Effect of Alendronate on Risk of Fracture in Women With Low Bone Density but Without Vertebral Fractures (2024)

Context.—Alendronate sodium reduces fracture risk inpostmenopausal women who have vertebral fractures, but its effects onfracture risk have not been studied for women without vertebralfractures.

Objective.—To test the hypothesis that 4 years ofalendronate would decrease the risk of clinical and vertebral fracturesin women who have low bone mineral density (BMD) but no vertebralfractures.

Design.—Randomized, blinded, placebo-controlled trial.

Setting.—Eleven community-based clinical research centers.

Subjects.—Women aged 54 to 81 years with a femoral neck BMDof 0.68 g/cm² or less (Hologic Inc, Waltham, Mass) but novertebral fracture; 4432 were randomized to alendronate or placebo and4272 (96%) completed outcome measurements at the final visit (anaverage of 4.2 years later).

Intervention.—All participants reporting calcium intakes of1000 mg/d or less received a supplement containing 500 mg of calciumand 250 IU of cholecalciferol. Subjects were randomly assigned toeither placebo or 5 mg/d of alendronate sodium for 2 years followed by10 mg/d for the remainder of the trial.

Main Outcome Measures.—Clinical fractures confirmedby x-ray reports, new vertebral deformities detected by morphometricmeasurements on radiographs, and BMD measured by dual x-rayabsorptiometry.

Results.—Alendronate increased BMD at all sites studied(P<.001) and reduced clinical fractures from 312 in theplacebo group to 272 in the intervention group, but not significantlyso (14% reduction; relative hazard [RH], 0.86; 95% confidenceinterval [CI], 0.73-1.01). Alendronate reduced clinical fractures by36% in women with baseline osteoporosis at the femoral neck (>2.5SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82;treatment-control difference, 6.5%; number needed to treat [NNT],15), but there was no significant reduction among those with higher BMD(RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk ofradiographic vertebral fractures by 44% overall (relative risk, 0.56;95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60).Alendronate did not increase the risk of gastrointestinal or otheradverse effects.

Conclusions.—In women with low BMD but without vertebralfractures, 4 years of alendronate safely increased BMD and decreasedthe risk of first vertebral deformity. Alendronate significantlyreduced the risk of clinical fractures among women with osteoporosisbut not among women with higher BMD.

OSTEOPOROSIS results in millions offractures,¹ more than 400,000 hospital admissions,more than 44 million patient-days in nursing homes, and $13.8 billionin health care expenditures among women and men yearly in the UnitedStates alone.² Alendronate sodium increases the density ofmineral in bone and reduces the risk of vertebralfractures in women with osteoporosis.^3,4 In the FractureIntervention Trial (FIT), we showed that 3 years of alendronate alsoreduced the risk of hip and wrist fractures by about 50% among womenwho had low bone mineral density (BMD) and vertebralfractures.⁵ However, only 10%to 15% of postmenopausal women have vertebralfractures,^6,7 and the effectiveness of treatments for thelarger group of women who have low BMD but no prior vertebral fractureshas not been specifically studied. The clinical fracture arm of FIT wasdesigned to test the hypothesis that 4 years of treatment withalendronate would also reduce the risk of clinical fractures inpostmenopausal women who have low BMD but no vertebral fracture. Asplanned, we analyzed the effect of alendronate in subgroups of women bytertile of initial levels of femoral neck BMD.

The trial was conducted at 11 clinical centers in the United States,with a coordinating center at the University of California, SanFrancisco.⁸ The FIT had 2 arms: the vertebral fracturearm,⁵ which included women who had vertebral fractures, andthe clinical fracture arm, which included women without vertebralfractures and is the subject of this article.

We aimed to enroll 4000 women aged 55 through 80 years who had beenpostmenopausal for at least 2 years and had femoral neck BMD of 0.68g/cm² (QDR-2000, Hologic Inc, Waltham, Mass) or less. Atthe time of enrollment, this was believed to correspond to a BMD valueof at least 2 SDs below the mean of normal young adult white women,based on the manufacturer's reference values. Subsequently, resultsfrom the Third National Health and Nutritional Examination Surveyindicated that our inclusion criteria instead corresponded to 1.6 SD ormore below the normal young adult mean.⁶ Consequently,about one third of women in the trial actually had higher BMD thanexpected. Women were recruited principally by mass mailings (Figure1).

