Incidence of invasive breast cancer in postmenopausal women after discontinuation of long-term raloxifene administration.

BACKGROUND: Postmenopausal women with osteoporosis had a 66% relative risk reduction for invasive breast cancer over 8 years of raloxifene therapy in the randomized, placebo-controlled 4-year MORE (Multiple Outcomes of Raloxifene Evaluation) trial and the CORE (Continuing Outcomes Relevant to Evista) trial, a 4-year follow-up to MORE. PATIENTS AND METHODS: The first post hoc analysis examined the effects of raloxifene on the cumulative incidence of invasive breast cancer on a yearly basis. Another analysis compared the incidence of invasive breast cancer in 3967 patients who continued raloxifene for 8 years (RLX-C, n = 2280), discontinued raloxifene after 4 years in MORE (RLX-D, n = 401), or took placebo (n = 1286) for a mean 2.9 years' treatment duration (57,338 patient-years). RESULTS: The unadjusted breast cancer incidence rate was 5.39 per 1000 patient-years in the placebo group compared with 2.26 in the RLX-C group (hazard ratio [HR], 0.41 [95% CI 0.21-0.81]) and 3.59 in the RLX-D group (HR, 0.69 [95% CI 0.23-2.01]). Because the choice of taking the study drug was not randomized in CORE, propensity scores were used to adjust for potential imbalances in baseline characteristics before CORE. Results after adjustment by the propensity score method were similar to the unadjusted results. CONCLUSION: This analysis suggests a persistent effect for breast cancer risk reduction in patients who discontinued raloxifene, although this conclusion is limited by the small sample size.

Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint.

Antiresorptive treatments for postmenopausal osteoporosis have been studied extensively, but due to the volume of published data and lack of head-to-head trials, it is difficult to evaluate and compare their fracture reduction efficacy. The objective of this review is to summarize the results from clinical trials that have fracture as an endpoint and to discuss the factors in study design and populations that can affect the interpretation of the results. Although there are numerous observational studies suggesting that estrogen and hormone replacement therapies may reduce the risk of vertebral and nonvertebral fractures, there is no large, prospective, randomized, placebo-controlled, double-blind clinical trial demonstrating fracture efficacy. The effects of raloxifene, alendronate, risedronate, and salmon calcitonin on increasing bone mineral density (BMD) and decreasing fracture risk have been shown in randomized, placebo-controlled, double-blind clinical trials of postmenopausal women with osteoporosis. Although the increases in lumbar spine BMD vary greatly in these trials, the decrease in relative risk of vertebral fractures is similar among therapies. However, nonvertebral fracture efficacy has not been consistently demonstrated. Combined administration of two antiresorptive therapies results in greater BMD increases, but the effects on fracture risk are unknown. Direct comparisons of clinical trial results should be considered carefully, given the differences in study design and populations. Differences in study design that may influence the efficacy of fracture risk reduction include calcium and vitamin D supplementation, primary fracture endpoints, definition of vertebral deformity or fracture, discontinuation rates, and statistical power. Factors in the study population that may influence fracture efficacy include the age of the population and the proportion of subjects with prevalent fractures. The use of surrogate endpoints such as BMD to predict fracture risk should be approached with caution, as the relationship between BMD changes and fracture risk reduction with antiresorptive therapies is uncertain. Consideration of these results from clinical trials can contribute to clinical judgment in selecting the best treatment option for postmenopausal osteoporosis.

Selective estrogen receptor modulators: an update on recent clinical findings.

