- Email: [email protected]
Alendronate and Vertebral Fracture Risk: In Response
LETTERS TO THE EDITOR
ence is based on the reported 60% reduction in clinical and 43% reduction in radiographic fractures in a subgroup of the Fracture Intervention Trial (FIT). This subgroup was generated by unprespecified post hoc pooling of patients with FN osteopenia with prevalent fracture from FIT I and patients with FN osteopenia without prevalent fracture from FIT II. In patients with FN osteopenia alone, there was no statistically significant reduction in fracture risk (95% confidence intervals overlapped unity; 0.16-1.17 for clinical and 0.381.10 for radiographic vertebral fractures). Even if the relative risks are accepted at face value as “reductions,” Table 1 in their article provides no ranges for spine BMD; therefore, the pooled sample or the subgroups with and without prevalent vertebral fractures may have had spinal osteoporosis masking as osteopenia due to degenerative disease. I would like to ask the following questions: (1) Did the pooled sample and the 2 subgroups have spinal osteoporosis? (2) What was the anti–vertebral fracture efficacy in patients with spinal osteopenia with and without prevalent vertebral fracture? (3) What was the risk reduction for nonvertebral fractures? (4) Among women with the “real thing”—spinal osteopenia alone—what was the number needed to treat to avert 1 fracture? The problem of fracture prevention in osteopenia is a challenge because degenerative disease may mask osteoporosis, the low absolute risk limits the power of studies to detect a real risk reduction, and the large number needed to treat makes the decision to initiate drug treatment difficult. Randomized prospective studies designed to address these challenges in patients with spinal or nonspinal osteopenia are unavailable. Ego Seeman, MD Austin Hospital, University of Melbourne Melbourne, Australia 1. Quandt SA, Thompson DE, Schneider DL, et al, 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. Mayo Clin Proc. 2005;80:343-349.
In reply: Drs Mikhail and Cope raise an interesting statistical issue regarding the principle of reporting P values for subgroup analyses. Unfortunately, this principle is violated in many publications. Our cohort of interest was women with a BMD score between –1.6 and –2.5 at the femoral neck, regardless of fracture status at baseline. The statistical significance, or lack thereof, within the 2 subgroups defined by fracture status (present vs absent) at baseline considered in this article should not change the overall inference to be made from our analysis. Our findings apply equally to patients with or without prevalent vertebral fracture. In such an analysis, the inference within subgroups should focus on the P values for the interaction and not on the P values within the subgroups.1-3 In our analysis, the interaction (baseline fracture status × treatment group) was not significant: P=.44 for clinical vertebral fracture and P=.54 for radiographic vertebral fracture. To elucidate this point, it is easy to conceive of a hypothetical trial in which the overall treatment effect is positive, but inappro1238
Mayo Clin Proc.
•
priate subgroup analyses report nonsignificant findings for 2 subgroups (eg, sex) when analyzed separately. We would arrive at the interesting conclusion that the drug is effective in the whole population but not effective in men or in women! If the treatment effect is independent (statistically) of the subgroup assignment, it is not appropriate to focus on P values within the subgroups. Hence, treatment decisions cannot be broken down into specific subgroups either. Thus, we stand by our conclusion that the effect of alendronate on clinical or radiographic vertebral fracture is independent of fracture status at baseline. To address the second issue, we first need to note that there is no uniform definition of nonvertebral fracture. The most liberal definition (hereafter called definition 1) has been used in alendronate studies4-7 in which nonvertebral fracture was defined as any fracture except a vertebral fracture. The most conservative definition (hereafter called definition 2), which includes only fracture of the hip, clavicle, humerus, wrist, pelvis, or leg, was used in the risedronate studies.8,9 The effect of alendronate on nonvertebral fracture (definition 1) was not statistically significant among patients with existing vertebral fracture.4 When definition 2 of nonvertebral fractures is used, alendronate reduced the risk of nonvertebral fracture by 36% (P=.002). In both cases, the results were not dependent on baseline BMD. Specifically, the study included patients with existing vertebral fracture and T scores between –1.6 and –2.5 at the femoral neck. Among