[show abstract][hide abstract] ABSTRACT: This 2-year trial evaluated the efficacy and tolerability of a monthly oral regimen of risedronate. Postmenopausal women with osteoporosis were randomly assigned to double-blind treatment with risedronate 75 mg on 2 consecutive days each month (2CDM) or 5 mg daily. The primary end point was the percentage change from baseline in lumbar spine bone mineral density (BMD) at 12 months. Secondary end points included the change in BMD of the lumbar spine and proximal femur and in bone turnover markers as well as the number of subjects with at least one new vertebral fracture over 24 months. Among 1,229 patients who were randomized and received at least one dose of risedronate, lumbar spine BMD was increased in both treatment groups: mean percentage change from baseline was 4.2 ± 0.19 and 4.3 ± 0.19 % in the 75 mg 2CDM and 5 mg daily groups, respectively, at month 24. The treatment difference was 0.17 (95 % confidence interval -0.35 to 0.68). There were no statistically significant differences between treatment groups on any secondary efficacy parameters. Both treatment regimens were well tolerated. Risedronate 75 mg 2CDM was noninferior in BMD efficacy and did not show a difference in tolerability compared to 5 mg daily after 24 months of treatment in women with postmenopausal osteoporosis. This monthly regimen may provide a more convenient dosing schedule to some patients with postmenopausal osteoporosis.
Calcified Tissue International 11/2012; · 2.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis.
In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age to receive an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months. Participants received daily calcium and vitamin D supplementation. The primary end point was the proportion of participants with one or more new morphometric vertebral fractures over a period of 24 months.
The rate of any new morphometric vertebral fracture was 1.6% in the zoledronic acid group and 4.9% in the placebo group over the 24-month period, representing a 67% risk reduction with zoledronic acid (relative risk, 0.33; 95% confidence interval, 0.16 to 0.70; P=0.002). As compared with men who received placebo, men who received zoledronic acid had fewer moderate-to-severe vertebral fractures (P=0.03) and less height loss (P=0.002). Fewer participants who received zoledronic acid had clinical vertebral or nonvertebral fractures, although this difference did not reach significance because of the small number of fractures. Bone mineral density was higher and bone-turnover markers were lower in the men who received zoledronic acid (P<0.05 for both comparisons). Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ significantly with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%).
Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture among men with osteoporosis. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00439647.).
New England Journal of Medicine 11/2012; 367(18):1714-23. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: FREEDOM was a phase 3 trial in 7808 women aged 60-90yr with postmenopausal osteoporosis. Subjects received placebo or 60 mg denosumab subcutaneously every 6mo for 3yr in addition to daily calcium and vitamin D. Denosumab significantly decreased bone turnover; increased dual-energy X-ray absorptiometry (DXA) areal bone mineral density (aBMD); and significantly reduced new vertebral, nonvertebral, and hip fractures. In a subset of women (N=209), lumbar spine, total hip, and femoral neck volumetric BMD (vBMD) were assessed by quantitative computed tomography at baseline and months 12, 24, and 36. Significant improvement from placebo and baseline was observed in aBMD and vBMD in the denosumab-treated subjects at all sites and time points measured. The vBMD difference from placebo reached 21.8%, 7.8%, and 5.9%, respectively, for the lumbar spine, total hip, and femoral neck at 36mo (all p≤0.0001). Compared with placebo and baseline, significant increases were also observed in bone mineral content (BMC) at the total hip (p<0.0001) largely related to significant BMC improvement in the cortical compartment (p<0.0001). These results supplement the data from DXA on the positive effect of denosumab on BMD in both the cortical and trabecular compartments.
Journal of Clinical Densitometry 05/2012; · 1.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: Denosumab is an approved therapy for postmenopausal women with osteoporosis at high or increased risk for fracture. In the FREEDOM study, denosumab reduced fracture risk and increased bone mineral density (BMD). We report the spine and hip dual-energy X-ray absorptiometry (DXA) BMD responses from the overall study of 7808 women and from a substudy of 441 participants in which more extensive spine and hip assessments as well as additional skeletal sites were evaluated. Significant BMD improvements were observed as early as 1mo at the lumbar spine, total hip, and trochanter (all p<0.005 vs placebo and baseline). BMD increased progressively at the lumbar spine, total hip, femoral neck, trochanter, 1/3 radius, and total body from baseline to months 12, 24, and 36 (all p<0.005 vs placebo and baseline). BMD gains above the least significant change of more than 3% at 36 months were observed in 90% of denosumab-treated subjects at the lumbar spine and 74% at the total hip, and gains more than 6% occurred in 77% and 38%, respectively. In conclusion, denosumab treatment resulted in significant, early, and continued BMD increases at both trabecular and cortical sites throughout the skeleton over 36mo with important gains observed in most subjects.
