Treatment satisfaction in postmenopausal women suboptimally adherent to bisphosphonates who transitioned to denosumab compared with risedronate or ibandronate.

CONTEXT: For many patients, adhering to postmenopausal osteoporosis treatment is a challenge. Higher treatment satisfaction is associated with greater persistence with these therapies, which is associated with better outcomes. OBJECTIVE: This study aimed to evaluate the change in treatment satisfaction in postmenopausal women who were suboptimally adherent to daily or weekly oral bisphosphonates and who transitioned to denosumab vs a monthly oral bisphosphonate. DESIGN AND SETTING: Pooled data of outpatients from two international, multicenter, randomized, open-label studies were analyzed. PATIENTS: Postmenopausal women (n = 1703) age 55 years or greater with low bone mineral density who were suboptimally adherent with prior oral bisphosphonate therapy, as assessed by the Osteoporosis-Specific Morisky Medication Adherence Scale, were included in the study. INTERVENTIONS: Patients received denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand, 60 mg s.c. every 6 months vs the oral bisphosphonates ibandronate or risedronate, 150 mg once monthly for 12 months. MAIN OUTCOME MEASURES: Change in treatment satisfaction scores from baseline to months 6 and 12 were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM is a validated tool that measures perception of four domains of treatment satisfaction: effectiveness, side effects, convenience, and global satisfaction. RESULTS: Patients in both treatment groups showed improvement from baseline for all four TSQM domains at 6 and 12 months. However, the denosumab group had significantly (all P < .001) greater improvements among all four TSQM domains at 6 and 12 months compared with the oral bisphosphonate group. CONCLUSIONS: Women with low adherence to oral bisphosphonates reported greater treatment satisfaction when transitioned to denosumab vs switching to a monthly oral bisphosphonate.

Dual-energy x-ray absorptiometry: interpreting reports and serial measurements.

Physicians and other health care providers requesting dual-energy x-ray bone density studies must be able to critically review and interpret such studies. This requires an understanding of the computerized result components of the studies and how such data can be applied in clinical practice. The timing and interpretation of serial bone density studies is governed by the concepts of precision and least significant change. These statistical concepts are well within the purview of the practicing physician. Serial bone density studies cannot be interpreted without prior knowledge of the precision and least significant change of the test.

Effects of odanacatib on BMD and safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate: a randomized placebo-controlled trial.

CONTEXT: Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis. OBJECTIVE: The effects of ODN were evaluated on bone mineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate. DESIGN: This was a randomized, double-blind, placebo-controlled, 24-month study. SETTING: The study was conducted at private or institutional practices. PARTICIPANTS: Postmenopausal women (n = 243) ≥ 60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score ≤-2.5 but >-3.5 without prior fracture or ≤-1.5 but >-3.5 with prior fracture) on alendronate for ≥ 3 years. INTERVENTION: The intervention included ODN 50 mg or placebo weekly. MAIN OUTCOME MEASURES: The primary end point was percentage change from baseline of femoral neck BMD at month 24. BMD was assessed by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen, urinary N-telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months. RESULTS: In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups. CONCLUSIONS: ODN provided incremental BMD gains in osteoporotic women after alendronate treatment.

Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial.

OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was -81.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified.

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.

Monitoring changes in bone density.

The relationship between declining bone density and increasing fracture risk is firmly established; the relationship between increasing bone density and decreasing fracture risk is less clear. Because of this, the clinical utility of assessing the therapeutic efficacy of prescription therapies to reduce fracture risk by measuring changes in bone density has been called into question. However, there is substantial clinical trial data to support this approach. Nevertheless, an apparent increase or decrease in the bone density may be misinterpreted without an understanding of the statistical concepts of precision and least significant change. These concepts are not difficult and are of profound clinical importance. If the least significant change is not known, serial measurements of bone density cannot be interpreted. These concepts will be discussed and illustrated, and the rationale for the importance of changes in bone mineral density on therapy will be explored.

Descriptive analysis of concomitant prescription medication patterns from 1999 to 2004 among US women receiving daily or weekly oral bisphosphonate therapy.