patients without existing vertebral fracture at baseline, we reported an important statistical interaction of the effect of alendronate on nonvertebral fracture using definition 1.6 Thus, we concluded that among patients without existing vertebral fracture, alendronate was effective for those with T scores less than –2.5 but not effective for those with T scores between –1.6 and –2.5. The same is true if definition 2 is used. We also reported5 that alendronate was effective in reducing nonvertebral (definitions 1 and 2) fracture among patients with T scores less than –2.5 and without existing vertebral fracture. Thus, it would not be prudent from a statistical viewpoint to combine subgroups when the responses were different. It is for this very reason, even though the analysis was prespecified, that we have not reported on the effect of alendronate on nonvertebral fracture in any cohort in the FIT study that included patients with T scores between –1.6 and –2.5 from both arms of FIT. However, it is should be noted that in the Fosamax International Trial (FOSIT), which included patients with BMD T scores less than –1.0 at the femoral neck, alendronate reduced the risk of nonvertebral fracture (definition 1) by 47% after 1 year.7 This reduction was independent of baseline BMD. The baseline vertebral fracture status of these patients was not known. To address the questions from Dr Seeman, please note that our study used the T score at the femoral neck to define the cutoff for BMD. However, in clinical practice, the cutoff is based also on the T score from other sites. The standard of care for those who measure BMD by using a central measurement is to measure both spine and hip BMD and to use the lowest values of the sites (spine, hip neck, hip trochanter, or total hip)
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
1237
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
LETTERS TO THE EDITOR
to diagnose osteoporosis. Thus, a patient may have a World Health Organization–defined osteoporotic spine BMD T score of –2.6 and yet have nonosteoporotic hip BMD measurements (eg, T score of –1.8) and be correctly described as “osteoporotic.” In our cohort, in which osteopenia was defined according to the World Health Organization’s definition of a femoral neck BMD T score of –1.6 or less but greater than –2.5, 77% of patients had osteopenic spine. If we used a cohort of patients for whom all T scores (spine, hip neck, or total hip) were greater than –2.5, the findings would be somewhat different. The relative risk (RR) reductions would be 80% (RR, 0.20; 95% confidence interval [CI], 0.05-0.63) and 57% (RR, 0.43; 95% CI, 0.26-0.72) for clinical and radiographic vertebral fracture, respectively. If we limited the cohort to those with spinal osteopenia, then the RR reductions would be 41% (RR, 0.59; 95% CI, 0.32-1.00) and 46% (RR, 0.54; 95% CI, 0.39-0.76) for clinical and radiographic vertebral fracture, respectively. Finally, to address Dr Seeman’s question regarding the computation of a valid number needed to treat, we need a good estimate of the baseline risk. Rates in placebo groups in clinical trials are not surrogates for the true baseline risk for individual patients. Sara A. Quandt, PhD Wake Forest University School of Medicine Winston-Salem, NC Desmond E. Thompson, PhD Merck Research Laboratories Rahway, NJ Diane L. Schneider, MD, MSc University of California San Diego Michael C. Nevitt, PhD, MPH University of California San Francisco 1. Pocock SJ, Hughes MD, Lee RJ. Statistical problems in the reporting of clinical trials: a survey of three medical journals. N Engl J Med. 1987;317:426432. 2. Peto R. Misleading subgroup analyses in GISSI [letter]. Am J Cardiol. 1990;66:771-772. 3. Brookes ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials: risk of subgroup-specific analyses: power and sample size for the interaction test. J Clin Epidemiol. 2004;57:229236. 4. 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;348:1535-1541. 5. Black DM, Thompson DE, Bauer DC, et al, FIT Research Group. Fracture 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. 6. Cummings SR, Black DM, Thompson DE, et al, Fracture Intervention Trial Research Group. 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;280:2077-2082. 7. Pols HA, Felsenberg D, Hanley DA, et al, Foxamax International Trial Study Group. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women
1238 1240
Mayo Clin Proc.
•
with low bone mass: results of the FOSIT study. Osteoporos Int. 1999;9:461468. 8. Harris ST, Watts NB, Genant HK, et al, Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA. 1999;282:1344-1352. 9. Reginster J, Minne HW, Sorensen OH, et al, Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int. 2000;11:83-91.
