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University of Cincinnati (N.B.W.), Cincinnati, Ohio 45219; St. Michael’s Hospital (R.G.J.), University of Toronto, Toronto, Ontario, Canada M5C 2T2; East Tennessee State University (R.C.H.), Johnson City, Tennessee 37614; St. Peter’s Hospital (R.A.H.), Chertsey KT16 0PZ, United Kingdom; Procter & Gamble Pharmaceuticals (M.D.M., I.B.), Mason, Ohio 45040; Medical Diagnostics Australia (D.C.), Sydney 2204, Australia; Free University Berlin, University Hospital Benjamin Franklin (D.F.), Centre of Muscle and Bone Research, 12200 Berlin, Germany
Address all correspondence and requests for reprints to: Nelson B. Watts, M.D., 222 Piedmont Avenue, Suite 4300, Cincinnati, Ohio 45219. E-mail: nelson.watts{at}uc.edu.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Risedronate administered 5 mg/d has been shown to be an effective and well tolerated treatment for established osteoporosis in randomized, controlled clinical trials in over 15,000 patients (12, 13, 14, 15, 16, 17, 18). Treatment with risedronate 5 mg/d leads to significant reductions in the risk of vertebral fractures within 1 yr (12, 13). Because of this rapid effect, risedronate may be especially beneficial for patients at high risk of fracture, who are likely to sustain fractures within the near term. Although risedronate has been shown to significantly benefit postmenopausal women with established osteoporosis, its effects in women at very high risk for fracture are not well characterized. Because the severity of osteoporosis is not always apparent in patients seeking treatment, it is important to establish the effect of treatment across fracture risk subgroups. We conducted additional analyses of combined data from two large clinical trials with similar design and endpoints (12, 13) to determine whether the effects of risedronate treatment in patients at very high risk for fracture are similar to the effects in the overall populations of patients with established osteoporosis treated in these clinical trials. Because a large percentage of high-risk patients are likely to sustain new fractures within 1 yr of an index fracture (11), our analysis focused on the effect of treatment after 1 yr.
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Patients and Methods |
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Patients
VERT-MN enrolled 1226 postmenopausal women at 80 centers in Europe and Australia. Patients in this study were required to have two or more prevalent radiographically confirmed thoracolumbar (T4–L4) vertebral fractures. VERT-NA enrolled 2458 postmenopausal women at 110 centers in North America. Patients were required to have two or more prevalent radiographically confirmed vertebral fractures (T4–L4) or one vertebral fracture and low lumbar spine (L1–L4) bone mineral density [BMD; defined as 
0.83 g/cm2 (Hologic instrument) or 0.94 g/cm2 (Lunar instrument)]. The cutoff values for low lumbar spine BMD represent a T-score of -2 (2 SD values below the mean for young adults). In both studies, patients were required to be ambulatory, no older than 85 yr of age, and at least 5 yr postmenopausal. Women were excluded from the studies if they had conditions that might interfere with the evaluation of spinal bone loss, or if they had received drugs known to affect bone metabolism.
Assignment and treatment
In both studies, patients were randomly assigned to receive risedronate 5 mg/d, risedronate 2.5 mg/d, or placebo (control). All patients received calcium 1000 mg/d; up to 500 IU/d of vitamin D was provided if baseline serum 25-hydroxyvitamin D levels were below 40 nmol/liter.
Vertebral fracture assessments
Lateral thoracolumbar (T4–L4) radiographs were obtained at baseline and annually throughout each study and read in the order in which they were taken. Prevalent (baseline) and incident (new) vertebral fractures were diagnosed quantitatively (19) and semiquantitatively (20). A new vertebral fracture was defined quantitatively as a loss of 15% or more in the anterior, posterior, or middle vertebral height in a vertebra that was normal at baseline, and semiquantitatively as a change from grade 0 (normal) to grades 1 (mild), 2 (moderate), or 3 (severe). Discrepancies between the quantitative and semiquantitative methods were adjudicated by an independent radiologist. The radiologists remained blinded to treatment while performing all vertebral fracture assessments.
