Correspondence
Denosumab, Osteoporosis, and Prevention of Fractures
N Engl J Med 2009; 361:2188-2191November 26, 2009
- Article
To the Editor:
In the August 20 issue, Smith et al.1 and Cummings et al.2 report on findings that may herald a new era in therapy for osteoporosis. In spite of an adequate safety profile, concerns remain about adverse effects of denosumab in the long term. Do the authors have data on how effectively denosumab administered twice yearly blocks the receptor activator of nuclear factor-κB (RANK) signaling in cells other than osteoclasts (such as immune cells, activated endothelial cells, or hepatocytes)? Are there any metabolic effects that may translate into clinical harm (or benefit) over decades?
No excess risk of acute infections was reported in the two studies,1,2 and preliminary data provide evidence that suggests the safety of RANK ligand (RANKL) blockage from a cardiovascular perspective.3,4 However, potential tumor-promoting effects caused by the interference of denosumab with T-cell and dendritic-cell function require attention. We herein show that serum levels of both soluble, biologically active RANKL and osteoprotegerin — which are considered to reflect the overall activity of the osteoprotegerin–RANK–RANKL system — were not related to the risk of cancer and death in the general community in the Bruneck study3 (1990–2005) (Table 1Table 1
Association of Serum Levels of Soluble RANKL and Osteoprotegerin with the Risk of New-Onset Cancer and Deaths from Cancer among 894 Subjects.).4 ReferencesStefan Kiechl, M.D.
Johann Willeit, M.D.
Innsbruck Medical University, Innsbruck, Austria
stefan.kiechl@i-med. ac. at Georg Schett, M.D.
University of Erlangen-Nuremberg, Erlangen, Germany1
Smith MR ,Egerdie B ,Hernandez Toriz N , et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361:745-755
Full Text | Web of Science | Medline2
Cummings SR ,San Martin J ,McClung MR , et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-765
Full Text | Web of Science | Medline3
Kiechl S ,Schett G ,Schwaiger J , et al. Soluble receptor activator of nuclear factor-kappa B ligand and risk for cardiovascular disease. Circulation 2007;116:385-391
CrossRef | Web of Science | Medline4
Helas S ,Goettsch C ,Schoppet M , et al. Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol 2009;175:473-478
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To the Editor:
In the article on the prevention of fractures with the human monoclonal antibody denosumab, Cummings et al. report a significant reduction in the risk of vertebral, nonvertebral, and hip fractures after 36 months of therapy. Two areas of concern center on the fact that patients were not adequately accounted for at the end of the study. The authors do not provide an acceptable level of information on the 1390 patients who did not complete the study at 36 months. The reader is left to suppose that equal numbers of patients were missing from the treatment and placebo groups and that the characteristics of these patients were similar enough that their omission did not alter the results. The authors also report a significant reduction in nonvertebral fractures (20% risk reduction), even though the study had a power of 99% to detect a 40% reduction in the risk of fracture. Failure to achieve this threshold of reduction and the uncertainty associated with the missing patients cast doubt on the quality of a study of what is otherwise a seemingly promising therapy. Whither the missing?
Jordan Blackwood, M.D.
St. Luke's–Roosevelt Hospital Center, New York, NYTo the Editor:
Cummings et al. report on the initial findings of the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (ClinicalTrials.gov number, NCT00089791), and they conclude that denosumab was associated with a significant reduction in the risk of vertebral fractures in postmenopausal women with osteoporosis. They report that women who had taken oral bisphosphonates for less than 3 years were eligible for the study after 12 months of a washout of bisphosphonates. The authors do not state that the randomization process controlled for this variable, nor are the numbers of the subjects who previously received bisphosphonates reported in Table 1 of the article.
Investigators of the Fracture Intervention Trial Long-term Extension (FLEX) trial (NCT00398931)1 concluded that the risk of nonvertebral fractures remained unchanged for 5 years after discontinuation of oral alendronate. Thus, the results reported by Cummings et al. might be confounded by the previous administration of bisphosphonates in an unknown number of subjects. The same confounder might also apply to the results recently reported by Smith et al.
Finally, the inhibition of RANKL may not be a drawback of denosumab alone,2 since bisphosphonates have also been reported to inhibit RANKL.3
3 ReferencesAthanassios Kyrgidis, M.D., D.D.S.
Aristotle University of Thessaloniki, Thessaloniki, Greece
akyrgidi@gmail.com 1
Black DM ,Schwartz AV ,Ensrud KE , et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006;296:2927-2938
CrossRef | Web of Science | Medline2
Kyrgidis A ,Triaridis S ,Vahtsevanos K ,Antoniades K . Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients. Expert Rev Anticancer Ther 2009;9:1125-1134
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Kyrgidis A ,Triaridis S ,Antoniades K . Effects of bisphosphonates on keratinocytes and fibroblasts having a role in the development of osteonecrosis of the jaw. Biosci Hypotheses 2009;2:153-159
CrossRef
To the Editor:
Although yet another expensive drug that nobody will be able to use is not exciting, I do have concerns about the study of denosumab in women with osteoporosis. It seems that several thousand women with documented disease were assigned to receive placebo for 3 years, rather than offered the standard treatment. Not only is this assignment ethically questionable, but we should be tired of studies that compare the new, very expensive drugs with placebo, when we really need to see studies comparing them with conventional, often much less expensive, treatment.