Dietary Supplements and Stroke To the Editor: I read with interest the case reported by McDonald and Lane1 on dietary supplements and stroke, published in the March 2005 issue of the Mayo Clinic Proceedings. I wish to report a case of thalamic infarction that occurred in a healthy, young adult during prolonged and excessive use of Eleutherococcus senticosus (ES) (Siberian ginseng, ciwuja) supplements. Report of a Case. A 26-year-old man presented for evaluation of persistent left-sided numbness, which began the previous night, along with a severe headache and diplopia, which resolved subsequently. Non–contrast-enhanced computed tomography of the head showed a hypodense area in the right basal ganglia, suggestive of ischemic stroke. Magnetic resonance imaging (MRI) with MR angiography confirmed acute infarction of the right thalamus and showed no evidence of vascular abnormality. The patient had been training vigorously for a marathon. To enhance his performance, he had used various ES preparations daily for the past year in the form of high-energy drinks, energy capsules, and power gels containing both ES and small amounts of caffeine (Endurox R4, Endurox Excel caplets and tablets [Pacific Health Laboratories, Inc, Matawan, NJ]; the approximate daily dose of ES extract, 1500-2000 mg along with about 50-100 mg of caffeine). The patient’s exercise regimen had consisted of a high-intensity aerobic workout and weight lifting for 2 hours per day at least 5 to 7 days per week. He was a nonsmoker, did not drink alcohol, and used no recreational drugs. Extensive evaluation (2-dimensional echocardiography, transesophageal echocardiography, telemetry monitoring for 48 hours, and hypercoagulable state work-up including protein C, protein S, antithrombin III, antiphospholipid antibodies, lupus anticoagulant, resistance to activated protein C, homocysteine, lipid profile, antinuclear antibodies, erythrocyte sedimentation rate, VDRL test, Lyme disease serology, and urine and serum toxicology screen) failed to reveal the etiology of the patient’s stroke. There was no personal or family history of hypertension, migraine headache, or stroke. The patient denied use of any other over-the-counter or prescription medicine. Repeated MRI in 6 months showed persistence of abnormal signal in the right thalamus. The patient continues to take aspirin and has minimal residual numbness of the left side of his body. Discussion. E senticosus is a popular herbal product used to improve physical stamina and enhance the immune system.
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
ence is based on the reported 60% reduction in clinical and 43% reduction in radiographic fractures in a subgroup of the Fracture Intervention Trial (FIT). This subgroup was generated by unprespecified post hoc pooling of patients with FN osteopenia with prevalent fracture from FIT I and patients with FN osteopenia without prevalent fracture from FIT II. In patients with FN osteopenia alone, there was no statistically significant reduction in fracture risk (95% confidence intervals overlapped unity; 0.16-1.17 for clinical and 0.381.10 for radiographic vertebral fractures). Even if the relative risks are accepted at face value as “reductions,” Table 1 in their article provides no ranges for spine BMD; therefore, the pooled sample or the subgroups with and without prevalent vertebral fractures may have had spinal osteoporosis masking as osteopenia due to degenerative disease. I would like to ask the following questions: (1) Did the pooled sample and the 2 subgroups have spinal osteoporosis? (2) What was the anti–vertebral fracture efficacy in patients with spinal osteopenia with and without prevalent vertebral fracture? (3) What was the risk reduction for nonvertebral fractures? (4) Among women with the “real thing”—spinal osteopenia alone—what was the number needed to treat to avert 1 fracture? The problem of fracture prevention in osteopenia is a challenge because degenerative disease may mask osteoporosis, the low absolute risk limits the power of studies to detect a real risk reduction, and the large number needed to treat makes the decision to initiate drug treatment difficult. Randomized prospective studies designed to address these challenges in patients with spinal or nonspinal osteopenia are unavailable. Ego Seeman, MD Austin Hospital, University of Melbourne Melbourne, Australia 1. Quandt SA, Thompson DE, Schneider DL, et al, 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. Mayo Clin Proc. 2005;80:343-349.
