Oral ibandronate in postmenopausal osteoporotic women alters micromechanical properties independently of changes in mineralization.

Postmenopausal osteoporotic (PMOP) women treated with ibandronate had higher bone mineral density, lower bone turnover, and decreased incidence of new vertebral fractures. The aim of this study was to investigate the effect of daily or intermittent oral ibandronate on the degree of mineralization (DMB) of bone and microhardness (Hv) at the bone tissue and bone structural unit (BSU) levels. A total of 110 iliac biopsies were taken from patients treated for 22 or 34 months with an oral placebo (n = 36), 2.5 mg daily oral ibandronate (n = 40), or 20 mg intermittent oral ibandronate (n = 34). These regimens provide annual cumulative exposures (ACEs) that are about half of the therapeutic doses currently licensed for PMOP women. DMB and Hv were measured at the global level (i.e., cortical or cancellous) and the focal level (i.e., BSU). At the global level, DMB and its distribution were not significantly different from placebo after 22 and 34 months of treatment. Hv was significantly higher in the cortical, cancellous, and total bone after 22 and 34 months of ibandronate versus placebo for both regimens. At the focal level, DMB and Hv, measured simultaneously in 3,760 BSUs, were significantly and positively correlated in all groups (r = 0.59-0.65, p < 0.0001). However, analysis of covariance highlighted the differences in the y intercepts of the linear regressions of the placebo- and ibandronate-treated groups. We infer that a low ACE of oral ibandronate altered the bone micromechanical properties irrespective of changes in secondary mineralization.

Association of age and overall survival in capecitabine-treated patients with metastatic breast cancer in clinical trials.

We sought to determine if an association exists between age and capecitabine efficacy among patients with metastatic breast cancer (MBC). Pooled analysis of five phase II or III registration trials of capecitabine 2,500-2,510 mg/m(2)/day for 2 weeks and 1 week off, or combination therapy was performed. Four trials enrolled patients previously exposed to other chemotherapy, generally a taxane. Of 570 patients, 193 (34%) were 18-49 years old, 246 (43%) were 50-64, and 131 (23%) were ≥ 65. Median average daily dose was 2,067 mg/m² in the 18- to 49-year-old group and 2,105 mg/m² in the 50-64 and ≥ 65 year groups. Overall survival (OS) in all groups was similar by log-rank test for the individual trials (P = 0.71-0.95) and Cox regression of the pooled trials. Univariate analysis demonstrated no difference in clinical benefit or objective response between groups. Treatment failure analysis showed 283 (50%) patients experienced progressive disease, while 114 (20%) withdrew for safety. Serious adverse events (AEs) occurred in 71 (36.8%), 85 (34.6%), and 59 (45.0%) patients in the 18-49, 50-64, and ≥ 65 years groups, respectively. There was no statistically significant association between age and OS, clinical benefit, or objective response in patients with MBC treated with capecitabine. Frequency of AEs and serious AEs was not related to age at treatment, although women ≥ 65 years were more likely to withdraw from treatment because of an AE than younger women.

Cost comparison of capecitabine in patients with breast cancer.

OBJECTIVE: Capecitabine may have a higher acquisition cost compared with other select chemotherapy agents; however, its use is not associated with many of the costs typically encountered with intravenous chemotherapy, such as costs incurred through administration procedures and the management of subsequent tolerability issues. This study compared the cost of capecitabine- and taxane-based regimens in the treatment of breast cancer. STUDY DESIGN: Thomson Reuters MarketScan, a US employer claims database, was used to identify patients with a breast cancer diagnosis between 2000 and 2005 and at least one chemotherapy claim or hormone treatment in 2004 or 2005. METHODS: Cost data for treatment administration and management of selected chemotherapy-related adverse events were collected. Multivariate analyses were performed to adjust for differences in patient demographic and clinical factors. RESULTS: A total of 3630 patients were included in this analysis; 4216 treatment episodes were recorded. Mean unadjusted total monthly expenditures were lowest for capecitabine regimens compared with taxane plus anthracycline or other taxane regimens ($8445 vs. $13,295 and $12,323, respectively; P < 0.0001). The adjusted total monthly cost for capecitabine regimens was lower than the cost for taxane plus anthracycline regimen ($10,895 vs. $13,115) and other taxane regimens ($9253 vs. $12,116). Adjusted complication costs for taxane treatment episodes were almost double than those seen with capecitabine ($5509 for anthracycline plus taxane vs. $2940, and $3829 for other taxane regimens vs. $1750). CONCLUSIONS: Lower complication-related expenditures with capecitabine therapy accounted for majority of the cost differential seen in comparison with taxane-based therapy.