Recent clinical data on selective estrogen receptor modulators (SERMs) have provided the basis for reassessment of the SERM concept. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor (ER), causing conformational changes which facilitate interactions with coactivator or corepressor proteins, and subsequently initiate or suppress transcription of target genes. SERM activity is intrinsic to each ER ligand, which accomplishes its unique profile by specific interactions in the target cell, leading to tissue selective actions. We discuss the estrogenic and anti-estrogenic effects of early SERMs, such as clomiphene citrate, used for treatment of ovulation induction, and the triphenylethylene, tamoxifen, which has ER antagonist activity in the breast, and is used for prevention and treatment of ER-positive breast cancer. Since the development of tamoxifen, other triphenylethylene SERMs have been studied for breast cancer prevention, including droloxifene, idoxifene, toremifene, and ospemifene. Other SERMs have entered clinical development more recently, including benzothiophenes (raloxifene and arzoxifene), benzopyrans (ormeloxifene, levormeloxifene, and EM-800), lasofoxifene, pipendoxifene, bazedoxifene, HMR-3339, and fulvestrant, an anti-estrogen which is approved for breast cancer treatment. SERMs have effects on tissues containing ER, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities. Differences in the patterns of action of SERMs suggest that each clinical end point must be evaluated individually, and conclusions about any particular SERM can only be established through appropriate clinical trials.

Use of lowest single lumbar spine vertebra bone mineral density T-score and other T-score approaches for diagnosing osteoporosis and relationships with vertebral fracture status.

For diagnosing osteoporosis, International Society for Clinical Densitometry guidelines suggest using the lowest bone mineral density T-score of the lumbar spine (LS), femoral neck (FN), or total hip (TH). For the LS, use of the total spine (L1-L4) T-score is suggested. Although controversial, some authors have suggested using a single lumbar vertebra of L1-L4 with the lowest T-score to diagnose osteoporosis. We compared the ability of various T-score approaches [lowest single LS vertebra of L1-L4; total spine; FN; TH; and the lowest T-score of total spine, FN, or TH to diagnose osteoporosis in 2560 postmenopausal women from the Multiple Outcomes of Raloxifene Evaluation trial placebo group. The discriminatory ability of each T-score approach to identify women with or without vertebral fracture was compared using the area under receiver-operating characteristic curve. When the lowest single LS T-score of L1-L4 and the total spine T-score were used, 77% and 57% of women were categorized as having osteoporosis, respectively. These T-score approaches had similar ability for discriminating between women with or without prevalent vertebral fractures and for predicting the risk of incident vertebral fractures. The lowest single LS vertebra T-score identified a greater proportion of women with osteoporosis than currently accepted approaches. Thus, the WHO diagnostic classification should not be applied to single vertebral T-scores. This analysis supports the current International Society for Clinical Densitometry position to use the total spine T-score for osteoporosis diagnosis.

Identifying insulin treatment responders with a composite measure: beyond Hba1c < 7% in patients with type 2 diabetes.

OBJECTIVES: Many insulin-treated patients with type 2 diabetes (T2D) do not reach hemoglobin A1c (HbA1c) < 7%, but have clinically relevant HbA1c reductions. Using an integrated database (IDB) of 53 insulin lispro clinical trials and a real-world evidence (RWE) database of T2D patients initiating insulin therapy, an expanded HbA1c measure was used to identify responders to insulin therapy. METHODS: Analysis included 4,908 patients (IDB) and 1,134 patients (RWE) with T2D treated with any insulin regimen with a baseline and ≥1 post-baseline HbA1c. Responders were defined as patients with endpoint HbA1c < 7% (cut point [CP]) and/or either ≥1% absolute (ABS) decrease, and/or ≥10% relative (REL) decrease in HbA1c from baseline. The percentage of responders with CP vs ABS and concordance between ABS and REL were calculated. As the ABS and REL measures were highly correlated (94%), the ABS measure was used to compare characteristics of responders and non-responders by age, diabetes duration, race/ethnicity, baseline HbA1c, and insulin regimen at 24 weeks. RESULTS: In both databases, more responders were identified with ABS or REL (>62%) than CP (<41%). More ABS responders had a baseline HbA1c ≥ 9% and a shorter diabetes duration than non-responders. Basal insulin-treated patients in the IDB had 78.2% responders at 24 weeks, compared to 69.7% with basal/bolus or pre-mixed insulin (75.4%). Results were similar in the IDB and RWE. CONCLUSION: Composite HbA1c measures identified more patients with clinically meaningful responses to therapy than the broadly accepted HbA1c < 7% and may be useful in assessing clinical trials, clinical care, and quality measures.