Stephen L. Blythe, D.O.
Melbourne Internal Medicine Associates, Melbourne, FL
stephen.blythe@mima. com Author/Editor Response
With regard to the query by Kiechl et al.: on the basis of preclinical evidence on RANKL inhibition, there is no expectation that there would be off-target effects (e.g., on liver function and metabolic variables apart from those attributable to osteoclast inhibition) occurring in people after exposure to denosumab. Specifically, clinical data have not shown potential tumor-promoting effects of denosumab. Preclinical data indicate that RANKL inhibition has no major immunosuppressive effects on immune system function in adults or impact on immune-cell subgroups and immunoglobulin production; these facts are important for immune surveillance.1,2 These results are consistent with our article in the Journal, which indicated that denosumab did not have a significant effect on the risk of infection or on new malignant conditions or the progression of underlying prostate cancer, as compared with placebo. Notably, among patients with cancer who received a dosing regimen of denosumab for bone metastasis that was 12 times higher than that used in our study, no differences in overall disease progression and overall survival have been observed with denosumab as compared with zoledronic acid, a current standard of care for these patients.3,4 Although determinations of serum levels of RANKL and osteoprotegerin have not yet been established as surrogates for clinical outcomes, the results reported by Kiechl et al. provide support for the clinical observation that RANKL inhibition does not promote a new malignant condition or cancer progression.
4 ReferencesMatthew R. Smith, M.D., Ph.D.
Massachusetts General Hospital Cancer Center, Boston, MA
smith.matthew@mgh. harvard. edu 1
Ferrari-Lacraz S ,Ferrari S . Effects of RANKL inhibition on inflammation and immunity. IBMS BoneKEy 2009;6:116-126
CrossRef2
Leibbrandt A ,Penninger JM . RANK/RANKL: regulators of immune response and bone physiology. Ann N Y Acad Sci 2008;1143:123-150
CrossRef | Web of Science | Medline3
Stopeck A, Body JJ, Fujiwara Y, et al. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Presented at joint 15th Congress of the European Cancer Organization and the 34th Congress of the European Society for Medical Oncology, Berlin, September 20–24, 2009.
4
Henry D, von Moos R, Vadhan-Raj S, et al. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Presented at the joint 15th Congress of the European Cancer Organization and the 34th Congress of the European Society for Medical Oncology, Berlin, September 20–24, 2009.
Author/Editor Response
With regard to Blackwood's queries: 17.9% of subjects who received placebo and 16.1% of subjects who received denosumab discontinued the trial; 2.1% and 2.4%, respectively, discontinued because of adverse events. The baseline characteristics of the patients who discontinued the study were similar in the placebo and denosumab groups: the mean age was 74 years, and the bone mineral density T scores were −2.3 at the femoral neck and −2.8 at the lumbar spine in both treatment groups. On the basis of the original assumptions and specifications, the study had a power of 91% to detect a 40% reduction in the risk of hip fracture, a power of more than 99% to detect a 70% reduction in the risk of vertebral fracture, and a power of 80% to detect a 20% reduction in the risk of nonvertebral fracture.
In reply to Kyrgidis: the proportion of patients who had received a bisphosphonate was small and similar between the groups (13.2% in the placebo group vs. 12.0% in the denosumab group, P=0.10) and therefore would probably not bias the results.
We agree with Blythe that trials comparing active treatments would be ideal. Two trials have compared the effects of denosumab and alendronate on bone mineral density.1,2 A trial comparing the effects of two agents on fracture reduction would require a much larger sample size than the 7868 subjects in the FREEDOM trial. Regarding the use of placebos: in the United States, treatment is generally recommended for patients with a T score of less than −2.5 at the hip or spine; however, treatment guidelines and reimbursement differ and are often more conservative in the other countries that accounted for most of the subjects in our trial. Furthermore, a recent consensus conference in the United States which included research ethicists concluded that placebo-controlled trials are acceptable, with no restriction on bone density for participation, if patients are fully informed of the benefits, risks, and alternative therapies.3 As described in our article, all potential subjects were informed about the potential benefits and risks of participation in the trial and the availability of alternative treatments, and the ethics of the trial were reviewed and approved by the responsible institutional review boards.
3 ReferencesSteven R. Cummings, M.D.
San Francisco Coordinating Center, San Francisco, CA
hglicklandes@sfcc-cpmc.net Ethel Siris, M.D.
Columbia University, New York, NYAndrea Wang, M.A.
Amgen, Thousand Oaks, CA1
Brown JP ,Prince RL ,Deal C , et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24:153-161
CrossRef | Web of Science | Medline2
Kendler DL, Roux C, Benhamou CL, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res 2009 July 13 (Epub ahead of print).
3
Silverman SL ,Cummings SR ,Watts NB . Recommendations for the clinical evaluation of agents for treatment of osteoporosis: consensus of an expert panel representing the American Society for Bone and Mineral Research (ASBMR), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation (NOF). J Bone Miner Res 2008;23:159-165
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