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Fractures in women treated with raloxifene or alendronate: a retrospective database analysis
© Foster et al.; licensee BioMed Central Ltd. 2013
Received: 12 September 2012
Accepted: 18 March 2013
Published: 23 March 2013
Raloxifene and alendronate are anti-resorptive therapies approved for the prevention and treatment of postmenopausal osteoporosis. Raloxifene is also indicated to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk of invasive breast cancer. A definitive study comparing the fracture effectiveness and rate of breast cancer for raloxifene and alendronate has not been published. The purpose of this retrospective cohort study was to evaluate fracture and breast cancer rates among patients treated with raloxifene or alendronate.
Females ≥45 years who initiated raloxifene or alendronate in 1998–2006 Truven Health Analytics MarketScan® Databases, had continuous enrollment 12 months prior to and at least 12 months after the index date, and had a treatment medication possession ratio ≥80% were included in this study. Rates of vertebral and nonvertebral fractures and breast cancer during 1, 3, 5, 6, 7, and 8 years of treatment with raloxifene or alendronate were evaluated. Fracture rates were adjusted for potential treatment bias using inverse probability of treatment weights. Multivariate hazard ratios were estimated for vertebral and nonvertebral fractures.
Raloxifene patients had statistically significantly lower rates of vertebral fractures in 1, 3, 5, and 7 years and for nonvertebral fractures in 1 and 5 years. There were no statistically significant differences in the adjusted fracture rates between raloxifene and alendronate cohorts, except in the 3-year nonvertebral fracture rates where raloxifene was higher. Multivariate hazard ratios of raloxifene versus alendronate cohorts were not significantly different for vertebral and nonvertebral fracture in 1, 3, 5, 6, 7, and 8 years. Unweighted and weighted breast cancer rates were lower among raloxifene recipients.
Patients treated with alendronate and raloxifene had similar adjusted fracture rates in up to 8 years of adherent treatment, and raloxifene patients had lower breast cancer rates.
Osteoporosis is the most common bone disease in the United States, affecting approximately 10 million Americans with an additional 34 million people at risk . Osteoporosis contributes to more than 1.5 million fractures each year and is the primary underlying cause of fractures in the elderly . Millions of individuals are at risk for fracture due to risk factors such as low bone mass and advanced age [1, 3]. It is expected that in 2025 there will be as many as 3 million osteoporotic-related fractures in the United States .
Alendronate and raloxifene are anti-resorptive therapies approved for the prevention and treatment of postmenopausal osteoporosis. Alendronate is incorporated into the bone matrix and acts to inhibit osteoclasts [5, 6]. Raloxifene binds to estrogen receptors and appears to act as an estrogen agonist in bone . Both drugs reduce bone turnover and increase bone mineral density, though alendronate has a stronger effect on these domains than raloxifene . Raloxifene is also indicated to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk of invasive breast cancer [9, 10]. Raloxifene is not indicated for the treatment of invasive breast cancer, reduction of the risk of recurrence of breast cancer, or reduction of the risk of noninvasive breast cancer. Although both therapies have established efficacy from randomized clinical trials, comparative, real-world evidence on these therapies for post-menopausal women may provide important information for health care providers to supplement the clinical trial evidence.
A definitive study comparing the fracture effectiveness of raloxifene and alendronate has not been published . The EVA trial (Evista Alendronate Comparison trial) was designed to be the first double-blind, randomized comparison trial to compare osteoporosis therapies head-to-head for fracture risk reduction among 3,000 postmenopausal women . However, the study enrollment was stopped early due to difficulties with timely recruitment of treatment naïve women. Only 122 patients reached the 2-year endpoint, and the statistical power became too low for establishing non-inferiority between drugs for fracture risk reduction.