Occurrence of hypercalciuria in patients with osteoporosis treated with teriparatide.

CONTEXT: Teriparatide (TPTD) [recombinant human PTH(1-34)] given sc once daily transiently increases serum calcium concentrations at 4-6 h after dosing, but its effects on urinary calcium excretion are less well studied. OBJECTIVE: Our objective was to evaluate urinary calcium excretion, a prespecified safety endpoint, for up to 12 months of TPTD treatment. DESIGN: This study included two prospective, randomized, double-blind placebo-controlled clinical trials. PARTICIPANTS: A total of 2074 participants with osteoporosis or low bone mass (study 1, 1637 postmenopausal women; study 2, 437 men) were included. INTERVENTIONS: Participants were given calcium (1000 mg/d) and vitamin D (400-1200 IU/d) supplements, and were randomized to placebo, TPTD 20 mug/d, or TPTD 40 mug/d. MAIN OUTCOME MEASURES: Urinary calcium excretion was measured in 24-h collections at baseline, 1, 6, and 12 months. RESULTS: In each study, baseline urinary calcium excretion was similar among groups. All groups had significantly increased urinary calcium excretion, compared with baseline, at most post-baseline time points. Post-baseline urinary calcium excretion was increased in the TPTD 20 microg/d group by up to 32 mg/d compared with placebo at the same time point (P < 0.05) in study 1. A total of seven participants (0.3%), of which three and four were in the placebo and TPTD groups, respectively, discontinued study drug due to repeated hypercalciuria (>300 mg/d). CONCLUSION: Urinary calcium excretion was increased with TPTD treatment for up to 12 months, compared with placebo and baseline values, but the magnitude of these changes is unlikely to be clinically relevant or warrant urinary calcium monitoring for most patients.

Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass.

UNLABELLED: The double-blind, randomized raloxifene alendronate comparison trial was the first study designed to compare two osteoporosis therapies head-to-head for fracture risk reduction. The original protocol planned to treat 3000 postmenopausal women with alendronate 10 mg/day (ALN) or raloxifene 60 mg/day (RLX) for 5 years, and to recruit women (50-80 years old) with a femoral neck bone mineral density (BMD) T-score between -2.5 and -4.0, inclusive, no prevalent vertebral fractures, and no prior bone-active agent use. The trial was stopped early, due to difficulty in finding treatment-naïve women to meet enrollment goals within the planned timeline, resulting in insufficient power to show non-inferiority between therapies in the primary endpoint (number of women with >or=1 new osteoporotic vertebral or nonvertebral fracture). Except for vertebral fractures, fracture analyses were based upon 1412 of the 1423 women randomized (mean age of 66 years). After 312+/-254 days (mean+/-SD), 22 women in the ALN group and 20 in the RLX group had new vertebral or nonvertebral fractures. Four women in the ALN group and none in the RLX group had moderate/severe vertebral fractures, a pre-specified endpoint (P=0.04). Lumbar spine, femoral neck, and total hip BMD were increased from baseline at 2 years in each group (P<0.001), with greater increases in the ALN group (each P<0.05). Similar numbers of women in each group had >or=1 adverse event and discontinued due to an adverse event. The only adverse events with an incidence that differed between groups were colonoscopy, diarrhea, and nausea; each was more common with ALN treatment (each P<0.05). One woman in each group had a venous thromboembolic event. One case of breast cancer occurred in each group. In summary, as this trial was terminated early, there was insufficient power to compare the fracture risks between alendronate and raloxifene. Safety profiles were as expected from clinical trial and post-marketing reports. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00035971.

