Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Antiresorptive Drugs: Proportion of Treatment Effect Explained.

Few analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction seeking to estimate the proportion of treatment effect explained (PTE) by BTMs. Pooling such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from up to 62,000 participants enrolled in 12 bisphosphonate (BP) and four selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and one bone resorption marker (C-terminal telopeptide of type I collagen [CTX]) and incident fracture outcome data, we estimated the PTE using two different models. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 5 years of follow-up. For vertebral fracture, the results showed that changes in all three BTMs at 6 months explained a large proportion of the treatment effect of ARs (57 to >100%), but not for and non-vertebral or hip fracture. We conclude that short-term AR treatment-related changes in bone ALP, PINP, and CTX account for a large proportion of the treatment effect for vertebral fracture. Change in BTMs is a useful surrogate marker to study the anti-fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials.

Meta-analyses conducted >15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual-energy X-ray absorptiometry (DXA)-based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents. © 2019 American Society for Bone and Mineral Research.

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression.

Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. Such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from 28,000 participants enrolled in 11 bisphosphonate (BP) and three selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2 = 0.82 [p < 0.001] and r2 = 0.75 [p = 0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2 = 0.33 [p = 0.053] and r2 = 0.53 [p = 0.065], respectively) and hip fracture (r2 = 0.17 [p = 0.24] and r2 = 0.43 [p = 0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2017 American Society for Bone and Mineral Research.

Effects of odanacatib on the radius and tibia of postmenopausal women: improvements in bone geometry, microarchitecture, and estimated bone strength.

The cathepsin K inhibitor odanacatib (ODN), currently in phase 3 development for postmenopausal osteoporosis, has a novel mechanism of action that reduces bone resorption while maintaining bone formation. In phase 2 studies, odanacatib increased areal bone mineral density (aBMD) at the lumbar spine and total hip progressively over 5 years. To determine the effects of ODN on cortical and trabecular bone and estimate changes in bone strength, we conducted a randomized, double-blind, placebo-controlled trial, using both quantitative computed tomography (QCT) and high-resolution peripheral (HR-p)QCT. In previously published results, odanacatib was superior to placebo with respect to increases in trabecular volumetric BMD (vBMD) and estimated compressive strength at the spine, and integral and trabecular vBMD and estimated strength at the hip. Here, we report the results of HR-pQCT assessment. A total of 214 postmenopausal women (mean age 64.0 ± 6.8 years and baseline lumbar spine T-score -1.81 ± 0.83) were randomized to oral ODN 50 mg or placebo, weekly for 2 years. With ODN, significant increases from baseline in total vBMD occurred at the distal radius and tibia. Treatment differences from placebo were also significant (3.84% and 2.63% for radius and tibia, respectively). At both sites, significant differences from placebo were also found in trabecular vBMD, cortical vBMD, cortical thickness, cortical area, and strength (failure load) estimated using finite element analysis of HR-pQCT scans (treatment differences at radius and tibia = 2.64% and 2.66%). At the distal radius, odanacatib significantly improved trabecular thickness and bone volume/total volume (BV/TV) versus placebo. At a more proximal radial site, odanacatib attenuated the increase in cortical porosity found with placebo (treatment difference = -7.7%, p = 0.066). At the distal tibia, odanacatib significantly improved trabecular number, separation, and BV/TV versus placebo. Safety and tolerability were similar between treatment groups. In conclusion, odanacatib increased cortical and trabecular density, cortical thickness, aspects of trabecular microarchitecture, and estimated strength at the distal radius and distal tibia compared with placebo.

Bone density, turnover, and estimated strength in postmenopausal women treated with odanacatib: a randomized trial.