We conducted a retrospective database study examining patients who initiated raloxifene or alendronate and were adherent to treatment during 6 time periods. Vertebral and nonvertebral fracture rates were compared during each respective treatment period. Due to the clinical importance of breast cancer risk reduction in some postmenopausal women with osteoporosis, we also compared breast cancer rates in the raloxifene and alendronate cohorts. However, we did not specifically examine the rates of invasive breast cancer versus the rates of recurrent breast cancer or noninvasive breast cancer.
Study samples were drawn from 1998 to 2008 Truven Health Analytics MarketScan® Commercial Claims and Encounters (CCAE) and Medicare Supplemental and Coordination of Benefits (COB) Databases (MDCR). Both databases contain de-identified health insurance enrollment information and claims data for inpatient and outpatient medical services as well as outpatient prescriptions. Enrollee demographic information is available and medical claims include key data elements such as service date, treatment setting, diagnosis, procedure, and provider type. The CCAE database includes employees, spouses, and dependents covered by employer-sponsored private health insurance. The MDCR database profiles the healthcare experience of retirees with Medicare supplemental insurance paid by employers. Together, both databases consist of an average of 19 million lives annually during the study period of 1998 to 2008. The patient data used in this analysis were de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA) regulations; thus, the study did not require Institutional Review Board approval.
The study’s primary endpoints were the comparative vertebral and nonvertebral fracture rates (i.e. the percent of patients having a fracture) among patients with 1, 3, 5, 6, 7, and 8 years of adherent treatment with raloxifene versus alendronate. Fracture rates were compared between treatment groups during 6 separate observation periods. Multivariate models were used to estimate the hazard ratios of fractures in the 6 cohorts. Additionally, a sensitivity analysis excluding patients with any pre-index fracture diagnosis was performed in the 3-year cohort.
The rate of breast cancer (i.e. the percent of patients having breast cancer) during 1, 3, 5, 6, 7, and 8 years of treatment with raloxifene versus alendronate was also evaluated. A sensitivity analysis was conducted excluding pre-index breast cancer.
Fracture was identified by primary or secondary diagnosis (International Classification of Disease, 9th Edition, Clinical Modification [ICD-9-CM]) indicating a fracture on a non-diagnostic claim of inpatient, emergency room, or outpatient service. Diagnostic claims, such as lab or radiology claims, were excluded since they do not conclusively confirm the presence of a fracture. Fractures due to trauma, identified either by an E code for motor vehicle accident on the same claim, or by 3 or more different fractures within 7 days before or after the fracture of interest, were excluded. Additionally, open fractures were excluded because they are more likely to be related to trauma rather than osteoporosis . Pathological fractures were included if patients were verified as not having cancer prior to and within 6 months after the pathological fracture diagnosis was observed. This is consistent with the recommendation by Curtis and colleagues to include pathological fractures in epidemiologic studies of osteoporotic fractures . In addition, stress fractures were included. In order to appropriately identify treatment-emergent fractures, fractures occurring during the first 90 days of follow-up were excluded. This was similar to the method Meijer and colleagues used in assessing the impact of compliant osteoporosis treatment on fracture risk .
The occurrence of fracture during the post-period was identified and fracture rates were calculated for clinical vertebral fracture and nonvertebral fracture (hip, upper leg, lower leg, pelvis, humerus, wrist/forearm, clavicle/rib, and other). Fracture sites were determined by 3-digit ICD-9-CM diagnosis codes. Due to the difficulty of using medical claims to positively identify new fractures at the same site or to distinguish fractures of the right arm/leg from the left, only the first fracture at each of the fracture sites was counted.
Breast cancer was identified by either ICD-9-CM diagnosis codes or ICD-9-CM and CPT procedure codes indicating surgical procedure to treat breast cancer. Binary variables were created to flag the presence of breast cancer in the pre-period and in the 6 follow-up periods. A sensitivity analysis was performed by evaluating breast cancer rates in the post-period in patients without a code indicative of breast cancer in the pre-period.
