.(36) The associations between QUALEFFO domains and NHP and EQ-5D were assessed by the Pearson product moment correlation.

Data on QUALEFFO scores are presented as unadjusted mean with SD. The evaluation of the impact of VFX on HRQOL was performed using ANCOVA with appropriate adjustment for differences in age and country of origin. The effect of thoracic and lumbar fractures was compared after exclusion of patients with fractures in both sites. The impact of adjacent VFX was assessed in a group of patients with at least two VFX and adjusted for the number of fractures. All differences were tested at a two-sided significance level of 0.05. All statistical analyses were performed using SAS version 6.08 (SAS Institute, Inc., Cary, NC, U.S.A.).(41)

RESULTS

A total of 751 postmenopausal women from 7 countries participated in the HRQOL study. Patients from various countries displayed substantial differences in age, prevalence of VFX and HRQOL (data not shown). Patients from Sweden were older. Patients from Sweden and Italy had, on average, more VFX. Patients from the United Kingdom and the The Netherlands had consistently better HRQOL than patients from Italy and Belgium, with patients from Sweden falling in between.

Among study subjects, 302 had no VFX and 449 had at least one VFX (Table 1). In comparison to patients with VFX, those without fractures were younger, had higher lumbar spinal BMD (T score), and had lower prevalence of non-VFX, especially forearm fracture. Subjects with and without VFX were not different with respect to the age at which they entered menopause. The majority of women without VFX were recruited from The Netherlands and the United Kingdom (by study design). Prevalence of VFX increased with age. In the lowest tertile for age distribution, 51% had no VFX whereas 24% had two or more VFX. In the highest tertile for age distribution, the percentages were, respectively, 26% and 48% (p < 0.001).

Table Table 1. Characteristics of Participants by Prevalence of VFX8
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QUALEFFO validation results were in agreement with the validation study.(36) In general, there was a good response rate to all questions. Thirty-three questions had correlation coefficients with their own domain higher than 0.4 (convergent validity). Discriminant validity also was adequate. Each domain had a Cronbach's α higher than 0.7, similar for each translation (data not shown). All five domains and the total scores showed a strong association with the two generic instruments (NHP and EQ-5D, see Table 2). In particular, the correlation coefficients were high between the corresponding domains in QUALEFFO and NHP and EQ-5D. For example, the physical function domain of QUALEFFO had a correlation of 0.81 with the NHP physical mobility domain and a correlation of 0.59 with the EQ-5D mobility domain.

Table Table 2. Correlation Between Domains of QUALEFFO and Generic Health Measures (NHP and EQ-5D)8
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Patients with VFX had higher QUALEFFO scores (i.e., worse HRQOL) than patients without VFX (Table 3). The differences between patients without fractures and patients with at least one fracture were statistically significant (p < 0.05) for all domains and total scores except mental function. In addition, an increasing trend in HRQOL scores with number of prevalent VFX was observed for all but the mental function domains (p < 0.001), indicating the progressive worsening effect on HRQOL with increasing number of VFX. The analysis also showed that with just one VFX, HRQOL was significantly decreased with regard to pain, physical function, general health, and total scores (p < 0.05). The association between the number of VFX and HRQOL was observed consistently within each age subgroup. When the patients were divided according to age tertiles (below 65 years, 65–71 years, and above 71 years), the progressive worsening trend with increasing number of VFX was observed in each age tertile. Figure 1 depicts the joint impact of age and number of VFX on the total score.

Table Table 3. Relation Between Number of Prevalent VFX and HRQOL8
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Figure FIG. 1..

Impact of age and number of VFX on HRQOL (QUALEFFO total score 1; ANOVA, adjusted for country of origin). Results for the total score 2 (average of all questions) are similar.

Analyses performed for NHP and EQ-5D showed similar results (Table 3). When the number of VFX increased, HRQOL declined progressively and the magnitude of this decline depended on fracture location. This was most obvious for pain and physical mobility domains from NHP and for health utility from EQ-5D.