CONTEXT: Odanacatib, a cathepsin K inhibitor, increases spine and hip areal bone mineral density (BMD) in postmenopausal women with low BMD and cortical thickness in ovariectomized monkeys. OBJECTIVE: The objective of the study was to examine the impact of odanacatib on the trabecular and cortical bone compartments and estimated strength at the hip and spine. DESIGN: This was a randomized, double-blind, 2-year trial. SETTING: The study was conducted at a private or institutional practice. PARTICIPANTS: PARTICIPANTS included 214 postmenopausal women with low areal BMD. INTERVENTION: The intervention included odanacatib 50 mg or placebo weekly. MAIN OUTCOME MEASURES: Changes in areal BMD by dual-energy x-ray absorptiometry (primary end point, 1 year areal BMD change at lumbar spine), bone turnover markers, volumetric BMD by quantitative computed tomography (QCT), and bone strength estimated by finite element analysis were measured. RESULTS: Year 1 lumbar spine areal BMD percent change from baseline was 3.5% greater with odanacatib than placebo (P < .001). Bone-resorption marker C-telopeptide of type 1 collagen was significantly lower with odanacatib vs placebo at 6 months and 2 years (P < .001). Bone-formation marker procollagen I N-terminal peptide initially decreased with odanacatib but by 2 years did not differ from placebo. After 6 months, odanacatib-treated women had greater increases in trabecular volumetric BMD and estimated compressive strength at the spine and integral and trabecular volumetric BMD and estimated strength at the hip (P < .001). At the cortical envelope of the femoral neck, bone mineral content, thickness, volume, and cross-sectional area also increased from baseline with odanacatib vs placebo (P < .001 at 24 months). Adverse experiences were similar between groups. CONCLUSIONS: Over 2 years, odanacatib decreased bone resorption, maintained bone formation, increased areal and volumetric BMD, and increased estimated bone strength at both the hip and spine.

The osteoclast, bone remodelling and treatment of metabolic bone disease.

BACKGROUND: Bone remodelling maintains skeletal integrity by osteoclasts removing foci of damaged bone and osteoblasts replacing them with new bone. Diseases associated with increased bone resorption have increased remodelling often with inadequate bone formation and increased risk of fracture. New therapies are needed for these diseases to reduce resorption and increase formation. DESIGN: The molecular mechanisms regulating osteoclast and osteoblast functions have become better understood in the past 20 years and have led to questioning of the long-held notion that osteoblastic cells have the dominant regulatory role over osteoclastic cells in bone remodelling. Here, we review current knowledge of how osteoclast formation and functions are regulated and describe how enhanced understanding of these has led to development of new drugs for the management of common bone diseases characterized by increased bone resorption. RESULTS: Osteoclast formation and functions are regulated by cytokines, especially receptor activator of NF-κB ligand (RANKL) and macrophage-colony-stimulating factor (M-CSF). The differentiation, activity and lifecycle of osteoclasts are regulated in part by other cells that reside within the bone. These include osteoblasts, osteocytes and immune cells, which express these cytokines in response to most factors that promote bone resorption. RANKL and M-CSF activate numerous signalling pathways, which are potential targets for therapeutic intervention. Importantly, osteoclastic cells also function as positive and negative regulators of osteoblastic bone formation. CONCLUSIONS: There are multiple targets within osteoclasts for pharmacologic intervention to prevent bone loss in osteoporosis and other resorptive bone diseases. However, novel therapies could also affect osteoblastic cell functions.

Longitudinal evaluation of the effects of alendronate on MRI bone microarchitecture in postmenopausal osteopenic women.