Gastrointestinal tolerability with ibandronate after previous weekly bisphosphonate treatment.

Data from two open-label trials (PRIOR and CURRENT) of women with postmenopausal osteoporosis or osteopenia were evaluated to assess whether monthly oral and quarterly intravenous (IV) ibandronate dosing improved self-reported gastrointestinal (GI) tolerability for patients who had previously experienced GI irritation with bisphosphonate (BP) use. In PRIOR, women who had discontinued daily or weekly BP treatment due to GI intolerance received monthly oral or quarterly IV ibandronate for 12 months. The CURRENT subanalysis included women receiving weekly BP treatment who switched to monthly oral ibandronate for six months. GI symptom severity and frequency were assessed using the Osteoporosis Patient Satisfaction Questionnaire. In PRIOR, mean GI tolerability scores increased significantly at month 1 from screening for both treatment groups (oral: 79.3 versus 54.1; IV: 84.4 versus 51.0; p < 0.001 for both). Most patients reported improvement in GI symptom severity and frequency from baseline at all post-screening assessments (>90% at Month 10). In the CURRENT subanalysis >60% of patients reported improvements in heartburn or acid reflux and >70% indicated improvement in other stomach upset at month 6. Postmenopausal women with GI irritability with daily or weekly BPs experienced improvement in symptoms with extended dosing monthly or quarterly ibandronate compared with baseline.

Patient satisfaction in postmenopausal women treated with a weekly bisphosphonate transitioned to once-monthly ibandronate.

OBJECTIVE: CURRENT, a large, open-label, 6-month, multicenter study, was designed to assess patient satisfaction levels and patient treatment preference after switching from weekly oral bisphosphonates to monthly oral ibandronate for a period of 6 months. METHODS: This study enrolled postmenopausal women who had taken a weekly oral bisphosphonate for at least 3 months for prevention or treatment of osteoporosis or osteopenia at the time of screening. Enrolled patients were switched to 150 mg monthly ibandronate. At baseline and 6 months, patients completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q), consisting of four domains. Scores were converted to composite satisfaction scores (scale of 0-100). At 6 months, patients completed the Preference Questionnaire. Adverse events were monitored throughout. RESULTS: The intent-to-treat population comprised 1678 patients. OPSAT-Q composite satisfaction scores improved by 9 points by month 6 despite the high mean baseline summary scores (80.1 points). Convenience, overall satisfaction, and quality of life domain scores improved by 15.6, 12, and 9.2 points, respectively. Increased satisfaction was reported by the majority of patients at month 6 (70.4%). Patients who reported stomach upset or suboptimal compliance with prestudy weekly bisphosphonate treatment were more likely to report improved satisfaction (odds ratio [OR] for stomach upset 2.98, 95% CI 1.52, 6.50, p = 0.0026; suboptimal compliance 1.82, 95% CI 1.13-3.04, p = 0.017). After 6 months, 73.6% of patients preferred monthly ibandronate to weekly bisphosphonates. The most frequently occurring adverse events were upper respiratory tract infection (3.2% of patients), dyspepsia (2.5%), fracture (2.4%), arthralgia (2.3%), and gastroesophageal reflux disease, diarrhea, and nausea (2.2% each). CONCLUSIONS: Patients previously using weekly bisphosphonates reported improved satisfaction with monthly ibandronate dosing.