The association between prevalent VFX and HRQOL depended on the fracture location (Table 4). Patients with fractures only in the lumbar region (L1-L4) had significantly worse HRQOL than patients without fractures in all domains including mental function (p < 0.05). In contrast, HRQOL for patients with thoracic fractures only (T4-T12) was not significantly different from HRQOL in patients without VFX. A significant linear trend was found between number of thoracic or lumbar fractures and QUALEFFO total score (Table 5). The differences in HRQOL between patients with thoracic fractures only and patients with lumbar fracture only were significant for physical function, general health perception, and total scores (p < 0.05) and borderline significant for pain (p = 0.079). No differences were found between patients with and without adjacent VFX nor between patients with mild and moderate VFX (data not shown).

Table Table 5. Association Between Location of VFX and QUALEFFO Total Score in Patients with Osteoporosis8
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Table Table 4. Relation Between Location of Prevalent VFX and HRQOL8
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DISCUSSION

This study confirms impaired HRQOL for patients with VFX. The subjects had osteoporosis according to the World Health Organization (WHO) definition,(42) but HRQOL was still dependent on VFX status. All QUALEFFO domain scores and both total scores were higher (e.g., worse HRQOL) in patients with VFX than in those without VFX. Moreover, QUALEFFO scores (except mental function) progressively increased with increasing number of prevalent VFX and the effect of the first fracture was already statistically significant. Progressive decline in HRQOL with increasing number of prevalent VFX also was found when HRQOL was assessed in other subpopulations of the MORE study, using the Osteoporosis Assessment Questionnaire (OPAQ).(32, 43) Similarly, a correlation was found between the number of recent VFX and back pain or physical functioning.(11, 12) Moreover, the number of patients complaining of pain and disability was increased with increasing numbers of severe VFX.(13) A complex measure combining number and severity of vertebral deformations, the spine deformity index (SDI), showed a correlation with physical function rather than with pain.(16) Although the cited studies used different subject selection criteria, different constructs for assessment of HRQOL components, and different models (longitudinal vs. cross-sectional), they all point out that progression of spinal osteoporosis results in progressive decline in HRQOL. It needs to be stressed that decreased HRQOL for patients with spinal osteoporosis also could be attributed to comorbidity. In general, the prevalent VFX are a risk factor for incident VFX,(44) non-VFX,(45, 46) and mortality.(47, 48)

In contrast to other domains, the scores for mental function did not show progressive changes with number of VFX, nor was there a significant difference between patients with and without VFX. This relatively small contrast between patients with and without VFX could be a result of acceptance because of the natural expectations of physical decline in elderly women.(18) This is in agreement with previous observations in which patients with a single VFX were able to handle their osteoporosis quite effectively.(18) An alternative explanation could be that QUALEFFO data were obtained at the beginning of a clinical trial for treatment of osteoporosis. Participation in the clinical trial could reduce a participant's previous anxiety(49, 50) and other psychological distress.

In comparison to thoracic fractures, lumbar fractures had significantly stronger impact on the QUALEFFO domains of physical activity, general health perception, and on total scores. Also several domains from NHP (pain, physical mobility) and EQ-5D (health utility) showed a statistically different HRQOL in patients with thoracic fractures versus lumbar fractures. This is in agreement with another study of postmenopausal women with osteoporosis within the MORE study in which the relation between VFX and HRQOL was assessed using OPAQ.(43) According to a population-based study,(5) when VFX, after moderate trauma, were evaluated, lumbar fractures were more often symptomatic than thoracic fractures (90% vs. 72%). A cross-sectional study on kyphosis, a result of thoracic fractures, revealed that women with greater degrees of kyphosis were only slightly more likely to report back-related disability.(51)

The described differences in consequences of thoracic and lumbar fractures could be explained by the fact that the thoracic spine is relatively rigid when compared with the lumbar spine,(52) so the absolute impairment of spinal mobility after a vertebral deformity could be greater in the lumbar spine than in the thoracic spine. Differences in mobility and location between lumbar and thoracic spine also imply differences in frequency and degree of pain provocation (nociprocal stimulation).(20) Furthermore, lower spinal (lumbar) deformities probably have a greater impact on postural stability than higher (thoracic) deformities. The change in shape of a vertebral body after a deformity alters the position of that spinal segment and affects the alignment of the entire trunk.(18) Functional impairment caused by VFX concerns mostly walking,(14–16, 18, 49) bending,(15, 16) rising,(14, 16) and carrying or lifting objects.(49) It is uncertain whether lumbar deformities have more functional consequences for vital organs than thoracic deformities.