In reply: Drs Mikhail and Cope raise an interesting statistical issue regarding the principle of reporting P values for subgroup analyses. Unfortunately, this principle is violated in many publications. Our cohort of interest was women with a BMD score between –1.6 and –2.5 at the femoral neck, regardless of fracture status at baseline. The statistical significance, or lack thereof, within the 2 subgroups defined by fracture status (present vs absent) at baseline considered in this article should not change the overall inference to be made from our analysis. Our findings apply equally to patients with or without prevalent vertebral fracture. In such an analysis, the inference within subgroups should focus on the P values for the interaction and not on the P values within the subgroups.1-3 In our analysis, the interaction (baseline fracture status × treatment group) was not significant: P=.44 for clinical vertebral fracture and P=.54 for radiographic vertebral fracture. To elucidate this point, it is easy to conceive of a hypothetical trial in which the overall treatment effect is positive, but inappro1238
Mayo Clin Proc.
•
priate subgroup analyses report nonsignificant findings for 2 subgroups (eg, sex) when analyzed separately. We would arrive at the interesting conclusion that the drug is effective in the whole population but not effective in men or in women! If the treatment effect is independent (statistically) of the subgroup assignment, it is not appropriate to focus on P values within the subgroups. Hence, treatment decisions cannot be broken down into specific subgroups either. Thus, we stand by our conclusion that the effect of alendronate on clinical or radiographic vertebral fracture is independent of fracture status at baseline. To address the second issue, we first need to note that there is no uniform definition of nonvertebral fracture. The most liberal definition (hereafter called definition 1) has been used in alendronate studies4-7 in which nonvertebral fracture was defined as any fracture except a vertebral fracture. The most conservative definition (hereafter called definition 2), which includes only fracture of the hip, clavicle, humerus, wrist, pelvis, or leg, was used in the risedronate studies.8,9 The effect of alendronate on nonvertebral fracture (definition 1) was not statistically significant among patients with existing vertebral fracture.4 When definition 2 of nonvertebral fractures is used, alendronate reduced the risk of nonvertebral fracture by 36% (P=.002). In both cases, the results were not dependent on baseline BMD. Specifically, the study included patients with existing vertebral fracture and T scores between –1.6 and –2.5 at the femoral neck. Among patients without existing vertebral fracture at baseline, we reported an important statistical interaction of the effect of alendronate on nonvertebral fracture using definition 1.6 Thus, we concluded that among patients without existing vertebral fracture, alendronate was effective for those with T scores less than –2.5 but not effective for those with T scores between –1.6 and –2.5. The same is true if definition 2 is used. We also reported5 that alendronate was effective in reducing nonvertebral (definitions 1 and 2) fracture among patients with T scores less than –2.5 and without existing vertebral fracture. Thus, it would not be prudent from a statistical viewpoint to combine subgroups when the responses were different. It is for this very reason, even though the analysis was prespecified, that we have not reported on the effect of alendronate on nonvertebral fracture in any cohort in the FIT study that included patients with T scores between –1.6 and –2.5 from both arms of FIT. However, it is should be noted that in the Fosamax International Trial (FOSIT), which included patients with BMD T scores less than –1.0 at the femoral neck, alendronate reduced the risk of nonvertebral fracture (definition 1) by 47% after 1 year.7 This reduction was independent of baseline BMD. The baseline vertebral fracture status of these patients was not known. To address the questions from Dr Seeman, please note that our study used the T score at the femoral neck to define the cutoff for BMD. However, in clinical practice, the cutoff is based also on the T score from other sites. The standard of care for those who measure BMD by using a central measurement is to measure both spine and hip BMD and to use the lowest values of the sites (spine, hip neck, hip trochanter, or total hip)
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
1237
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
LETTERS TO THE EDITOR