The results were adjusted for potential confounding using inverse probability of treatment weights (IPTWs) [15–17]. First, a binary logistic regression model was fitted to calculate the propensity score, the probability of a subject initiating raloxifene versus alendronate, conditional on the observed baseline covariates. IPTWs were created using the propensity score: for the raloxifene cohort, the IPTW was [1/propensity score]; for the alendronate cohort, the IPTW was [1/(1 – propensity score)]. The outcomes were weighted by applying the IPTWs to each observation. Covariates in the logistic regression model included demographic characteristics (age, Medicare eligibility, region, urban residence, insurance capitation status, and provider type that was closest to the fill date of index prescription), baseline Deyo Charlson Comorbidity Index, pre-period bone mineral density (BMD) screening or mammography, presence of pre-index fracture, presence of baseline comorbid conditions (HIV/AIDs, liver disease, cancer, osteoporosis, renal disease, rheumatoid arthritis, heart disease, hypertension, gastric disease, vasomotor symptoms, osteonecrosis of the jaw, diabetes, alcoholism, deep venous thrombosis/pulmonary embolism, osteodystrophy, thyroid disease, metabolic disorders, dysphagia, and dyslipidemia), and pre-period use of other medications (glucocorticoids, immunosuppressants, anticonvulsants, estrogen/hormone therapy, hormone deprivation therapy, prescription aspirin/acetaminophen, NSAIDS, opioids, benzodiazepines, and skeletal muscle relaxants).
Statistical tests of significance for differences between raloxifene and alendronate were conducted. Chi-square tests were used to evaluate the statistical significance of differences for categorical variables; independent t tests were used for evaluating significance of continuous variables. To assess the validity of propensity score weighting, standardized differences were calculated to assess group balances before and after the weights were applied to the variables entered as covariates in the propensity model .
To further adjust for the remaining imbalances between the raloxifene and alendronate cohort, we obtained the hazard ratios for vertebral and nonvertebral fractures in 6 separate observation periods. In the nonvertebral fracture model, patients could potentially have multiple fractures of different sites during the observation period. For example, a patient could have a fracture of the lower leg and then later a hip fracture. Under this circumstance, the marginal proportional hazards model is considered as an appropriate specification  and was used to obtain an overall hazard ratio for the hazard of multiple fractures. For the vertebral fracture model, the hazard ratio was obtained using the standard Cox model since we only captured a patient’s first vertebral fracture event due to the challenge of identifying subsequent fracture at the same fracture site using administrative claims. Alendronate served as the reference group in all models. The models were weighted using the IPTWs and the same list of covariates was included in all models: age, pre-index BMD screening or mammography, pre-index use of glucocorticoids, immunosuppressants, anticonvulsants, aspirin/acetaminophen, NSAIDS, opioids, benzodiazepines, skeletal muscle relaxants, pre-index dyslipidemia, rheumatoid arthritis, heart disease, vasomotor symptoms, gastric disease, osteoporosis, and fracture. A sensitivity analysis was conducted which excluded patients with a pre-index fracture diagnosis for the 3-year cohort.
Unweighted patient demographic and baseline clinical characteristics a
Number of Patients
Age (Mean, SD)
Insurance Plan Typesb
Preferred provider organization
Point-of-service plan with capitation
Health maintenance organization
Charlson Comorbidity Index (Mean, SD)
Other Cardiovascular Disease
Ischemic heart disease
Hormone Deprivation Therapy
Pre-period All-cause Healthcare Cost ($, Mean, SD)
Pre-period Osteoporosis-related Healthcare Cost ($, Mean, SD)
Provider closest to Index Prescription
Prior to beginning treatment, a lower proportion of patients treated with raloxifene had a fracture compared to patients treated with alendronate. Differences in pre-period fracture rates ranged from 2.5 to 3.8 percentage points and these differences were significant with the exception of the 8-year cohorts (Table 1). After applying the IPTWs, the pre-period fracture rates for the raloxifene cohorts became higher than the alendronate cohorts in the 1-year (7.9%/raloxifene versus 6.8%/alendronate, p < 0.001), 3-year (7.5% versus 5.9%, p < 0.001), and 5-year (7.2% versus 5.0%, p < 0.001) follow-up period. The weighted pre-period fracture rates were not significantly different between patients treated with raloxifene and alendronate in the 6-year (6.3% versus 5.5%, p = 0.305), 7-year (4.5% and 5.1%, p = 0.563), and 8-year cohort (3.7% versus 5.0%, p = 0.455).
