[show abstract][hide abstract] ABSTRACT: Context: Men with low bone mineral density (BMD) were treated with denosumab. Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ≤ 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups. Conclusions: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.
The Journal of clinical endocrinology and metabolism 06/2012; 97(9):3161-9. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < -2.5 and not < -4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%-61%] and 51% [95% CI: 39%-66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% - >100%] and 72% [95% CI: 24% - >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2011; 27(3):687-93. · 6.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: The pharmacologic properties, clinical efficacy, and safety profile of the injectable agent denosumab for the treatment of postmenopausal women with osteoporosis are reviewed.
Denosumab, a human monoclonal antibody that targets a key protein mediator of bone resorption, was approved by the Food and Drug Administration in June 2010 for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture, including "patients who have failed or are intolerant to other available osteoporosis therapy." Available in a 60-mg prefilled syringe, denosumab should be administered subcutaneously by a health care professional at six-month intervals. In Phase III clinical efficacy trials involving nearly 10,000 postmenopausal women, the use of denosumab was associated with a number of significant benefits: reduced bone resorption, increased bone mass, and reduced rates of vertebral, nonvertebral, and hip fractures. Results of two comparison studies indicated that denosumab therapy increased bone mineral density (BMD) at various skeletal sites to a significantly greater extent than alendronate therapy. In the largest clinical trial of the drug to date, adverse effects occurring significantly more often with denosumab versus placebo included eczema-related effects and cellulitis; long-term safety evaluations are ongoing.
Denosumab has been shown to decrease bone resorption; increase BMD at all skeletal sites measured; and significantly reduce rates of vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. Denosumab appears to have a favorable risk:benefit profile and provides a new treatment option for many patients in this population.
American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 08/2011; 68(15):1409-18. · 2.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab-treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C-telopeptide of type I collagen [CTX] and tartrate-resistant acid phosphatise [TRACP-5b]) and bone formation (serum procollagen type I N-terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab-treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab-treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = -0.24 to -0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2011; 26(3):530-7. · 6.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: View the National Osteoporosis Foundation Clinician's Guide Postmenopausal osteoporosis is a major concern to public health. Fractures are the major clinical consequence of osteoporosis and are associated with substantial morbidity, mortality, and health care costs. Despite the availability of screening and treatment guidelines, osteoporosis diagnosis and treatment remain low. Health care providers may consult guidelines in the clinical management of their patients with osteoporosis, including those from the National Osteoporosis Foundation, and the new fracture risk assessment tool from the World Health Organization. Bisphosphonates are the most commonly used treatment for postmenopausal osteoporosis. Although these agents are effective in preventing fractures and bone loss, the benefits of treatment may be limited by suboptimal adherence and compliance. Denosumab is a human monoclonal antibody that targets and inhibits RANK ligand, an essential mediator of bone resorption. In clinical trials in postmenopausal women with osteoporosis, denosumab 60 mg given subcutaneously every 6 months was well tolerated and statistically significantly reduced the risk of vertebral, nonvertebral, and hip fractures. The introduction of denosumab into clinical practice provides physicians with another option for the treatment of postmenopausal osteoporosis, and the twice-yearly dosing regimen has the potential to improve adherence.
Postgraduate Medicine 11/2010; 122(6):176-87. · 1.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Persistence with osteoporosis treatment is poor but is important for maximum benefit.
The objective of the study was to assess the impact of physician reinforcement using bone turnover markers (BTMs) on persistence with risedronate treatment.
This was a 1-yr multinational prospective, open-label, blinded study in 171 osteoporosis centers in 21 countries.
A total of 2382 postmenopausal women (65-80 yr old) with spine/hip T-score -2.5 or less or T-score -1.0 or less with a low-trauma fracture.
Intervention included calcium 500 mg/d, vitamin D 400 IU/d, and risedronate 5 mg/d for 1 yr. Centers were randomized to reinforcement (RE+) or no reinforcement (RE-). At 13 and 25 wk, reinforcement based on urinary N-telopeptide of type I collagen change from baseline was provided to the RE+ patients using the following response categories: good (>30% decrease), stable (-30% to +30% change), or poor (>30% increase).
Persistence assessed with electronic drug monitors was measured.
In the overall efficacy population (n=2302), persistence was unexpectedly high and was similar for both groups (RE-, 77%; RE+, 80%; P=0.160). A significant relationship between the type of message and persistence was observed (P=0.017). Compared with RE-, intervention based on a good BTM response was associated with a significant improvement in persistence [hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53-0.95]. Persistence was unchanged (HR 1.02; 95% CI 0.74-1.40) or lower (HR 2.22; 95% CI 1.27-3.89) when reinforcement was based on a stable or poor BTM response, respectively. Reinforcement was associated with a lower incidence of new radiologically determined vertebral fractures (odds ratio 0.4; 95% CI, 0.2-1.0).