UNLABELLED: We evaluated longitudinal effects of alendronate on MRI-based trabecular bone structure parameters derived from dual thresholding and fuzzy clustering (BE-FCM) trabecular bone segmentation. Treatment effects were observed in the distal tibia after 24 months. The BE-FCM method increased correlations to HR-pQCT-based parameters. INTRODUCTION: High-resolution magnetic resonance imaging (MRI) allows for non-invasive bone microarchitecture analysis. The goal of this study was to examine the potential of MRI-based trabecular bone structure parameters to monitor effects of alendronate in humans in vivo, and to compare the results to HR-pQCT and DXA measurements. MATERIALS AND METHODS: Postmenopausal osteopenic women were divided into alendronate treatment and control groups, and imaged at baseline, 12 months, and 24 months (n = 52 at baseline) using 3T MRI, HR-pQCT, and DXA. Image acquisition sites included distal tibia (MRI and HR-pQCT), distal radius (MRI, DXA, and HR-pQCT), and the proximal femur (MRI and DXA). Two different regions of interest were evaluated. One contained the trabecular bone region within the entire MRI acquisition, and the second contained a subregion matched to the region contained in the HR-pQCT acquisition. The trabecular bone was segmented using two different methods; dual thresholding and BE-FCM. Trabecular bone structure parameters included bone volume fraction (BV/TV), number (Tb.N), spacing (Tb.Sp), and thickness (Tb.Th), along with seven geodesic topological analysis (GTA) parameters. Longitudinal changes and correlations to HR-pQCT and DXA measurements were evaluated. RESULTS: Apparent Tb.N and four GTA parameters showed treatment effects (p < 0.05) in the distal tibia after 24 months in the entire MRI region using BE-FCM, as well as Tb.N using dual thresholding. No treatment effects after 24 months were observed in the HR-pQCT or in MRI analysis for the HR-pQCT-matched regions. Apparent BV/TV and Tb.N from BE-FCM had significantly higher correlations to HR-pQCT values compared to those derived from thresholding. CONCLUSIONS: This study demonstrates the influence of computational methods and region of interest definitions on measurements of trabecular bone structure, and the feasibility of MRI-based quantification of longitudinal changes in bone microarchitecture due to bisphosphonate therapy. The results suggest that there may be a need to reevaluate the current standard HR-pQCT region definition for increased treatment sensitivity.

A longitudinal HR-pQCT study of alendronate treatment in postmenopausal women with low bone density: Relations among density, cortical and trabecular microarchitecture, biomechanics, and bone turnover.

The goal of this study was to characterize longitudinal changes in bone microarchitecture and function in women treated with an established antifracture therapeutic. In this double-blind, placebo-controlled pilot study, 53 early postmenopausal women with low bone density (age = 56 ± 4 years; femoral neck T-score = -1.5 ± 0.6) were monitored by high-resolution peripheral quantitative computed tomography (HR-pQCT) for 24 months following randomization to alendronate (ALN) or placebo (PBO) treatment groups. Subjects underwent annual HR-pQCT imaging of the distal radius and tibia, dual-energy X-ray absorptiometry (DXA), and determination of biochemical markers of bone turnover (BSAP and uNTx). In addition to bone density and microarchitecture assessment, regional analysis, cortical porosity quantification, and micro-finite-element analysis were performed. After 24 months of treatment, at the distal tibia but not the radius, HR-pQCT measures showed significant improvements over baseline in the ALN group, particularly densitometric measures in the cortical and trabecular compartments and endocortical geometry (cortical thickness and area, medullary area) (p < .05). Cortical volumetric bone mineral density (vBMD) in the tibia alone showed a significant difference between treatment groups after 24 months (p < .05); however, regionally, significant differences in Tb.vBMD, Tb.N, and Ct.Th were found for the lateral quadrant of the radius (p < .05). Spearman correlation analysis revealed that the biomechanical response to ALN in the radius and tibia was specifically associated with changes in trabecular microarchitecture (|ρ| = 0.51 to 0.80, p < .05), whereas PBO progression of bone loss was associated with a broad range of changes in density, geometry, and microarchitecture (|ρ| = 0.56 to 0.89, p < .05). Baseline cortical geometry and porosity measures best predicted ALN-induced change in biomechanics at both sites (ρ > 0.48, p < .05). These findings suggest a more pronounced response to ALN in the tibia than in the radius, driven by trabecular and endocortical changes.

Response to oral bisphosphonates in subgroups of younger and older postmenopausal women.

BACKGROUND: Although the effects of bisphosphonates in bone are known for postmenopausal women, it is not known if younger postmenopausal women have a similar response. Furthermore, it is not known if the effects of alendronate and risedronate differ in postmenopausal women in regard to age, specifically in women at or younger than the mean age of natural menopause. Our aim was to examine the effects of two oral bisphosphonates in postmenopausal women by age. METHODS: This was a post-hoc analysis of postmenopausal women <55 or > or =55 years old with low bone mineral density (BMD), randomized to once weekly alendronate 70 mg or risedronate 35 mg for 1 year with 1-year extensions in U.S. and International Fosamax Actonel Comparison Trials. RESULTS: In both age subgroups of postmenopausal women, alendronate produced significantly greater mean BMD increases from baseline than risedronate at hip trochanter, lumbar spine, total hip, and femoral neck. Changes in BMD were not significantly different between younger and older alendronate-treated women, although treatment differences favoring alendronate were numerically greater for younger than older postmenopausal women at all sites. Significantly greater reductions in bone turnover markers also occurred with alendronate vs. risedronate in both subgroups. Tolerability was similar between treatments. CONCLUSIONS: In this post-hoc subgroup analysis of older and younger postmenopausal women receiving alendronate or risedronate, larger treatment differences in BMD gain in younger compared with older women suggest that patient age may affect the relative efficacy of these antiresorptive drugs.