BACKGROUND: To improve medication-taking behavior, it is important to identify factors that may contribute to suboptimal compliance and persistence with osteoporosis medications. OBJECTIVE: The purpose of this descriptive analysis was to identify concurrent prescription medication use (number and type) among women receiving daily or weekly oral bisphosphonate therapy. METHODS: Patient prescription data were collected from November 1999 to June 2004 from a US patient claims database accessed through Wolters Kluwer Health (formerly NDC Health), which represents >65 million patients annually. Women aged >or=50 years who were receiving daily or weekly oral bisphosphonate medication during the study months were included. Concomitant medications were defined based on >or=14 days of prescription supply in the same month as bisphosphonate therapy. Data were examined to determine the frequency with which certain drugs and drug classes were prescribed concomitantly with bisphosphonates. Each study month was treated independently to assess concomitant medication use. RESULTS: Over the study period, the number of female bisphosphonate recipients in the database increased from 78,909 to 250,286. At the end of the study, 16.2%, 12.2%, 8.7%, and 19.1% of bisphosphonate recipients were prescribed 3, 4, 5, or >or=6 concomitant medications, respectively. The most commonly prescribed concomitant drug classes were cholesterol reducers, diuretics, beta-blockers, calcium channel blockers, synthetic thyroid hormones, angiotensin-converting enzyme inhibitors, systemic analgesics/anti-inflammatory drugs, and antispasmodics/antisecretory drugs. From July 2001 until the end of the study, the number of concomitant medications was higher for women receiving daily bisphosphonates than for those receiving weekly bisphosphonates, 4.16 versus 3.77 as of June 2004. In addition, the mean number of concomitant medications prescribed increased with age: in the aged 50 to 64 years cohort, the aged 65 to 74 years cohort, and the aged >or=75 years cohort, the mean number was 3.09, 3.62, and 3.97, respectively, as of June 2004. CONCLUSION: This analysis suggests that women prescribed bisphosphonates have a high medication burden, with the majority of patients (56%) taking >or=3 concomitant prescription medications.

Noninvasive assessments of bone strength.

PURPOSE OF REVIEW: Description of new noninvasive technologies or modifications of existing technologies with which individual components of bone strength and bone strength as a whole can be quantified. RECENT FINDINGS: Although bone mineral density has served as an able surrogate for bone strength, it is clear that aspects of bone strength are either not captured or are not discernible within the measurement of bone density. New, noninvasive technologies have been developed to quantify aspects of bone strength such as biomechanical parameters based on geometry and scale and topological parameters of microarchitecture. Finite element modeling utilizes sophisticated mathematical approaches to predict the strength of the whole bone. At present, most of these technologies remain beyond the reach of clinicians, with the exception of hip structural or strength analysis. SUMMARY: Hip strength or structural analysis is widely available because of its incorporation with dual energy X-ray absorptiometry and has been extensively used in clinical research. None of these new approaches has been shown to be superior to the measurement of bone density in the prediction of fracture risk. This fact does not diminish their potential to enhance the understanding of the pathophysiology of fracture and the mechanisms of therapeutic efficacy.

Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density.

OBJECTIVE: Bisphosphonates such as alendronate are widely used for postmenopausal osteoporosis. Supplemental calcium is also generally recommended. This trial directly compares alendronate to supplemental calcium and examines the effect of calcium supplementation on alendronate treatment. METHODS: This 2-year, randomized, double-blind, multicenter trial enrolled healthy, postmenopausal women with low bone mineral density (BMD). Patients with a dietary calcium intake > or = 800 mg/day received daily vitamin D 400 IU and alendronate 10 mg/calcium-placebo, alendronate 10 mg/elemental calcium 1000 mg, or alendronate-placebo/calcium 1000 mg (2:2:1). Endpoints included BMD, bone turnover markers (BTMs), and adverse events. RESULTS: Randomized patients (N = 701) were an average of 20.4 years postmenopausal. After 24 months, increases in lumbar spine BMD differed significantly between patients receiving calcium alone (0.8%) and either alendronate alone (5.6%) or alendronate + calcium (6.0%) (p < 0.001). Significant differences were also seen at the trochanter and femoral neck (p < 0.001). BTMs were significantly lower with alendronate-containing treatments than calcium alone (p < 0.001). Addition of calcium supplementation to alendronate did not significantly increase BMD compared to alendronate alone (p = 0.29 to 0.97), but did result in a statistically significant, though small, additional reduction in urinary NTx. Adverse events were similar among treatment groups. Limitations include no assessment of vitamin D levels and a discontinuation rate of approximately 30%, although discontinuation rates were similar among treatment groups. CONCLUSIONS: In postmenopausal women with a daily intake of > or =800 mg calcium and 400 IU vitamin D, 24-month treatment with alendronate 10 mg daily with or without calcium 1000 mg resulted in significantly greater increases in BMD and reduction of bone turnover than supplemental calcium alone. Addition of supplemental calcium to alendronate treatment had no effect on BMD and resulted in a small, though statistically significant, additional reduction in NTx.