VFX is an age-related condition.(5, 7, 8, 14) In our study, this is reflected in the age distributions of patients with and without VFX. Age also had an important effect on QUALEFFO total score. This finding stresses the necessity of preventive strategies in elderly patients.

Country of origin was a confounding variable in all assessed models. A reason for this could be that the study populations from various countries differed with respect to recruitment procedures: population-based approach versus clinical data sets. Patients without VFX were recruited mainly from United Kingdom and The Netherlands. HRQOL assessment is vulnerable to country-specific factors that are not necessarily compensated by adequate translation procedures (forward and back-translations and review and pretesting).(53–56) However, QUALEFFO was designed by an international working party in order to eliminate such country-specific items. After statistical adjustment for country of origin, the relationship between number of VFX and QUALEFFO total score remained statistically significant, confirming the net effect of VFX on HRQOL.

Although QUALEFFO total score discriminated well between patients with and without VFX and showed increasing scores with increasing number of VFX, only a small proportion of variance could be explained by this relationship. This is not surprising(16, 49, 57) because the analysis concerned the number of prevalent VFX as assessed in a cross-sectional approach. Further inclusion of time since fracture may improve the model because it is well known that pain and disability after VFX decrease gradually in the following years.(10) Analysis according to fracture severity, using SID, could provide additional information.(16)

In our study, the effect of VFX on HRQOL could be underestimated. First, patients with major spinal deformations (scoliosis > 15°) were excluded from the MORE study. In addition, patients with long-standing established postmenopausal osteoporosis were not likely to participate in the MORE study, either because they probably were taking antiosteoporotic medication or because of concomitant health problems.(14) Indeed, given the users manuals, patients without prevalent VFX had similar mean NHP and EQ-5D scores to the mean scores for healthy women >65 years old.(37, 38)

When compared with patients with VFX, those without VFX had a similar prevalence of concomitant joint complaints such as osteoarthritis, arthralgia, or arthritis (24% vs. 29%; p = 0.09), a known cause of back pain(10–12, 58) and physical impairment.(15) On the other hand, spinal may osteoarthritis also result in vertebral deformities confounding the assessed estimates.(46) We did not adjust for the prevalence of concomitant joint complaints or other health problems because the data were obtained from the list of spontaneously reported preexistent conditions without further validation of objectivity.

This study expands results of the QUALEFFO validation study,(36) in which the relationship between number of VFX and QUALEFFO scores was less pronounced, probably as a consequence of a less homogeneous and smaller population. Comparison of QUALEFFO with other established instruments such as the NHP and EQ-5D showed that QUALEFFO discriminated better between patients with and without VFX than the NHP and EQ-5D. As was previously reported, QUALEFFO scores correlated well with SF-36 and showed better discriminatory properties than the SF-36 in the domains of pain and physical function.(36)

Because of good discriminative properties, QUALEFFO is a promising measure for the impact of VFX on HRQOL and can be used in clinical trials for patients with postmenopausal osteoporosis.(24) The sensitivity of QUALEFFO to longitudinal changes, such as improvement after treatment or deterioration after incident VFX, needs to be investigated in a longitudinal setting. In this study, as in the validation study,(36) floor and ceiling effects are small, enabling detection of improvement or deterioration.

In patients with low BMD, another disease-targeted instrument (OPAQ), also was able to show diminished HRQOL in patients with a single prevalent VFX, independent of severity.(43) The satisfying sensitivity of both disease-targeted questionnaires is likely because of inclusion of items that have relevance to osteoporotic patients. Indeed, from the two generic instruments (NHP and EQ-5D), only health utility from EQ-5D was able to distinguish between patients without and with one VFX (p < 0.02). Another advantage of a disease-specific questionnaire, such as QUALEFFO, is that it reduces the burden to the patient and may improve responsiveness.

This study confirms impaired HRQOL for patients with VFX and especially lumbar fractures. For patients with low BMD, QUALEFFO scores are higher in those with VFX than those without VFX, and progressively increase with increasing number of prevalent VFX. QUALEFFO is a promising measure of the impact of VFX on HRQOL for use in international clinical trials. The sensitivity of QUALEFFO to longitudinal changes, such as incident VFX or improvement after treatment, is now being investigated using the MORE study cohort.

