Summary
Romosozumab, which binds sclerostin, rebuilds the skeletal foundation before transitioning to antiresorptive treatment. This subgroup analysis of an international, randomized, double-blind ...study in postmenopausal women with osteoporosis showed efficacy and safety outcomes for romosozumab followed by denosumab in Japanese women were generally consistent with those for the overall population.
Purpose
In the international, randomized, double-blind, phase 3 FRActure study, in postmenopausal woMen with ostEoporosis (FRAME; NCT01575834), romosozumab followed by denosumab significantly improved bone mineral density (BMD) and reduced fracture risk. This report evaluates Japanese women in FRAME.
Methods
Postmenopausal women with osteoporosis (T-score − 3.5 to − 2.5 at total hip or femoral neck) received romosozumab 210 mg or placebo subcutaneously monthly for 12 months, then each group received denosumab 60 mg subcutaneously every 6 months for 24 months. The key endpoint for Japanese women was BMD change. Other endpoints included new vertebral, clinical, and nonvertebral fracture; the subgroup analysis did not have adequate power to demonstrate statistically significant reductions.
Results
Of 7180 enrolled subjects, 492 (6.9%) were Japanese (247 romosozumab, 245 placebo). BMD increases from baseline were greater (
P
< 0.001) for romosozumab-to-denosumab than placebo-to-denosumab at the lumbar spine (36 months, 12.7%), total hip (4.2%), and femoral neck (4.1%). Fracture risk was lower through 36 months for romosozumab-to-denosumab vs placebo-to-denosumab for new vertebral (1.7% vs 4.5%; relative risk reduction (RRR) 63%,
P
= 0.070), clinical (3.2% vs 7.3%; RRR 53%,
P
= 0.072), nonvertebral (2.8% vs 6.1%; RRR 50%,
P
= 0.12), and all other fracture types evaluated. Rates of adverse events and positively adjudicated serious cardiovascular events were generally balanced between groups.
Conclusions
Efficacy and safety for romosozumab-to-denosumab were similar between Japanese women and the overall population. The sequence of romosozumab to rebuild the skeletal foundation before transitioning to antiresorptive treatment with denosumab is a promising regimen for Japanese postmenopausal women with osteoporosis at high risk of fracture.
This phase 3 study evaluated the efficacy and safety of 6-month treatment with romosozumab in Korean postmenopausal women with osteoporosis.
Sixty-seven postmenopausal women with osteoporosis (bone ...mineral density BMD T-scores ≤-2.5 at the lumbar spine, total hip, or femoral neck) were randomized (1:1) to receive monthly subcutaneous injections of romosozumab (210 mg; n=34) or placebo (n=33) for 6 months.
At month 6, the difference in the least square (LS) mean percent change from baseline in lumbar spine BMD (primary efficacy endpoint) between the romosozumab (9.5%) and placebo (-0.1%) groups was significant (9.6%; 95% confidence interval, 7.6 to 11.5; P<0.001). The difference in the LS mean percent change from baseline was also significant for total hip and femoral neck BMD (secondary efficacy endpoints). After treatment with romosozumab, the percent change from baseline in procollagen type 1 N-terminal propeptide transiently increased at months 1 and 3, while that in C-terminal telopeptide of type 1 collagen showed a sustained decrease. No events of cancer, hypocalcemia, injection site reaction, positively adjudicated atypical femoral fracture or osteonecrosis of the jaw, or positively adjudicated serious cardiovascular adverse events were observed. At month 9, 17.6% and 2.9% of patients in the romosozumab group developed binding and neutralizing antibodies, respectively.
Treatment with romosozumab for 6 months was well tolerated and significantly increased lumbar spine, total hip, and femoral neck BMD compared with placebo in Korean postmenopausal women with osteoporosis (ClinicalTrials.gov identifier NCT02791516).
Among postmenopausal women with osteoporosis and a high risk of fracture, treatment with the monoclonal antibody romosozumab for 12 months followed by alendronate resulted in a significantly lower ...risk of fracture than alendronate for 12 months followed by alendronate.