The effects of combined raloxifene and oral estrogen on vasomotor symptoms and endometrial safety.

OBJECTIVE: To compare effects of 52 weeks' treatment with either raloxifene 60 mg/day alone (RLX) or in combination with 17beta-estradiol 1 mg/day (RLX + E) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy. DESIGN: In this randomized, double-blind clinical trial, the frequency of vasomotor symptoms, hot flashes, and night sweats was assessed for up to 52 weeks. Endometrial thickness was assessed by transvaginal ultrasonography at baseline and at 12 and 52 weeks. An exit endometrial biopsy was performed at study completion or early termination. RESULTS: The frequency of vasomotor symptoms, hot flashes, and night sweats was unchanged from baseline with RLX but was significantly reduced in women treated with RLX + E, from baseline (all P < 0.001) and the RLX group at 6, 12, 24, 36, and 52 weeks (all P < 0.01). Women in the RLX + E group had significantly increased endometrial thickness (0.74 +/- 0.28 mm, mean +/- SEM) at 52 weeks, from baseline and RLX (P < 0.05), with no statistically significant changes in women treated with RLX. Two women, both in the RLX + E group, had endometrial hyperplasia (one with atypia) on the exit biopsy. CONCLUSIONS: In women transitioning from estrogen-progestin therapy, occurrence of vasomotor symptoms was unchanged from baseline with RLX treatment, but these symptoms were significantly reduced with combined RLX + E therapy. Signs of endometrial stimulation were observed in the RLX + E group. Further studies using different estrogen doses and preparations are needed before concomitant use of raloxifene with systemic estrogens can be recommended.

Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.

UNLABELLED: In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE. INTRODUCTION: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. MATERIALS AND METHODS: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were > or =80% compliant with study medication in CORE. RESULTS: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio [HR], 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene. CONCLUSION: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.

The effect of raloxifene therapy on the risk of new clinical vertebral fractures at three and six months: a secondary analysis of the MORE trial.

OBJECTIVE: Raloxifene treatment (60 mg/day) significantly decreases the risk of new clinical vertebral fractures by 68% at 1 year compared with placebo. The objective of the present analysis is to evaluate the effects of raloxifene on the incidence of new clinical vertebral fractures at 3 and 6 months after initiation of treatment. RESEARCH DESIGN AND METHODS: A double-blind, randomized, placebo-controlled, 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial was conducted in 180 study centers. Postmenopausal women with osteoporosis (N = 7705) were randomized to placebo, or raloxifene at 60 or 120 mg/day. MAIN OUTCOME MEASURES: Vertebral radiographs were obtained when patients reported symptoms suggestive of vertebral fracture at or between clinic visits, which were held at 3 and 6 months, and every 6 months thereafter. If a new adjudicated fracture was found, this was considered as a clinical vertebral fracture. The analyses included all randomized patients with a baseline and at least one follow-up radiograph (n = 6828). RESULTS: One woman treated with raloxifene 60 mg/day (n = 2259) and 10 in the placebo group (n = 2292) had a clinical vertebral fracture in the first 6 months, resulting in a 90% relative risk (RR) reduction [RR 0.10 (95% CI 0.01, 0.63)] and a 0.39% absolute risk reduction (ARR). Similar results were observed with raloxifene 120 mg/day at 6 months. When the raloxifene groups were pooled, a significant (p = 0.034) decrease in clinical vertebral fracture risk [RR 0.20 (95% CI 0.03, 0.90), ARR 0.17%] was seen as early as 3 months. CONCLUSION: The risk of new clinical vertebral fractures was reduced after 3 or 6 months of raloxifene.

Similar proportions of women lose bone mineral density with raloxifene or alendronate treatment.

