Kristine D. Harper

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.

The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from the Multiple Outcomes of Raloxifene Evaluation Study.

OBJECTIVE To examine the effect of both prevalent and incident vertebral fractures on health-related quality of life (HRQOL) in postmenopausal women with osteoporosis and to characterize the effect of prevalent vertebral fractures on HRQOL with respect to number, location, severity, and adjacency. METHODS Participants were a subset of women (n = 1,395, mean age 68.5 years) from the Multiple Outcomes of Raloxifene Evaluation trial who had low bone mineral density and/or prevalent vertebral fractures. Vertebral fractures were measured by radiography at baseline, 2 years, and 3 years. HRQOL was assessed using the Osteoporosis Assessment Questionnaire (OPAQ), a validated disease-targeted instrument, at baseline and annually for 3 years. RESULTS Both prevalent and incident radiographic vertebral fractures were associated with decreased HRQOL. At baseline, women with a prevalent vertebral fracture had significantly lower OPAQ scores on physical function, emotional status, clinical symptoms, and overall HRQOL compared with women without a prevalent fracture (all P < 0.01). HRQOL scores were lower with each subsequent fracture. The effect of prevalent vertebral fracture was dependent on the location within the spine and was strongest in the lumbar region (L1-L4). Incident vertebral fractures significantly decreased OPAQ scores on physical function, emotional status, clinical symptoms, and overall HRQOL (all P < 0.001). CONCLUSION Our findings demonstrate the importance of treating postmenopausal women who have prevalent vertebral fractures to prevent further decreases in HRQOL associated with subsequent incident vertebral fracture.

Bone Histomorphometric and Biochemical Marker Results of a 2-Year Placebo-Controlled Trial of Raloxifene in Postmenopausal Women†

Raloxifene is a selective estrogen receptor modulator that has been shown to increase bone density. The purpose of this study was to examine the effects of raloxifene on bone tissue by studying bone biopsy specimens before and after 2 years of raloxifene or placebo therapy. The women in this study were participants of the double‐blind, placebo‐controlled, multicenter study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Subjects from two U.S. sites and two European sites were included if they consented to a bone biopsy. Iliac crest bone biopsies were performed at baseline and after 2 years. Tetracycline labeling preceded each biopsy. A total of 65 paired biopsy specimens were evaluated with 25, 22, and 18 patients in the placebo, raloxifene HCl (60 mg) and raloxifene HCl (120 mg) treatment groups, respectively. They were analyzed using standard histomorphometry. None of the biopsy specimens showed evidence of toxic effects on bone or bone cells or met criteria for osteomalacia. Biopsy specimens in the placebo and raloxifene groups had the appearance of normal bone, with no evidence of marrow fibrosis or increases in the amount of woven bone or numbers of empty osteocyte lacunae. Compared with the baseline, the bone formation rate (BFR) decreased significantly in both raloxifene groups. The change in BFR in the group treated with 120 mg of raloxifene was −62.3%, which was significantly lower than the change in the placebo group of −21.0% (p = 0.03). No change in resorption parameters could be measured by histomorphometry, but there was a decrease in urinary type I collagen excretion. The results from this study suggest that raloxifene has actions on bone tissue that are similar to those observed with estrogen. The depressive effects on bone remodeling are less marked than the effects seen with alendronate.

Effects of Raloxifene on Fracture Severity in Postmenopausal Women with Osteoporosis: Results from the MORE Study

