Summary
Stopping denosumab after 8 years of continued treatment was associated with bone loss during a 1-year observation study in patients who were not prescribed osteoporosis treatment. Bone loss ...was attenuated in patients who began another osteoporosis therapy. Treatment to prevent bone loss upon stopping denosumab should be considered.
Introduction
This study aimed to understand osteoporosis management strategies during a 1-year observational follow-up after up to 8 years of denosumab treatment in a phase 2 study.
Methods
During the observational year, patients received osteoporosis management at the discretion of their physician and returned to the clinic for BMD assessment and completion of an osteoporosis management questionnaire. Incidence of serious adverse events and fractures was collected. Analyses were descriptive.
Results
Of 138 eligible patients, 82 enrolled in and completed the observation study. Most (65 79%) did not receive prescription osteoporosis medication, with “my doctor felt I no longer needed a medication” being the most common reason (23 35%). Of the 17 patients who took osteoporosis medications, 8 discontinued therapy during the observation study. In patients treated with denosumab for 8 years (
N
= 52), BMD decreased during the 1-year observation study (6.7% lumbar spine, 6.6% total hip). Those who took osteoporosis medication during the observation study showed a smaller decline in BMD than those who did not. No new safety concerns were identified. Eight patients (9.8%), all of whom had at least one predisposing risk factor, experienced 17 fractures. This included seven patients who experienced one or more vertebral fractures.
Conclusions
Consistent with denosumab’s mechanism of action, treatment cessation led to reversal of the drug’s effect on BMD and perhaps fracture risk. For patients who took osteoporosis therapy, bone loss was attenuated. For patients at high fracture risk, switching to another osteoporosis therapy if denosumab is discontinued seems appropriate.
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.)
Abstract Vertebral fractures are common and can result in acute and chronic pain, decreases in quality of life, and diminished lifespan. The identification of vertebral fractures is important because ...they are robust predictors of future fractures. The majority of vertebral fractures do not come to clinical attention. Numerous modalities exist for visualizing suspected vertebral fracture. Although differing definitions of vertebral fracture may present challenges in comparing data between different investigations, at least 1 in 5 men and women aged >50 years have one or more vertebral fractures. There is clinical guidance to target spine imaging to individuals with a high probability of vertebral fracture. Radiology reports of vertebral fracture need to clearly state that the patient has a “fracture,” with further pertinent details such as the number, recency, and severity of vertebral fracture, each of which is associated with risk of future fractures. Patients with vertebral fracture should be considered for antifracture therapy. Physical and pharmacologic modalities of pain control and exercises or physiotherapy to maintain spinal movement and strength are important components in the care of vertebral fracture patients.
Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that ...display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.
Summary
Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone ...mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial.
Introduction
Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN.
Methods
The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D
3
(5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg.
Results
Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension.
Conclusions
This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.
Once‐monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3‐year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At ...least equivalent efficacy and similar safety and tolerability were shown after 1 year.
Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose‐free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens.
Materials and Methods: MOBILE is a 2‐year, randomized, double‐blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly.
Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C‐telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated.
Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.
Summary
One year after discontinuation of three year’s treatment with risedronate, BMD decreased at the lumbar spine and femoral neck and bone turnover markers returned to control group levels. ...Despite these changes, the risk of new morphometric vertebral fractures remained lower in previous risedronate patients compared with previous control patients.
Introduction
Differences in bisphosphonate pharmacology and pharmacokinetics could influence persistence or resolution of the effects once treatment is stopped. We investigated changes in intermediate markers—bone mineral density (BMD) and bone turnover markers (BTM)—and fracture risk after discontinuation of treatment with risedronate.
Methods
Patients who received risedronate 5 mg daily (N = 398) or placebo (N = 361) during the VERT-NA study stopped therapy per protocol after 3 years but continued taking vitamin D (if levels at study entry were low) and calcium and were reassessed one year later.
Results
In the year off treatment, spine BMD decreased significantly, but remained higher than baseline (
p
≤ 0.001) and placebo (
p
< 0.001), with similar findings at the femoral neck and trochanter. Urinary NTX and bone-specific alkaline phosphatase, which decreased significantly with treatment, were not significantly different from placebo after 1 year off treatment. Despite the changes in intermediate markers, the incidence of new morphometric vertebral fractures was 46% lower in the former risedronate group compared with the former placebo group (RR 0.54 95% CI, 0.34, 0.86,
p
= 0.009).
Conclusions
Despite the apparent resolution of effect on BMD and BTM, the risk reduction of new vertebral fractures remained in the year after treatment with risedronate was stopped.
Summary
In a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab ...treatment was well tolerated throughout the 8-year study.
Introduction
The purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study.
Methods
In the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab.
Results
Of the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (
N
= 88) and total hip (
N
= 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort.
Conclusion
Continued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.
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