Improved GI tolerability with monthly ibandronate in women previously using weekly bisphosphonates.

OBJECTIVE: This subanalysis of CURRENT, an open-label, 6-month, multicenter study, assesses changes in gastrointestinal (GI) tolerability with once-monthly oral ibandronate in women who switched from once-weekly bisphosphonates and had reported GI symptoms with their previous weekly bisphosphonate regimen. METHODS: Postmenopausal women currently taking a weekly bisphosphonate switched to 150 mg monthly ibandronate. At the start of the treatment phase and after 6 months of therapy, all participants completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q), a validated instrument consisting of four domains: convenience, satisfaction, quality of life, and side effects. This subanalysis assessed GI tolerability in those women who reported GI symptoms at baseline in the side effects domain of OPSAT-Q and change in satisfaction in those who had reported stomach upset within 48 hours of taking their previous bisphosphonate at screening. RESULTS: Of women who reported GI symptoms at baseline, >60% reported an improvement in heartburn or acid reflux after switching to monthly ibandronate. Further, >70% reported improvements in stomach upset (excluding heartburn or acid reflux). Of those women who reported stomach upset within 48 hours of taking their previous weekly bisphosphonate at screening (n = 89), >80% reported improved overall satisfaction compared with baseline. Monthly ibandronate was generally well tolerated. CONCLUSION: A majority of women who experienced GI tolerability issues with weekly bisphosphonates reported improvements in GI symptoms after transitioning from a weekly bisphosphonate to monthly ibandronate for 6 months.

In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models.

Modifying the capecitabine dosing schedule from 14 days on, 7 days off (14/7) to 7 days on, 7 days off (7/7) may enable higher doses and improved antitumor efficacy in colorectal cancer xenografts. Capecitabine 14/7 (267 or 400 mg/kg) and 7/7 (467 or 700 mg/kg) schedules in doublet and triplet combinations with optimally dosed bevacizumab (5 mg/kg) and oxaliplatin (6.7 mg/kg) were studied in female athymic nude mice bearing HT29 colorectal xenografts. Additional studies of suboptimally dosed bevacizumab (2.5 mg/kg) and capecitabine 7/7 (360 mg/kg) were done in a similar Colo205 tumor xenograft model. Monotherapy and combination regimens were administered to groups of 10 animals and compared with vehicle controls. In the HT29 model, tumor growth inhibition and increase in life span (ILS) were significantly greater with capecitabine 7/7 than with 14/7 (P<0.05). The additional benefit of capecitabine 7/7 versus 14/7 was biologically significant according to National Cancer Institute criteria (>25% ILS). Adding bevacizumab to capecitabine 7/7 resulted in significantly greater survival relative to either agent alone (P<0.0001). When oxaliplatin was added, efficacy was significantly better with the triplet combination including capecitabine 7/7 (tumor growth inhibition>100% and ILS 234%) compared with 14/7 (95% and 81%, respectively). In the Colo205 model, combination therapy with capecitabine 7/7 plus bevacizumab resulted in significantly greater survival relative to either agent alone (P<0.0001). In conclusion, in athymic nude mice bearing moderately thymidine phosphorylase-expressing HT29 or Colo205 colorectal xenografts, a capecitabine 7/7 schedule permits increased drug delivery compared with traditional 14/7 regimens, greatly improving monotherapy activity without major toxicity.

Ibandronate dose response is associated with increases in bone mineral density and reductions in clinical fractures: results of a meta-analysis.