The ISCD recommends that bone mineral density (BMD) be monitored in patients undergoing antiresorptive therapy to identify patients with a significant BMD loss. This analysis compares the proportions of postmenopausal women treated with raloxifene 60 mg/d (n=82) or alendronate 10 mg/d (n=83) who had significant BMD loss in a randomized, double-blind, placebo-controlled trial that assessed changes in lumbar spine and femoral neck BMD from baseline to 1 yr, measured using dual-energy X-ray absorptiometry. According to ISCD criteria, significant BMD loss was defined as greater than the least significant change, calculated as precision multiplied by 2.77 (95% confidence interval). Assuming a 1% precision at the lumbar spine, the proportions of women with a loss of BMD greater than the least significant change (3%) were similar (p>0.05) between the raloxifene (3%) and alendronate (2%) groups. Assuming 2% precision at the femoral neck, the proportions of women with a loss greater than the least significant change (6%) were similar (p>0.05) between the raloxifene (1%) and alendronate (2%) groups. In conclusion, similar proportions of women did not respond to raloxifene or alendronate therapy, as measured by changes in lumbar spine or femoral neck BMD, when precision error was taken into account.

Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis.

BACKGROUND: Raloxifene hydrochloride therapy reduces the risk for vertebral fractures at 3 years, but the effects on clinical vertebral fractures in the first year are not known. METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial enrolled 7705 women with osteoporosis, defined by prevalent vertebral fractures and/or a bone mineral density (BMD) T score at or below -2.5, who were treated with placebo or raloxifene at a dosage of 60 or 120 mg/d for 3 years. New clinical vertebral fractures were defined as incident vertebral fractures associated with signs and symptoms suggestive of vertebral fractures, such as back pain, and were diagnosed by means of postbaseline adjudicated spinal radiographs. Scheduled spinal radiographs were obtained at baseline and at 2 and 3 years. In addition, unscheduled spinal radiographs were obtained in women who reported signs or symptoms suggestive of vertebral fracture, and these radiographs subsequently underwent adjudication. If an adjudicated fracture was identified, this was also considered a clinical fracture. RESULTS: At 1 year, raloxifene, 60 mg/d, decreased the risk for new clinical vertebral fractures by 68% (95% confidence interval [CI], 20%-87%) compared with placebo in the overall study population, and by 66% (95% CI, 23%-89%) in women with prevalent vertebral fractures, who are at greater risk for subsequent fracture. The risk for clinical vertebral fractures in the raloxifene, 60 mg/d, group was decreased by 46% (95% CI, 14%-66%) at 2 years and by 41% (95% CI, 17%-59%) at 3 years. The cumulative incidence of new clinical vertebral fractures was lower in the group receiving raloxifene, 60 mg/d, compared with placebo (P<.001). We found no significant differences in the risk reductions for clinical vertebral fractures between the raloxifene groups at 1, 2, or 3 years. CONCLUSION: The early risk reduction for new clinical vertebral fractures with 1 year of raloxifene treatment was similar to that reported with other antiresorptive agents.

Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy.

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene-treated patients had a statistically significantly lower vertebral fracture risk compared with placebo-treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.

Efficacy and safety of raloxifene 60 milligrams/day in postmenopausal Asian women.

