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Original Investigation |

Effect of Alendronate on Limited-Activity Days and Bed-Disability Days Caused by Back Pain in Postmenopausal Women With Existing Vertebral Fractures FREE

Michael C. Nevitt, PhD, MPH; Desmond E. Thompson, PhD; Dennis M. Black, PhD; S. R. Rubin, MPH; Kris Ensrud, MD, MPH; A. John Yates, MD; Steven R. Cummings, MD ; for the Fracture Intervention Trial Research Group
[+] Author Affiliations

From the Departments of Epidemiology and Biostatistics (Drs Nevitt, Black, and Cummings and Ms Rubin) and Medicine (Dr Cummings), University of California, San Francisco; Scientific Communications Group (Dr Thompson) and Clinical Research (Dr Yates), Merck & Co, Rahway, NJ; and Department of Medicine, Veterans Affairs Medical Center, University of Minnesota, Minneapolis (Dr Ensrud).


Arch Intern Med. 2000;160(1):77-85. doi:10.1001/archinte.160.1.77.
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Published online

Background  Women with new vertebral fractures have an increased risk of back pain and functional limitation because of back pain. Alendronate sodium treatment reduces the risk of new vertebral fracture by 50% in postmenopausal women with osteoporosis.

Objective  To determine the effect of alendronate therapy on days affected by back pain in postmenopausal women with existing vertebral fractures.

Design  Three-year, placebo-controlled, randomized, double-blind study.

Setting  Fifteen university-based research clinics in the United States.

Participants  A total of 2027 postmenopausal women aged 55 to 81 years with low femoral neck bone density and a preexisting vertebral fracture.

Intervention  Alendronate sodium (5 mg/d for 2 years and 10 mg/d for the third year) or placebo.

Main Outcome Measures  Occurrence and severity of back pain, number of days with back pain, and number of days of bed rest or limited activity because of back pain during 3 years of follow-up.

Results  Irrespective of treatment assignment, women with new, clinically recognized vertebral fractures during follow-up had an increased risk of days of bed disability and days of limited activity because of back pain after the fracture. Women receiving alendronate reported an average of 3.2 fewer days of bed rest (P = .001) and 11.4 fewer days of limited activity (not including days of bed rest) because of back pain (P = .04) during follow-up than those receiving placebo. In the alendronate group, relative to the placebo group, there was a reduced risk of 1 or more bed-rest days (relative risk, 0.68; 95% confidence interval, 0.53-0.87), of 7 or more bed-rest days (0.44; 0.30-0.64), and of 7 or more limited-activity days (0.87; 0.76-0.99). There were no statistically significant differences between treatment groups in the frequency of days of back pain or increases in back-related disability between baseline and study end.

Conclusion  In postmenopausal women with preexisting vertebral fracture, alendronate therapy for 3 years reduced the number of days of bed disability and days of limited activity caused by back pain.

Figures in this Article

OSTEOPOROSIS IS a common disorder that results in millions of fractures and a substantial burden in health care costs and disability among older women.1 Vertebral fractures are the most common osteoporotic fracture: 5% of 50-year-old white women and 25% of 80-year-old white women have at least 1 prevalent vertebral fracture.2 The rate of new vertebral fracture is less than 0.5% per year in 50-year-old white women, 2% to 3% per year in 80-year-old white women,3 and 3 to 4 times higher in women with an existing vertebral fracture than in those without fracture.4

Women with new vertebral fractures have an increased risk of back pain and functional limitation because of back pain.5,6 Nevitt and colleagues5 found that, among women who had a preexisting vertebral fracture, new vertebral fractures during a 4-year period were associated with increases in back pain, physical disability caused by back pain, and number of days of bed rest and limited activity because of back pain assessed periodically during the same interval. However, because the acute pain of new vertebral fracture is usually transient, resolving within a few weeks to a few months, women with older vertebral fractures may not have greater back pain or disability than women without fractures.5,6 Osteoporosis treatments that reduce the incidence of new vertebral fractures may also reduce the occurrence of episodes of back pain and activity limitation caused by back pain in women with osteoporosis. However, to our knowledge, this has not been demonstrated in clinical trials of osteoporosis treatment.

Black et al7 previously reported results from the Fracture Intervention Trial demonstrating that, in postmenopausal women with low bone mass and an existing vertebral fracture, treatment with the bisphosphonate alendronate sodium, a potent antiresorptive agent that increases bone mineral density, resulted in a 55% reduction in the risk of new symptomatic clinical vertebral fracture and a 47% reduction in the risk of morphometric vertebral fracture as assessed by measurement of vertebral heights on serial radiographs. The present analysis uses data from the same randomized trial to determine whether alendronate therapy reduces back pain and days of functional limitation caused by back pain in postmenopausal women with osteoporosis.

PATIENTS

Details of recruitment and inclusion criteria for the Fracture Intervention Trial have been previously published.7,8 The trial was conducted at 11 clinical centers in the United States. Subjects were recruited primarily via mass mailings to age-eligible women. All women in the Fracture Intervention Trial were between the ages of 55 and 81 years at baseline, had been postmenopausal for at least 2 years, and had a femoral neck bone mineral density (BMD) of 0.68 g/cm2 or less (measured by dual-energy x-ray absorptiometry [QDR2000; Hologic, Waltham, Mass]) or 1.6 or more SDs below the normal mean of young persons for the US population.9 The study was carried out as 2 separate studies in women with and without vertebral fractures on x-ray films at baseline. This report concerns results from 2027 women with at least 1 vertebral fracture at baseline who were enrolled in the vertebral fracture arm. These women were randomized to receive alendronate sodium (5 mg/d for 2 years and 10 mg/d for the third year) or placebo. Treatment and follow-up continued for a total of 3 years.