Journal of Clinical Densitometry 04/2012; · 1.71 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: Dosing regimens of oral bisphosphonates are inconvenient and contribute to poor compliance. The bone mineral density response to a once weekly delayed-release formulation of risedronate given before or following breakfast was non-inferior to traditional immediate-release risedronate given daily before breakfast. Delayed-release risedronate is a convenient regimen for oral bisphosphonate therapy.
We report the results of a randomized, controlled, clinical study assessing the efficacy and safety of a delayed-release (DR) 35 mg weekly oral formulation of risedronate that allows patients to take their weekly risedronate dose before or immediately after breakfast.
Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5 mg immediate-release (IR) daily (n = 307) at least 30 min before breakfast, or risedronate 35 mg DR weekly, either at least 30 min before breakfast (BB, n = 308) or immediately following breakfast (FB, n = 307). Bone mineral density (BMD), bone turnover markers (BTMs), fractures, and adverse events were evaluated. The primary efficacy variable was percent change from baseline in lumbar spine BMD at Endpoint.
Two hundred fifty-seven subjects (83.7%) in the IR daily group, 252 subjects (82.1%) in the DR FB weekly group, and 258 subjects (83.8%) in the DR BB weekly group completed 1 year. Both DR weekly groups were determined to be non-inferior to the IR daily regimen. Mean percent changes in hip BMD were similar across groups. The magnitude of BTM response was similar across groups; some statistical differences were seen that were small and deemed by investigators to have no major clinical importance. The incidence of adverse events leading to withdrawal and serious adverse events were similar across treatment groups. All three regimens were well tolerated.
Risedronate 35 mg DR weekly is similar in efficacy and safety to risedronate 5 mg IR daily, and will allow patients to take their weekly risedronate dose immediately after breakfast.
Osteoporosis International 09/2011; 23(1):267-76. · 4.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Denosumab is a fully human monoclonal antibody that neutralizes the activity of RANKL, leading to the inhibition of osteoclast maturation, bone-resorbing activity, and survival. Evaluation of trans-iliac crest bone biopsy specimens in the phase 3 pivotal fracture study with denosumab in postmenopausal women with osteoporosis showed evidence of reduced bone turnover at the tissue level in subjects receiving denosumab, and up to one-third of subjects did not have evidence of tetracycline labeling in trabecular or cortical bone. Discontinuation of denosumab therapy has demonstrated that the effects of denosumab are reversible, as assessed by biochemical markers of bone turnover (BTM) and BMD. The precise nature of changes that occur at the tissue level with denosumab discontinuation have not been explored. Fifteen subjects were enrolled in a cohort study to evaluate the effects of denosumab discontinuation at the tissue level. Subjects had discontinued osteoporosis treatment for a mean time of 25.1 months (range 21 to 29 months). Bone histomorphometry results were compared with results from placebo-treated women with osteoporosis in the denosumab phase 3 pivotal fracture bone biopsy substudy, and BTMs were compared with subjects' pretreatment values. The results of this study showed normal histology and bone remodeling similar to those observed in untreated postmenopausal women with osteoporosis. With treatment cessation, 100% of biopsy specimens had evidence of tetracycline labels. Biochemical markers were comparable to and highly correlated with pretreatment levels. These data confirm that the effects of denosumab on bone turnover at the tissue level are fully reversible.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2011; 26(11):2737-44. · 6.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Arzoxifene increased bone mineral density and decreased bone turnover to a significantly greater extent than raloxifene. The hot flush incidence was lower with arzoxifene than raloxifene.
To assess the effect of arzoxifene versus raloxifene on change in lumbar spine (LS) bone mineral density (BMD) in postmenopausal women with osteoporosis.
In this 12-month study (NEXT trial), participants were randomly assigned to arzoxifene 20 mg/day (N = 158) or raloxifene 60 mg/day (N = 162). All received daily calcium and vitamin D. Change in LS BMD was assessed by DXA. Secondary objectives included assessment of femoral neck (FN) and total hip BMD, serum bone turnover markers, and safety.
Treatment groups were similar at baseline (mean age 63 years, mean LS BMD T-score -2.9). At 12 months, the increase in LS BMD with arzoxifene was greater than with raloxifene (+2.75% vs. +1.66%), as was FN and total hip BMD (P < 0.05). For LS and FN, this effect was also evident at 6 months. Arzoxifene reduced bone turnover to a greater extent than raloxifene at 3, 6, and 12 months (P < 0.05). The proportion of women reporting ≥ 1 adverse event did not differ between treatment groups, nor did vaginal bleeding. No cases of endometrial polyps, hyperplasia, or cancer were reported. Nasopharyngitis and bronchitis were reported more frequently with arzoxifene versus raloxifene (10.1% vs. 2.5%, and 5.1% vs. 0%, respectively) and new/worsening hot flushes were reported less frequently with arzoxifene (7.0% vs. 16.7%) (P < 0.05).