Abstract: Raloxifene reduces the risk of new vertebral fractures, but its effect on the severity of these new fractures has not been determined. The MORE (Multiple Outcomes of Raloxifene Evaluation) trial studied the effects of placebo, raloxifene 60 or 120 mg/day in 7705 postmenopausal women with osteoporosis. Radiologists assessed new vertebral fractures from radiographs and graded the fracture severity as normal (no fracture) or mild, moderate or severe. New clinical vertebral fractures were defined as new vertebral fractures associated with symptoms, such as back pain, and confirmed in radiographs. In the total study population, the majority (76.4%) of the women who experienced clinical vertebral fractures were diagnosed with new moderate/severe vertebral fractures. In turn, women with moderate/severe vertebral fractures in the overall population were more likely to experience clinical symptoms suggestive of fracture than were women who had new mild-only vertebral fractures. The incidence of new mild-only and moderate/severe fractures was the same in women without prevalent vertebral fractures, but the incidence of new moderate/severe fractures was 2 to 3 times higher than that for new mild-only fractures in women with prevalent vertebral fractures. Raloxifene 60 mg/day decreased the risk of at least 1 new moderate/severe vertebral fracture by 61% in women without prevalent vertebral fractures [RR 0.39 (95% CI 0.17, 0.69)], and by 37% in women with prevalent vertebral fractures [RR 0.63 (95% CI 0.49, 0.83)] at 3 years. The risk reductions for at least 1 new moderate/severe vertebral fracture were not significantly different between the raloxifene doses, in women with and without prevalent vertebral fractures. The effects of raloxifene on significantly decreasing the risk of new moderate/severe vertebral fractures may explain the risk reduction for new painful clinical vertebral fractures observed with raloxifene, and is particularly important in postmenopausal women with severe osteoporosis who are at higher risk for moderate or severe fractures.

Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial on the effects of three years of raloxifene treatment on glycemic control and cardiovascular disease risk factors in women with and without type 2 diabetes.

BACKGROUND The long-term effects of the selective estrogen-receptor modulator raloxifene hydrochloride on glycemic control and markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes mellitus are unknown. OBJECTIVE The aim of this analysis was to compare the effects of 3-year treatment with raloxifene 60 mg/d versus placebo on glycemic control and markers of cardiovascular disease risk in osteoporotic postmenopausal women with and without type 2 diabetes. METHODS In this analysis, we included women from the Multiple Outcomes of Raloxifene Evaluation trial (a multicenter, double-masked trial) who were randomized to receive raloxifene 60 mg/d (n = 2557) or placebo (n = 2576). Baseline and 36-month fasting plasma glucose (FPG) and total cholesterol (TC) were measured for all participants. Glycated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein (apo) A-I, apo B, and fibrinogen were assessed in approximately 1800 participants from selected larger sites. RESULTS At baseline, 202 of all 5133 women (3.9%) had type 2 diabetes. Of the approximately 1800 women who were assessed for HbA1c, LDL-C, TGs, apo A-I, apo B, and fibrinogen, 70 (3.9%) had type 2 diabetes at baseline. Compared with placebo, raloxifene did not significantly affect HbA1c, FPG, HDL-C, or TGs in women with or without diabetes. Raloxifene produced statistically significant reductions in TC, LDL-C, and fibrinogen both in women with diabetes (all P < or = 0.004) and without diabetes (all P < 0.001). Raloxifene significantly increased apo A-I (P < 0.001) and reduced apo B (P < 0.001) in women without diabetes. In the raloxifene-treated group, body weight increased by a mean 0.31 kg (P < 0.001) in women without diabetes. CONCLUSIONS In osteoporotic postmenopausal women with or without type 2 diabetes, raloxifene 60 mg/d did not affect glycemic control and had favorable effects on TC, LDL-C, and fibrinogen levels.

Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials.

Dulaglutide is a once‐weekly glucagon‐like peptide‐1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin‐to‐creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean ± standard deviation values: dulaglutide vs placebo: 87.8 ± 17.7 vs 88.2 ± 17.9 mL/min/1.73 m2, P = .075; dulaglutide vs active comparators: 89.9 ± 16.7 vs 88.8 ± 16.3 mL/min/1.73 m2, P = .223; and dulaglutide vs insulin glargine: 85.9 ± 18.2 vs 83.9 ± 18.6 mL/min/1.73 m2, P = .423). Lower UACR values were observed for dulaglutide vs placebo, active comparators and insulin glargine (at 26 weeks, median [Q1‐Q3] values were: dulaglutide vs placebo: 8.0 [4.4‐20.4] vs 8.0 [4.4‐23.9] mg/g, P = .023; dulaglutide vs active comparators: 8.0 [4.4‐21.2] vs 8.9 [4.4‐27.4] mg/g, P = .013; and dulaglutide vs insulin glargine: 8.9 [4.4‐29.2] vs 12.4 [5.3‐50.5] mg/g, P = .029). AEs reflecting potential acute renal failure were 3.4, 1.7 and 7.0 events/1000 patient‐years for dulaglutide, active comparators and placebo, respectively. In conclusion, dulaglutide treatment of clinical trial participants with T2D did not affect eGFR and slightly decreased albuminuria.

