Denosumab Administration Research Articles

Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association?

SummarySerious adverse events of infections that occurred in subjects receiving denosumab or placebo in the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were examined in detail. Serious adverse events of infections in denosumab subjects had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.IntroductionDenosumab reduces the risk for new vertebral, hip, and nonvertebral fractures compared with placebo. In the pivotal phase 3 fracture trial (FREEDOM), the overall safety profile and incidence of adverse events including adverse events of infections were similar between groups. Serious adverse events of erysipelas and cellulitis were more frequent in denosumab-treated subjects. In this report, we further evaluate the details of infectious events in FREEDOM to better understand if RANKL inhibition with denosumab influences infection risk.MethodsFREEDOM was an international multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with osteoporosis randomly assigned to receive placebo (n = 3,906) or denosumab 60 mg every 6 months (n = 3,902). The incidence of adverse events and serious adverse events categorized within the Medical Dictionary for Regulatory Activities system organ class, “Infections and Infestations,” was compared between the placebo and denosumab groups by body systems and preferred terms. The temporal relationship between occurrence of serious adverse events of infections of interest and administration of denosumab was explored.ResultsSerious adverse events of infections involving the gastrointestinal system, renal and urinary system, ear, and endocarditis were numerically higher in the denosumab group compared with placebo, but the number of events was small. No relationship was observed between serious adverse events of infections and timing of administration or duration of exposure to denosumab.ConclusionsSerious adverse events of infections that occurred with denosumab treatment had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.Electronic supplementary materialThe online version of this article (doi:10.1007/s00198-011-1755-2) contains supplementary material, which is available to authorized users.

Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate

In this study, 250 women with osteoporosis were randomized to 12 months with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly, then crossed over to the other treatment. The primary endpoint, treatment adherence at 12 months, was 76.6% for alendronate and 87.3% for denosumab. The purpose of this study is to evaluate treatment adherence with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly. In this multicenter, randomized, open-label, 2-year, crossover study, 250 postmenopausal women with low bone mineral density received denosumab or alendronate for 12 months, then the other treatment for 12 months. The alendronate bottle had a medication event monitoring system cap to monitor administration dates. Definitions were as follows: compliance, receiving both denosumab doses 6 (± 1) months apart or 80-100% of alendronate doses; persistence, receiving both denosumab doses and completing the month 12 visit within the visit window or ≥ 2 alendronate doses in the final month; adherence, achieving both compliance and persistence. This report includes data from the first 12 months. The primary study endpoint, adherence in the first 12 months, was 76.6% (95/124) for alendronate and 87.3% (110/126) for denosumab. Risk ratios for denosumab compared with alendronate at 12 months were 0.58 (p = 0.043) for non-adherence, 0.48 (p = 0.014) for non-compliance, and 0.54 (p = 0.049) for non-persistence. Subject ratings for treatment necessity, preference, and satisfaction were significantly greater for denosumab and ratings for treatment bother were significantly greater for alendronate. Adverse events were reported by 64.1% of alendronate-treated subjects and 72.0% of denosumab-treated subjects (p = 0.403). The most common adverse events were arthralgia, back pain, pain in extremity, cough, and headache (each in <10% of subjects in each group). Significantly greater treatment adherence was observed for subcutaneous administration of denosumab every 6 months than for oral alendronate once weekly.

Emerging Options for the Treatment of Postmenopausal Osteoporosis: Focus on Denosumab

Objective: Denosumab, a fully human monoclonal antibody, is an antiresorptive drug in a late-stage of clinical development that neutralizes receptor activator of nuclear factor κB ligand (RANKL), thereby inhibiting osteoclast-mediated bone resorption. The purpose of this paper was to discuss the antifracture efficacy and safety of the subcutaneous administration of denosumab for the treatment of postmenopausal osteoporosis. Methods: PubMed was searched and strictly conducted randomized controlled trials (RCTs) regarding the effect of denosumab on skeletal health in postmenopausal women were identified. Results: The results of RCTs showed that a single subcutaneous dose of denosumab rapidly and profoundly reduced bone resorption and sustained (up to 6 months) this effect in postmenopausal women. Denosumab (60 mg, every 6 months) resulted in a sustained decrease in bone turnover, a rapid increase in bone mineral density (BMD), and an improvement of geometric parameters associated with bending and axial strength and cortical stability at purely cortical and mixed cortical/trabecular sites of the proximal femur in postmenopausal women with a low BMD. Denosumab (60 mg every 6 months) reduced the 3-year incidence of vertebral, nonvertebral, and hip fractures (Hazard ratios: 0.32, 0.80, and 0.60, respectively) in postmenopausal women with osteoporosis. Denosumab was well tolerated, and no related severe adverse events were observed. Conclusions: The subcutaneous administration of denosumab every six months effectively decreased bone resorption, increased the BMD, and reduced the risk of vertebral, nonvertebral, and hip fractures in postmenopausal women. Denosumab offers an emerging option for the treatment of postmenopausal osteoporosis.