Statistical analysis
The efficacy analyses compared the risedronate 2.5- and 5-mg groups with the control group at the 5% level of significance. Analyses were performed on an intent-to-treat basis. This paper focuses on patients who received risedronate 5 mg/d, the commercial dose; data on the patients who received risedronate 2.5 mg/d are included in the tables and graphs for completeness.
Subgroup analyses were post hoc. The primary objective of these analyses was to evaluate the effect of risedronate 5 mg on the incidence of new vertebral fractures in patients at high risk for fracture. The high-risk subgroups that were analyzed consisted of patients at least 70 yr of age (the median age for this population), patients with at least two prevalent vertebral fractures (the median number of prevalent fractures), patients with low lumbar spine BMD, and patients with low femoral neck BMD. T-scores of -2.5 or less were used to define the low BMD subgroups on the basis of the World Health Organization definition of osteoporosis (1). The pooling of data from the two large studies was possible because the studies were similar in design and because the study-by-treatment interaction was not statistically significant (P = 0.804).
Demographic and baseline characteristics were summarized for the risedronate 2.5 mg, risedronate 5 mg, and control groups. The analysis of new vertebral fracture incidence was consistent with the methodology used in the primary analyses of time-to-first fracture in the individual studies, described previously (12, 13). Subgroup analyses focused on patients younger than 70 yr old and patients 70 or older at baseline, patients with at least two prevalent vertebral fractures, and patients with low baseline BMD (
2.5 SD below the mean for young adults) at the lumbar spine or femoral neck (mean femoral neck BMD for young adults was based on the third National Health and Nutrition Examination Survey (NHANES III) reference database; Ref. 21). The incidence of multiple new vertebral fractures (defined as the percentage of patients with at least two incident new vertebral fractures) was assessed in patients with known fracture status for all 13 vertebral levels. The proportion of patients with multiple incident new vertebral fractures was analyzed by the Cochran-Mantel-Haenszel test.
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Results |
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A total of 1226 patients in VERT-MN and 2458 patients in VERT-NA meeting the entry criteria were randomized to treatment with placebo or risedronate 2.5 or 5 mg/d. The characteristics and disposition of the patients in the individual studies have been reported in detail elsewhere (12, 13). The treatment groups were similar at baseline with respect to demographic and disease characteristics both within the study population as a whole and within the various high-risk subgroups (Table 1
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Overall, as reported previously (12, 13), the incidence of new vertebral fractures after 1 yr was significantly lower in the risedronate 5 mg group than in the control group in both VERT-MN and VERT-NA. The risk of new vertebral fractures in the risedronate 5 mg group was reduced by 61% vs. control [relative risk (RR), 0.39; 95% confidence interval (CI), 0.22, 0.68; P < 0.001] in VERT-MN and by 65% vs. control (RR, 0.35; 95% CI, 0.19, 0.62; P < 0.001) in VERT-NA (Table 2). When the two study populations were pooled, the risk of new vertebral fractures in the risedronate 5 mg group was reduced by 62% vs. control (RR, 0.38; 95% CI, 0.25, 0.56; P < 0.001; Table 2 and Fig. 1).
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and Fig. 1).
Treatment with risedronate 5 mg/d for 1 yr was also associated with significant decreases in the incidence of new vertebral fractures compared with control in the subgroups of patients with at least two existing fractures at baseline. The incidence of fractures in this subgroup of patients was higher than that for the study population as a whole in both the control (12.0%) and risedronate 5 mg (4.1%) groups. In patients with at least two prevalent fractures, the risk of new vertebral fractures in the risedronate 5 mg group was reduced 68% vs. control (RR, 0.32; 95% CI, 0.20, 0.49; P < 0.001; Table 2 and Fig. 1).