Prediction of changes in bone mineral density in postmenopausal women treated with once-weekly bisphosphonates.

BACKGROUND: In clinical practice, bone mineral density (BMD) determined by dual-energy x-ray absorptiometry is used to monitor response to osteoporosis therapy. However, 1 to 2 yr are usually required to assess patients' BMD responses. The possibility of earlier indicators of a response or nonresponse to treatment, such as changes in bone turnover markers (BTMs), is of interest to physicians and patients. METHODS: In this post hoc analysis of women treated with once-weekly bisphosphonates, we examined the association of tertile percentage change from baseline in BTMs at 3 or 6 months and association of several baseline clinical characteristics with 24-month percentage change from baseline in BMD and with percentage of patients showing BMD nonresponse (defined as BMD loss at two or more of four sites) at 24 months. Multivariable analysis was performed to determine which factors were independently associated with BMD nonresponse. RESULTS: Patients in the tertile with the greatest decrease in each of the BTMs had the greatest mean increase in BMD and the lowest percentage of BMD nonresponders at 24 months. Several characteristics were independently associated with BMD nonresponse, including smaller 3-month reductions from baseline in serum C-terminal telopeptide of type 1 collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type 1 procollagen; younger age of menopause; a family history of osteoporosis; and higher baseline trochanteric BMD. Baseline BTMs were not predictive of 24-month BMD response to therapy. The strongest associations were for changes in BTMs with treatment. CONCLUSION: In groups of patients, short-term changes in markers of bone turnover appear to be predictors of longer term BMD response and nonresponse to bisphosphonate therapy.

In vivo determination of bone structure in postmenopausal women: a comparison of HR-pQCT and high-field MR imaging.

UNLABELLED: Bone structural measures obtained by two noninvasive imaging tools-3T MRI and HR-pQCT-were compared. Significant but moderate correlations and 2- to 4-fold discrepancies in parameter values were detected, suggesting that differences in acquisition and analysis must be considered when interpreting data from these imaging modalities. INTRODUCTION: High-field MRI and high resolution (HR)-pQCT are currently being used in longitudinal bone structure studies. Substantial differences in acquisition and analysis between these modalities may influence the quantitative data produced and could potentially influence clinical decisions based on their results. Our goal was to compare trabecular and cortical bone structural measures obtained in vivo by 3T MRI and HR-pQCT. MATERIALS AND METHODS: Postmenopausal osteopenic women (n = 52) were recruited for this study. HR-pQCT imaging of the radius and tibia was performed using the XtremeCT scanner, with a voxel size of 82 x 82 x 82 microm(3). MR imaging was performed on a 3T Signa scanner using SSFP imaging sequences, with a pixel size of 156 x 156 microm(2) and slice thickness of 500 microm. Structure parameters were calculated using standard HR-pQCT and MRI analysis techniques. Relationships between measures derived from HR-pQCT, MRI, and DXA were studied. RESULTS: Significant correlations between HR-pQCT and MRI parameters were found (p < 0.0001) and were strongest for Tb.N (r(2) = 0.52), Ct.Th (r(2) = 0.59), and site-specific Tb.Sp (r(2) = 0.54-0.60). MRI and HR-pQCT provided statistically different values of structure parameters (p < 0.0001), with BV/TV and Tb.Th exhibiting the largest discrepancies (MR/HR-pQCT = 3-4). Although differences in the Tb.N values were statistically significant, the mean differences were on the order of our reproducibility measurements. Systematic differences between MRI and HR-pQCT analysis procedures leading to discrepancies in cortical thickness values were observed, with MRI values consistently higher. Minimal correlations were found between MRI or HR-pQCT parameters and DXA BMD or T-score, except between HR-pQCT measures at the radius and the ultradistal radius T-scores, where moderate correlations were found (r(2) = 0.19-0.58). CONCLUSIONS: This study provides unique insight into two emerging noninvasive tools for bone structure evaluation. Our findings highlight the significant influence of analysis technique on results of in vivo assessment and underscore the importance of accounting for these differences when interpreting results from these modalities.

