Correspondence
Denosumab in Postmenopausal Women with Low Bone Mineral Density
N Engl J Med 2006; 354:2390-2391June 1, 2006
- Article
To the Editor:
McClung et al. (Feb. 23 issue)1 do not adequately report adverse events in their article on denosumab in postmenopausal women with low bone mineral density. They state that no significant differences in adverse events were observed among the groups. However, there were six cases of neoplasm in the denosumab group (mentioned only in Table 2 but not in the Discussion section) and none in the other groups. There were numerically more serious adverse events in the denosumab group, as well as more withdrawals because of these events.
The authors do not discuss the possibility of a type II error, which could very likely be the reason for the numbers reported. No information is given about the types of cancer that were reported, the duration of treatment before diagnosis, and the outcomes. We think,2 along with others,3,4 that complete and correct analysis of adverse events that are associated with new treatments is critical. Scientific publications have to be forthcoming with any potentially important data regarding adverse events and possible confounding factors, which need to be discussed and shared with readers. This article, in our opinion, fails to do that.
4 ReferencesJulie Schwartzman, M.D.
Yusuf Yazici, M.D.
New York University Hospital for Joint Diseases, New York, NY 10003
yusuf.yazici@nyumc. org 1
McClung MR ,Lewiecki EM ,Cohen SB , et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821-831
Full Text | Web of Science | Medline2
Yazici Y ,Yazici H . Annual incidence risk of the general population is an inappropriate comparator for reporting TNF-alpha antagonist associated adverse events. Arthritis Rheum 2004;50:S302-S302
CrossRef | Web of Science3
Ioannidis JPA ,Lau J . Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA 2001;285:437-443
CrossRef | Web of Science | Medline4
Ioannidis JP ,Evans SJ ,Gotzsche PC , et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004;141:781-788
Web of Science | Medline
To the Editor:
McClung et al. report on an industry-supported study comparing denosumab, alendronate, and placebo in the treatment of postmenopausal women with low bone mineral density. I am concerned about the ethics of the inclusion of a placebo group in this study. The authors report that women with bone-mineral-density T scores as low as −4.0 at the lumbar spine and −3.5 at either the femoral neck or the total hip were included in the study. Patients with T scores lower than −2.5 would qualify for the diagnosis of osteoporosis. Furthermore, patients with only one grade 1 vertebral fracture or an osteoporosis-related fracture more than two years earlier were eligible to be included. According to published guidelines and prominent reviews of clinical practice, patients with clear osteoporosis and, most especially, with previous fractures should be offered pharmacologic treatment, which has been shown to reduce the risk of fracture by up to 50 percent.1-3 I do not see how equipoise could be argued in this study. Would anyone be willing to assign his or her loved ones with clear osteoporosis to a year of placebo therapy?
3 ReferencesWilliam D. Rifkin, M.D.
Yale University School of Medicine, New Haven, CT 06510
william.rifkin@yale. edu 1
National Osteoporosis Foundation. Physician's guide to prevention and treatment of osteoporosis. 1999, updated January 2003. (Accessed May 11, 2006, at http://www.nof.org.)
2
Hodgson SF ,Watts NB ,Bilezikian JP , et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 2003;9:544-564[Erratum, Endocr Pract 2004;10:90.]
Medline3
Rosen CJ . Postmenopausal osteoporosis. N Engl J Med 2005;353:595-603
Full Text | Web of Science | Medline
Author/Editor Response
Drs. Schwartzman and Yazici assert that we did not adequately report adverse events, provide enough information about neoplasm, or discuss the possibility of a type II error in the comparison of the rates of adverse events among treatment groups. We believe that adverse events were adequately described in Tables 2 and 3, which listed the incidence of overall adverse events across treatment groups and the incidence of specific adverse events that occurred in at least 10 percent of patients. Of the six neoplasms reported in the denosumab groups, five were malignant (breast, ovarian, pancreatic, and gastric cancer and melanoma in situ) and one was benign (monoclonal hypergammaglobulinemia). The small size of the study sample precluded us from drawing any conclusions about the potential clinical significance of these differences, beyond providing a nominal P value to describe the numerical differences observed among the groups. Indeed, since 77 percent of the patients were in the denosumab groups, it would not be unexpected to have all six patients with neoplasm come from these groups. Throughout this study and in the phase 3 studies, safety data (including data on such adverse events as neoplasms) have been and will continue to be reviewed for potential safety signals and trends by an independent data monitoring committee.