Treatment with risedronate 5 mg/d led to similar decreases in the risk of new vertebral fractures in patients with low BMD (T-score, -2.5 or less) at the femoral neck or lumbar spine. The incidence of fractures in the subgroup of patients with low BMD at the femoral neck was higher than that for the study population as a whole in both the control and risedronate 5 mg groups. Among patients with low BMD at the femoral neck, the incidence of new vertebral fractures was 12.8% in the control group, compared with 5.6% in the risedronate 5 mg group, reflecting a reduction in fracture risk in the risedronate-treated patients of 60% vs. control (RR, 0.40; 95% CI, 0.23, 0.67; P < 0.001; Table 2 and Fig. 1). Among patients with low BMD at the lumbar spine, the incidence of new vertebral fractures was 6.9% in the control group, compared with 3.7% in the risedronate 5 mg group, reflecting a reduction in fracture risk in the risedronate-treated patients of 48% vs. control (RR, 0.52; 95% CI, 0.29, 0.93; P = 0.029; Table 2 and Fig. 1).
As shown in Table 2, the results of the subgroup analyses for VERT-MN and VERT-NA combined were similar to those for each individual study.
Multiple new vertebral fractures
Treatment with risedronate 5 mg/d sharply and significantly reduced the incidence of multiple new vertebral fractures (at least two incident vertebral fractures) after 1 yr. In VERT-MN and VERT-NA combined, the incidence of multiple new vertebral fractures was 3.1% in the control group and 0.3% in the risedronate 5 mg group, reflecting a reduction in risk in the risedronate-treated patients of 90% vs. control (RR, 0.10; 95% CI, 0.04, 0.26; P < 0.001; Fig. 2).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We conducted additional analyses in high-risk subgroups to determine whether the response to risedronate treatment in patients at very high risk for fracture would be similar to that in the general population of women with osteoporosis. These additional analyses showed that risedronate 5 mg/d led to significant reductions in fracture risk in subgroups of patients at higher risk for fracture because of age, prevalent fractures, or low BMD. Furthermore, these reductions were consistent across the subgroups analyzed and similar to those for the overall population of patients (Table 2 and Fig. 1). The effect of risedronate 2.5 mg/d on the incidence of vertebral fracture at 1 yr was similar to that of risedronate 5 mg/d (confidence intervals overlap).
Risedronate 5 mg led to significant reductions in fracture risk after just 1 yr. A rapid treatment effect is of paramount importance in osteoporosis therapies because, once a fracture has occurred, subsequent fractures occur in rapid succession. Among women who develop a vertebral fracture, 20% will sustain another new vertebral fracture within 1 yr (11). Prompt, effective intervention is key to avoiding further bone loss, maintaining skeletal integrity, and preventing the first and subsequent fractures.
Our analyses showed that the incidence of new vertebral fractures in the high-risk subgroups was generally greater than that in the study population as a whole (Fig. 1), demonstrating that the subgroups evaluated were truly at high risk for fracture. The low lumbar spine BMD subgroup differed from the other subgroups in that the median number of prevalent fractures was two, as opposed to three (Table 1). Because the number of preexisting fractures is an important determinant of fracture risk (6, 7, 8, 9), it is possible that this difference contributed to the lower incidence of new vertebral fractures noted in this subgroup. At 1 yr, the incidence of new vertebral fractures in the control group of the study population as a whole was very high, about 9%, and incidences in the high-risk subgroups of control patients were higher still; fracture rates in the control group were 10.8% in patients at least 70 yr of age, 12.0% in patients with at least two prevalent fractures, and 12.8% in patients with low femoral neck BMD. These findings underscore the need for identification and treatment of patients who are at high risk for fracture because of age, low BMD, or prevalent fractures.