BACK PAIN AND FUNCTIONAL MEASURES

Outcome measures were assessed by means of a previously described questionnaire5,10 that asked about back pain and the number of days of limited activity caused by back pain. Every 3 months we asked participants, "Have you had any back pain since your last clinic visit, about 3 months ago?" Those who answered "yes" were asked how many days they had back pain and, when they had back pain, how severe it was on average, with response categories ranging from "very mild" to "very severe." In addition, women who reported back pain were asked, "Because of back pain or back problems, did you cut down on the things that you usually do, such as going to work or working around the house?" Women who reported cutting down on activities were asked, "On how many days did you cut down on the things that you usually do because of back pain or back problems, not including days spent in bed?" They were also asked, "How many days did you stay in bed more than half the day because of back pain or back problems?" These questions were adapted from previous national health survey questionnaires designed to assess days of limited activity caused by health conditions.11,12

Physical disability related to back pain was assessed at the baseline visit and at the closeout visit only. Women were asked about the degree of difficulty (0-3 scale, with 0 indicating no difficulty and 3, unable to do) in 6 activities that involve the back (bending, lifting, reaching, putting on socks and shoes, transfer, and standing).5,10 Women who reported "much difficulty" or were "unable" in 1 or more activity because of back pain at closeout but not at baseline were categorized as having developed new disability. For women with disability at baseline, an increase of 3 points on the composite score (range, 0-18) was considered a worsening of disability during follow-up.5

ASSESSMENT OF VERTEBRAL FRACTURE

Methods for assessment of vertebral fractures in the Fracture Intervention Trial have been described.7,8 Briefly, lateral radiographs were obtained at baseline and 36 months after randomization. We assessed prevalent and incident radiographic fractures by means of quantitative vertebral morphometry. A woman was classified as having a baseline prevalent fracture if any of the ratios of vertebral heights (anterior-posterior, middle-posterior, or posterior–adjacent posterior and anterior–adjacent anterior) were more than 3 SDs below the mean population norm for that vertebral level.13,14 New (incident) radiographic vertebral fractures were defined as a decrease of 20% and at least 4 mm in any vertebral height from baseline to follow-up. Incident radiographic fractures were confirmed by the study radiologist. New (incident) clinical vertebral fractures were defined as those that came to medical attention and were reported to the clinic by the participants. To confirm the clinical diagnosis of a new vertebral fracture, a copy of the radiograph obtained by the patient's physician was compared with the baseline study radiograph by the study radiologist using a semiquantitative reading.15 Among women with a confirmed new clinical fracture, 73% were also classified as having a new morphometric fracture.

ANALYSIS

Days of back pain, limited-activity days, and bed-rest days because of back pain reported at each follow-up contact were summed during the entire follow-up period. For missing visits, these values were assigned as 0. For days of back pain, we summed the number of days on which back pain was reported to be moderate to very severe and, in a separate measure, the number of days on which the pain was considered to be severe or very severe. We categorized women by the total number of days affected by back pain during follow-up: for days of bed-rest because of back pain, none vs 1 or more days, and, for days of back pain, days of limited activity, and days of bed rest because of back pain, less than 7 days vs 7 or more days. We also calculated the cumulative incidence of women who were categorized as reaching the above thresholds for total number of days affected on each measure by the end of each 3-month follow-up period.

To evaluate the association of new clinical vertebral fracture during follow-up with the number of days affected by back pain, we divided each participant's time at risk into the period before and the period after the date of the first new clinical vertebral fracture. Women without a new clinical vertebral fracture contributed time at risk only to the prefracture period. For the prefracture and postfracture time at risk, we calculated the time to occurrence, and the number of women per 100 person-years of follow-up, for each end point: 7 or more days of back pain (moderate or worse, and severe or worse pain); 7 or more limited-activity days; 1 or more bed-rest days; and 7 or more bed-rest days. The association of new clinical vertebral fracture with time to occurrence of each end point was analyzed in a proportional hazards model with clinical vertebral fracture as a time-dependent covariate. This method was fully described by Crowley and Hu.16

To compute the adjusted relative risk (RR), we included the following variables in the time-dependent proportional hazards model: age, health status, previous back pain, smoking, hip BMD, history of previous fracture, and treatment group. Age and hip BMD were used as continuous variables. Health status (good or better vs fair or poor), previous back pain (none vs any), smoking (current or former vs never), history of previous fracture (yes since age 45 years vs no), and treatment group (alendronate vs placebo) were treated as categorical variables. Since women who suffered a new clinical vertebral fracture may have differed on other correlates of back pain for which we did not adjust, we assessed the potential for residual confounding by comparing the prefracture and postfracture experience of women who had fractures.

We analyzed the effect of treatment on back pain–related outcomes by means of survival analysis techniques to compare the cumulative incidence of women reporting 7 or more days of back pain, 7 or more limited-activity days, 1 or more bed-rest days, and 7 or more bed-rest days between the alendronate and placebo groups. Relative hazards for incidence comparisons were derived from a proportional hazards model by the likelihood ratio method. We assessed significance of treatment group differences by the log-rank method. We also compared the mean number of days affected by back pain in the alendronate and placebo groups. We assessed group differences by the Wilcoxon rank sum test, which takes into account the skewed distribution of the number of days. We confirmed the results by means of parametric tests in models in which data were transformed to stabilize variance. Statistical significance was defined as P<.05 (global change), 2 sided. We analyzed the proportion of women with new or worsened disability with the RR, calculated as the proportion of women with the outcome in the alendronate group compared with the placebo group. We used the Mantel-Haenszel χ2 statistic to test the significance of differences between groups.