Dr. Rifkin raises the important and complex issue of including placebo groups in studies that include women with osteoporosis, an issue reviewed by Dr. Levine of Yale University School of Medicine.1 Strong agreement exists that patients at high risk for fracture should not be enrolled in placebo-controlled trials, but trials with patients at low risk for a significant adverse event are justified if the question being addressed is scientifically valid and medically important and if patients are appropriately informed.2-4 We excluded subjects who were at high risk for fracture (more than one grade 1 or any grade 2 or 3 vertebral fracture), and 68 percent of the patients had baseline bone-mineral-density values consistent with osteopenia. All patients received treatment with calcium and vitamin D, which has been shown to decrease the risk of fracture in patients with osteoporosis, and chose to participate after being fully informed about the availability and effectiveness of current treatments and the known potential risks associated with denosumab.
4 ReferencesMichael R. McClung, M.D.
Oregon Osteoporosis Center, Portland, OR 97213
mmcclung@orost.com 1
Levine RJ . Placebo controls in clinical trials of new therapies for osteoporosis. J Bone Miner Res 2003;18:1154-1159
CrossRef | Web of Science | Medline2
Food and Drug Administration, Center for Drug Evaluation and Research. Endocrinologic and Metabolic Drugs Advisory Committee meeting, September 25, 2002. (Accessed May 11, 2006, at http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3888T1.htm.)
3
Kanis JA ,Alexandre JM ,Bone HG , et al. Study design in osteoporosis: a European perspective. J Bone Miner Res 2003;18:1133-1138
CrossRef | Web of Science | Medline4
Brody BA ,Dickey N ,Ellenberg SS , et al. Is the use of placebo controls ethically permissible in clinical trials of agents intended to reduce fractures in osteoporosis? J Bone Miner Res 2003;18:1105-1109
CrossRef | Web of Science | Medline
- Citing Articles (6)
Citing Articles
1
T. Lin, C. Wang, X.-Z. Cai, X. Zhao, M.-M. Shi, Z.-M. Ying, F.-Z. Yuan, C. Guo, S.-G. Yan. (2012) Comparison of clinical efficacy and safety between denosumab and alendronate in postmenopausal women with osteoporosis: a meta-analysis. International Journal of Clinical Practiceno-no
CrossRef2
Athanasios D. Anastasilakis, Stergios A. Polyzos, Chrysostomos D. Anastasilakis, Konstantinos A. Toulis, Polyzois Makras. (2011) Denosumab and bisphosphonates: Rivals or potential “partners”? A “hybrid” molecule hypothesis. Medical Hypotheses 77:1, 109-111
CrossRef3
M. Sosa Henríquez, D. Hernández Hernández. (2009) Tratamiento de las osteoporosis. Revista Clínica Española 209, 41-47
CrossRef4
Kathryn E Ackerman. (2008) Is denosumab a safe and effective treatment for postmenopausal osteoporosis?. Nature Clinical Practice Endocrinology & Metabolism 4:7, 376-377
CrossRef5
Stanley B. Cohen, Robin K. Dore, Nancy E. Lane, Peter A. Ory, Charles G. Peterfy, John T. Sharp, Désirée van der Heijde, Lifen Zhou, Wayne Tsuji, Richard Newmark, . (2008) Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: A twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis & Rheumatism 58:5, 1299-1309
CrossRef6
(2006) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 15:11, i-xii
CrossRef