Effect of raloxifene on serum triglycerides in postmenopausal women: Influence of predisposing factors for hypertriglyceridemia

BACKGROUND Estrogen increases serum triglyceride (TG) levels and induces hypertriglyceridemia in susceptible women. The effect of raloxifene (RLX), a selective estrogen-receptor modulator, on serum TG has not been studied in detail. OBJECTIVE The purpose of this study was to examine the effect of RLX on serum TG levels in postmenopausal women with and without osteoporosis, including those with predisposing factors for hypertriglyceridemia. METHODS Fasting serum TG levels were assessed over 36 months in 2738 osteoporotic postmenopausal women (mean age, 67 years) assigned to placebo or RLX (60 or 120 mg/d) in an osteoporosis treatment trial and over 24 months in 1318 postmenopausal women without osteoporosis (mean age, 54 years) assigned to placebo or RLX (60 or 150 mg/d) in 3 osteoporosis prevention trials. RESULTS In the osteoporosis treatment trial, the median serum TG concentration decreased in all groups, but significantly more in the placebo group (placebo, -3.4%; RLX 60 mg/d, -1.4%; RLX 120 mg/d, -1.3%; P = 0.002). In the osteoporosis prevention trials, the percentage change in median serum TG concentration was not significantly different among treatments (P = 0.22). Among women with varying degrees of hypertriglyceridemia at baseline (>2.82, >3.39, and >4.51 mmol/L), the median serum TG level at the end of the study decreased from baseline in all groups, with no significant differences among treatments (P > or = 0.13). The effect of RLX on serum TG level was not influenced by age, smoking status, use of alcohol, or presence of diabetes (P > or = 0.10 for all interactions). Among women in the highest tertile of body mass index (>26.4 kg/m2), RLX increased serum TG levels significantly compared with placebo (placebo, -3%; RLX 60 mg/d, 6%: RLX 120 mg/d, 4%; P < 0.05); the absolute increase from baseline with RLX in this subgroup was 0.05 mmol/L (4.4 mg/dL). CONCLUSIONS RLX did not increase serum TG in postmenopausal women overall or among women with elevated TG levels or evidence of diabetes at baseline. TG levels increased slightly but statistically significantly in women in the upper tertile of body mass index who were treated with RLX.

Effect of raloxifene on the incidence of elevated low density lipoprotein (LDL) and achievement of LDL target goals in postmenopausal women

SUMMARY Objective: To determine the extent to which raloxifene can maintain low density lipoprotein cholesterol (LDL-C) levels below 160 mg/dL or reduce elevated LDL-C levels to below lipidlowering goals in postmenopausal women. Patients and methods: The Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial randomized 7705 postmenopausal women to placebo or raloxifene (60 mg or 120 mg) daily for a core treatment phase of 3 years. Changes in LDL-C and other serum lipids in a subset of women was a predefined secondary objective. This post-hoc analysis included the 2413 women who did not take lipid-lowering medications at any time during the trial and for whom LDL-C measurements were available. The threshold for high LDL-C (≥ 160 mg/dL) and LDL-C lipid-lowering goals were defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines. Results: The percent of women with LDL-C < 160 mg/dL was comparable between treatment groups at baseline (placebo, 57.5%; raloxifene 60 mg, 56.4%; raloxifene 120 mg, 56.8%). At 3 years, the percent of these women whose LDL-C had increased to above 160 mg/dL was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 65% (95% CI, 44%–78%) and 64% (95% CI, 43%–77%), respectively. Among women with elevated (defined for these analyses as ≥ 160 mg/dL) LDL-C at baseline, the proportion having elevated LDL-C at 3 years was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 32% (95% CI, 24%–40%) and 40% (95% CI, 32%–48%), respectively. Fifty percent and 13% of these women achieved LDL-C goals of <160 mg/dL and <130 mg/dL, respectively (P <0.001 vs. placebo for both) in the raloxifene 60 mg group, with similar results for the raloxifene 120 mg group. Conclusions: In postmenopausal women with osteoporosis not taking concurrent lipid-lowering therapy, raloxifene significantly reduced the incidence of LDL-C ≥ 160 mg/dL and significantly increased the proportion achieving LDL-C goals for lipid-lowering compared with placebo. Whether these and other effects of raloxifene on cardiovascular risk markers will improve cardiovascular outcomes requires further study.