This meta-analysis pooled data from the four phase III clinical trials of ibandronate to assess the relationship between ibandronate dose, changes in bone mineral density, and rates of both clinical and non-vertebral fractures. Individual patient data from the intent-to-treat population of the BONE, IV fracture prevention, MOBILE, and DIVA studies were included for analysis. The relationship between ibandronate dose and bone mineral density at both the lumbar spine and at the total hip was assessed qualitatively. The relationship between lumbar spine bone mineral density and clinical fracture rate, and the relationship between total hip bone mineral density and non-vertebral fracture rate, were assessed both qualitatively and using mathematical models. A total of 8710 patients were included in this analysis. Both lumbar spine and total hip bone mineral density were observed to increase with increasing ibandronate dose. The incidence of all clinical fractures was observed to decrease as lumbar spine bone mineral density increased. A statistically significant inverse linear relationship was observed between percent change in lumbar spine bone mineral density and the rate of clinical fractures (P=0.005). A non-significant curvilinear relationship was observed between percent change in total hip bone mineral density and non-vertebral fracture rate. Increased ibandronate exposure is associated with increasing gains in the lumbar spine bone mineral density and decreasing clinical fracture rates. A non-linear relationship may exist between increases in the total hip bone mineral density and non-vertebral fracture rate.

Bone turnover marker profile in relation to the menstrual cycle of premenopausal healthy women.

OBJECTIVE: To explore the bone turnover marker profile during the menstrual cycle of premenopausal women. DESIGN: This was a noninterventional study. Levels of bone turnover markers, including serum C-terminal telopeptide of type I collagen (sCTX), bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 N propeptide, and urinary N-terminal telopeptide of type I collagen, were measured in blood and urine samples during one menstrual cycle. Levels were expressed as raw test results and percent change from serum luteinizing hormone peak. Differences in mean levels of bone turnover markers between menstrual phases and subphases were examined. RESULTS: Fifty-five women comprised the per-protocol population. Mean sCTX values were 0.48 ng/mL during the follicular phase (FP), 0.47 ng/mL at serum luteinizing hormone peak, and 0.43 ng/mL during the luteal phase (LP). Additionally, the mean percent change from luteinizing hormone peak varied from +4.35% during the FP to -5.11% during the LP (P = 0.0014). Mean sCTX levels during the early and through mid FP were significantly higher than levels during the mid and late LP. The pattern for urinary N-terminal telopeptide of type I collagen was similar to that of sCTX but not statistically significant. There was a statistically significant tendency for procollagen type I N propeptide levels to be lower during the FP relative to the LP. Levels of osteocalcin and bone-specific alkaline phosphatase did not vary significantly during the menstrual cycle. CONCLUSIONS: Levels of some bone turnover markers varied during the menstrual cycle. A statistically significant change in sCTX (9.46%) occurred between the FP and LP of the menstrual cycle.

Progression of efficacy with ibandronate: a paradigm for the development of new bisphosphonates.

While initial preclinical studies provide an important starting point for dose selection, they may not provide adequate information to identify the optimal dosage for an extended treatment regimen. Determining the best dose for use in an extended dosing regimen requires ongoing development, illustrated best with the bisphosphonate, ibandronate. As mandated for regulatory purposes, the daily oral regimen of ibandronate was proven effective in significantly reducing the rate of new vertebral fractures assessed prospectively, and nonvertebral fractures in a high-risk population, assessed retrospectively. Extended dosing regimens, namely monthly and quarterly intravenous formulations, were developed subsequently to improve the convenience and enhance persistence, while maintaining or increasing efficacy. The continuing and progressive evolution of data led to the understanding that extension of drug-free interval requires higher annual cumulative skeletal exposures (ACE), which were not simply numerical multipliers of the interval and daily dose. For ibandronate, this led to dose selection for the oral monthly 150 mg (ACE 10.8 mg) and intravenous quarterly 3 mg (ACE 12 mg) formulations that proved superior in increasing bone mineral density (BMD) compared with oral daily 2.5 mg (ACE 5.5 mg) ibandronate. Pooling data from clinical trials with high ACE regimens (monthly and quarterly) led to the evolution of statistical evidence for a reduction in clinical and nonvertebral fractures with ibandronate. The ibandronate story should serve as an important future paradigm for bisphosphonate development.

Patterns of bisphosphonate use in the United States in the treatment of metastatic bone disease.