The results of these analyses are consistent with previously reported findings (5, 6, 7, 8, 9, 11, 22, 23). Studies have consistently demonstrated that each decrease of 1 SD in BMD increases the risk of fracture 2- to 3-fold (7, 23, 24). In contrast, studies of the relationship between the increases in BMD (and other surrogate markers for fracture) and the changes in fracture risk in patients treated with antiresorptive therapies have produced inconsistent findings. Some reports have suggested that greater increases in BMD are associated with a lower fracture risk (25, 26, 27), whereas others have not (28, 29, 30, 31, 32). Meta-analyses based on summary statistics have shown that increases in BMD account for a significant portion of the reductions in fracture risk associated with antiresorptive treatment (26, 27, 33). In contrast, analyses based on data from individual patients have suggested that increases in BMD account for only 4–28% of the reductions in fracture risk in response to antiresorptive treatments (31, 32, 33). This discrepancy may be due to methodological differences; studies based on summary statistics and those based on individual patient data have been shown to produce different conclusions (34, 35). We consider analyses based on individual patient data to be more relevant because they capture and account for the response in each patient and are generally more comprehensive and reliable than analyses based on summary statistics taken from publications (36). Studies based on individual patient data indicate that the increases in BMD in response to any antiresorptive agent explain only a small percentage of the observed reductions in fracture risk associated with that agent (13, 28, 29, 30, 31, 32, 33).
In addition to BMD, potential contributors to reductions in fracture risk include preservation of bone microarchitecture and reductions in bone turnover. The contribution of these factors to the reductions in fracture risk seen at 1 yr in patients treated with risedronate is supported by the temporal association between these fracture reductions and improvements in measures of trabecular architecture, which occur within 1 yr (37), and reductions in bone turnover markers, which occur within 3 months (38). Preexisting fractures were also significant contributors to the risk of additional fracture in our study and in others (6, 7, 8, 9). Whether prevalent fractures are predictive of new fractures because they are an indicator of skeletal microarchitectural integrity, because they affect spinal biomechanics and load bearing and predispose unaffected vertebrae to fracture, or because they are an indicator of an increased likelihood of falling are important and currently unresolved questions (6, 7, 8). Because the relationship between existing vertebral fractures and the risk of subsequent fracture appears to be independent of the risk of falling (9), prevalent vertebral fractures are more likely an indicator of overall skeletal health.
The current analysis is limited in that it is post hoc. In addition, the studies included only patients with prevalent vertebral fractures. Despite the limitations of this study, the populations of patients analyzed in the two studies were large and are most likely representative of the patients who receive treatment in clinical practice. Therefore, the findings from these analyses would be expected to be applicable to the broad population of patients who will be treated with risedronate. In other osteoporosis studies, a vertebral height loss of 20% was used as the criterion for fracture (39, 40), in contrast to the 15% vertebral height loss used as the criterion in our study. When we applied the 20% fracture criterion in retrospective analyses of fracture risk for the overall study population, consistent results were obtained (41).
In conclusion, treatment with risedronate 5 mg/d significantly reduced the incidence of new vertebral fracture in subgroups of postmenopausal women at high risk for fractures. These reductions were consistent across the subgroups analyzed and similar to those for the overall population of patients. Significant reductions in fracture risk in response to treatment were evident within the first year, an important benefit in patients at high risk for fracture. These findings underscore the importance of early identification of patients at high risk for fracture, prompt intervention, and a rapid effect of treatment in this patient population.