To determine whether any differences in back pain outcomes between treatment groups could be explained by a reduction in the incidence of new vertebral fractures in the alendronate group, we also analyzed the association of treatment with time to 7 or more limited-activity days and time to 1 or more, and 7 or more, bed-rest days in proportional hazards models adjusting for the number of new morphometric fractures and number of new clinical vertebral fractures during follow-up. Because the occurrence of fractures during follow-up is probably associated with baseline covariates of the back pain outcomes, we first analyzed the effect of treatment on outcomes with adjustment for these covariates, including baseline back pain, number of days of bed rest and days of limited activity because of back pain in the preceding year, age, lumbar spine BMD, weight, health status, smoking, and number of prevalent vertebral fractures. Adjustment for these covariates did not alter estimates of the effect of alendronate treatment on back pain outcomes. The covariate-adjusted models were then repeated with inclusion of the variables for new vertebral fractures during follow-up.

BASELINE CHARACTERISTICS

A total of 2027 postmenopausal women were randomized to double-blind treatment with alendronate (1022) or placebo (1005). Alendronate and placebo groups were balanced on important baseline characteristics, including those that might affect back pain and functional limitation, such as age, health status, prevalent back pain, and bed-rest days and limited-activity days because of back pain in the year before the study (Table 1). The participant population was mostly white (97.8%), with a mean age of 71 years. Mean lumbar spinal BMD was 0.79 g/cm2 in both groups.

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Patient Population by Treatment Group*
DAYS AFFECTED BY BACK PAIN DURING FOLLOW-UP

Back pain and its consequences during follow-up were very common regardless of whether women experienced a new clinical or morphometric vertebral fracture by the end of the study (Table 2). For example, among those who did not have any new vertebral fractures, nearly two thirds (64.2%) reported at least 7 days of moderate or worse back pain, while more than one third (36.8%) had 7 or more days of limited activity. Among women who had at least 1 new morphometric vertebral fracture by the end of the study, the vast majority reported at least 7 days of moderate to severe back pain (90.6%) and at least 7 days of limited activity because of back pain (76.2%), while more than half (55.6%) had 7 or more days of severe or worse back pain, and a quarter (26.9%) had 7 or more days of bed rest because of back pain. As expected, women with a new clinically recognized vertebral fracture had a very high frequency of days affected by back pain; for example, more than half (52.7%) reported 7 or more days of bed rest.

Table Graphic Jump LocationTable 2. Frequency of Back Pain and Its Effects Observed Among Women During Follow-up Period (3 Years) by Vertebral Fracture Status at the End of the Study
DAYS AFFECTED BY BACK PAIN BEFORE AND AFTER A NEW CLINICAL VERTEBRAL FRACTURE

Despite the very high background levels of back problems among participants, the incidence of days of limited activity and bed rest caused by back pain was significantly increased in the period after a new clinical vertebral fracture, as compared with the period before a clinical vertebral fracture (Table 3). This increase was similar in women receiving alendronate and those receiving placebo (data not shown). The incidence of 7 or more limited-activity days and 7 or more bed-rest days increased sharply immediately after a clinical vertebral fracture (Figure 1). By 3 months after a new fracture, about 30% of women had experienced 7 or more bed-rest days and about 80% had 7 or more limited-activity days. Relative risks were somewhat reduced but still indicated a large effect of new fractures, when we compared the rate of events in the same women before and after they experienced a clinical vertebral fracture. For example, the RR of 7 or more limited-activity days after fracture (vs before fracture) was 6.8 (95% confidence interval [CI], 3.9-11.1) and for 7 or more bed-rest days was 17.8 (95% CI, 6.8-46.3).

Table Graphic Jump LocationTable 3. Incidence and Relative Risk of Women With 7 Days of More of Back Pain, Activity Limitation, and Bed-Rest Days Because of Back Pain, per 100 Person-years, Before and After Occurrence of a Clinical Vertebral Fracture, Irrespective of Treatment Allocation (Alendronate Sodium or Placebo)
Place holder to copy figure label and caption
Figure 1.

Cumulative incidence of women experiencing 7 or more days of bed rest (top) and 7 or more days of limited activity (bottom) in the periods before and after the occurrence of a clinical vertebral fracture. The prefracture period includes time at risk among women who did not have a clinical vertebral fracture.

Graphic Jump Location
TREATMENT GROUP COMPARISONS

Women in the alendronate-treated group had 63% fewer bed-rest days because of back pain compared with those in the placebo group (Table 4). By the end of follow-up, the cumulative incidence of women with at least 1 day of bed rest was significantly lower in the alendronate group than in the placebo group (Figure 2, top). At each time point during follow-up, the percentage of patients having reported at least 1 day of bed rest was consistently lower in the alendronate group than in the placebo group (data not shown). The effect of alendronate therapy was even more pronounced for the cumulative incidence of 7 or more days of bed rest: 4.2% of women receiving alendronate reported this more severe degree of functional limitation, compared with 8.7% of women receiving placebo (Figure 2, bottom).

Table Graphic Jump LocationTable 4. Back Pain Outcomes by Treatment Group
Place holder to copy figure label and caption
Figure 2.

Cumulative incidence of patients reporting 1 or more (top) and 7 or more (bottom) bed-rest days, by treatment group. Relative risk (RR) and 95% confidence interval (in parentheses) were estimated from a proportional hazards model.

Graphic Jump Location

The mean number of days of limited activity because of back pain (not including bed-rest days) was 16% less (P = .04) in the alendronate group than in the placebo group (Table 4). The difference in cumulative incidence at 3 years of women who reported 7 or more days of limited activity in the alendronate group compared with the placebo group was marginally significant (RR, 0.87; 95% CI, 0.76-0.99; P = .06; Figure 3).

Place holder to copy figure label and caption
Figure 3.

