Mayo Clin Proc. • March 2005;80(3):343-349 • www.mayoclinicproceedings.com
VERTEBRAL FRACTURE RISK
From the Department of Public Health Sciences, Wake Forest University
School of Medicine, Winston-Salem, NC (S.A.Q.); Merck Research Laborato-
ries, Rahway, NJ (D.E.T.); Department of Medicine, University of California,
San Diego (D.L.S.); and Department of Epidemiology and Biostatistics, Univer-
sity of California, San Francisco (M.C.N., D.M.B.).
This research was supported by Merck Research Laboratories, Rahway, NJ.
Dr Thompson is a Merck employee, Dr Schneider is a Merck consultant, and
Dr Black serves on the Merck speakers bureau.
Members of the Fracture Intervention Trial Research Group are listed in
Address reprint requests and correspondence to Sara A. Quandt, PhD,
Department of Public Health Sciences, Wake Forest University School of
Medicine, Winston-Salem, NC 25717-1063 (e-mail: email@example.com).
© 2005 Mayo Foundation for Medical Education and Research
SARA A. QUANDT, PHD; DESMOND E. THOMPSON, PHD; DIANE L. SCHNEIDER, MD, MSC;
MICHAEL C. NEVITT, PHD, MPH; AND DENNIS M. BLACK, PHD,
FOR THE FRACTURE INTERVENTION TRIAL RESEARCH GROUP
Effect of Alendronate on Vertebral Fracture Risk in Women
With Bone Mineral Density T Scores of –1.6 to –2.5 at the Femoral Neck:
The Fracture Intervention Trial
BMD = bone mineral density; CI = confidence interval; FIT = Fracture
Intervention Trial; MORE = Multiple Outcomes of Raloxifene Evalua-
tion; NHANES III = National Health and Nutrition Examination Survey III;
NNT = number needed to treat; RR = relative risk; WHO = World Health
OBJECTIVES: To determine the efficacy of alendronate treatment
on risk of vertebral fracture in a subgroup of women from the
Fracture Intervention Trial who had bone mineral density T scores
between –1.6 and –2.5 at the femoral neck and to describe how
soon after initiation of therapy alendronate becomes effective and
whether it is consistent in women with and without existing radio-
graphic vertebral fracture.
PATIENTS AND METHODS: From May 1992 to March 1997, post-
menopausal women aged 55 to 80 years were randomized to
receive alendronate at 5 mg/ d for 2 years and 10 mg/ d thereafter
or placebo for up to 4.5 years (mean, 3.8 years) in a controlled,
double-blind, multicenter study.
RESULTS: A total of 3737 postmenopausal women were included
in the study, 1878 in the alendronate group and 1859 in the
placebo group. Risk of vertebral fracture was significantly reduced
by alendronate compared with placebo for clinical (relative risk
[RR], 0.40; 95% confidence interval [CI], 0.19-0.76; P=.005) and
radiographic (RR, 0.57; 95% CI, 0.41-0.81; P=.002) fracture. The
reductions in vertebral fracture risk were consistent in women
with and without an existing radiographic vertebral fracture for
clinical (RR, 0.34; 95% CI, 0.12-0.84; and RR, 0.46; 95% CI, 0.16-
1.17; respectively) and radiographic (RR, 0.53; 95% CI, 0.34-
0.82; and RR, 0.64; 95% CI, 0.38-1.10; respectively) fractures. In
both groups, the effect of alendronate on clinical vertebral frac-
ture was noted soon after therapy was initiated. The absolute risk
of vertebral fracture was low in women without a baseline radio-
CONCLUSIONS: In women with low bone mass who do not meet
the bone mineral density criterion for osteoporosis, alendronate is
effective in reducing the risk of vertebral fractures. The absolute
benefit of this therapy in women with a T score between –1.6 and
–2.5 is greater in women with an existing vertebral fracture and/
or with other risk factors. The effect of alendronate occurs early.
Mayo Clin Proc. 2005;80(3):343-349
the young adult mean value (ie, a BMD T score between –1
and –2.5).1,2 The efficacy of pharmacological treatment of
low BMD has been established mainly for patients with
osteoporosis (ie, a BMD T score of less than –2.5). Al-
though therapeutic interventions are deferred occasionally
steopenia has been defined as a bone mineral density
(BMD) value more than 1 but less than 2.5 SDs below
in persons who do not attain the cutoff BMD T score of
–2.5, treating such individuals to reduce fracture risk may
be important.1 It is well established that a low adult peak
bone mass and an increased rate of postmenopausal or
aging-associated bone loss in women increase the likeli-
hood of developing osteoporosis.3 Each SD decrease in
BMD is known to be associated with an increased risk of
fracture. A BMD decrease of 2 SDs in women is associated
with a 4- to 6-fold increase in the risk of new vertebral
fractures,4 whereas each SD decrease in femoral neck
BMD increases the age-adjusted risk of hip fracture by
2.6.5 Consequently, in persons with a T score of –1.0 to
–2.5, the decision to intervene to reduce the risk of subse-
quent osteoporotic fractures has usually been made in those
who have progressive bone loss on serial BMD determina-
tions or in those with additional risk factors. Analysis of the
National Osteoporosis Risk Assessment indicates that post-
menopausal women classified as having osteoporosis
based on BMD experienced only 18% of the documented
osteoporotic fractures,6 suggesting that more efforts are
necessary to reduce fracture risk in women with BMD
scores higher than –2.5.