A cross-sectional study of bone turnover markers in healthy premenopausal women.

BACKGROUND: Biochemical markers of bone turnover (BTMs) provide useful information in the diagnosis and management of metabolic bone diseases. Currently, there exist few published reference ranges for bone markers in healthy premenopausal women using the newer, automated assays of bone turnover. This cross-sectional study of healthy premenopausal women was performed to determine reference ranges for four different markers of bone turnover and to compare reference ranges in users and non-users of oral contraceptives (OCs). METHODS: Urinary N-telopeptide of type 1 collagen (NTX) was determined from fasting second morning-void urine of healthy premenopausal women. In addition, fasting serum was collected for determination of C-telopeptide of type I collagen (CTX), bone-specific alkaline phosphatase (bone ALP), and N-terminal propeptide of type 1 procollagen (PINP). Subjects underwent central dual energy X-ray absorptiometry and completed a questionnaire regarding medical history and activities known to affect bone health. RESULTS: Serum and urine samples were collected from 237 healthy premenopausal women (119 OC users and 118 non-users) between the ages of 28 and 45 years. The mean age of subjects was 37 years, with a mean bone mineral density T-score of -0.1 at the lumbar spine and 0.0 at the total hip. Logarithmic transformation produced normal distributions for all markers but NTX. Mid-95% ranges for each marker were generally consistent with those reported by manufacturers. For each BTM examined, values were skewed toward the lower end of the range. Median NTX levels for OC users and non-users were 16.0 and 29.0 nmol/mmol creatinine, respectively. The mid-95% ranges for NTX in OC users and non-users were 3-60 and 4-64 nmol/mmol creatinine, respectively. Median levels of CTX, bone ALP, and PINP were also lower in OC users than non-users. The mean level of each BTM was significantly lower in OC users than non-users (P<0.01), whereas reference ranges (geometric mean+/-2 SD) were somewhat similar for the two groups. CONCLUSION: Values obtained from this well-characterized population provide reference ranges for BTMs in healthy premenopausal women. Median and mean BTM levels for OC users were consistently lower compared with non-users; thus, separate reference ranges are required for these two groups of premenopausal women. The relevance of premenopausal reference ranges for postmenopausal women remains uncertain.

Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years.

OBJECTIVE: A 1-yr extension of the Fosamax Actonel Comparison Trial was completed to compare changes in bone mineral density (BMD), bone turnover, and upper gastrointestinal tolerability over 2 yr of treatment. DESIGN: This was a randomized, double-blind extension conducted at 72 U.S. sites. PATIENTS AND METHODS: Of the 1053 women who completed yr 1, 833 postmenopausal women with low BMD entered the extension, continuing their same treatment allocation [once-weekly (OW) alendronate 70 mg or OW risedronate 35 mg]. Changes in BMD at the hip trochanter, total hip, femoral neck, and lumbar spine and in markers of bone turnover were compared at 24 months. Tolerability was assessed by adverse experience reporting. RESULTS: Alendronate produced greater increases from baseline in BMD at 24 months than did risedronate at the trochanter (alendronate, 4.6%; risedronate, 2.5%, P < 0.001) as well as at all other BMD sites. Significantly more alendronate than risedronate patients had measured BMD increases of 0% or more and 3% or more at all BMD sites (P < 0.001), and fewer alendronate patients had measured decreases of 3% or more at all BMD sites. Significantly greater reductions in all biochemical markers of bone turnover occurred with alendronate, compared with risedronate. No differences were seen in occurrence or discontinuations due to upper gastrointestinal adverse experiences. CONCLUSIONS: Patients receiving 70 mg OW alendronate had greater gains in BMD, were more likely to maintain or gain BMD, and had greater reductions in bone turnover markers than patients receiving 35 mg OW risedronate after 24 months, with no differences in upper gastrointestinal tolerability.