Denosumab for Prevention of Fractures in Postmenopausal Women With Osteoporosis

Denosumab is a fully human monoclonal antibody against the receptor activator of the cytokine, nuclear factor-κB ligand, which is of critical importance for the formation, function, and survival of osteoclasts. This antibody binds nuclear factor-κB ligand and reversibly inhibits osteoclast-mediated bone resorption in osteoclasts and osteoclast precursors. Earlier studies reported that subcutaneous administration of denosumab every 6 months reduced bone turnover and increased bone mineral density. This international, randomized, placebo-controlled trial evaluated the effect of denosumab on the risk of fracture in 7808 postmenopausal women with osteoporosis. Participants had a bone mineral density T score less than -2.5 at the lumbar spine or total hip. Women with T scores less than -4.0 were excluded. Their ages ranged from 60 to 90 years. The study subjects used in the final analysis had been randomized to receive subcutaneous injections of 60 mg of denosumab (n = 3902) or placebo (n = 3906) every 6 months for 36 months. A new vertebral fracture was the primary outcome. The occurrence of nonvertebral fracture and hip fracture were the secondary end points. At 36-months, the cumulative incidence of new radiographic vertebral fracture was reduced by 68% in the denosumab group compared to the placebo group (denosumab: 2.3% vs. placebo: 7.2%); the risk ratio was 0.32, with a 95% confidence interval [CI] of 0.26-0.41; P < 0.001). The risk of hip fracture was reduced by 40% with the drug compared to the placebo group (cumulative incidence of denosumab: 0.7% vs. placebo: 1.2%); the hazard ratio was 0.60, with a 95% CI of 0.37-0.97; P = 0.04. Similarly, denosumab reduced the cumulative incidence of nonvertebral fracture from 8.0% in the placebo group to 6.5% in the denosumab group (hazard ratio, 0.80; 95% CI, 0.67-0.95; P = 0.01)-a 20% relative reduction in risk. During the 36-months of the study, denosumab was not associated with a significant increase in the incidence of infection, cancer, or cardiovascular events. No increase was found in the occurrence of delayed fracture healing or hypocalcemia and other adverse effects associated with potent antiresorptive agents. Osteonecrosis of the jaw was not observed in either group. These findings show that subcutaneous injections of denosumab every 6 months for 36 months is associated with a significant reduction in the risk of vertebral, hip, and nonvertebral fractures among postmenopausal women with osteoporosis.

Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study

Denosumab increased lumbar spine bone mineral density (BMD) versus placebo in a 2-year, randomized, placebo-controlled, phase 3 study of patients with hormone-receptor-positive, non-metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy. In subgroup analyses at 12 and 24 months, we evaluated factors (duration and type of aromatase inhibitor, tamoxifen use, age, time since menopause, body mass index, T-score) that might influence BMD at the lumbar spine, total hip, femoral neck, and 1/3 radius. Patients were randomized to receive placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months. In all subgroups, 12 or 24 months' treatment with denosumab was associated with larger BMD gains than placebo across multiple skeletal sites. Most increases were statistically significant (P < 0.05). Twice-yearly administration of denosumab, regardless of patient subgroup or skeletal site, resulted in consistent increases in BMD versus placebo at 12 and 24 months.

Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer

Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, to protect against aromatase inhibitor-induced bone loss. Eligible women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (< or = 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.

Failure To Initiate Treatment In Patients With Osteoporosis

This study aimed to investigate the correlation between bone mineral density (BMD) and the turnover rate [√(MoMf2 + MoMr2), multiple of median formation (MoMf) was calculated as bone-specific alkaline phosphatase (BAP) value/18.6 and multiple of median resorption (MoMr) as tartrate-resistant acid phosphatase 5b (TRACP-5b) value/463] and the balance (MoMf/MoMr) and to compare differences in therapeutic effects evoked by differences in previous treatments.In 51 osteoporotic women treated with bisphosphonates (BPs) or selective estrogen receptor modulators (SERMs), BMD was measured at 0, 24, and 48 weeks after denosumab administration. The values of BAP and TRACP-5b were measured at 0, 4, 12, 24, 36, and 48 weeks.The turnover rate decreased at week 4 and decreased further at week 12. The balance indicated a relative predominantly formative state at week 4. This balance became higher in the SERM group than in the BP group at week 4. A correlation was observed between the rate of BMD change and turnover rate at weeks 0 and 4.It is necessary to evaluate the turnover rate and balance to determine the therapeutic effect of denosumab, which induces dissociation between the trends in the bone turnover markers. Turnover rate and balance during the early stages of denosumab treatment may be predictive factors of BMD. When switching from bone resorption inhibitors to denosumab, it was necessary to consider the beginning values that were affected by the previous treatment. The state of relative anabolism is greater at 4 weeks when the previous treatment involved SERMs rather than BPs.

On the Horizon From the ORS

On the Horizon From the ORS