In healthy Caucasian postmenopausal women, raloxifene increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and lowers low-density lipoprotein (LDL) cholesterol, without effects on high-density lipoprotein (HDL) cholesterol and triglycerides. This randomized, double-blind study examines the effects of raloxifene 60 mg/d (n = 483) or placebo (n = 485) in healthy postmenopausal Asian women (mean age 57 yr) from Australia, Hong Kong, India, Indonesia, Malaysia, Pakistan, Philippines, Singapore, Taiwan, and Thailand. Serum osteocalcin, serum N-telopeptide, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were assessed at baseline and 6 months. Lumbar spine BMD was measured at baseline and 1 yr in 309 women from 4 countries. Clinical adverse events were recorded at each interim visit. At 6 months, raloxifene 60 mg/d significantly decreased osteocalcin, N-telopeptide, total cholesterol, and LDL cholesterol by medians of 15.9%, 14.6%, 5.3%, and 7.7%, respectively, from placebo. Changes in HDL cholesterol and triglycerides were similar between raloxifene and placebo. Raloxifene 60 mg/d increased mean lumbar spine BMD (1.9%) from placebo at 1 yr (P = 0.0003). The incidences of hot flashes (placebo 3.5%, raloxifene 5.6%, P = 0.12), and leg cramps (placebo 2.7%, raloxifene 4.3%, P = 0.16) were not different between groups. No case of venous thromboembolism was reported. The effects of raloxifene 60 mg/d on bone turnover, BMD, and serum lipids in healthy postmenopausal Asian women were similar to that previously reported in Caucasian women.

Comparison of fracture, cardiovascular event, and breast cancer rates at 3 years in postmenopausal women with osteoporosis.

OBJECTIVES: To compare event rates for osteoporotic fractures, cardiovascular events, and breast cancer in postmenopausal women with osteoporosis. DESIGN: A prospective, observational study of the placebo group in the double-blind, randomized Multiple Outcomes of Raloxifene Evaluation trial. SETTING: One hundred eighty clinical research centers in 25 countries. PARTICIPANTS: Postmenopausal women (n=2,565, mean age=67) with osteoporosis were given calcium (500 mg/d) and vitamin D (400-600 IU/d) supplements. MEASUREMENTS: The occurrence of at least one new fracture, cardiovascular event, or breast cancer diagnosis at 3 years was identified and adjudicated. RESULTS: The occurrence of any fracture was the most common event in these women. In women without prevalent vertebral fractures (n=1,627), the event rates per 1,000 patient-years were 45.4 for any fracture, 15.2 for vertebral fracture, 4.7 for clinical vertebral fracture, 0.9 for hip fracture, 8.3 for any cardiovascular event, and 5.2 for all breast cancer. In women with prevalent vertebral fractures (n=938), the event rates per 1,000 patient-years were 117.4 for any new fracture, 77.1 for new vertebral fracture, 25.7 for clinical vertebral fracture, 5.8 for hip fracture, 15.1 for any cardiovascular event, and 2.6 for all breast cancer. The effect of prevalent fracture status on event rates was not dependent on whether women were older or younger than 65, but women aged 65 and older had a 3.6 times greater occurrence of cardiovascular events than younger women, irrespective of prevalent fracture status. CONCLUSION: These data on the relative incidence of clinically significant skeletal and extra-skeletal outcomes may be useful in choosing an agent for health maintenance for postmenopausal women with osteoporosis.

Raloxifene reduces risk of vertebral fractures [corrected] in postmenopausal women regardless of prior hormone therapy.

OBJECTIVE: We examined whether past use of hormone therapy influences the effects of raloxifene on the risk of new vertebral fracture, cardiovascular events, or breast cancer. STUDY DESIGN: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial examined vertebral fracture incidence as the primary endpoint, breast cancer incidence as a secondary endpoint. Cardiovascular events were collected as secondary safety endpoints. POPULATION: The MORE trial enrolled 7705 postmenopausal women. Of the 7682 women who reported their previous HT use status, 29% used HT before screening. OUTCOMES MEASURED: Separate logistic regression models analyzed the relationships between prior HT use and the risk of vertebral fracture, cardiovascular events, or breast cancer. Interaction terms with P<.10 were considered to be statistically significant. Confidence intervals for relative risks (RR) were calculated using the Mantel-Haenszel method. RESULTS: Raloxifene 60 mg/d, the clinically approved dose for osteoporosis prevention and treatment, reduced the risk of vertebral fractures by 54% (RR=0.46) and 29% (RR=0.71) in women with and without prior HT use, respectively (interaction P=.05). A lower incidence of invasive breast cancer in women with prior HT use (RR=0.23) and in women without prior HT use [RR=0.31; interaction P=.60] was observed in women receiving raloxifene (pooled doses). Irrespective of prior HT use, women treated with raloxifene (pooled doses) had no change in incidence of cardiovascular events (interaction P=.56). CONCLUSIONS: The risk of vertebral fractures was lower in women treated with raloxifene, regardless of prior HT use, but there was a suggestion that the effect was greater in women who had used HT. Women randomized to receive raloxifene exhibited a decreased incidence of invasive breast cancer, compared with women receiving placebo. No change occurred in the incidence of cardiovascular events, regardless of prior HT use.