Arzoxifene increased BMD and suppressed bone turnover to a greater extent than raloxifene and resulted in a lower incidence of new/worsening hot flushes. Based on subsequent findings from a fracture outcome study, this difference did not translate into improved fracture efficacy.
Osteoporosis International 03/2011; 23(3):1091-101. · 4.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Arzoxifene is a selective estrogen receptor modulator (SERM) that has been shown to be more potent in preclinical testing than currently available agents. Its effects on clinical outcomes are not known. In a randomized, blinded trial, women aged 60 to 85 years with osteoporosis, defined as a femoral neck or lumbar spine bone mineral density T-score of -2.5 or less or a vertebral fracture, and women with low bone mass, defined as a bone density T-score of -1.0 or less and above -2.5, were assigned to arzoxifene 20 mg or placebo daily. The primary endpoints were new vertebral fracture in those with osteoporosis and invasive breast cancer in the overall population. After 3 years, the cumulative incidence of vertebral fractures in patients with osteoporosis was 2.3% lower in the arzoxifene group than in the placebo group, a 41% relative risk reduction [95% confidence interval (CI) 0.45-0.77, p < .001]. In the overall population, the cumulative incidence of invasive breast cancer over 4 years was reduced by 1.3%, with a 56% relative reduction in risk (hazard ratio = 0.44, 95% CI 0.26-0.76, p < .001); there was no significant decrease in nonvertebral fracture risk. Arzoxifene increased the cumulative incidence of venous thromboembolic events by 0.7%, with a 2.3-fold relative increase (95% CI 1.5-3.7). Like other SERMs, arzoxifene decreased vertebral fractures and invasive breast cancer while the risk of venous thromboembolic events increased.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2011; 26(2):397-404. · 6.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the safety and efficacy of full-length parathyroid hormone, PTH(1-84), treatment for up to 36 months by evaluating bone mineral density (BMD) changes, bone histomorphometric indices, and clinical fracture incidence in postmenopausal women with osteoporosis.
The TOP trial demonstrated increased lumbar spine BMD (6.9%) versus placebo after 18 months of PTH(1-84) treatment and reduced the incidence of new vertebral fractures (61%; p = 0.001). The therapeutic benefits of long-term treatment of postmenopausal women with PTH(1-84) are unknown.
The safety and efficacy of 36 months of once-daily dosing with 100 µg PTH(1-84) in postmenopausal women with osteoporosis were assessed. Women receiving placebo during the TOP trial were eligible for PTH(1-84) in the extension study.
Lumbar spine BMD increased by 8.5% above baseline (p < 0.001) at 36 months of PTH(1-84) treatment, remaining stable during the last 12 months of treatment. Increases in total hip and femoral neck BMD occurred more slowly, reaching 3.2% and 3.4%, respectively above baseline at 36 months (p < 0.001). The total hip BMD showed no signs of reaching a limiting value although the femoral neck plateaued from months 24 to 36. Seven patients had vertebral fractures during the placebo phase of the TOP trial and before entering the extension study, but this rate decreased with the introduction of PTH(1-84) therapy, resulting in a single worsened vertebral fracture in the first 6 months and no further vertebral fractures from months 6 to 36. Treatment over 36 months with PTH(1-84) was well-tolerated and iliac crest biopsies showed no adverse effects on bone. Limitations: There was no placebo group for BMD comparisons. The number of patients assessed for fracture incidence was small.
PTH(1-84) treatment for 36 months resulted in significant increases in BMD at the lumbar spine and hip, was associated with a lower incidence of vertebral fracture when compared to before therapy initiation, and was well-tolerated. The continuous increases in total hip BMD suggest that prolonged PTH(1-84) treatment may be beneficial for postmenopausal osteoporosis. Increased BMD at the femoral neck and lumbar spine also showed favourable changes but plateaued between 24 and 36 months. Long-term treatment was not associated with abnormalities in bone biopsies.
Current Medical Research and Opinion 10/2010; 26(11):2627-33. · 2.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.
In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.
Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.
In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)
New England Journal of Medicine 02/2010; 362(8):686-96. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.
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.
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.
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.)
New England Journal of Medicine 09/2009; 361(8):756-65. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain.
In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels.
During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.
Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)
New England Journal of Medicine 08/2008; 359(7):697-708. · 51.66 Impact Factor