Rate of vertebral and nonvertebral fracture
Unweighted and weighted fracture rates in 1, 3, 5, 6, 7, 8 years of adherent treatment with RLX and ALN
Length of followup
Before propensity weighting
After propensity weighting
Lower 95% CI
Upper 95% CI
Lower 95% CI
Upper 95% CI
Lower 95% CI
Upper 95% CI
Lower 95% CI
Upper 95% CI
After applying the IPTWs, no statistically significant differences were found in the rates of vertebral fractures between the raloxifene and alendronate cohorts in all 6 time periods. There were also no statistically significant differences in the rates of nonvertebral fractures between the raloxifene and alendronate cohorts in each of the time periods, with the exception of the 3-year cohort (7.3%/raloxifene versus 6.7%/alendronate, p = 0.034).
Risk of fracture
The sensitivity analysis including only patients without pre-index fracture and examining the risk of vertebral and nonvertebral fracture in the 3-year cohort showed similar findings. There were no statistically significant differences in the risk of vertebral fracture (HR = 0.78, 95% CI: 0.56 – 1.09, p = 0.149) or nonvertebral fracture (HR = 1.06, 95% CI: 0.95 – 1.19, p = 0.287) during 3 years of adherent treatment with raloxifene or alendronate.
Rate of breast cancer
This study examined fracture risk reduction during adherent use of raloxifene and alendronate in claims data. Patients treated with raloxifene were younger, had a lower pre-period incidence of fracture, and had a lower incidence of osteoporosis diagnosis than patients treated with alendronate. After adjusting for baseline demographic and clinical characteristics by applying the IPTWs, the rates of vertebral and nonvertebral fracture were not significantly different between the patients treated with alendronate and raloxifene in most of the follow-up periods examined. In the 3-year cohort, there was no significant difference in vertebral fracture but a significant difference in nonvertebral fracture (7.3%/raloxifene versus 6.7%/alendronate, p = 0.034) was observed. Once time-to-fracture was taken into consideration, no significant difference in the risk of vertebral or nonvertebral fracture was found in all 6 observation periods. In addition, a similar result was observed when restricting to patients without pre-index fracture in the 3-year cohort. These results suggest that patients experienced a similar reduction in fracture risk during treatment with raloxifene and alendronate.
Randomized clinical trials (RCTs) and claims based retrospective studies examining the effectiveness of bisphosphonates and raloxifene have been published [5–7, 9, 21–23]. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial found the relative risk of nonvertebral fracture (excluding traumatic fractures) for patients treated with raloxifene was not significantly different from patients receiving placebo after 3 years (RR = 0.9, 95% CI: 0.8 - 1.1)  and 4 years of observation (RR = 0.93, 95% CI: 0.81 - 1.06) . In the Fracture Intervention Trial (FIT) of the effect of alendronate, the relative risk of nonvertebral fracture (excluding traumatic fractures) was 0.88 (95% CI: 0.74 - 1.04) among patients without a baseline vertebral fracture at 4 years  and 0.80 (95% CI: 0.63 - 1.01) among patients with a baseline vertebral fracture at 3 years . In a double-blind, randomized comparison of patients treated with alendronate or raloxifene, Recker and colleagues examined postmenopausal women with a femoral neck BMD T-score between −2.5 and −4.0, inclusive, no prevalent vertebral fractures, and no prior bone-active agent use . Although the trial was stopped early, resulting in insufficient power to show non-inferiority between therapies, the primary endpoint of ≥1 new osteoporotic vertebral or nonvertebral fracture occurred in 22/713 alendronate (3.1%) patients and 20/699 raloxifene (2.9%) patients.