We excluded women who had recent peptic ulcers or ulcers that requiredhospitalization, dyspepsia requiring daily treatment, significant renalor hepatic dysfunction, medical problems that precluded 3 years ofparticipation, severe malabsorption, blood pressure exceeding 210 mm Hgsystolic or 105 mm Hg diastolic, myocardial infarction within 6 months,unstable angina, hypothyroidism, hyperthyroidism, orhyperparathyroidism. We also excluded women who had taken estrogen orcalcitonin within the preceding 6 months or bisphosphonates or sodiumfluoride (>1 mg/d) at any time. Although women taking estrogen wereexcluded from entry into the trial, 246 (11.1%) in the placebo groupand 204 (9.2%) in the alendronate group took estrogen at some timeduring the study. All women provided written informed consent and theprotocol was approved by the appropriate institutional review boards.

Women were randomized in blocks of 10 that were stratified withinclinical center. Treatment was assigned by computer-generated codes.Each bottle of medication was labeled with a nonrepeating allocationnumber that could be revealed only for safety concerns. Those whogenerated the allocation schedule were not allowed to communicate withanyone who assigned the study drugs.

The dosage of alendronate sodium was 5 mg/d for 2 years but wasincreased to 10 mg/d at the second annual visit because other trialssuggested that 10 mg/d had greater effects on BMD. Participants wereinstructed to take the study drug with at least 120 mL (4 oz) of waterin a fasting state and not lie down or eat or drink any other food orliquid for at least a half hour. Prescription medications that had tobe taken in the fasting state could be taken before breakfast.Participants were instructed to take calcium supplements, antacids,tetracycline, sucralfate, or bile acid–binding resins after breakfast.Eighty-two percent of participants in each treatment group had dietarycalcium intakes of less than 1000 mg/d; they were asked to take adaily supplement containing 500 mg of elementalcalcium (OsCal) and 250 IU of cholecalciferol (vitamin D). Women hadstudy visits semiannually and all information regarding clinicalfractures was forwarded to the coordinating center.

Clinical Fractures.— A clinical fracture was defined as one diagnosed by a physician. Self-reports of fractures wereconfirmed by written reports of radiographs or other tests. We excludedpathologic fractures or fractures due to trauma sufficient to fracturea normal bone in most young adults. Facial and skull fractures wereexcluded because they are not associated with low BMD.⁹

Before study unblinding, subgroups of clinical fractures were definedas nonspine fractures, hip fractures, wrist fractures, clinicalvertebral fractures and clinical fractures other than a wrist, spine,or hip fracture. Participants could have more than 1 type of fractureand so could appear in more than 1 category.

Radiographic Evidence of Vertebral Fractures.— Lateral spine radiographs were obtained according topublished guidelines¹⁰ at baseline and 4 years afterrandomization. Women with vertebral fractures assessed bymorphometry^5,10-12 were excluded from this arm of thestudy.

A new deformity, or radiographic vertebral fracture, was defined as adecrease of 20% and 4 mm or more in any vertebral height from baselineto the end of the study^5,12 and confirmed by a repeatmeasurement of the involved vertebral body. All assessments wereblinded to treatment allocation.

Bone Mineral Density.— Bone mineral density wasmeasured at the hip, posterior-anterior spine, and in the whole body onall participants using Hologic QDR 2000 densitometers. Forearm BMD wasmeasured (one third of the way up from the wrist to the elbow) in a20% random sample of participants and lateral spine BMD was measuredon 82% of participants. All BMD measurements were repeated annuallyexcept total body BMD, which was obtained at the start and end of thestudy. Quality control measures have been detailedelsewhere.⁸

Stature.— Height was calculated as the mean of 2 repeat measurements using Harpenden stadiometers (Holtain Ltd,Crymmych, Pembrookshire, England).

Adverse Experiences.— Patients were questioned at each contact regarding adverse events, defined as any untoward condition,including minor illnesses such as common colds. We analyzed all adverseexperiences, including those requiring hospitalization ordiscontinuation of study medication. Because of reports aboutbisphosphonates and upper gastrointestinal tractdisorders,¹³ we analyzed upper gastrointestinal tractevents by specific symptoms and diagnoses.

We maintained blinding in several ways. Collection and review of datawere blinded to treatment assignment. Results of bone densitometryduring follow-up were not available to participants or cliniciansexcept when bone loss (monitored by the coordinating center) exceededpredetermined rates (8% over 1 year, 10% over 2 years, 12% over 3years, etc, at the total hip or posterior-anterior spine). Theappropriate clinical center investigator was informed of the bone lossbut not the treatment assignment, and he/she, in turn, informed theparticipants or their primary care physicians. Finally, treatmentassignments were kept in a locked file by 1 statistician at thecoordinating center who was responsible for preparing reports to thedata safety and monitoring board.