A randomized, cross-over comparison of preference between two reusable insulin pen devices in pen-naïve adults with diabetes.

OBJECTIVE: To evaluate final preference and ease-of-use attributes of two reusable pen injectors, HPS (HumaPen Savvio) and HPL (HumaPen Luxura), in adults with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 1 day, randomized, two-period crossover, open-label, simulated-injection study in 203 pen-naïve subjects (mean age 58.4 years). MAIN OUTCOME MEASURES: Functional and ease-of-use attributes of insulin pen injectors were evaluated using a 16-item survey (7 point scale) where higher scores reflected greater preference and equal scores reflected no preference. The primary objective was final pen preference, with statistical gate-keeping to the ease of detecting an insufficient remaining dose (IRD) of insulin upon dose selection. RESULTS: For final overall pen preference, HPS was chosen by 150 of 203 subjects (73.9%, 95% confidence interval [CI] = 67.3%-79.8%). For the IRD item, 'It is easy to know when there is not enough insulin left in the cartridge for the dose I need before I inject', HPS was preferred by 94 of 107 subjects with a preference (87.9%, 95% CI = 80.1%-93.4%). In 14 of the remaining 15 survey items, 64.3% to 87.7% of subjects with a preference statistically significantly preferred HPS over HPL. To confirm the results, subjects with no preference for either pen, which ranged between 95 and 148, were included in a Bayesian analysis. KEY LIMITATIONS: Injection simulation, use of an unvalidated survey, and office setting which did not allow for direct clinical experience with the devices. CONCLUSIONS: The majority of pen-naïve subjects preferred HPS over HPL. For all ease-of-use attributes, the majority of subjects with a preference chose HPS over HPL. Some attributes of both pens were equally acceptable, as many subjects had no preference.

Expectations about insulin therapy, perceived insulin-delivery system social acceptability, and insulin treatment satisfaction contribute to decreases in insulin therapy self-efficacy in patients with type 2 diabetes after 36 weeks insulin therapy.

BACKGROUND: Self-efficacy plays a critical role in diabetes self-care. Herein we explore factors contributing to decreased insulin therapy self-efficacy in insulin-naïve patients with type 2 diabetes mellitus (T2DM) initiating and managing insulin therapy over 36 weeks. METHODS: The study was conducted within an international, randomized clinical trial comparing two insulin therapies administered by insulin pen in patients with T2DM inadequately controlled with oral antihyperglycemic medications. Patients completed the Self-Efficacy about Insulin Therapy Questionnaire (SEITQ) at baseline and endpoint. Patients also completed patient-reported measures assessing expectations about insulin therapy at baseline and perceptions about insulin therapy and insulin-delivery system (IDS) satisfaction at endpoint. Baseline and endpoint SEITQ scores were compared. Using prespecified criteria, patients were classified as having "decreased" or "no change/improved" insulin self-efficacy. Demographic, clinical, and patient-reported variables were entered into a logistic regression model with decreased insulin self-efficacy (yes or no) as the dependent variable. RESULTS: Baseline and endpoint SEITQ data were available for 450 insulin-naïve T2DM patients (mean age 59 years; 53% female; 57% Caucasian; mean baseline HbA1c 9.4%; 80.0 mmol/mol). Insulin therapy self-efficacy improved from baseline to endpoint (74.0 vs 77.5; P<0.001). Logistic regression analysis indicated that lower IDS satisfaction (P<0.0001), lower IDS social acceptability (P=0.004), and more positive expectations of insulin therapy (P<0.0001) were associated with decreased insulin self-efficacy. CONCLUSIONS: A candid discussion between clinicians and their insulin-naïve T2DM patients about the benefits and challenges of insulin therapy may prevent unrealistic expectations that could potentially undermine insulin self-efficacy.