HSA: beyond BMD with DXA.

The measurement of bone mineral density is a surrogate for the measurement of bone strength. Bone strength is comprised of many components including, but not limited to bone architecture, geometry, cortical porosity and tissue mineralization density. A new application for dual energy X-ray absorptiometry (DXA), called hip structural or hip strength analysis (HSA), allows the measurement of geometric contributions to bone strength in the proximal femur. With this approach, the cross-sectional area, section modulus and buckling ratio can be quantified. These parameters are measures of strength in axial compression or bending. The limitations of HSA with DXA are primarily those associated with the two-dimensional nature of DXA. Because of the two-dimensional nature of DXA, assumptions must be made regarding the symmetry of the bone cross-sections used in the HSA regions of interest. In one proprietary approach to HSA, an index, called the Femur Strength Index, has been created in an attempt to relate the force of a fall on the greater trochanter to the strength of the proximal femur. Studies using HSA with DXA have demonstrated discordant behaviors between the bone mineral density (BMD) and the section modulus. The geometric parameters are predictive of fracture risk although they do not seem to be better predictors of risk than a conventional measurement of BMD. Various bone active agents have been shown to have desirable effects on these geometric parameters. Direct measurement of these components of bone strength may result in improved fracture risk prediction or therapeutic monitoring. Minimally, a better understanding of the changes in these components of bone strength in disease and during therapy may result from HSA.

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.

Monitoring osteoporosis therapy: bone mineral density, bone turnover markers, or both?

Monitoring the efficacy associated with antiresorptive therapy is an intuitive yet integral part of successful osteoporosis management. Although response rates to bisphosphonates in clinical trials--as judged by changes in bone mineral density (BMD)--are generally high, a small percentage of compliant patients do not respond. Accordingly, monitoring may help identify noncompliant patients and allow for other, possibly more successful, therapeutic interventions. Dual energy x-ray absorptiometry is the accepted method of assessing BMD to determine the need for treatment and to monitor its effects. Change in BMD is considered a valid intermediate end point for efficacy of fracture risk reduction. However, clinical trials have shown that the reduction in fracture risk associated with antiresorptive therapy may occur before changes in BMD become apparent. Vertebral fracture benefit is observed even among women who maintain rather than gain BMD during antiresorptive therapy. Clinical trials show that suppression of bone turnover markers after as little as 3 months of therapy is strongly associated with reductions in risk for fracture. Although formal guidelines for monitoring bone turnover markers do not yet exist, there are data to suggest that changes in these markers are valid intermediate endpoints for efficacy of fracture risk reduction that may provide valuable additional data on therapeutic success, particularly early in treatment and before changes in BMD become apparent.

Osteoporosis in men and women.

Osteoporosis is a cause of significant morbidity and mortality in postmenopausal women as well as men. In both men and women, increasing age and low bone mineral density (BMD) are the 2 most important independent risk factors for an initial vertebral or nonvertebral fracture. Although the prevalence of osteoporosis is greater in women, mortality after fracture is higher among men. In both men and women, the incidence of vertebral fracture increases with age, although the increase is more marked in women than in men. The diagnostic criteria for postmenopausal osteoporosis in women are well established; however, there is ongoing debate about the appropriate T-scores and BMD thresholds to diagnose osteoporosis in men. Alendronate and risedronate are considered first-line therapy for the treatment of both postmenopausal osteoporosis and male osteoporosis. The efficacy and safety of these agents have been evaluated extensively in randomized clinical trials. Studies suggest that these agents are similarly efficacious in men and women. The anabolic agent teriparatide may also be used to treat men with osteoporosis at high risk for fracture. Studies suggest that treatment with an anabolic agent like teriparatide should be followed by an antiresorptive agent.

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.

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.

Current controversies in bone densitometry.

In the face of increasing use of all types of bone densitometry in the diagnosis and management of osteoporosis, the limitations of the World Health Organization criteria for the diagnosis of osteoporosis based on bone density measurements have become apparent. Controversy has arisen about whether these criteria should be used for the diagnosis of osteoporosis. Using densitometry to monitor changes in bone density as a measure of therapeutic efficacy has been criticized. It has been suggested that changes in bone density are not surrogates for reduction in fracture risk and that regression to the mean invalidates serial testing. There is both truth and fallacy in these controversies. The resolutions are critical to the role of densitometry in clinical practice.