Assuming a 4% annual incidence of clinical fracture in placebo-treatedwomen, the trial required 4000 women to detect a 25% decrease in riskwith 90% power and an α level of .05.⁸ We recruited 4432women and observed a 3.5% annual incidence of fracture in the placebogroup, which provided 88% power to detect a 25% reduction in risk.

Clinical fractures and adverse experiences are reported asthe proportion ofwomen with 1 or more events. We used survivalanalysis with the log-rank test to analyze and test the statisticalsignificance of differences between treatment groups. We present theresults as the number and percentage of women with fractures along withrelative hazards (RHs) and 95% confidence intervals (CIs) calculatedby the likelihood ratio method.¹⁴

We analyzed the proportion of women with 1 or more radiographicallydetected vertebral fracture and present the rates in each group alongwith the relative risk (RR), calculated as the ratio of the proportionof women with fractures in the alendronate group compared with theplacebo group. We used the Mantel-Haenszel χ²statistic to test the significance of differences between treatmentgroups. We used t tests to compute the statisticalsignificance of differences between the treatment groups for changes inBMD and height. All P values are 2-sided. We also estimatedthe number needed to treat (NNT) for 4.25 years to prevent 1 fracture.All analyses followed an intention-to-treat design.

Before unblinding, we planned to analyze the effects ofalendronate on the risk of clinical fractures, vertebral fractures, andbone densities in subgroups stratified by tertile of baseline BMD; inthis analysis we use femoral neck BMD. The cutoff for the bottomtertile (femoral neck BMD <0.571 g/cm²) represented a Tscore of −2.55 or less, which is similar to the World HealthOrganization definition of osteoporosis as a T score of less than−2.5.¹² The middle tertile was 2.06 (0.631g/cm²) to 2.56 SD, and the highest tertile was 1.6 (0.681g/cm²) to 2.05 SDs below the normal young adult mean. Thus,for simplicity of presentation, we report the results in 3 ranges of Tscores: −2.5 or less, −2.0 to −2.5, and −1.6 to −2.0 or more.

We tested the statistical significance of any interactions between BMDand the effect of treatment on the risk of clinical fractures byperforming a proportional hazards analysis, which included terms fortreatment, BMD (continuous), and treatment-by-BMD interaction.

An independent data and safety monitoring board examined endpoints and adverse events by treatment group semiannually. Adjustmentsfor repeated tests of significance required P = .046 forstatistical significance of the main result.

A total of 4432 women were randomized, 2214 to alendronateand 2218 to placebo (Figure 1). Participants had a mean age of 68years, 97% were white, and potential confounding variables wereequally distributed between the 2 treatment groups (Table1). Subjects were followed up for an average of4.2 years; closeout contacts were completed by 4272 (96%) of theparticipants. At closeout, 82.5% of surviving participants randomizedto placebo and 81.3% of those assigned to alendronate were stilltaking study medication. Of those taking study medication, 96% in eachof the 2 treatment groups had taken at least 75% of their pills.Thirty-four participants (22 in the placebo group and 12 in thealendronate group) had stopped taking their study medication becausetheir rate of bone loss exceeded predetermined limits.

Compared with placebo, treatment with alendronateincreased average BMD at all measured sites (Figure2). After 4 years, women in the placebo group lostan average of 0.8% of femoral neck BMD, while women in the alendronategroup gained 3.8% (difference, 4.6%; P<.001). The placebogroup lost an average of 1.6% of BMD in the total hip, while thealendronate group gained 3.4% (difference, 5.0%; P<.001).In the lumbar spine, the placebo group gained 1.5% vs an 8.3% gain inthe alendronate group (difference, 6.6%; P<.001). Women whor*ceived alendronate also gained significantly more BMD than theplacebo group in the trochanter (difference, 6.8%), total body(difference, 2.0%), lateral spine (difference, 7.1%), and ultradistalforearm (difference, 3.1%).

Alendronate increased BMD similarly in all subgroups of initial BMD.For example, it increased femoral neck BMD by 4.6% (95% CI,4.0%-5.1%) in those with baseline femoral neck T scores of −2.5 orless, 4.8% (95% CI, 4.2%-5.3%) in those with T scores of −2.0 to−2.5, and 4.8% (95% CI, 4.2%-5.4%) in those with T scores of −1.6to −2.0 or more.