Cumulative incidence of patients reporting 7 or more limited-activity days, by treatment group. Relative risk (RR) and 95% confidence interval (in parentheses) were estimated from a proportional hazards model.

Graphic Jump Location

The mean numbers of days with any back pain (265 and 271 in the alendronate and placebo groups, respectively) and moderate or worse back pain (Table 4) were similar between the 2 treatment groups. The cumulative incidences of 7 or more days of moderate or worse and 7 or more days of severe or worse back pain were also similar between the 2 groups (RR, 0.96; 95% CI, 0.86-1.06; and RR, 0.89; 95% CI, 0.74-1.06, respectively). However, the mean number (Table 4) and cumulative incidence of any days of severe or worse back pain (Figure 4) were somewhat less (P = .07 for both) among patients treated with alendronate than among those treated with placebo.

Place holder to copy figure label and caption
Figure 4.

Cumulative incidence of patients reporting 1 or more days of severe or worse back pain, by treatment group. Relative risk (RR) and 95% confidence interval (in parentheses) were estimated from a proportional hazards model.

Graphic Jump Location

Of the 1843 women with complete data on the back disability measure, 156 (8.5%) had either new or worsened disability at the closeout visit. Of women taking alendronate, 7.8% had new or worsened disability compared with 9.2% of women taking placebo (RR, 0.85; 95% CI, 0.63-1.15; P = .29). There were no significant differences between treatment groups for change in disability score from baseline to study end (data not shown).

The RRs for back pain end points in alendronate vs placebo groups were not altered when we excluded women who had experienced the specific end point (for example, 7 or more days of bed rest because of back pain) in the 12 months before randomization.

The RRs for back pain end points in alendronate vs placebo groups were reduced (namely, closer to 1.0) in proportional hazards models that adjusted for the number of new vertebral fractures during follow-up. Adjusting for new clinical vertebral fractures reduced (RR, 0.92; 95% CI, 0.80-1.06), and adjusting for new radiographic fractures nearly eliminated (RR, 0.97; 95% CI, 0.84-1.12), the treatment effect for 7 or more limited-activity days. In contrast, the RRs for 7 or more bed-rest days by treatment group were also reduced after adjustment for new clinical fractures (RR, 0.52; 95% CI, 0.36-0.78) or new radiographic fractures (RR, 0.57; 96% CI, 0.39-0.86), but women receiving alendronate still had a lower risk of these outcomes. Caution must be exercised in interpreting these adjusted analyses, since the variables (new clinical vertebral fracture and new radiographic vertebral fracture) adjusted for may have occurred after the events (occurrence of bed-rest days or limited-activity days) of interest.

Previously published results from the Fracture Intervention Trial7 and other randomized trials of alendronate17 have demonstrated that long-term therapy with alendronate reduces the rate of vertebral fracture in postmenopausal women by approximately 50%. In the present analysis of data from the Fracture Intervention Trial, we found that, in addition to experiencing fewer vertebral fractures, postmenopausal women with preexisting vertebral fractures randomized to alendronate reported fewer days affected by back pain (days of bed rest and limited activity) than those receiving placebo. In the alendronate group, relative to the placebo group, the incidence of 1 or more bed-rest days was reduced by 32%, that of 7 or more bed-rest days by 56%, and that of 7 or more limited-activity days by 13%. Alendronate therapy reduced the mean reported number of bed-rest days by 63% (from 5.1 to 1.9 days) and mean number of limited-activity days (not including days in bed) by 16% (from 73.2 to 61.8 days). There were no statistically significant differences between treatment groups in the occurrence of days of back pain, although the occurrence of severe or worse back pain was somewhat lower in the alendronate-treated group than in the placebo group. We did not find a significant difference in the proportion of women with new or worsened back-related physical disability at the study end.

All women in this study had at least 1 preexisting vertebral fracture at baseline, and back pain and back problems were extremely common during follow-up. This is illustrated by the high proportion of women with 7 or more days of moderate or worse back pain and 7 or more days of activity limitation because of back pain, even among those who did not have a new vertebral fracture during the study. Since a probable mechanism by which alendronate treatment affects the risk of back problems is a reduction in the incidence of new vertebral fractures, the high frequency of back problems in women who do not have a new fracture may make it more difficult to discern an effect of treatment on end points related to back pain. On the other hand, even with these high background levels of back problems, the incidence of days affected by back pain increased sharply in the period immediately after a clinical vertebral fracture as compared with the prefracture period. This is consistent with a previous study demonstrating that, among women with preexisting vertebral fractures, new vertebral fractures detected by radiography are associated with increases in back pain, physical disability, and days of bed rest and limited activity because of back pain.5

Despite a high background rate of back problems among women in the study, and the fact that there are numerous causes of back problems in addition to vertebral fractures,18 we found that alendronate treatment reduced the occurrence of days affected by back pain. The reduction was greater for the more severe and less frequent event, days in bed because of back pain, than for the less severe and more common events, limited-activity days and days with back pain. This suggests that, in older women, days of bed rest because of back pain are a relatively specific outcome of new, painful vertebral fractures. This is supported by the finding in this study of a greater increase in risk of bed-rest days, compared with limited-activity days or days of back pain, after a clinically diagnosed vertebral fracture and by a previous study showing a stronger association of days of bed rest with new radiographic vertebral fractures.5 It is also consistent with the frequent use of bed rest in the treatment of painful vertebral fractures.19 In addition, it is possible that bed-rest days are recalled more accurately and assessed more reliably than days of back pain or days of limited activity. Treatment effects would tend to be underestimated for measures with greater random error.