Acknowledgements

We thank all investigators and study nurses involved in this project. We are grateful to Nicolette Pliester, Elisabeth Moseley, and Sunny Xie for data management. This work was supported by a grant from Eli Lilly and Company. We also thank the Working Party for Quality of Life of the International Osteoporosis Foundation for comments and advice in the planning and reporting of this study. Members (in addition to P.L., C.C., and J.K.) include D. Agnusdei (Siena), F. Caulin (Paris), A. Leplege (Paris), O. Johnell (Malmö), U.A. Liberman (Petah Tiqva), H. Minne (Bad Pyrmont), J. Reeve (Cambridge), C. Todd (Cambridge), J.Y. Reginster (Liège), M.C. deVernejoul (Paris), and I. Wiklund (Mölndal).

MORE Investigators Involved in QUALEFFO Project:

Belgium: Thierry Appelboom, M.D., Hospital Universitaire Erasme; Jean J. Body, M.D., Institut Jules Bordet; Anne Peretz, M.D., Hospital Universitaire Brugmann; Jean P. Devogelaer, M.D., Cliniques Universitaires Saint Luc, Brussels; Jan Dequeker, M.D., Universitaire Ziekenhuis Pellenberg Lubbeek; Piet Geusens, M.D., Limburgs Universitaire Centrum Diepenbeek; Jean-Marck Kaufman, M.D., Universitaire Ziekenhuis, Gent; Jean-Yves Reginster, M.D., Policliniques Universitaires L. Brull, Liege. France: Christian Alexandre, M.D., CHU De St. Etienne Hospital Bellevue; Daniel Briancon, M.D., Hospital Reine Hortense; Pierre Delmas, M.D. Ph.D., INSERM, Lyon; Patrice Fardellone, M.D., CHU D'Amiens Hospital Sud; Jacques LeClere, M.D., CHU De Nancy Hospital D'Adultes De Brabois; Claude Ribot, M.D., CHU De Toulouse Hospital De Rangueil. Germany: Elmar Keck, M.D., Landesarztekammer Hessen, Wiesbaden; Peter Maier, M.D., Staedt. Kurbetriebe Bad Waldsee; J. Semler and Christian Wuester, M.D., Universitat Heidelberg. Italy: Maria Luisa Brandi, M.D., Ph.D., Department of Clinical Physiopathology, Univerity of Florence; Pasquale Oriente, M.D., Universita “Federico II,” Napoli; Carmelo Fiore, M.D., Universita Di Catania; Andrea R. Genazzani, M.D., Ospedale Santa Chiara Di Pisa; Carlo Gennari, M.D., Institute of Internal Medicine, University of Siena; Giancarlo Isaia, M.D., University of Torino; Gianfranco Mazzoouli, M.D., Universita La Sapienza, Roma; Gian B. Melis, M.D., Universita Di Cagliari; Torquato Nencioni, M.D., Instituto Mangiagalli, Milano; Mario Passeri, M.D., Universita Di Parma; and Leonardo Sartori, M.D., Ph.D., Universita Di Padova. The Netherlands: Paul Lips, M.D., Ph.D., Academic Hospital Vrije Universiteit, Amsterdam; Henk Mulder, M.D., Medisch Onderzoekscentrum GCP, Huibert A. Pols, M.D., Ph.D., Erasmus University Medical Center, Rotterdam. Sweden: Karin Larsson, M.D., Academic Hospital Uppsala; Dan Mellstrøm, M.D., Ph.D., Goteborg University, Goteborg; Britt-Marie Nyhäll-Wåhlin, M.D., Mats Palmér, M.D., Uppsala University, Orebro; Goran Toss, M.D., Uppsala University, Linkoping. United Kingdom: Richard Eastell, B.Sc., M.B., Ch.B., The Osteoporosis Center, University of Sheffield; Ignac Fogelman, B.Sc., M.D., Guy's Hospial, London; Robert Landray, M.C.C.C.H.B., Synexus Ltd; David W. Purdie, M.B., Ch.B., M.D., The University of Hull, Center for Metabolic Bone Disease; David M. Reid, M.B., Ch.B., M.D., University of Aberdeen; Ian Smith, B.M.S., M.B., Ch.B., NHS Trust Royal Preston Hospital, Lancashire; Michael D. Stone, B.A., M.B., B.S., Llandough Hospital, South Glamorgan.

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