Clinical fractures, the primary end point, occurred in 312 women(14.1%) in the placebo and 272 women (12.3%) in the alendronate group(RH, 0.86; 95% CI, 0.73-1.01) (Table 2 and Figure3). Twenty-four women (1.1%) in the placebo groupand 19 women (0.9%) in the alendronate group had hip fractures (14%reduction; RH, 0.79; 95% CI, 0.43-1.44), while 70 (3.2%) in theplacebo group and 83 (3.7%) in the alendronate group fractured a wrist(RH, 1.19; 95% CI, 0.87-1.64). Fewer women assigned to alendronate (n= 182, 8.2%) than to placebo (n = 227, 10.2%) had fractures at sitesother than spine, hip, or wrist (RH, 0.79; 95% CI, 0.65-0.96;placebo-treatment difference, 2.0%; NNT, 50).

The effect of treatment on the risk of clinical fracturesdepended on initial femoral neck BMD (P = .01 for theinteraction) (Table 3 and Figure4). Alendronate significantly reduced the risk ofclinical fractures by 36% (RH, 0.64; 95% CI, 0.50-0.82;placebo-treatment difference, 6.5%; NNT, 15) in women whose initialfemoral neck T score was −2.5 or less. However, 4 years ofalendronate did not significantly affect risk of clinical fracture inthose with higher BMD. We observed a 22% lower risk of clinicalfracture in those whose T scores were more than 2.0 SDs below thenormal mean (RH, 0.78; 95% CI, 0.65-0.94; placebo-treatmentdifference, 3.3%; NNT, 30) (Figure 4). Alendronate did not decreasethe risk of fracture amongsubjects whose initial T scores were greater than−2.5 (RH, 1.08; 95% CI, 0.87-1.35).

In post hoc analyses, alendronate reduced the risk of hipfractures by 56% among women with a femoral neck T score of −2.5 orless: 18 (2.2%) in the placebo group vs 8 (1.0%) in the alendronategroup (RH, 0.44; 95% CI, 0.18-0.97; placebo-treatment difference,1.2%; NNT, 81). There was no reduction in risk among those whosefemoral neck T scores were more than −2.5: 6 (0.4%) in the placebogroup vs 11 (0.8%) in the alendronate group (RH, 1.84; 95% CI,0.70-5.36).

The effect of alendronate on the risk of wrist fracturesalso varied by baseline femoral neck BMD. There was no significantreduction among women with a T score of −2.5 or less: 38 (4.7%) inthe placebo and 34 (4.2%) in the alendronate group (RH, 0.88; 95% CI,0.55-1.40). Similarly, we observed no reduction in risk among womenwith T scores of −2.0 to −2.5: 20 (2.8%) in the placebo group vs 27(3.7%) in the alendronate group (RH, 1.33; 95% CI, 0.75-2.4). Amongthose whose femoral neck T scores were more than −2.0, more fracturesoccurred in the treatment group (n = 22, 3.3%) than in the placebogroup (n = 12, 1.7%; RH, 1.9; 95% CI, 1.0-4.0;placebo-treatment difference, 1.6%).

Stratification of the results by BMD of the total hip, spine, orother sites indicated that alendronate consistently decreased the riskof nonspine fractures among women with BMD T scores of −2.5 or lessbut not among women with BMD T scores of more than −2.0. The apparentthreshold for a significant effect of treatment on risk of clinicalfractures varied by BMD measurement site from a T score of −2.5 orless at the femoral neck and spine to less than −2.0 at the total hip.

We obtained final follow-up radiographs for 4134participants (95% of those surviving at that time). Alendronatereduced the overall risk of new radiographic vertebral fractures by44%: 78 women (3.8%) in the placebo group developed at least 1 newfracture compared with 43 (2.1%) in the alendronate group (44%reduction; RR, 0.56; 95% CI, 0.39-0.80; P = .001;placebo-treatment difference, 1.7%; NNT, 60) (Table 2). The risk ofradiographic vertebral fractures was highest among women with thelowest BMD. Consequently, estimated NNTs increased from 35 among womenwith a femoral neck BMD T score of less than −2.5 to 59 for those withT scores of −2.5 to −2.0, and to approximately 363 for those with Tscores of −2.0 to −1.6.

Alendronate also reduced the mean loss of height by 1.5 mm over 4years: 8.5 mm in the placebo group vs 7.0 mm in the alendronate group(P<.001).

Permanent discontinuations of study medication due to adverseexperiences were similar in the 2 groups (Table4). Similarly, there were no significantdifferences in rates of death or adverse experiences resulting inhospitalization. There were no significant differences between thegroups in rates of abdominal pain, esophagitis, esophageal ulcer,gastric ulcer, duodenal ulcer, or other adverse upper gastrointestinaltract effects.

