Fracture Prevention with Zoledronate in Older Women with Osteopenia

TO THE EDITOR: In the trial reported by Reid et al. (Dec. 20 issue),1 zoledronic acid led to a lower risk of fragility fractures than placebo among postmenopausal women with osteopenia. We have concerns about the conclusion.
First, nonvertebral fractures were seen in 24% of the participants at screening. A clinical diag- nosis of osteoporosis includes the presence of fragility fractures.2,3 Thus, more than 24% of the participants actually had osteoporosis rather than osteopenia.
Second, if the 10-year risk of major osteopo- rotic fractures among women with osteopenia is estimated to be 3.9% by the Fracture Risk As- sessment Tool (FRAX; developed by the World Health Organization), a hazard ratio of 0.65 with zoledronate provides a number needed to treat of 74 to prevent the occurrence of a single fragility fracture. We do not think that the abso- lute effect is similar in higher-risk patients (i.e., those with osteoporosis). Would the authors pro- vide data regarding the incidence of fragility fractures among patients who completely ful- filled the diagnosis of osteopenia?
Third, additional baseline characteristics are
important considerations in evaluating the prob- ability of falls. These characteristics include cataracts, glaucoma, dysuria, neurologic disor- ders (e.g., stroke, Parkinson’s disease, and epi- lepsy), anemia, arrhythmia, frequency of previous falls, and measures of activities of daily living (e.g., with the Barthel scale), all of which might be confounders.
Shotaro Suzuki, M.D. Noboru Hagino, M.D., Ph.D.
Teikyo University Chiba Medical Center Ichihara, Japan [email protected]
Eishu Nango, M.D., Ph.D.
Tokyo Kita Medical Center Tokyo, Japan
No potential conflict of interest relevant to this letter was re- ported.
1. Reid IR, Horne AM, Mihov B, et al. Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med 2018; 379:2407-16.
2. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of a WHO study group. World Health Organ Tech Rep Ser 1994;843:1-129.
3. Siris ES, Adler R, Bilezikian J, et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int 2014;25:1439-43.
DOI: 10.1056/NEJMc1900923

TO THE EDITOR: The osteoporotic fracture rate at 6 years was much higher than expected in this trial. Although the baseline expected osteopo- rotic fracture rate at 10 years was approximately 12.0% in each group, after 6 years of follow-up, 12.2% of the patients in the zoledronate group and 19.0% of those in the placebo group had an osteoporotic fracture (derived from data regard- ing the number of women with fracture, as pre- sented in Table 2 of their article). However, this was not true for hip fractures, which occurred at a rate that was close to the one expected. A recent study showed an increased risk of falls among older adults receiving doses of vitamin D as low as 60,000 IU per month for 12 months.1 Given the fact that patients in the two trial groups re- ceived 50,000 IU of vitamin D monthly, the in- creased incidence of falls might have led to in- creased fracture rates in the two groups. It would be helpful for the authors to present the baseline and follow-up rates of falls, as discussed in their protocol. Caution is appropriate before zoledro- nate is prescribed in older women with osteope- nic bone mineral density values at the hip, be- cause the reportedly lower rate of fractures with zoledronate than with placebo was higher than expected.
Fatih Tufan, M.D.
Silivrikapi mh. Hisaralti cd. Fatih sitesi. A1/9 Fatih Istanbul, Turkey
[email protected]
No potential conflict of interest relevant to this letter was re- ported.

1. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med 2016;176:175-83.
DOI: 10.1056/NEJMc1900923

TO THE EDITOR: The results of the trial conducted by Reid et al. are exciting with regard to the low- er risk of fracture and may have considerable bearing on morbidity and quality of life in the elderly population. However, clarifications regard- ing certain aspects of this trial are warranted.
First, the trial design was not pragmatic be- cause it excluded the dominant population at risk for fractures, such as patients with systemic ill- ness, those with metabolic bone disease, and those who use glucocorticoids. Hence the exter- nal validity of these data remain questionable.

