Alfred H. Moffett

Bio: Alfred H. Moffett is an academic researcher. The author has contributed to research in topics: Denosumab & Osteoporosis. The author has an hindex of 11, co-authored 13 publications receiving 1953 citations.

Denosumab in Postmenopausal Women with Low Bone Mineral Density

Abstract: Background Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action. Methods The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Results Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. Conclusions In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.).

Denosumab in postmenopausal women with low bone mineral density

Abstract: Despite the availability of drugs that lower the risk of bone fracture in osteoporotic patients, few patients comply fully with current treatments. The investigators evaluated denosumab-previously known as AMG 162-a fully human monoclonal antibody (immunoglobulin G 2 ) that binds strongly and specifically to RANKL or receptor activator of nuclear factor-KB ligand. RANKL is a protein expressed by osteoblastic stromal cells and is the major mediator of osteoclast differentiation, activation, and survival. RANKL underlies osteoclast-mediated bone resorption. Denosumab acts by blocking the interaction of RANKL with RANK and mimics the effects of osteoprotegerin. This randomized, placebo-controlled study examined the effects of subcutaneously administered denosumab over 12 months in 412 postmenopausal women aged up to 80 years with low bone mineral density (BMD) defined as a T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur. Participants were assigned to receive denosumab either every 3 months in a dose of 6, 14, or 30 mg or every 6 months in a dose of 14, 60, 100, or 120 mg; alendronate orally in a dose of 70 mg once a week (on an open-label basis); or placebo. The primary end point was the percentage change in BMD at the lumbar spine after 12 months. A total of 369 women, 90% of the original sample, completed 12 months of treatment. BMD at the lumbar spine increased from 3.0% to 6.7% at 12 months in women given denosumab compared with a decrease of 0.8% in placebo recipients (P <.001). Total hip BMD increased by a mean of 1.9% to 3.6% with denosumab treatment and fell 0.6% in placebo patients (P <.001). BMD also increased in the distal radius in women given denosumab. Alendronate increased BMD compared with placebo at 12 months. Serum levels of C-telopeptide, a marker of bone turnover, decreased in women given denosumab compared with placebo patients. Alendronate also lowered markers of bone turnover. A small reduction in the albumin-adjusted serum calcium level was noted in the denosumab group, and concentrations of intact parathyroid hormone increased. Side effects were similar in all groups except for dyspepsia, which was significantly more frequent in women given alendronate. Denosumab deserves further study as a possible treatment for osteoporosis in postmenopausal women.

Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women.

Abstract: Both hormone replacement therapy (HRT) and bisphosphonates are efficacious in the prevention and treatment of postmenopausal osteoporosis. Combined therapy with bisphosphonate and HRT is likely to be used in clinical practice, and limited data are available regarding its efficacy and safety. This was a 1-yr, double blind, placebo-controlled study in which 524 postmenopausal women received daily treatment with conjugated equine estrogens (0.625 mg) alone or in combination with risedronate (5 mg). Women who had not undergone hysterectomy received medroxyprogesterone acetate (up to 5 mg, daily or cyclically) at the discretion of the investigator. The primary efficacy end point was the percent change from baseline in mean lumbar spine bone mineral density (BMD) at 1 yr. Changes in BMD at the proximal femur and forearm, bone turnover markers, and histology and histomorphometry were also assessed. At 12 months, significant (P < 0.05) increases from baseline in lumbar spine BMD were observed in both treatment gr...

Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene.

Abstract: OBJECTIVE Osteoporosis is a significant health problem in postmenopausal women Consequently, new and effective therapies are being sought to preserve bone mass and prevent osteoporosis in this population of women The objective of this study was to compare the effects of lasofoxifene with raloxifene and placebo on indices of bone health in postmenopausal women DESIGN A randomized, double-blind, placebo- and active treatment-controlled study of 2 years duration was conducted Women included 410 postmenopausal women aged 47 to 74 years The four treatment groups were: lasofoxifene 025 mg/day, or 10 mg/day, raloxifene 60 mg/day, or placebo daily All women received daily calcium and vitamin D supplements The primary endpoint was percent change from baseline to 2 years in lumbar spine bone mineral density (BMD) in all women having baseline and at least one follow-up bone density measurement Total hip BMD, biochemical markers of bone turnover, low-density lipoprotein cholesterol, and safety were also evaluated in all women RESULTS Both doses of lasofoxifene significantly increased lumbar spine BMD compared with raloxifene (P < or = 005) and with placebo treatment (P < or = 005) Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 36% (19, 52) for lasofoxifene 025 mg/day, 39% (24, 55) for lasofoxifene 10 mg/day, and 17% (03, 30) for raloxifene The two doses of lasofoxifene and raloxifene were equally effective at increasing total hip BMD Lasofoxifene and raloxifene significantly reduced the levels of biochemical markers of bone turnover compared with placebo In general, the effects of lasofoxifene were greater than the responses to raloxifene At 2 years, lasofoxifene significantly (P < or = 005) reduced low-density lipoprotein cholesterol levels by 206% and 197% with 025 mg/day and 1 mg/day, respectively, compared with raloxifene (121%) and placebo (32%) Lasofoxifene and raloxifene had a similar adverse event profile with low rate of discontinuations due to adverse events CONCLUSIONS Lasofoxifene may be an effective and well-tolerated treatment option for the prevention of bone loss in postmenopausal women

Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

Abstract: Background Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. Methods In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. Results In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P = 0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P = 0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P = 0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. Conclusions The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

Abstract: Methods We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. Results As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001) — a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P = 0.04) — a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) — a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. Conclusions Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Metastatic Behavior of Breast Cancer Subtypes

Abstract: Purpose Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected. Methods Patients with early-stage breast cancer diagnosed between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression. Results Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P < .001). Bone was the most ...