We previously showed that alendronate decreased the riskof vertebral, hip, and wrist fractures by about 50% and all clinicalfractures by 28% among women with vertebral fractures.⁵ Wehave now found that 4 years of alendronate also decreased the risk ofall clinical fractures, hip fractures, and vertebral deformity in womenwith hip BMD T scores below −2.5 who did not have a vertebralfracture. An analysis by the National Osteoporosis Foundation concludedthat estrogen or alendronate should be offered to postmenopausal womenwho have either vertebral fractures or osteoporosis confirmed by bonedensitometry.¹⁵ Our findings support those recommendationsfor the use of alendronate.

Although alendronate increased BMD to a similar degreeregardless of initial density, we did not observe a significantdecrease in the risk of clinical fractures in nonosteoporotic women. Itis important to note that our study was not designed to pinpoint athreshold for this effect; it varied between T scores of −2.5 or lessat the femoral neck and spine to −2.0 or less at thetotal hip measurement sites. Why alendronatereduced clinical fractures more effectively in those with the lowestBMD is not clear. Alendronate may increase bone strength at least inpart by decreasing the number of resorption pits on bonesurfaces^16-18; this might make a critical difference forthe most fragile bones.

Alendronate reduced the risk of radiographically detectedvertebral fractures by about half. Although most vertebral deformitieselude clinical diagnosis, many cause pain anddisability.^19,20 Women with radiographic vertebralfractures have an increased risk of vertebral, hip, or otherfractures.^21,22 Thus, prevention of the first radiographicevidence of vertebral fracture may prevent disability and herald adecreased risk of other types of fractures. One needs to treatrelatively few patients with osteoporosis, who have a high risk offractures, to prevent a radiographic vertebral fracture, clinicalfracture, or hip fracture. Although NNT estimates are not precise, itmay be necessary to treat a few hundred women to prevent 1 radiographicvertebral fracture among women with a femoral neck T score of −2.0 ormore.

In 2 previous studies, alendronate reduced the risk of wrist fracturesby 50% in women with vertebral fractures orosteoporosis.^4,5 In contrast, we found no overall reductionin risk of wrist fracture; alendronate appeared to increase the risk ofwrist fractures in women with a femoral neck T score of more than−2.0.

It is not clear how long alendronate should be continued.To our knowledge, there are no data and no prospective study is underway to estimate the effect of more than 4 years of alendronate on riskof fractures. Treatment beyond 4 years may continue to improve orpreserve BMD and maintain reduced bone turnover; this is being studied.Much of the antifracture effect of alendronate may be caused byreduction in bone resorption that occurs early and is sustained butdoes not increase over time.^16,23-25 Turnover repairsnaturally accumulating microscopic damage.²⁶ There is noevidence that alendronate has detrimental effects on bone strength,microscopic bone structure, or fracture healing²⁷; theeffects of more than 4 years of treatment deserve study. Additionally,alendronate accumulates in bone and recirculates when bone containingalendronate is remodeled.²⁷ Thus, many years of treatmentmay produce self-sustaining concentrations of alendronate in bone suchthat the skeletal benefits of alendronate may continue after treatmentis stopped.²⁸ On the other hand, if alendronate were tocause an adverse effect that has not yet been recognized, endogenousexposure to alendronate would also continue after stopping treatment.

Our results indicate that it would take more than 4 years of treatmentto produce a substantial reduction in risk of clinical fractures inwomen who do not have osteoporosis. Some physicians may recommendlong-term treatment with alendronate to preserve the density andstructural integrity of bone in women without osteoporosis. Others maydecide that it would be more prudent and cost-effective to limitalendronate treatment to women with osteoporosis, for whom there isclear evidence of reduction in risk of clinical fractures.

Four years of alendronate therapy did not significantly increase therisk of abdominal symptoms or gastrointestinal diagnoses. The risk ofesophagitis, which has been occasionally reported with alendronatetherapy,¹³ was very low and not significantly differentfrom placebo. We carefully instructed our participants to take theirmedication with at least 120 mL (4 oz) of water and not to lie down fora half hour. With the exception of some cases of esophagitis, ourresults indicate that when patients take alendronate correctly,upper gastrointestinal tract problems should not be attributed toalendronate and usually do not necessitate stopping treatment.

We conclude that 4 years of treatment with alendronate safely increasesbone density and decreases the risk of radiographic vertebral fracturesamong women with low BMD. Alendronate treatment reduces the risk ofclinical fractures among women with osteoporosis but not among thosewith hip or spine T scores of −2.0 or more. The antifractureeffectiveness of more than 4 years of treatment, especially among womenwithout osteoporosis, is unknown.