OUR RESULTS suggest that the effect of alendronate on days affected by back pain is explained, at least in part, by the 50% reduction in the occurrence of new vertebral fractures among women receiving alendronate in this study. Twenty-seven fewer women in the alendronate group than the placebo group had a clinically diagnosed vertebral fracture; these fractures are sufficiently painful for the participant to seek medical care. Prevention of painful vertebral fractures that did not come to medical attention may also account for some of the observed treatment effect.5 In multivariate analyses, adjusting for the number of new vertebral fractures during follow-up accounted for most of the treatment group difference for limited-activity days. Whether the reduced number of new fractures among women receiving alendronate accounts for most of the average of 3.2 fewer days of bed rest per participant during the study (more than 3000 fewer days overall) compared with placebo is uncertain. In analyses adjusting for the number of new vertebral fractures during follow-up, a significant effect of alendronate treatment on days of bed rest remained. There are several potential explanations for this finding. The reduced occurrence of nonvertebral fracture among women taking alendronate7 may have influenced the decision to treat back pain with bed rest. Mild fractures and endplate deformities not detected by our morphometry methods may cause back pain and be prevented by alendronate. Mechanical overloading of weakened bone in women with severe osteoporosis may contribute to back pain19 and may be prevented by treatment that strengthens bone. Osteoarthritis of the facet joints and spinal disk degeneration both involve periarticular bone reaction, which may contribute to back pain20; antiresorptive agents may reduce the bone reaction in osteoarthritis.21 There are no known central nervous system–mediated analgesic effects of alendronate.22 However, bisphosphonates are known to relieve bone pain in high turnover disorders, such as Paget disease. In addition, a 12-month, randomized but nonblinded trial in women with existing vertebral fractures showed a reduction in back pain after treatment with intravenous alendronate.23

Several aspects of our study deserve comment. While back pain is very common in older women, by comparison, new vertebral fractures are relatively uncommon during the time span of a few years. Our study was large enough, and the risk of new vertebral fracture was high enough, to demonstrate a beneficial effect on activity limitation and bed disability caused by back pain for a treatment that prevents vertebral fractures. To our knowledge, this is the first randomized, double-blind fracture prevention trial to do so. Several studies suggest that salcatonin may have an analgesic effect in women with acute back pain of vertebral fracture.24,25 We assessed days affected by back pain every 3 months, which increased sensitivity to the transient impact of fracture and enhanced the ability of participants to report accurately. The dramatic increase in the risk of days affected by back pain after a clinical vertebral fracture, and the reduced risk of these outcomes from preventing vertebral fractures, lend further support to the view that vertebral osteoporosis is an important cause of back pain and back problems in older women.

Our study has several limitations. Our results may not be generalizable to women without a vertebral fracture or other populations with a lower risk of vertebral fracture. Our results may not be generalizable to other effective treatments for osteoporosis, although it seems likely that other antiresorptive agents that prevent new vertebral fractures would also reduce limitations caused by back pain. Women receiving active treatment in the Fracture Intervention Trial received 5 mg of alendronate sodium per day for the first 2 years and 10 mg per day during the third year. Other studies suggest that a 10-mg dose is associated with greater increases in bone density,17 but it is not known if the higher dose is also more effective in reducing fracture risk. The effect of alendronate treatment on chronic back-related disability and quality of life25 may differ from the effect we observed on days of back pain, bed rest, and activity limitation. We did not find a treatment group difference on a measure of back-related physical disability at closeout compared with baseline. In a previous study in which this measure was assessed repeatedly during follow-up, new vertebral fractures during the same period were associated with increased disability at 1 or more follow-up contacts.5 The single prefracture and postfracture assessment in the present study may have limited this measure's sensitivity to the transient effects of vertebral fractures.5,6 Chronic physical disability associated with older vertebral fractures may be limited to women with multiple severe deformities,10 making it difficult to detect a treatment effect in a short fracture-prevention trial. Alternative outcome measures may indicate a greater effect of osteoporosis treatment on chronic disability and deserve further study. Nevertheless, ability to maintain normal activities on a day-to-day basis is important to quality of life for older women with osteoporosis26 and other common chronic conditions.27

Potential adverse effects of treatment could have an impact on overall quality of life. However, our study does not address cost-effectiveness, which would require balancing the overall benefits of alendronate treatment with all of its costs and risks. The cost-effectiveness of alendronate has been addressed in other publications.28 The potential side effects of alendronate have also been evaluated extensively in previous publications, and upper gastrointestinal tract side effects are not significantly different in women randomized to alendronate compared with placebo.7,17 Our estimates of the postfracture increase in days affected by back pain may include the effect of subsequent vertebral fractures. However, these increases largely occurred within 3 to 6 months of the first fracture. Preexisting back pain may increase the likelihood that a woman will be diagnosed with a new clinical vertebral fracture, inflating the apparent impact of these fractures on back problems. However, we obtained similar results when we compared days affected by back pain before and after clinical fractures in the same women.

In conclusion, we found that treatment with alendronate sodium in doses of 5 to 10 mg/d during a 3-year period in this population of postmenopausal women with at least 1 preexisting vertebral fracture not only was effective in preventing new vertebral fractures but reduced the burden of activity limitation and bed disability caused by back pain. Our results suggest that bed-rest days because of back pain and, to a lesser extent, limited-activity days because of back pain are responsive measures of osteoporosis treatment outcome. Bed-disability days because of back pain, in particular, appear to be closely linked with new vertebral fractures. A woman's ability to engage in her usual activities is important to her quality of life. These measures should be considered for future clinical trials of osteoporosis treatment. The results of the Fracture Intervention Trial suggest that, in postmenopausal women with low bone mass and preexisting vertebral fracture, treatment with alendronate provides significant protection against new vertebral fractures and the attendant reduction in ability to maintain the usual level of daily activity.