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Second, it would be interesting for the au- thors to assess the FRAX scores (if available) to know the baseline fracture-risk difference be- tween the two groups. Finally, it would be infor- mative if the authors provided a separate assess- ment using the T score at the spine, which may be discordantly low in postmenopausal women owing to an estrogen-deficient state, and the difference between the two groups regarding the spine–hip T-score difference, which is a FRAX- independent risk factor for major osteoporotic fracture.1
Arghya Chattopadhyay, M.D. Sanjay Jain, M.D., D.M.
Postgraduate Institute of Medical Education and Research Chandigarh, India
[email protected]
No potential conflict of interest relevant to this letter was re- ported.

1. Leslie WD, Kovacs CS, Olszynski WP, et al. Spine-hip T-score difference predicts major osteoporotic fracture risk independent of FRAX(®): a population-based report from CAMOS. J Clin Den- sitom 2011;14:286-93.
DOI: 10.1056/NEJMc1900923

THE AUTHORS REPLY: Although the women in the trial all had bone densities indicating osteope- nia, there was a substantial diversity in baseline risk factors for fracture. The correspondents ask whether particular characteristics identify spe- cific groups of women who benefit more than others from the use of zoledronate. In brief, no interaction between baseline characteristics and the antifracture efficacy of zoledronate was seen (data not shown). Specifically, antifracture effi- cacy was independent of age (P = 0.58) and base- line bone density (P = 0.54 for hip; P = 0.97 for spine). Thus, zoledronate leads to a lower risk of fracture than placebo among women with T scores in the range of −1.0 to −1.5 (hazard ra- tios for fragility fracture, 0.52 to 0.58).
Suzuki et al. question whether zoledronate
prevents fractures in patients with osteopenia. Our article states that a lower risk of fracture is present among women who have osteopenia ac- cording to the most conservative definition, which also excludes women with previous frac- tures (hazard ratio for nonvertebral fragility fracture vs. placebo, 0.57; 95% confidence inter-

val, 0.37 to 0.86). In this cohort, the risk accord- ing to FRAX, shown in Table 1 of our article, underestimated the risk of fragility fractures but overestimated the gradient of risk across the cohort, so we find similarly lower fracture num- bers with zoledronate than with placebo across the cohort and a lower number needed to treat than theoretical considerations would have pre- dicted.
Tufan hypothesizes that the vitamin D sup- plement that was used in our trial may have in- creased the risk of falls and the incidence of fractures. We think that this is unlikely, since the incidence of hip fracture in the placebo group was as predicted, so the likely explanation for the higher number of fragility fractures is that we used a broader definition of fragility fracture than FRAX does or that FRAX is poorly calibrated for fragility fractures in this particu- lar population. Since vitamin D was given to both groups, this suggestion does not cast doubt on the antifracture efficacy of zoledronate. A total of 21% of the women had a history of falls in the year before recruitment — a percentage that was similar in the two groups and remained unchanged in the last year of the trial.
Contrary to what Chattopadhyay and Jain
suggest, most fractures in older women occur in those who do not have overt bone disease or osteoporotic bone density.1,2 Our trial establishes the antifracture efficacy of a bisphosphonate in that population. The efficacy of bisphosphonates in patients with osteoporosis is already well es- tablished.
Ian R. Reid, M.D.
Anne M. Horne, M.B., Ch.B. Gregory D. Gamble, M.Sc.
University of Auckland Auckland, New Zealand [email protected]
Since publication of their article, the authors report no fur- ther potential conflict of interest.

1. Tei RMH, Ramlau-Hansen CH, Plana-Ripoll O, Brink O, Langdahl BL. OFELIA: prevalence of osteoporosis in fragility fracture patients. Calcif Tissue Int 2019;104:102-14.
2. Trajanoska K, Schoufour JD, de Jonge EAL, et al. Fracture incidence and secular trends between 1989 and 2013 in a pop- ulation based cohort: the Rotterdam study. Bone 2018;114:116- 24.
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