Correspondence

Bisphosphonates and Osteoporosis

N Engl J Med 2002; 346:2088-2089June 27, 2002

Article

To the Editor:

The prospect of a quick fix for the problem of postmenopausal osteoporosis by means of intermittent administration of intravenous bisphosphonate is exciting. Reid et al. (Feb. 28 issue)1 report that bone mineral density was increased for up to one year after intermittent intravenous therapy with zoledronic acid. The authors do not discuss the rate of nonvertebral fractures, which, if anything, was higher in the treated group than in the placebo group. The authors do point out that all the women in their study had base-line bone-mineral-density values that were high enough that therapy would not have been recommended, according to the current guidelines. Although treatment may have salutary effects on surrogate markers of bone turnover and on bone density, a reduction in the rate of fracture is the gold standard of efficacy. Thus, it seems surprising that the authors do not mention the observed fracture rates in their discussion. Specifically, were the fractures that occurred in bones that were less favorably affected by the treatment (e.g., the radius) or were they hip fractures?

Elizabeth R. Jenny-Avital, M.D.
Jacobi Medical Center, Bronx, NY 10461
jennyavita@aol.com

1 References

1
Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653-661
Full Text | Web of Science | Medline

To the Editor:

It struck me as somewhat ominous that one year after the administration of a single 4-mg dose of zoledronic acid, markers of bone turnover remained suppressed. I understand that bone turnover remodels the skeleton about every 10 years.1 According to current theory, this remodeling serves to repair microfractures.2 I worry about administering a drug that has long-term suppressive effects on the remodeling of microfractures in the bones of women in their 50s and 60s. The increase in bone density provided by these drugs may not result in improved bone function in the long term. Ten years from now, will we see spontaneous fractures or other complications of decreased microfracture repair in women over the age of 60 years?

A quick search of PubMed revealed a few studies in animals that suggest this possibility.3-5 Although the results of these studies in animals cannot be directly applied to humans, I would urge that we heed Hippocrates and make sure we do no harm in our efforts to help our patients. These powerful medications are certainly appropriate and necessary for certain patients but should be used with caution in those who are younger and who have less severe disease that might be better managed with vitamins D and K, calcium, magnesium, and weight-bearing exercise.

Valori Treloar, M.D.
65 Walnut St., Wellesley, MA 02481
trescon@rcn.com

5 References

1
Bone remodeling: Wheeless' textbook of orthopaedics. 1996. (Accessed June 6, 2002, at http://www.medmedia.com/o2/57.htm.)

2
Li J, Mashiba T, Burr DB. Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tissue Int 2001;69:281-286
CrossRef | Web of Science | Medline

3
Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB. Does suppression of bone turnover impair mechanical properties by allowing microdamage accumulation? Bone 2000;27:13-20
CrossRef | Web of Science | Medline

4
Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2000;15:613-620
CrossRef | Web of Science | Medline

5
Mashiba T, Turner CH, Hirano T, et al. Effects of high-dose etidronate treatment on microdamage accumulation and biomechanical properties in beagle bone before occurrence of spontaneous fractures. Bone 2001;29:271-278
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We concur with Dr. Jenny-Avital's comments — the critical criterion for establishing the efficacy of a novel therapy for osteoporosis is the demonstration that it prevents fractures. Our study was a one-year, phase 2, dose-finding study in women with a low risk of fracture. The incidence of nonvertebral fractures was 1.7 fractures per 100 patient-years in the pooled zoledronic acid groups and in the placebo group, and the maximal number of fractures in any group was 2. Apart from one pelvic fracture in a woman randomly assigned to receive zoledronic acid, all fractures occurred in the appendicular skeleton; four were in the upper limb, and one was in the lower limb. There were no hip fractures. This is the expected pattern of fractures in a population of women whose age and bone density are similar to those of the study population. It is not possible to make inferences from these data about the site specificity of an antifracture effect of zoledronic acid.

Dr. Treloar's concern that bisphosphonates may reduce bone turnover to a level at which the normal processes of remodeling and repair are impeded has been expressed since the earliest reports on the use of bisphosphonates, 15 years ago. Although very high doses, such as those used in the studies of animals that Dr. Treloar cited, may cause “frozen bone,” this is not the case with the doses used in clinical practice, which reduce bone turnover only to normal premenopausal levels. Thus, microfracture repair should proceed normally, a contention supported by the demonstration that fractures are less frequent in women treated with bisphosphonates1,2 and that fracture rates remain low for up to seven years of observation.3,4 Our study of zoledronic acid demonstrated reductions in markers of bone turnover that were similar to those caused by the oral bisphosphonate regimens previously shown to prevent fractures, so similar effects on fractures are to be expected. Confirmation must await the outcome of phase 3 trials, which are still enrolling patients. However, Dr. Treloar's caution with regard to the use of these powerful drugs in higher doses or for substantially longer periods than have been studied in clinical trials is entirely appropriate, and continued monitoring of fracture rates in patients receiving long-term therapy is important.

Ian R. Reid, M.D.
University of Auckland, Auckland, New Zealand
i.reid@auckland.ac.nz

Peter Burckhardt, M.D.
Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland

Jacques P. Brown, M.D.
Université Laval, Quebec, QC G1V 4G2, Canada

4 References

1
Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-1541
CrossRef | Web of Science | Medline

2
McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333-340
Full Text | Web of Science | Medline

3
Miller PD, Watts NB, Licata AA, et al. Cyclical etidronate in the treatment of postmenopausal osteoporosis -- efficacy and safety after seven years of treatment. Am J Med 1997;103:468-476[Erratum, Am J Med 1998;104:608.]
CrossRef | Web of Science | Medline

4
Tonino RP, Meunier PJ, Emkey R, et al. Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. J Clin Endocrinol Metab 2000;85:3109-3115
CrossRef | Web of Science | Medline

Citing Articles (1)