Globally, one in five men aged >50 years is predicted to experience an osteoporotic fracture. Because of the treatment gap in osteoporosis and the paucity of bone-forming agents for men, new ...osteoporosis treatments are needed.
To evaluate the safety and efficacy of romosozumab in men with osteoporosis.
Phase III randomized BRIDGE study (placebo-controlled double-blind study evaluating the efficacy and safety of romosozumab in treating men with osteoporosis; ClinicalTrials.gov identifier, NCT02186171) for 12 months.
Thirty-one centers in Europe, Latin America, Japan, and North America.
Men aged 55 to 90 years with a baseline bone mineral density (BMD) T-score at the lumbar spine (LS), total hip (TH), or femoral neck of ≤-2.5 or ≤-1.5 with a history of a fragility nonvertebral or vertebral fracture.
The subjects were randomized 2:1 to receive romosozumab 210 mg subcutaneously monthly or placebo for 12 months.
The primary efficacy endpoint was percentage change from baseline in LS BMD at month 12.
In 245 subjects (163 romosozumab, 82 placebo), at month 12, the mean percentage change from baseline in the LS and TH BMD was significantly greater for the romosozumab group than for the placebo group (LS, 12.1% vs 1.2%; TH, 2.5% vs -0.5%; P < 0.001). Adverse events and serious adverse events were balanced between the two groups, with a numerical imbalance in the positively adjudicated cardiovascular serious adverse events romosozumab, 8 (4.9%) vs placebo, 2 (2.5%).
Treatment with romosozumab for 12 months increased the spine and hip BMD compared with placebo and was well tolerated in men with osteoporosis.
Romosozumab binds sclerostin, increases bone formation, and decreases bone resorption. Postmenopausal women with osteoporosis were assigned to romosozumab or placebo for 1 year, followed by 1 year of ...denosumab. Romosozumab was associated with lower vertebral and clinical fracture risk.
Osteoporosis can lead to fragility fractures, which result in clinical burden and increased mortality.
1
,
2
Even after a fracture, fewer than 25% of patients receive pharmacologic treatment for osteoporosis.
3
–
5
After the discovery that sclerostin deficiency causes rare genetic conditions that are characterized by high bone mass and resistance to fracture,
6
,
7
sclerostin became a therapeutic target for the treatment of osteoporosis. Sclerostin, a negative regulator of bone formation that is secreted by osteocytes,
8
inhibits Wnt signaling, down-regulating this stimulus for osteoblast development and function.
9
Romosozumab (Amgen and UCB Pharma) is a monoclonal antibody that binds and inhibits sclerostin, with . . .
Romosozumab is a monoclonal antibody that inhibits sclerostin and rapidly increases bone mineral density (BMD) through a dual effect on bone by increasing bone formation and decreasing bone ...resorption, as shown in a global phase 2 study in postmenopausal women with low bone mass. Here, we report the key results of a phase 2, double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of romosozumab in postmenopausal Japanese women with osteoporosis.
Participants were postmenopausal Japanese women with osteoporosis aged 55–85years with a lumbar spine, total hip, or femoral neck dual-energy X-ray absorptiometry T-score≤−2.5. Women were randomized to receive placebo or romosozumab (70, 140, or 210mg) subcutaneously once monthly (QM) for 12months. The primary efficacy endpoint was the percentage change from baseline in lumbar spine BMD at month 12. Secondary efficacy endpoints included the percentage change from baseline in lumbar spine BMD at month 6, total hip and femoral neck BMD at months 6 and 12, and serum bone turnover markers procollagen type 1N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at multiple visits.
This study enrolled 252 women who had a mean age of 67.7years and mean T-scores of −2.7, −1.9, and −2.3 at the lumbar spine, total hip, and femoral neck, respectively. All romosozumab doses significantly increased BMD at month 12 compared with placebo (p<0.01), with the largest mean gains from baseline observed with romosozumab 210mg QM (lumbar spine=16.9%, total hip=4.7%, and femoral neck=3.8%). All doses of romosozumab significantly increased the levels of bone-formation marker P1NP and reduced the levels of bone-resorption marker CTX by week 1 (p<0.001 vs placebo). In the 210mg QM group, P1NP levels peaked at month 1 and fell below placebo levels by month 12; CTX levels were lowest at week 1 and remained below placebo through month 12. The patient incidences of adverse events and serious adverse events were generally comparable between treatment groups.