Accepted for publication April 5, 1999

This study was supported by a grant from Merck Research Laboratories, Rahway, NJ.

Clinical Centers:Wake Forest University, Winston-Salem, NC: S. A. Quandt, PhD (principal investigator), C. Furberg, MD, PhD (co–principal investigator), G. Tell, DPhil, MPH (coinvestigator), T. Pope, MD (coinvestigator), E. M. Cody, RN (project director), S. Marion, RN (clinic coordinator), J. Stough, RN (clinic coordinator).

Kaiser Permanente Center for Health Research, Portland, Ore: T. M. Vogt, MD MPH (principal investigator), A. Hortado, MD (co–principal investigator), E. Orwoll, MD (coinvestigator), J. Blank (project director), D. Towery (clinic coordinator), H. Houston (clinic nurse), C. Romero (bone mineral density technician), J. Downing (data manager).

Group Health Cooperative of Puget Sound, Seattle, Wash: A. Z. LaCroix, PhD, and S. M. Ott, MD (co–principal investigators), D. Scholes, PhD (recruitment coordinator), D. Edgerton, RN, BSN (project director).

Stanford Medical Center, Palo Alto, Calif: W. L. Haskell, PhD (principal investigator), R. Marcus, MD (co–principal investigator), M. L. Villa, MD (medical director), J. Fair, NP, MS (project coordinator), J. Myll, MS (data manager), A. Mylod, RD (recruitment coordinator).

University of California, San Diego: E. Barrett-Connor, MD (principal investigator), M. Schulman, MD (coinvestigator), M. L. Carrion-Petersen, BSN (project director), M. Wong, BA (data manager), D. Price, BA (radiology technician), K. Kadlec, BSN (clinic nurse), N. Komantigue, RN (clinic nurse), C. Kotewa, RN, MS (nurse practitioner).

University of Iowa, Iowa City: R. B. Wallace, MD (principal investigator), J. C. Torner, PhD (co–principal investigator), K. A. Brake (site coordinator), C. Van Hofwegen, RN (site coordinator), T. Peters (study nurse clinician), K. Brasch (study nurse clinician), K. Canady (study nurse clinician), T. Neill (data manager).

University of Maryland, Baltimore: M. C. Hochberg, MD (principal investigator), J. C. Scott, DrPH (co–principal investigator), R. Sherwin, MD (coinvestigator), J. C. Lewis, RN (project director), B. Ballard, RN (clinic coordinator).

University of Miami Medical School, Miami, Fla: R. J. Prineas, MD, PhD (principal investigator), A. Sampson, MD (coinvestigator, project director), C. Crutchfield, RMA (medical technician), T. I. Blake, RT (radiologic technologist, clinic coordinator), E. Eismont (radiologic technologist), C. Casanova, MD (research associate), C. H. Lee (data manager).

University of Minnesota, Minneapolis: K. Ensrud, MD, MPH (principal investigator), C. Bell, BA, MBA (project director), L. Stocke (clinic coordinator), J. Griffith (research assistant), F. Galle (nurse clinician), C. Quinton (nurse clinician), R. Hansen (nurse clinician), K. Pladsen (data manager).

University of Pittsburgh, Pittsburgh, Pa: J. Cauley, DrPH (principal investigator), R. McDonald, MD (coinvestigator), M. Vogt, PhD (project director, coinvestigator), J. Bonk, RN, MPH (recruitment coordinator), L. Harper (clinic coordinator), K. Lucas, RN (clinic coordinator).

University of Tennessee, Memphis: W. Applegate, MD, MPH (principal investigator), N. Miles, MSN, FNP (project director), J. Elam, BA (data quality control officer), L. Lichtermann, BSN (recruitment coordinator), K. Phillips, RN, BSN (project director), S. Satterfield, MD, DPH (coinvestigator).

Coordinating Center and Radiology Group:University of California, San Francisco: S. R. Cummings, MD (principal investigator), D. M. Black, PhD (co–principal investigator, project director), M. C. Nevitt, PhD, MPH (coinvestigator, director, Fracture Intervention Trial radiology group), H. K. Genant, MD (coinvestigator, study radiologist), D. Bauer, MD (coordinator of clinical activities), S. R. Rubin, MPH (project coordinator, co-coordinator of clinical activities), T. Fuerst, PhD (coinvestigator, radiologist), M. Jergas, MD (former coinvestigator), C. Fox, MA (senior programmer), L. Palermo, MA (statistical programmer), P. Ramsay (administrative coordinator), L. Christianson, RN (morphometry technician), M. Dockrell (densitometry technician), B. Forsyth (programmer), F. Harris, MS (statistical programmer), L. Laidlaw (fracture coordinator), R. San Valentin, MD (morphometry technician), H. Tabor (research assistant), L. Vallee (data manager).

Sponsor: Merck Research Laboratories, Rahway, NJ: T. A. Musliner, MD (clinical monitor), D. E. Thompson, PhD (biostatistician), S. Pryor-Tillotson, MS (clinical project manager), and D. Walters (medical program coordinator), A. Santora, MD (senior research physician), D. B. Karpf, MD (former clinical monitor), A. J. Yates, MD (senior director), J. Coon, P. Flermonte, S. Holk, P. Kane, R. Reyes (medical program coordinators), T. Capizzi, PhD, and L. Oppenheimer, PhD (biostatisticians), D. Arnold (programmer).

Data and Safety Monitoring Board: D. L. DeMets, PhD (chair), R. J. Levine, MD, L. Raisz, MD, E. Shane, MD, L. Rosenberg, PhD, S. L. Hui, PhD, B. L. Strom, MD, MPH.