to diagnose osteoporosis. Thus, a patient may have a World Health Organization–defined osteoporotic spine BMD T score of –2.6 and yet have nonosteoporotic hip BMD measurements (eg, T score of –1.8) and be correctly described as “osteoporotic.” In our cohort, in which osteopenia was defined according to the World Health Organization’s definition of a femoral neck BMD T score of –1.6 or less but greater than –2.5, 77% of patients had osteopenic spine. If we used a cohort of patients for whom all T scores (spine, hip neck, or total hip) were greater than –2.5, the findings would be somewhat different. The relative risk (RR) reductions would be 80% (RR, 0.20; 95% confidence interval [CI], 0.05-0.63) and 57% (RR, 0.43; 95% CI, 0.26-0.72) for clinical and radiographic vertebral fracture, respectively. If we limited the cohort to those with spinal osteopenia, then the RR reductions would be 41% (RR, 0.59; 95% CI, 0.32-1.00) and 46% (RR, 0.54; 95% CI, 0.39-0.76) for clinical and radiographic vertebral fracture, respectively. Finally, to address Dr Seeman’s question regarding the computation of a valid number needed to treat, we need a good estimate of the baseline risk. Rates in placebo groups in clinical trials are not surrogates for the true baseline risk for individual patients. Sara A. Quandt, PhD Wake Forest University School of Medicine Winston-Salem, NC Desmond E. Thompson, PhD Merck Research Laboratories Rahway, NJ Diane L. Schneider, MD, MSc University of California San Diego Michael C. Nevitt, PhD, MPH University of California San Francisco 1. Pocock SJ, Hughes MD, Lee RJ. Statistical problems in the reporting of clinical trials: a survey of three medical journals. N Engl J Med. 1987;317:426432. 2. Peto R. Misleading subgroup analyses in GISSI [letter]. Am J Cardiol. 1990;66:771-772. 3. Brookes ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials: risk of subgroup-specific analyses: power and sample size for the interaction test. J Clin Epidemiol. 2004;57:229236. 4. 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;348:1535-1541. 5. Black DM, Thompson DE, Bauer DC, et al, FIT Research Group. Fracture 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. 6. Cummings SR, Black DM, Thompson DE, et al, Fracture Intervention Trial Research Group. 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;280:2077-2082. 7. Pols HA, Felsenberg D, Hanley DA, et al, Foxamax International Trial Study Group. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women
1238 1240
Mayo Clin Proc.
•
with low bone mass: results of the FOSIT study. Osteoporos Int. 1999;9:461468. 8. Harris ST, Watts NB, Genant HK, et al, Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA. 1999;282:1344-1352. 9. Reginster J, Minne HW, Sorensen OH, et al, Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int. 2000;11:83-91.
Dietary Supplements and Stroke To the Editor: I read with interest the case reported by McDonald and Lane1 on dietary supplements and stroke, published in the March 2005 issue of the Mayo Clinic Proceedings. I wish to report a case of thalamic infarction that occurred in a healthy, young adult during prolonged and excessive use of Eleutherococcus senticosus (ES) (Siberian ginseng, ciwuja) supplements. Report of a Case. A 26-year-old man presented for evaluation of persistent left-sided numbness, which began the previous night, along with a severe headache and diplopia, which resolved subsequently. Non–contrast-enhanced computed tomography of the head showed a hypodense area in the right basal ganglia, suggestive of ischemic stroke. Magnetic resonance imaging (MRI) with MR angiography confirmed acute infarction of the right thalamus and showed no evidence of vascular abnormality. The patient had been training vigorously for a marathon. To enhance his performance, he had used various ES preparations daily for the past year in the form of high-energy drinks, energy capsules, and power gels containing both ES and small amounts of caffeine (Endurox R4, Endurox Excel caplets and tablets [Pacific Health Laboratories, Inc, Matawan, NJ]; the approximate daily dose of ES extract, 1500-2000 mg along with about 50-100 mg of caffeine). The patient’s exercise regimen had consisted of a high-intensity aerobic workout and weight lifting for 2 hours per day at least 5 to 7 days per week. He was a nonsmoker, did not drink alcohol, and used no recreational drugs. Extensive evaluation (2-dimensional echocardiography, transesophageal echocardiography, telemetry monitoring for 48 hours, and hypercoagulable state work-up including protein C, protein S, antithrombin III, antiphospholipid antibodies, lupus anticoagulant, resistance to activated protein C, homocysteine, lipid profile, antinuclear antibodies, erythrocyte sedimentation rate, VDRL test, Lyme disease serology, and urine and serum toxicology screen) failed to reveal the etiology of the patient’s stroke. There was no personal or family history of hypertension, migraine headache, or stroke. The patient denied use of any other over-the-counter or prescription medicine. Repeated MRI in 6 months showed persistence of abnormal signal in the right thalamus. The patient continues to take aspirin and has minimal residual numbness of the left side of his body. Discussion. E senticosus is a popular herbal product used to improve physical stamina and enhance the immune system.
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.