Reinforcement using BTMs influences persistence with treatment in postmenopausal women with osteoporosis, depending on the BTM response observed.
[show abstract][hide abstract] ABSTRACT: Accurate radiographic diagnosis of vertebral fractures is important. This multicenter, multinational study assessed radiographic diagnoses of vertebral fracture in 2451 postmenopausal women with osteoporosis. Comparison between local and central readings yielded a false-negative rate of 34%. Underdiagnosis of vertebral fracture is a worldwide problem.
Vertebral fractures are the most common complication of osteoporosis. Although they are associated with significant morbidity, they frequently do not come to clinical attention. Accurate radiographic diagnosis is important.
In a multicenter, multinational prospective study (the IMPACT trial), the accuracy of radiographic diagnosis of vertebral fracture was evaluated in postmenopausal women 65-80 years of age newly diagnosed with osteoporosis (based on BMD measurement). Lateral radiographs of the thoracolumbar spine were evaluated for identification of vertebral fractures, first locally and subsequently at a central reading center, using a validated semiquantitative method. False-positive and false-negative rates were calculated based on adjudicated discrepancies between the initial interpretation at the local site and the subsequent central reading, considered the "reference standard."
Of 2451 women with an evaluable radiograph both centrally and locally, 789 (32%) had at least one vertebral fracture. Adjudicated discrepancies (n = 350 patients) between local and central readings because of undetected vertebral fracture (68%) or equivocal terminology in the local radiology report (32%) yielded a false-negative rate of 34%.
Underdiagnosis of vertebral fractures was observed in all geographic regions (false-negative rates: North America, 45.2%; Latin America, 46.5%; Europe/South Africa/Australia, 29.5%). The false-positive rate was 5% globally. Underdiagnosis of vertebral fracture is a worldwide problem attributable in part to a lack of radiographic detection, use of ambiguous terminology in the radiology report, or both. Efforts to improve accuracy and reduce variability in terminology and interpretation may increase the effectiveness of spinal radiography for detecting vertebral fractures in patients with osteoporosis.
Journal of Bone and Mineral Research 05/2005; 20(4):557-63. · 6.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: It is unclear whether the antifracture efficacy of bisphosphonates depends on pretreatment bone turnover. We analyzed the risedronate phase III clinical programs using the urinary excretion of deoxypyridinoline (uDPD) as an index of pretreatment bone resorption rates. Risedronate reduced incident vertebral fractures in women with postmenopausal osteoporosis independent from pretreatment bone resorption.
Earlier studies on postmenopausal osteoporosis have suggested that the therapeutic efficacy of antiresorptive therapies might be influenced by pretreatment bone turnover. Because all of these studies have used bone mineral density (BMD) as the primary endpoint, it remains unclear whether this association holds true for incident fractures.
This study aims to answer this question in a post hoc analysis of a subset of the risedronate phase III clinical programs, using the urinary excretion of deoxypyridinoline (uDPD) as an index of pretreatment bone resorption (PBR). A total of 1593 women with postmenopausal osteoporosis that had baseline uDPD values and paired spinal radiographs available were pooled, in similar proportions, from the risedronate multinational and North American VERT, and from the risedronate HIP trials. Patients from treatment and placebo groups were stratified by the uDPD premenopausal normative median. The four resulting groups were balanced for age, years since menopause, body mass index, baseline femoral neck BMD, and number of prevalent fractures, but baseline lumbar spine BMD was significantly higher in patients with low PBR rates.
In all groups, the proportion of patients with new vertebral fractures was higher in patients with baseline uDPD levels above the normative median. The incidence of vertebral fracture was significantly lower in groups assigned to risedronate compared with placebo. This effect was independent of PBR: in patients with high PBR, the relative risk (RR) of vertebral fracture after 1 year of risedronate was 0.28 (p = 0.03 compared with controls, absolute risk reduction 7.1%). In patients with low PBR, the RR of fracture after 1 year was 0.33 (p < 0.001, absolute risk reduction 4%). After 3 years, the RR of fracture was 0.52 (p = 0.042, absolute risk reduction 8.3%) in patients with high PBR, and 0.54 (p = 0.002, absolute risk reduction 7.1%) in patients with low PBR. Results were similar after adjusting for age, baseline lumbar spine BMD, and prevalent fractures. The number needed to treat to avoid one vertebral fracture at 12 months was 15 in the group of patients with high PBR and 25 in patients with low PBR. Risedronate significantly increased lumbar spine BMD. During the first year of treatment, women with high PBR gained lumbar spine BMD at a faster rate than patients with low PBR. Treatment-by-PBR status interactions were not significantly different over time.
The efficacy of risedronate to reduce incident vertebral fractures in women with postmenopausal osteoporosis is largely independent of pretreatment bone resorption rates.
Journal of Bone and Mineral Research 03/2004; 19(2):323-9. · 6.13 Impact Factor