Cadarette and colleagues published an insurance claims-based cohort study of 43,135 patients aged at least 65 years who initiated oral bisphosphonates, nasal calcitonin, or raloxifene while enrolled in 2 statewide pharmaceutical benefit programs . The mean age was 79 years and 96% were women. The primary outcome was nonvertebral fracture (hip, humerus, or radius or ulna) within 12 months of treatment initiation. Similar to our findings, significant differences in fracture risk were not found between alendronate, risedronate, and raloxifene. However, among those with a fracture history, patients treated with raloxifene experienced more nonvertebral fractures within 12 months (HR = 1.78, 95% CI: 1.20 to 2.63) compared with those treated with alendronate.
The Cadarette et al. study included Medicare enrollees from 2 states with an average age of 79 years, whereas our study included patients with both commercial and Medicare supplemental insurance, with an average age of 61 to 65 years old. In the Cadarette et al. study, an intent-to-treat approach was used and patients were only required to receive treatment with raloxifene or bisphosphonate at index. Our study took an on-treatment approach and required a minimum MPR of 80% of index medication in each of the follow-up periods. Additionally, patients were required not to switch to another osteoporosis medication during the follow-up period. Our study examined fracture rates during longer treatment periods including 3-, 5-, 6-, 7-, and 8-year cohorts. In addition to nonvertebral fracture, we also evaluated the rate of vertebral fracture and found no significant differences between adherent treatment of raloxifene and alendronate. Our sensitivity analysis based on only patients without pre-index fracture confirmed that there was no significant difference in the risk of vertebral or nonvertebral fracture after 3 years of adherent treatment with raloxifene or alendronate.
Raloxifene has been shown to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer [9, 10]. Recent analysis has suggested that bisphosphonates might also reduce the risk of breast cancer . In this study, the rate of breast cancer was lower in the raloxifene group compared with the alendronate group and the gap between the groups increased in the cohorts with longer duration of follow-up.
Consistent with previous studies, [21, 25] we found that patients treated with raloxifene were younger, less likely to be diagnosed with osteoporosis and have BMD screening, and had lower rates of pre-period fracture than those treated with alendronate. We used IPTW methodology to adjust for these and other confounders and achieved cohort balance after weighting. Due to the limitations of administrative claims data, we were unable to adjust for clinical risk factors such as BMD score. Only clinically-diagnosed fractures recorded in medical claims were analyzed. We included closed fracture, pathological, and stress fracture as a proxy of osteoporosis-related fracture but we were unable to review patients’ medical records to validate this assumption. Due to the difficulty of identifying re-fracture of the same fracture site using medical claims, we only reported the first fracture at a given fracture site. This is a conservative approach with inherent underestimation of the fracture rate. Patients were required to be eligible for insurance and adherent with their medication during the fixed-length period and could not switch to another study medication. This could potentially underestimate the fracture rate, but the same criteria were applied to both treatment groups. This study was not designed to specifically evaluate reduction of breast cancer risk thus we did not specifically control for risk factors such as family history of breast cancer. Additionally, the sample sizes of longer follow-up length cohorts were small which should be taken into consideration when evaluating these findings. Finally, these findings may not be generalizable to populations outside of those evaluated in this study.
Fracture is the major consequence of osteoporosis and prevention of fracture is central to cost containment in the management of osteoporosis. In this study, raloxifene- and alendronate-treated patients had similar weighted fracture rates, and raloxifene-treated recipients had lower rates of breast cancer.
Financial support information
This study was fully funded by Eli Lilly and Company.
Eli Lilly and Company funded this study and collaborated with Truven Health Analytics in study design and reporting of study results. The study team would like to thank Dr. Joseph Lane and Dr. Kenneth Saag for their contribution to the study design. The results of this study were presented as a poster presentation at the American Society for Bone and Mineral Research Conference, Toronto, CA, October 2010.
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