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Acknowledgments |
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Footnotes |
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Members of the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group: J. Adachi, Hamilton, Ontario, Canada; S. Adami, Centro Ospedaliero, Valeggio, Italy; R. Altman, Miami, FL; D. J. Appelrouth, Atlanta, GA; J. Assini, Schenectady, NY; A. D. Bankhurst, University of New Mexico School of Medicine, Albuquerque, NM; M. Baron, Jewish General Hospital, Montreal, Quebec, Canada; D. J. Baylink, Loma Linda, CA; H. Beck-Nielsen, Odense University Hospital, Odense C, Denmark; N. H. Bell, VA Medical Center, Charleston, SC; W. Bensen, Hamilton, Ontario, Canada; M. B. Block, Clinical Research Center, Phoenix, AZ; R. S. Bockman, New York, NY; E. Boling, Rancho Cucamonga, CA; M. Bolognese, Gaithersburg, MD; S. L. Bonnick, Center for Research on Women’s Health, Denton, TX; S. Bowman, Tampa Bay Medical Research, Clearwater, FL; M. L. Brandi, Universitá di Firenze, Firenze, Italy; B. Bresnihan, St. Vincent’s Private Hospital, Dublin, Ireland; W. Briney, Denver, CO; J. Brown, Le Center Hospitalier de l’Universite Laval, Sainte-Foy, Quebec, Canada; S. B. Broy, Lutheran General Medical Group, Chicago, IL; R. Burwood, Sussex Diagnostic Centre, Hove, UK; J. Cabral, Cleveland Clinic Florida, Ft. Lauderdale, FL; D. Cameron, Princess Alexandra Hospital, Woolloongabba, Australia; R. B. Cannon, Salt Lake Clinic Research Foundation, Salt Lake City, UT; M. Cawley, Rheumatology Research Unit, Southampton, UK; C. Chesnut III, University of Washington, Seattle, WA; Y. D. Coble, Jacksonville, FL; S. Cohen, Metroplex Clinical Research Center, Dallas, TX; S. A. Cohen, Clinical Research Consultants, Trumball, CT; G. M. Crawford, Community Pharmacology Services Ltd., Glasgow, UK; M. W. J. Davie, NHS Trust Hospital, Oswestry, UK; J. Davies, Royal National Hospital for Rheumatic Diseases, Bath, UK; M. Davis, Coastal Clinical Research Inc., Mobile, AL; W. Delaney, Primary Care of Danbury, Danbury, CT; M. d’Emden, Royal Brisbane Hospital, Brisbane, Australia; J. Dequeker, Pellenberg, Belgium; J. P. Devogelaer, UCL, Brussels, Belgium; G. B. Dewees, SORRA Research Center, Birmingham, AL; R. Dingler, Munich, Germany; W. Dodds, Lancaster Moor Hospital, Lancaster, UK; S. Doherty, Hull Royal Infirmary, Hull, UK; D. V. Doyle, Silverthorn Centre, Chingford, UK; M. Doyle, William Beaumont Hospital, Ferndale, MI; R. Eastell, University of Sheffield, Sheffield, UK; P. Ebeling, Royal Melbourne Hospital, Parkville, Australia; R. D. Emkey, Reading Hospital and Medical Center, Reading, PA; S. C. English, Deaconess Research Institute, Billings, MT; M. P. Ettinger, Regional Osteoporosis Center, Stuart, FL; A. Fairney, St. Mary’s Hospital Medical School, London, UK; J. Farrerons, Hospital Santa Creu y Sant Pau, Barcelona, Spain; N. R. Farris, Central Kentucky Research, Lexington, KY; A. Frank, Northwick Park Hospital, Harrow, UK; B. Fraser, Royal Liverpool University Hospital, Liverpool, UK; D. Freeman, North Carolina Arthritis & Allergy Care Center, Raleigh, NC; N. M. Friedman, Lovelace Scientific Resources, Albuquerque, NM; A. B. Galway, Health Science Center, St. Johns, New Brunswick, Canada; M. L. S. Gass, Reproductive Medical Research, Cincinnati, OH; H. Geisberg, Anderson, SC; H. K. Genant, University of California, San