PURPOSE: The purpose of this study was to determine the incidence of metastatic bone disease (MBD), the frequency of intravenous (I.V.) bisphosphonate use and its impact on skeletal-related events (SREs), and opioid use. PATIENTS AND METHODS: Patients diagnosed with MBD between 2000 and 2004 were identified using 2 Thomson MarketScan Research Databases. A total of 6783 patients, 1431 with breast cancer, fulfilled the criteria. Pain was assessed as the number of days on opioids, the strength of which was categorized according to the World Health Organization 3-step ladder for pain. RESULTS: Use of I.V. bisphosphonates steadily increased for all cancers from 17% in 2000 to 38% in 2004. For all patients, 61% received mild opioids and 35% received moderate to severe opioids at baseline. Use of I.V. bisphosphonates within the first 90 days after diagnosis of MBD was associated with a 63% decrease in SREs and reduction in use of moderate to severe opioids. Among patients with breast cancer, 10.6% received oral bisphosphonates before diagnosis of MBD, and 33.8% had pain at baseline. There was a 5.4% reduction in the use of moderate to severe opioids. CONCLUSION: Our data support the role of I.V. bisphosphonates in decreasing SRE and improving the quality of life for patients with MBD; the result is less pain and fewer SREs. More than 73% of all patients and 53% of patients with breast cancer never receive I.V. bisphosphonate treatment. Educational measures are warranted to increase the awareness by patients and physicians of the value of I.V. bisphosphonates in MBD.

Utility and sensitivity of the sore throat pain model: results of a randomized controlled trial on the COX-2 selective inhibitor valdecoxib.

The sore throat pain model was employed in this randomized, placebo-controlled trial to examine the sensitivity of the model in testing the efficacy of valdecoxib as an acute analgesic drug. Changes were made to the study design by employing a different diagnostic index for tonsillo-pharyngitis, a different rating scale (derived from Lasagna's pain thermometer), and alternative analyses, individual responder rates. Under double-blind conditions, 197 patients with painful pharyngitis were randomly allocated to valdecoxib 20 mg bid (n = 65), valdecoxib 40 mg qd (n = 66), or placebo (n = 66) for 24 hours. The expanded Tonsillo-Pharyngitis Assessment and the Lasagna Pain Scale were validated as sensitive study instruments. Both dosage regimens provided significantly greater pain relief compared with placebo on standard efficacy measures over the 24-hour study (all P < .05). Tests for individual response (eg, percentage of patients with at least moderate relief) confirmed these results, and other response rates identified the high sensitivity of the model itself (eg, only 5% of placebo-treated patients achieved >or=50% of maximum total pain relief over 6 hours). These findings indicate that sore throat is a sensitive model to assess analgesic efficacy.

Economic burden of metastatic bone disease in the U.S.

BACKGROUND: Previous research has documented the prevalence of primary bone cancer; however, there are few data available regarding the impact of metastatic bone disease (MBD) on national expenditure. In this study, the authors quantified the prevalence and direct medical care costs of patients with MBD and the resulting cost impact on U.S. oncology expenditure. METHODS: Anonymous, patient-level data on health care utilization and cost were obtained from the Thomson Medstat MarketScan research databases. In total, 396,200 patients who were diagnosed with cancer between 2000 and 2004 were selected for the study. Patients with MBD were matched subsequently to non-MBD controls. A 2-part linear regression model was used to compare cases with controls to quantify the incremental cost associated with the disease. RESULTS: Cancer prevalence in the U.S. during the study period was estimated at 4,861,987 cases annually, and 5.3% (n=256,137) of those patients had MBD. Rates of MBD were highest in patients with multiple myeloma (28.8%) and lung cancer (15.6%). The mean direct medical cost for all cancers combined was $75,329 for patients with MBD and $31,382 for controls. Regression-adjusted, incremental costs were $44,442 (P<.001) across all cancer types. The incremental cost was highest for patients with multiple myeloma ($63,455) and lowest for patients with lung cancer ($24,946). CONCLUSIONS: The national cost burden for patients with MBD was estimated at $12.6 billion, which is 17% of the $74 billion in total direct medical cost estimated by the National Institutes of Health, suggesting that MBD is a significant driver of overall oncology cost.