A randomized, placebo-controlled, 6-month study of once-weekly alendronate oral solution for postmenopausal osteoporosis.

OBJECTIVE: This study evaluated the overall safety and tolerability of once-weekly (OW) alendronate 70 mg oral solution (OS) versus OW placebo OS. METHODS: Postmenopausal, osteoporotic women were enrolled at 51 centers in the United States in a 6-month double-blind, randomized trial. Patients were randomized (1:1) to OW alendronate 70 mg OS or placebo OS. The primary end point was the proportion of patients reporting any upper gastrointestinal (UGI) adverse event (AE) at 6 months. Secondary end points included mean percentage change in urinary N-telopeptide of type I human collagen (NTx) and serum bone-specific alkaline phosphatase (BSAP) at 6 months. RESULTS: Initially, 454 women were enrolled; 392 (86.3%) completed the study. The mean (SD) age was 65.2 (10) years, and the mean (SD) time since menopause was 19.1 (12) years. The proportion of patients experiencing any UGI AE was significantly higher with alendronate OS (23.7%) compared with placebo solution (15.3%), with a treatment difference of 8.3% (95% CI, 0.8%-15.8%; P = 0.024). The proportion of patients experiencing any esophageal AE was 4.0% with alendronate and 3.0% with placebo (treatment difference, 1.0% [95% CI, -2.7% to 4.8%]). In addition, 4.5% of alendronate and 8.7% of placebo patients discontinued the study due to any clinical AE, and 3.3% of alendronate and 1.8% of placebo patients discontinued due to a UGI AE (difference, 1.5% [95% CI, -1.5% to 4.4%]). Alendronate OS produced significantly greater reductions in both NTx and BSAP than placebo (differences, -47.5% and -38.7%, respectively [both, P < 0.001]). CONCLUSIONS: In this 6-month study, patients receiving OW alendronate 70 mg OS had a higher rate of UGI AEs than placebo patients. However, rates of serious UGI AEs, discontinuations due to UGI AEs, and esophageal AEs were similar between groups. UGI AEs in the study were generally mild to moderate in severity and did not result in treatment discontinuation. In addition, OW alendronate 70 mg OS significantly reduced biochemical markers of bone turnover.

Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.

PURPOSE: To evaluate serum 25-hydroxyvitamin D [25(OH)D] concentrations and factors related to vitamin D inadequacy in postmenopausal North American women receiving therapy to treat or prevent osteoporosis. METHODS: Serum 25(OH)D and PTH were obtained in 1536 community-dwelling women between November 2003 and March 2004. Multivariate logistic regression was used to assess risk factors for suboptimal (<30 ng/ml) 25(OH)D. RESULTS: Ninety-two percent of study subjects were Caucasian, with a mean age of 71 yr. Thirty-five percent resided at or above latitude 42 degrees north, and 24% resided less than 35 degrees north. Mean (sd) serum 25(OH)D was 30.4 (13.2) ng/ml: serum 25(OH)D was less than 20 ng/ml in 18%; less than 25 ng/ml in 36%; and less than 30 ng/ml in 52%. Prevalence of suboptimal 25(OH)D was significantly higher in subjects who took less than 400 vs. 400 IU/d or more vitamin D. There was a significant negative correlation between serum PTH concentrations and 25(OH)D. Risk factors related to vitamin D inadequacy included age, race, body mass index, medications known to affect vitamin D metabolism, vitamin D supplementation, exercise, education, and physician counseling regarding vitamin D. CONCLUSIONS: More than half of North American women receiving therapy to treat or prevent osteoporosis have vitamin D inadequacy, underscoring the need for improved physician and public education regarding optimization of vitamin D status in this population.

Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study.