Bone formation markers in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate.

Reduced osteoblast function is a primary defect in glucocorticoid-induced osteoporosis (GIO), and is reflected by decreased biochemical markers of bone formation, such as serum osteocalcin (OC) and procollagen type I N-terminal propeptide (PINP). This analysis compared the effects of teriparatide and alendronate on OC and PINP in patients with GIO. In a double-blind study, women (N=159) and men (N=38) with GIO were randomized to either teriparatide 20 mug/day by subcutaneous injection or to alendronate 10 mg/day orally. OC and PINP were measured in fasting-state serum samples obtained at baseline and at 1, 6, 18, and 36 months. Baseline bone formation markers were below the reference interval (low) in 33% of patients for OC and in 4% of patients for PINP. On teriparatide therapy, the median OC and PINP levels increased by 92% and 108%, respectively, and this resulted in only 12% and 1% of patients being low at 6 months. On alendronate therapy, the median OC and PINP levels decreased by 40% and 53%, respectively, and this resulted in 68% and 34% of patients being low at 6 months. We conclude that bone formation as determined by surrogate markers was increased in teriparatide-treated patients with GIO and decreased in alendronate-treated patients with GIO.

Antiplatelet therapy use and the risk of venous thromboembolic events in the Raloxifene Use for the Heart (RUTH) trial.

BACKGROUND: Raloxifene use in postmenopausal women with osteoporosis increases the risk of venous thromboembolic events (VTE) 2-fold compared with placebo. Platelet activation is involved in the pathophysiology of arterial thromboses more than venous thromboses, but aspirin may reduce VTE risk associated with estrogen use. This analysis examines the effects of concomitant antiplatelet therapy on VTE risk in raloxifene-treated women. METHODS: In the Raloxifene Use for the Heart (RUTH) trial, 10,101 postmenopausal women from 177 sites in 26 countries at increased risk of coronary heart disease (CHD) (primary prevention cohort) or with CHD (secondary prevention cohort) were randomized to placebo or raloxifene 60 mg/day and followed for a median 5.6 years. Reports of clinical symptoms of VTE were assessed. Concomitant use of antiplatelet agents (aspirin, clopidogrel, ticlopidine, dipyridamole) was allowed. Cox proportional hazard models, with use of warfarin, presence of fracture, and hospitalization as covariates, were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Overall, raloxifene use was associated with an increased VTE risk (HR 1.44, 95% CI 1.06-1.95) vs. placebo. Most women (72%) reported using aspirin, and 14.2% reported using nonaspirin antiplatelet agents during the study period. Users of antiplatelet agents were older, more likely to have CHD, and more likely to be hyperlipidemic. They had a higher VTE risk than nonusers. No difference in VTE risk was observed in women who used raloxifene alone vs. those who used raloxifene with antiplatelet agents during the study. The increase in VTE risk with raloxifene compared with placebo was not different between women who used antiplatelet agents at baseline (HR 1.44, 95% CI 0.98, 2.10) and those who did not use antiplatelet agents (HR 1.37, 95% CI 0.83, 2.27) (interaction p = 0.88). Similar conclusions were noted for aspirin and nonaspirin antiplatelet use. CONCLUSIONS: In RUTH, postmenopausal women treated with raloxifene had an increased risk of VTE compared with placebo. Concomitant use of aspirin or nonaspirin antiplatelet agents along with raloxifene did not change VTE risk.