In postmenopausal Japanese women with osteoporosis, romosozumab treatment resulted in large and significant gains in BMD from baseline and compared with placebo. Romosozumab 210mg QM showed the largest gains in BMD and was generally well tolerated. The efficacy and safety of romosozumab 210mg QM in this phase 2 study of postmenopausal women with osteoporosis were similar to those in an international phase 2 study.
•This phase 2, double-blind, placebo-controlled, dose-ranging study assessed the efficacy and safety of romosozumab in postmenopausal Japanese women with osteoporosis•Romosozumab exerted a dual effect on bone, increasing bone formation and decreasing bone resorption, consistent with its mechanism of action•Romosozumab treatment resulted in large and significant gains in bone mineral density from baseline and compared with placebo•Adverse events and serious adverse events were generally comparable between groups•The efficacy and safety of romosozumab were similar between this study and an international phase 2 study of postmenopausal women
Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus ...teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy.
This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of −2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 μg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301.
Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and −0·6% (−1·0 to −0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 13% of 218 in the romosozumab group vs 22 10% of 214 in the teriparatide group), hypercalcaemia (two <1% vs 22 10%), and arthralgia (22 10% vs 13 6%). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal.
Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture.
Amgen, Astellas, and UCB Pharma.
This study shows that in postmenopausal women with low bone mineral density, the monoclonal antibody romosozumab, which binds to sclerostin, an osteoblast-activity inhibitor, was associated with ...increased bone mineral density and bone formation and decreased bone resorption.
Osteoporosis is characterized by low bone mass and defects in microarchitecture that are responsible for decreased bone strength and increased risk of fracture.
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Antiresorptive drugs for osteoporosis increase bone mineral density and prevent the progression of structural damage but may not restore bone structure. Stimulation of bone formation is necessary to achieve improvements in bone mass, architecture, and strength.
Sclerostin, encoded by the gene
SOST,
is an osteocyte-secreted glycoprotein that has been identified as a pivotal regulator of bone formation. By inhibiting the Wnt and bone morphogenetic protein signaling pathways, sclerostin impedes osteoblast proliferation and function, thereby decreasing bone formation. . . .
We evaluated the pharmacokinetics, pharmacodynamics, and safety of a single subcutaneous dose of romosozumab 210 mg, a monoclonal antibody against sclerostin, in an open‐label, parallel‐group study ...in participants with severe (stage 4) renal impairment (RI; n = 8) or end‐stage renal disease requiring hemodialysis (ESRD‐RH; n = 8), or healthy participants with normal renal function (n = 8). Compared with the group with normal renal function, the mean romosozumab exposure was 31% and 43% higher as measured by maximum observed serum concentration and area under the concentration‐time curve, respectively, in the severe RI group and similar to those in the ESRD‐RH group. For all 3 groups, the maximum mean percent increase in procollagen type 1 N terminal propeptide and decrease in serum C‐telopeptide levels from baseline were observed on day 15. Changes in procollagen type 1 N terminal propeptide and serum C‐telopeptide were of similar patterns in all 3 groups. The single dose of romosozumab 210 mg was well tolerated. Adverse events (AEs) were reported for 13 patients (7 patients with severe RI and 6 with ESRD‐RH), with no deaths, AEs, or serious AEs leading to withdrawal. The incidence of subjects with postbaseline transient decreases in serum calcium (severe RI, n = 1; ESRD‐RH, n = 5) and increases in intact parathyroid hormone (severe RI, n = 7; ESRD‐RH, n = 7; healthy, n = 3) were greater in severe RI and ESRD‐RH groups than in the healthy group. All reported events of hypocalcemia (severe RI, n = 1; ESRD‐RH, n = 4) were asymptomatic. These results support the use of romosozumab without dose adjustment in patients with severe RI or ESRD‐RH.
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