Anne E. de Papp

Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur

BACKGROUND A number of recent case reports and series have identified a subgroup of atypical fractures of the femoral shaft associated with bisphosphonate use. A population-based study did not support this association. Such a relationship has not been examined in randomized trials. METHODS We performed secondary analyses using the results of three large, randomized bisphosphonate trials: the Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT). We reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare (subtrochanteric and diaphyseal femur fractures) and to assess atypical features. We calculated the relative hazards for subtrochanteric and diaphyseal fractures for each study. RESULTS We reviewed 284 records for hip or femur fractures among 14,195 women in these trials. A total of 12 fractures in 10 patients were classified as occurring in the subtrochanteric or diaphyseal femur, a combined rate of 2.3 per 10,000 patient-years. As compared with placebo, the relative hazard was 1.03 (95% confidence interval [CI], 0.06 to 16.46) for alendronate use in the FIT trial, 1.50 (95% CI, 0.25 to 9.00) for zoledronic acid use in the HORIZON-PFT trial, and 1.33 (95% CI, 0.12 to 14.67) for continued alendronate use in the FLEX trial. Although increases in risk were not significant, confidence intervals were wide. CONCLUSIONS The occurrence of fracture of the subtrochanteric or diaphyseal femur was very rare, even among women who had been treated with bisphosphonates for as long as 10 years. There was no significant increase in risk associated with bisphosphonate use, but the study was underpowered for definitive conclusions.

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

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.

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.

In Vivo Determination of Bone Structure in Postmenopausal Women: A Comparison of HR-pQCT and High-Field MR Imaging†

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.

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

Eur J Clin Invest 2012; 42 (12): 1332–1341

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.

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

SUMMARY Objective: The FACT study (Fosamax Actonel Comparison Trial) was a 1-year head-to-head trial comparing the efficacy and tolerability of once weekly (OW) 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 ≥ 0%, ≥ 3%, and ≥ 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 I human collagen (NTX) ≥ 40%, and serum C-telopeptide of type I collagen (CTx) ≥ 60%, bone-specific alkaline phosphatase (BSAP) ≥ 30%, and N terminal propeptide of type I procollagen (P1NP) ≥ 50% at 3 months and 12 months was also determined. Tolerability, based on adverse experience reporting, was evaluated in a subgroup of patients with a history of UGI disorders at baseline. Results: A greater percentage of alendronate- than risedronate-treated patients had measured BMD gains (≥ 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 ≥ 3% and ≥ 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 ≥ 3% loss) at these 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.

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.

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.