Currently, nonpharmacological measures (eg, weight-
bearing exercises, diet and lifestyle modification) and cal-
cium supplements are the first-line interventions advocated
in patients with osteopenia. There have been no large-scale
randomized trials of the effect of pharmacological treat-
ment with bisphosphonates, vitamin D analogues, calcito-
Mayo Clin Proc. • March 2005;80(3):343-349 • www.mayoclinicproceedings.com
VERTEBRAL FRACTURE RISK
5. Cummings SR, Black DM, Nevitt MC, et al, Study of Osteoporotic
Fractures Research Group. Bone density at various sites for prediction of hip
fractures. Lancet. 1993;341:72-75.
6. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for
pharmacological intervention to prevent fractures. Arch Intern Med. 2004;164:
7. Black DM, Cummings SR, Karpf DB, et al, Fracture Intervention
Trial Research Group. Randomised trial of effect of alendronate on risk of
fracture in women with existing vertebral fractures. Lancet. 1996;348:1535-
8. Black DM, Thompson DE, Bauer DC, et al, FIT Research Group. Frac-
ture risk reduction with alendronate in women with osteoporosis: the Fracture
Intervention Trial [published correction appears in J Clin Endocrinol Metab.
2001;86:938]. J Clin Endocrinol Metab. 2000;85:4118-4124.
9. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate
on risk of fracture in women with low bone density but without vertebral
fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-
10. Ensrud KE, Black DM, Palermo L, et al. Treatment with alendronate
prevents fractures in women at highest risk: results from the Fracture Interven-
tion Trial. Arch Intern Med. 1997;157:2617-2624.
11. Black DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR.
Design of the Fracture Intervention Trial. Osteoporos Int. 1993;3(suppl 3):
12. Looker AC, Wahner HW, Dunn WL, et al. Proximal femur bone mineral
levels of US adults. Osteoporos Int. 1995;5:389-409.
13. Liberman UA, Weiss SR, Broll J, et al, Alendronate Phase III Osteoporo-
sis Treatment Study Group. Effect of oral alendronate on bone mineral density
and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med.
14. Kiel D, National Osteoporosis Foundation Working Group on Vertebral
Fractures. Assessing vertebral fractures [published correction appears in J
Bone Miner Res. 1995;10:1605]. J Bone Miner Res. 1995;10:518-523.
15. Genant HK, Wu CY, van Kuijk C, Nevitt MC. Vertebral fracture assess-
ment using a semiquantitative technique. J Bone Miner Res. 1993;8:1137-
16. Genant HK, Jergas M, van Kuijk C, eds. Vertebral Fracture in Os-
teoporosis. San Francisco, Calif: Radiology Research and Education Founda-
17. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time
Data. New York, NY: John Wiley & Sons; 1980.
18. Cox DR, Oakes D. Analysis of Survival Data. London, England:
Chapman and Hall; 1984.
19. Breslow NE, Day NE. Statistical methods in cancer research: the analy-
sis of case-control studies. IARC Sci Pub. 1980;1:5-338.
20. Kanis JA, Johnell O, Black DM, et al. Effect of raloxifene on the risk of
new vertebral fracture in postmenopausal women with osteopenia or os-
teoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation
trial. Bone. 2003;33:293-300.
21. Thompson DE. The effect of alendronate on age-specific incidence of
key osteoporotic fractures [abstract]. J Bone Miner Res. 2000;15(suppl 1):
S552. Abstract M404.
22. Nevitt MC, Ettinger B, Black DM, et al. The association of radiographi-
cally detected vertebral fractures with back pain and function: a prospective
study. Ann Intern Med. 1998;128:793-800.
23. Cook DJ, Guyatt GH, Adachi JD, et al. Quality of life issues in women
with vertebral fractures due to osteoporosis. Arthritis Rheum. 1993;36:750-756.
24. Black DM, Arden NK, Palermo L, Pearson J, Cummings SR, Study of
Osteoporotic Fractures Research Group. Prevalent vertebral deformities pre-
dict hip fractures and new vertebral deformities but not wrist fractures. J Bone
Miner Res. 1999;14:821-828.
25. Kotowicz MA, Melton LJ III, Cooper C, Atkinson EJ, O’Fallon WM,
Riggs BL. Risk of hip fracture in women with vertebral fracture. J Bone Miner
26. Cooper C. The crippling consequences of fractures and their impact on
quality of life. Am J Med. 1997;103(2A):12S-17S.
27. Cauley JA, Thompson DE, Ensrud KC, Scott JC, Black D. Risk of
mortality following clinical fractures. Osteoporos Int. 2000;11:556-561.
28. Ensrud KE, Thompson DE, Cauley JA, et al, Fracture Intervention Trial
Research Group. Prevalent vertebral deformities predict mortality and hospi-
talization in older women with low bone mass. J Am Geriatr Soc. 2000;48:241-