UNLABELLED: Once-weekly alendronate 70 mg and once-weekly risedronate 35 mg are indicated for the treatment of postmenopausal osteoporosis. These two agents were compared in a 12-month head-to-head trial. Greater gains in BMD and greater reductions in markers of bone turnover were seen with alendronate compared with risedronate with similar tolerability. INTRODUCTION: The nitrogen-containing bisphosphonates, alendronate and risedronate, are available in once-weekly (OW) formulations for the treatment of postmenopausal osteoporosis. A 12-month, head-to-head study was performed to compare these agents in the treatment of postmenopausal women with low BMD. MATERIALS AND METHODS: A total of 1053 patients from 78 U.S. sites were randomized to OW alendronate 70 mg (N = 520) or risedronate 35 mg (N = 533), taken in the morning after fasting. Endpoints included BMD changes over 6 and 12 months at the hip trochanter, total hip, femoral neck, and lumbar spine (LS); percent of patients with predefined levels of change in trochanter and LS BMD at 12 months; and change in biochemical markers of bone turnover at 3, 6, and 12 months. Tolerability was evaluated by adverse experience (AE) reporting. RESULTS: Significantly greater increases in hip trochanter BMD were seen with alendronate (3.4%) than risedronate (2.1%) at 12 months (treatment difference, 1.4%; p < 0.001) as well as 6 months (treatment difference, 1.3%; p < 0.001). Significantly greater gains in BMD were seen with alendronate at all BMD sites measured (12-month difference: total hip, 1.0%; femoral neck, 0.7%; LS, 1.2%). Significant differences were seen as early as 6 months at all sites. A greater percentage of patients had > or =0% (p < 0.001) and > or =3% (p < 0.01) gain in trochanter and spine BMD at 12 months with alendronate than risedronate. Significantly greater (p < 0.001) reductions in all biochemical markers of bone turnover occurred with alendronate compared with risedronate by 3 months. No significant differences were seen between treatment groups in the incidence of upper gastrointestinal AEs or AEs causing discontinuation. CONCLUSIONS: In this 12-month, head-to-head trial of alendronate and risedronate, given in accordance with the approved OW regimens for treatment of osteoporosis in postmenopausal women, alendronate produced greater gains in BMD and greater reductions in markers of bone turnover than risedronate. The greater antiresorptive effect of alendronate was seen as early as 3 months, and the tolerability profiles were similar.

Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis.

OBJECTIVE: To compare the efficacy and tolerability of once-weekly (OW) alendronate (ALN) 70 mg and raloxifene (RLX) 60 mg daily in the treatment of postmenopausal osteoporosis. DESIGN: This 12-month, randomized, double-blind study enrolled 456 postmenopausal women with osteoporosis (223 ALN, 233 RLX) at 52 sites in the United States. Efficacy measurements included lumbar spine (LS), total hip, and trochanter bone mineral density (BMD) at 6 and 12 months, biochemical markers of bone turnover, and percent of women who maintained or gained BMD in response to treatment. The primary endpoint was percent change from baseline in LS BMD at 12 months. Adverse experiences were recorded to assess treatment safety and tolerability. RESULTS: Over 12 months, OW ALN produced a significantly greater increase in LS BMD (4.4%, P < 0.001) than RLX (1.9%). The percentage of women with > or = 0% increase in LS BMD (ALN, 94%; RLX, 75%; P < 0.001) and > or =3% increase in LS BMD (ALN, 66%; RLX, 38%; P < 0.001) were significantly greater with ALN than RLX. Total hip and trochanter BMD increases were also significantly greater (P < or =0.001) with ALN. Greater (P < 0.001) reductions in N-telopeptide of type I collagen and bone-specific alkaline phosphatase were achieved with ALN compared with RLX at 6 and 12 months. No significant differences in the incidence of upper gastrointestinal or vasomotor adverse experiences were seen. CONCLUSION: ALN 70 mg OW produced significantly greater increases in spine and hip BMD and greater reductions in markers of bone turnover than RLX over 12 months. A greater percentage of women maintained or gained BMD on ALN than RLX. Both medications had similar safety and tolerability profiles.

Response to therapy with once-weekly alendronate 70 mg compared to once-weekly risedronate 35 mg in the treatment of postmenopausal osteoporosis.