Reprints: Michael C. Nevitt, PhD, MPH, Epidemiology and Biostatistics, Prevention Sciences Group Coordinating Center—UCSF, 74 New Montgomery, Suite 600, San Francisco, CA 94105 (e-mail: mnevitt@psg.ucsf.edu).

Ray  NChan  JKThmer  MMelton  LJ Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;1224- 35
Link to Article
Melton  LJKan  SHFrye  MAWahner  HWO'Fallon  WMRiggs  BL Epidemiology of vertebral fractures in women. Am J Epidemiol. 1989;1291000- 1011
Cummings  SRTabor  HK The epidemiology of vertebral fractures. Genant  HKJergas  Mvan  Kuijk CedsVertebral Fracture in Osteoporosis. San Francisco, Calif Radiology Research and Education Foundation1995;3- 14
Ross  PDDavis  JWEpstein  RWasnich  RD Pre-existing fractures and bone mass predict vertebral fracture incidence. Ann Intern Med. 1991;114919- 923
Link to Article
Nevitt  MCEttinger  BEBlack  DM  et al.  The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Ann Intern Med. 1998;128793- 800
Link to Article
Huang  CRoss  PDWasnich  RD Vertebral fractures and other predictors of back pain among older women. J Bone Miner Res. 1996;111026- 1032
Link to Article
Black  DMCummings  SRKarpf  DB  et al.  Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;3481535- 1541
Link to Article
Black  DMReiss  TFNevitt  MC  et al.  Design of the Fracture Intervention Trial. Osteoporos Int. 1993;3(suppl 3)S29- S39
Link to Article
Looker  ACJohnston  CC  JrWahner  HW  et al.  Prevalence of low femoral bone mineral density in older US women from NHANES III. J Bone Miner Res. 1995;10796- 802
Link to Article
Ettinger  BBlack  DMNevitt  MC  et al.  Contribution of vertebral deformities to chronic back pain and disability. J Bone Miner Res. 1992;7449- 456
Link to Article
Scholes  DLaCroix  AZWagner  EHGrothaus  LCHecht  JA Tracking progress toward national health objectives in the elderly: what do restricted activity days signify? Am J Public Health. 1991;81485- 488
Link to Article
Wagner  EHLaCroix  AZGrothaus  LCHecht  JA Responsiveness of health status measures to change among older adults. J Am Geriatr Soc. 1993;41241- 248
Black  DMPalermo  LNevitt  MC  et al.  Comparison of methods for defining prevalent vertebral deformities: the Study of Osteoporotic Fractures. J Bone Miner Res. 1995;10890- 902
Link to Article
Genant  HKJergas  MPalermo  L  et al.  Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res. 1996;11984- 996
Link to Article
Genant  HKWu  CYvan Kuijk  CNevitt  MC Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res. 1993;81137- 1148
Link to Article
Crowley  JHu  M Covariance analysis of heart transplant survival data. J Am Stat Assoc. 1977;7227- 36
Link to Article
Liberman  UAWeiss  SRBröll  J  et al.  Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 1995;3331437- 1443
Link to Article
Wipf  JEDeyo  RA Low back pain. Med Clin North Am. 1995;79231- 246
Frost  HM Personal experience in managing acute compression fractures, their aftermath, and the bone pain syndrome in osteoporosis. Osteoporos Int. 1998;813- 15
Link to Article
Dolan  ALRyan  PJArden  NK  et al.  The value of SPECT scans in identifying back pain likely to benefit from facet joint injection. Br J Rheumatol. 1996;351269- 1273
Link to Article
Manicourt  DHAltman  RDWilliams  JM  et al.  Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions. Arthritis Rheum. 1999;421159- 1167
Link to Article
Gertz  BJHolland  SDKline  WF  et al.  Clinical pharmacology of alendronate sodium. Osteoporos Int. 1993;3(suppl 3)13- 16
Link to Article
Passeri  MBaroni  MCPedrazzoni  M  et al.  Intermittent treatment with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) in the therapy of postmenopausal osteoporosis. Bone Miner. 1991;15237- 248
Link to Article
Plosker  GLMcTavish  D Intranasal salcatonin (salmon calcitonin): a review of its pharmacological properties and role in the management of postmenopausal osteoporosis. Drugs Aging. 1996;8378- 400
Link to Article
Lyritis  GPTsakalakos  NMagiasis  BKarachialios  TYiatzides  ATsekoura  M Analgesic effect of salmon calcitonin in osteoporotic verterbral fractures: a double-blind placebo-controlled clinical study. Calcif Tissue Int. 1991;49369- 372
Link to Article
Cook  DJGuyatt  GHAdachi  JD  et al.  Quality of life issues in women with vertebral fractures due to osteoporosis. Arthritis Rheum. 1993;36750- 756
Link to Article
Kosorok  MROmenn  GSDiehr  PKoepsell  TDPatrick  DL Restricted activity days among older adults. Am J Public Health. 1992;821263- 1267
Link to Article
National Osteoporosis Foundation, Osteoporosis: review of the evidence for prevention, diagnosis and treatment and cost-effectiveness analysis. Osteoporos Int. 1998;8(suppl 4)S1- S88

Figures

Place holder to copy figure label and caption
Figure 1.