Francisco, CA; C. Gennari, Universitá deglie Studi di Siena, Siena, Italy; G. Gerety, Albany, NY; P. Geusens, Dr. Willems Instituut, Diepenbeek, Belgium; J. Ginsburg, Royal Free Hospital, London, UK; M. Gittelman, South Florida Medical Research, Aventura, FL; M. Greenwald, Palm Springs, CA; T. N. Hangartner, Miami Valley Hospital, Dayton, OH; D. A. Hanley, Heritage Medical Research Center, Calgary, Alberta, Canada; T. Harrington, Jackson Foundation, Madison, WI; S. T. Harris, University of California, San Francisco, CA; D. J. Helfrich, Mercy Hospital of Pittsburgh, Pittsburgh, PA; M. Heller, Arthritis Associates Inc., Peabody, MA; M. Heur, The Climacteric Clinic, Gainesville, FL; M. C. Hochberg, University of Maryland, Baltimore, MD; A. Hodsman, St. Joseph’s Health Center, London, Ontario, Canada; M. Hooper, Repatriation General Hospital, Concord, Australia; D. Hosking, Nottingham City Hospital and NHS Trust, Nottingham, UK; T. H. Ittel, RWTH Aachen, Aachen, Germany; R. D. Jackson, Columbus, OH; A. J. Jacobs, Arthritis Center of Nebraska, Lincoln, NE; P. Jellinger, Hollywood, FL; O. Johnell, Ortopediska Kliniken, Malmö, Sweden; C. C. Johnston, Jr., Indiana University Medical Center, Indianapolis, IN; A. V. Jovaisas, Ottawa, Ontario, Canada; J. L. Juozevicius, Kalamazoo, MI; R. A. Kaplan, Concord, CA; J. M. Kaufman, U. Z. Gent, Gent, Belgium; M. Keller, San Diego, CA; D. L. Kendler, Vancouver Hospital and Health Science Centre, Vancouver, British Columbia, Canada; R. Khairi, Physicians Research Group, Indianapolis, IN; M. S. Kipnes, DGD Research, San Antonio, TX; A. J. Kivitz, Altoona, PA; J. Kotler, Holy Cross Hospital, Ft. Lauderdale, FL; N. Koval, Arthritis & Rheumatism Associates, Wheaton, MD; N. J. Kramer, Charlotte, NC; A. J. Laster, First Charlotte Physicians, Charlotte, NC; E. Leib, Fletcher Allen Health Center, Burlington, VT; R. M. Levy, Olympia Arthritis Clinic, Olympia, WA; A. A. Licata, Cleveland Clinic Foundation, Cleveland, OH; R. Lies, Wichita Clinic, Wichita, KS; T. Littlejohn, Piedmont Research Associates, Winston-Salem, NC; S. Ljunghall, Medicinska Kliniken, Uppsala, Sweden; R. Lorenc, Memorial Hospital, Warsaw, Poland; M. Lowenstein, Palm Harbor, FL; C. Lozano, Hospital Universitario San Carlos, Madrid, Spain; B. Lund, Copenhagen, Denmark; F. Maggiacomo, Silver Lake Medical Inc., Providence, RI; A. Mangione, Jenkintown, PA; E. Marcinowska- Suchowierska, Postgraduate Medical Center, Warsaw, Poland; R. E. Marcus, Rheumatology Associates of North Jersey, Teaneck, NJ; M. Maricic, University of Arizona Health Sciences Center, Tucson, AZ; M. R. McClung, Osteoporosis Research Center, Portland, OR; H. H. McIlwain, Tampa, FL; C. D. McKeever, Research for Health Inc., Houston, TX; M. J. McKenna, St. Michael’s Hospital, Dublin, Ireland; D. Mellström, Osteroporos kliniken, Göteborg, Sweden; C.-J. Menkes, Hôpital Cochin, Paris, France; P. Miller, Colorado Center for Bone Research, Lakewood, CO; S. S. Miller, San Antonio, TX; M. G. Molloy, Cork Regional Hospital, Cork, Ireland; H. W. Minne, Clinic for Metabolic Bone Disease, Bad Pyrmont, Germany; H. Mulder, Good Clinical Practice, Rotterdam, The Netherlands; A. Mulloy, Medical College of Georgia, Augusta, GA; J. Munoz, Hospital Clinic I Provincial, Barcelona, Spain; J. A. Napier, St. Petersburg, FL; G. Nicholson, The Geelong Hospital, Geelong, Australia; S. P. Nielsen, Hillerød Sygehus, Hillerød, Denmark; G. Nuki, University