OBJECTIVE: The FACT study (Fosamax Actonel Comparison Trial) was a 1-year-head-to-head trial comparing the efficacy and tolerability of once weekly (DW) alendronate 70 mg and OW risedronate 35 mg for the treatment of postmenopausal osteoporosis. The present analysis was performed to determine the percentage of patients who had changes during the study in BMD and biochemical markers (BCMs) of bone turnover above or below specific cut-off points. A subgroup analysis of upper gastrointestinal (UGI) tolerability was also performed. RESEARCH DESIGN AND METHODS: 1053 postmenopausal women with low BMD were randomized to alendronate 70 mg OW (N = 520) or risedronate 35 mg OW (N = 533). The percentage of patients who had measured BMD gains > or = 3%, and > or = 5% after 12 months at the hip trochanter, total hip, femoral neck, and lumbar spine (LS) was analyzed. The percentage of patients who experienced any bone loss, and those with measured losses of 3% or more at these sites after 12 months, was determined. The percentage of patients achieving reductions in urinary N-telopeptide of type 1 human collagen (NTX) > or = 40%, and serum C-telopeptide of type 1 collagen (CTx) > or = 60%, bone-specific phosphatase (BSAP) > or = 30%, and N terminal propeptide of type 1 procollagen (P1NP) > or = 50% at 3 months and 12 months was also determined. Tolerability, based on adverse experience reporting, was evaluated in a subgroup of patients with history of UGI disorders at baseline. RESULTS: A greater percentage of alendronate- than risedronate-treated patients had measured BMD gains (> or = 0%) (p < 0.05) at all sites at 12 months. Significantly more (p < 0.01) alendronate- than risedronate-treated patients had measured gains in BMD > or = 3% and > or = 5% at the hip trochanter, total hip, and LS spine. Significantly more (p < 0.05) risedronate- than alendronate-treated patients had an apparent loss of BMD (> 0% and > or = 3% loss) at the same sites. After 3 months, significantly (p < 0.001) more alendronate- than risedronate- treated patients achieved predefined reductions in all BCMs. Similar tolerability was demonstrated in both treatment groups, regardless of whether or not patients had a history of UGI disorders at baseline. CONCLUSIONS: Significantly more alendronate- than risedronate-treated patients achieved predefined increases in BMD at 12 months and reductions in BCMs at 3 months. Significantly more risedronate- than alendronate-treated patients were classified as apparent 'non-responders' (i.e. experienced any bone loss) after 12 months of therapy. The tolerability profiles of the two medications were similar.

Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the upper gastrointestinal (GI) tract tolerability of once-weekly oral alendronate, 70 mg, and placebo. PATIENTS AND METHODS: This was a 12-week multicenter, randomized, double-blind, placebo-controlled study. The first patient initiated treatment on June 5, 2000, and the last patient completed treatment on March 1, 2001. The study enrolled 450 postmenopausal women and men with osteoporosis (224 took alendronate, 226 took placebo) who were ambulatory and community dwelling at 48 outpatient study centers in the United States. By design, approximately half of the patients were naive to bisphosphonates. The primary end point was upper GI tract tolerability based on the incidence of any upper GI tract adverse events. Secondary end points included the number of discontinuations due to drug-related upper GI tract adverse events and the change from baseline in bone resorption, assessed by the urinary N-telopeptide-creatinine ratio at 12 weeks. A subgroup analysis of the primary and secondary end points was performed on the patients stratified by prior bisphosphonate use. The safety and tolerability of the weekly alendronate and placebo regimens were captured as clinical and laboratory adverse events. RESULTS: A total of 11% of the alendronate patients and 13% of the placebo patients reported an upper GI tract adverse event. Discontinuations due to drug-related upper GI tract adverse events occurred in 3% of alendronate patients and 1% of placebo patients. The differences between the treatment groups for the primary and secondary end points were not significant. For the primary end point, the upper limit of the 95% confidence interval of the difference was well within the prespecified 14% comparability bound (-2.2%; 95% confidence interval, -8.3% to 3.9%). The overall incidence of upper GI tract adverse events was lower in the subgroup of patients with prior bisphosphonate exposure (8%) than in those who were bisphosphonate naive (16%). However, regardless of prior bisphosphonate exposure, the incidence of upper GI tract adverse events was similar between the alendronate and placebo patients. The urinary N-telopeptide-creatinine ratio showed a significant decrease in the alendronate patients (72% of baseline, P<.001) compared with a slight increase in the placebo patients (106% of baseline) at week 12. CONCLUSION: In this 3-month study, the incidence of upper GI tract adverse events in patients treated with once-weekly alendronate, 70 mg, was comparable to that with placebo.