Cumulative incidence of women experiencing 7 or more days of bed rest (top) and 7 or more days of limited activity (bottom) in the periods before and after the occurrence of a clinical vertebral fracture. The prefracture period includes time at risk among women who did not have a clinical vertebral fracture.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Cumulative incidence of patients reporting 1 or more (top) and 7 or more (bottom) bed-rest days, by treatment group. Relative risk (RR) and 95% confidence interval (in parentheses) were estimated from a proportional hazards model.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Cumulative incidence of patients reporting 7 or more limited-activity days, by treatment group. Relative risk (RR) and 95% confidence interval (in parentheses) were estimated from a proportional hazards model.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Cumulative incidence of patients reporting 1 or more days of severe or worse back pain, by treatment group. Relative risk (RR) and 95% confidence interval (in parentheses) were estimated from a proportional hazards model.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Patient Population by Treatment Group*
Table Graphic Jump LocationTable 2. Frequency of Back Pain and Its Effects Observed Among Women During Follow-up Period (3 Years) by Vertebral Fracture Status at the End of the Study
Table Graphic Jump LocationTable 3. Incidence and Relative Risk of Women With 7 Days of More of Back Pain, Activity Limitation, and Bed-Rest Days Because of Back Pain, per 100 Person-years, Before and After Occurrence of a Clinical Vertebral Fracture, Irrespective of Treatment Allocation (Alendronate Sodium or Placebo)
Table Graphic Jump LocationTable 4. Back Pain Outcomes by Treatment Group

References

Ray  NChan  JKThmer  MMelton  LJ Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;1224- 35
Link to Article
Melton  LJKan  SHFrye  MAWahner  HWO'Fallon  WMRiggs  BL Epidemiology of vertebral fractures in women. Am J Epidemiol. 1989;1291000- 1011
Cummings  SRTabor  HK The epidemiology of vertebral fractures. Genant  HKJergas  Mvan  Kuijk CedsVertebral Fracture in Osteoporosis. San Francisco, Calif Radiology Research and Education Foundation1995;3- 14
Ross  PDDavis  JWEpstein  RWasnich  RD Pre-existing fractures and bone mass predict vertebral fracture incidence. Ann Intern Med. 1991;114919- 923
Link to Article
Nevitt  MCEttinger  BEBlack  DM  et al.  The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Ann Intern Med. 1998;128793- 800
Link to Article
Huang  CRoss  PDWasnich  RD Vertebral fractures and other predictors of back pain among older women. J Bone Miner Res. 1996;111026- 1032
Link to Article
Black  DMCummings  SRKarpf  DB  et al.  Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;3481535- 1541
Link to Article
Black  DMReiss  TFNevitt  MC  et al.  Design of the Fracture Intervention Trial. Osteoporos Int. 1993;3(suppl 3)S29- S39
Link to Article
Looker  ACJohnston  CC  JrWahner  HW  et al.  Prevalence of low femoral bone mineral density in older US women from NHANES III. J Bone Miner Res. 1995;10796- 802
Link to Article
Ettinger  BBlack  DMNevitt  MC  et al.  Contribution of vertebral deformities to chronic back pain and disability. J Bone Miner Res. 1992;7449- 456
Link to Article
Scholes  DLaCroix  AZWagner  EHGrothaus  LCHecht  JA Tracking progress toward national health objectives in the elderly: what do restricted activity days signify? Am J Public Health. 1991;81485- 488
Link to Article
Wagner  EHLaCroix  AZGrothaus  LCHecht  JA Responsiveness of health status measures to change among older adults. J Am Geriatr Soc. 1993;41241- 248
Black  DMPalermo  LNevitt  MC  et al.  Comparison of methods for defining prevalent vertebral deformities: the Study of Osteoporotic Fractures. J Bone Miner Res. 1995;10890- 902
Link to Article
Genant  HKJergas  MPalermo  L  et al.  Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res. 1996;11984- 996
Link to Article
Genant  HKWu  CYvan Kuijk  CNevitt  MC Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res. 1993;81137- 1148
Link to Article
Crowley  JHu  M Covariance analysis of heart transplant survival data. J Am Stat Assoc. 1977;7227- 36
Link to Article
Liberman  UAWeiss  SRBröll  J  et al.  Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 1995;3331437- 1443
Link to Article
Wipf  JEDeyo  RA Low back pain. Med Clin North Am. 1995;79231- 246
Frost  HM Personal experience in managing acute compression fractures, their aftermath, and the bone pain syndrome in osteoporosis. Osteoporos Int. 1998;813- 15
Link to Article
Dolan  ALRyan  PJArden  NK  et al.  The value of SPECT scans in identifying back pain likely to benefit from facet joint injection. Br J Rheumatol. 1996;351269- 1273
Link to Article
Manicourt  DHAltman  RDWilliams  JM  et al.  Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions. Arthritis Rheum. 1999;421159- 1167
Link to Article
Gertz  BJHolland  SDKline  WF  et al.  Clinical pharmacology of alendronate sodium. Osteoporos Int. 1993;3(suppl 3)13- 16
Link to Article
Passeri  MBaroni  MCPedrazzoni  M  et al.  Intermittent treatment with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) in the therapy of postmenopausal osteoporosis. Bone Miner. 1991;15237- 248
Link to Article
Plosker  GLMcTavish  D Intranasal salcatonin (salmon calcitonin): a review of its pharmacological properties and role in the management of postmenopausal osteoporosis. Drugs Aging. 1996;8378- 400
Link to Article
Lyritis  GPTsakalakos  NMagiasis  BKarachialios  TYiatzides  ATsekoura  M Analgesic effect of salmon calcitonin in osteoporotic verterbral fractures: a double-blind placebo-controlled clinical study. Calcif Tissue Int. 1991;49369- 372
Link to Article
Cook  DJGuyatt  GHAdachi  JD  et al.  Quality of life issues in women with vertebral fractures due to osteoporosis. Arthritis Rheum. 1993;36750- 756
Link to Article
Kosorok  MROmenn  GSDiehr  PKoepsell  TDPatrick  DL Restricted activity days among older adults. Am J Public Health. 1992;821263- 1267
Link to Article
National Osteoporosis Foundation, Osteoporosis: review of the evidence for prevention, diagnosis and treatment and cost-effectiveness analysis. Osteoporos Int. 1998;8(suppl 4)S1- S88

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