Low incidence of anti-drug antibodies in patients with type 2 diabetes treated with once-weekly glucagon-like peptide-1 receptor agonist dulaglutide.

Therapeutic administration of peptides may result in anti‐drug antibody (ADA) formation, hypersensitivity adverse events (AEs) and reduced efficacy. As a large peptide, the immunogenicity of once‐weekly glucagon‐like peptide‐1 (GLP‐1) receptor agonist dulaglutide is of considerable interest. The present study assessed the incidence of treatment‐emergent dulaglutide ADAs, hypersensitivity AEs, injection site reactions (ISRs), and glycaemic control in ADA‐positive patients in nine phase II and phase III trials (dulaglutide, N = 4006; exenatide, N = 276; non‐GLP‐1 comparators, N = 1141). Treatment‐emergent dulaglutide ADAs were detected using a solid‐phase extraction acid dissociation binding assay. Neutralizing ADAs were detected using a cell‐based assay derived from human endothelial kidney cells (HEK293). A total of 64 dulaglutide‐treated patients (1.6% of the population) tested ADA‐positive versus eight (0.7%) from the non‐GLP‐1 comparator group. Of these 64 patients, 34 (0.9%) had dulaglutide‐neutralizing ADAs, 36 (0.9%) had native‐sequence GLP‐1 (nsGLP‐1) cross‐reactive ADAs and four (0.1%) had nsGLP‐1 neutralization ADAs. The incidence of hypersensitivity AEs and ISRs was similar in the dulaglutide versus placebo groups. No dulaglutide ADA‐positive patient reported hypersensitivity AEs. Because of the low incidence of ADAs, it was not possible to establish their effect on glycaemic control.

Assessment of Pancreas Safety in the Development Program of Once-Weekly GLP-1 Receptor Agonist Dulaglutide

OBJECTIVE To assess the risk of acute pancreatitis during treatment with glucagon-like peptide 1 receptor agonist dulaglutide, placebo, and active comparators across phase 2/3 dulaglutide trials. RESEARCH DESIGN AND METHODS A total of 6,005 patients with type 2 diabetes participated (dulaglutide group N = 4,006 [dose range 0.1–3.0 mg]; active comparator group [metformin, sitagliptin, exenatide twice daily, insulin glargine] N = 1,541; placebo group N = 703; 245 placebo-treated patients subsequently received dulaglutide or sitagliptin and were also included in these groups) for up to 104 weeks. The following events were adjudicated: investigator-reported pancreatitis, adverse events (AEs) of severe or serious abdominal pain of unknown etiology, and confirmed asymptomatic increases in pancreatic enzymes ≥3× the upper limit of normal range. RESULTS Overall, 203 events from 151 patients underwent adjudication (dulaglutide group n = 108; comparator group including placebo n = 43). Acute pancreatitis was confirmed by adjudication in seven patients (dulaglutide n = 3, placebo n = 1, sitagliptin n = 3). Exposure-adjusted incidence rates were as follows: dulaglutide group 0.85 patients/1,000 patient-years, placebo group 3.52 patients/1,000 patient-years, sitagliptin group 4.71 patients/1,000 patient-years. No events of pancreatitis were confirmed by adjudication in patients treated with exenatide twice daily, metformin, or glargine. Increases in median values of lipase and pancreatic amylase within the normal range were observed with all treatments except glargine. These changes were not associated with AEs. CONCLUSIONS The exposure-adjusted incidence rate of acute pancreatitis in dulaglutide-treated patients was similar to the rates with placebo, with few reported cases during the entire program.