of Edinburgh, Edinburgh, UK; L. Olanksky, Oklahoma University Health Sciences Center, Oklahoma City, OK; W. Olszynski, Midtown Medical Center, Saskatoon, Saskatchewan, Canada; M. Palmér, Örebro Lasarett, Örebro, Sweden; A. Parsons, University of Warwick, Coventry, UK; S. A. Pasquale, University Hospital, New Brunswick, NJ; D. A. Podlecki, Longmont Clinic, Longmont, CO; B. Pornel, Brussels Menopause Center, Brussels, Belgium; J. J. Prendergast, Pacific Medical Research Services, Atherton, CA; T. Price, Cannock Chase Hospital, Cannock, UK; H. M. Prupas, Reno, NV; J. Przedlacki, Krajowe Centrum Osteoporozy, Warsaw, Poland; S. Quandt, Bowman Gray School of Medicine, Winston-Salem, NC; R. J. Rapoport, Fall River, MA; J.-Y. Reginster, Université de Liège, Liège, Belgium; D. Reid, University of Aberdeen, Aberdeen, UK; A. Roberts, Ashford International Research Centre, Ashford, Australia; J. M. Rodriguez, Hospital de Belvitge, Barcelona, Spain; T. Rooney, Des Moines, IA; C. Rosen, St. Joseph Hospital, Bangor, ME; S. Rosenblatt, Irvine, CA; C. Roux, Hôpital Cochin, Paris, France; J. B. Rubiò, Servicio de Reumatologia Hospital del Mar, Barcelona, Spain; L. G. Ste-Marie, Centre de Recherche Andre-Viallet, Montreal, Quebec, Canada; P. Salmela, Oulu University Central Hospital, Oulu, Finland; J. Salmni, Universitetsjukhuset, Tammerfors, Finland; B. Samuels, Stafford Medical Associates, Dover, NH; A. Z. Sawicki, Warsaw Centre of Osteoporosis and Calcium Metabolism, Warsaw, Poland; E. N. Schwartz, Foundation for Osteoporosis Research & Education, Oakland, CA; S. Scumpia, Center for Clinical Research, Austin, TX; J.-L. Sebert, Hopital Nord, Amiens, France; W. J. Shergy, Rheumatology Association of North Alabama, Huntsville, AL; G. Sigurdsson, Borgarspitalinn, Fossvogi, Iceland; S. L. Silverman, The Osteoporosis Medical Center, Beverly Hills, CA; C. L. Smith, Hennepin County Medical Center, Minneapolis, MN; I. G. Smith, Wrightington Hospital & NHS Trust, Wigan, UK; O. H. Sorensen, Copenhagen Municipal Hospital, Copenhagen, Denmark; J. G. Spiro, Harwell Laboratories, Didcot, UK; J. L. Stock, Clinical Research Office, Worcester, MA; H. Stracke, Medizinische Poliklinik Giessen, Giessen, Germany; H. Taggart, Belfast City Hospital, Belfast, UK; A. Tenenhouse, Clinical Research Group, Montreal, Quebec, Canada; L. Tessari, Istituto Scientifico San Raffaele, Milan, Italy; P. Thompson, Poole Hospital, Poole, UK; W. Tlustockowicz, Centralny Szpital Kliniczny, Warsaw, Poland; G. H. Tomkin, Adelaide Hospital, Dublin, Ireland; M. Välimäki, Third Department of Medicine, Helsingfors, Finland; A. Virshup, West Palm Beach, FL; R. D. Wasnick, Hawaii Osteoporosis Center, Honolulu, HI; N. Wei, Arthritis and Osteoporosis Center of Maryland, Frederick, MD; S. R. Weiss, San Diego, CA; T. J. Wilkin, University of Plymouth, Plymouth, UK; K. W. Woodhouse, University of Wales, Penarth, UK; A. Woolf, Royal Cornwall Hospital, Truro, UK; M. Yeates, Central Coast Radiology, Gosford, Australia; and T. M. Zizic, Baltimore, MD.
Abbreviations: BMD, Bone mineral density; CI, confidence interval; NHANES III, third National Health and Nutrition Examination Survey; RR, relative risk; VERT, Vertebral Efficacy with Risedronate Therapy; VERT-MN, VERT Multinational; VERT-NA, VERT North America.
Received March 13, 2002.
Accepted October 14, 2002.
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