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Patients with hyperlipidemia were assigned to receive the PCSK9 antibody evolocumab or placebo on a background of lipid-lowering therapy. At 52 weeks, the least-squares mean reduction in LDL cholesterol from baseline for evolocumab versus placebo was 57%. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that is produced predominantly in the liver, is secreted into the plasma and plays a major role in regulating levels of low-density lipoprotein (LDL) cholesterol by binding to hepatic LDL receptors and promoting their degradation. 1 , 2 In short-term (8-to-12-week), placebo-controlled, phase 2 trials, PCSK9 inhibitors have been shown to significantly reduce LDL cholesterol levels. 3 – 9 Four of these trials involved the use of evolocumab (AMG 145), a fully human monoclonal PCSK9 antibody, and assessed different doses and regimens in diverse patient populations with varying lipid phenotypes, cardiovascular disease risks, and baseline . . .

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. 1 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. . . .

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment. In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18–75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov, number NCT01375777. 406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from baseline with every 2 weeks AMG 145 70 mg −41·0% [95% CI −46·2 to −35·8]; 105 mg −43·9% [–49·0 to −38·7]; 140 mg −50·9% [–56·2 to −45·7]; every 4 weeks AMG 145 280 mg −39·0% [–44·1 to −34·0]; 350 mg −43·2% [–48·3 to −38·1]; 420 mg −48·0% [–53·1 to −42·9]; placebo every 2 weeks −3·7% [–9·0 to 1·6]; placebo every 4 weeks 4·5% [–0·7 to 9·8]; and ezetimibe −14·7% [–18·6 to −10·8]; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported. The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance. Amgen.

Romosozumab, a monoclonal anti‐sclerostin antibody that has the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. In a post hoc, exploratory analysis, we evaluated the effects of romosozumab after 12 months of denosumab in postmenopausal women with low bone mass who had not received previous osteoporosis therapy. This phase 2 trial (NCT00896532) enrolled postmenopausal women with a lumbar spine, total hip, or femoral neck T‐score ≤ −2.0 and ≥ −3.5. Individuals were randomized to placebo or various romosozumab dosing regimens from baseline to month 24, were re‐randomized to 12 months of denosumab or placebo (months 24–36), and then all received romosozumab 210 mg monthly for 12 months (months 36–48). Results for the overall population have been previously published. Here, we present results for changes in bone mineral density (BMD) and levels of procollagen type I N‐terminal propeptide (P1NP) and β‐isomer of the C‐terminal telopeptide of type I collagen (β‐CTX) from a subset of women who were randomized to placebo for 24 months, were re‐randomized to receive denosumab (n = 16) or placebo (n = 12) for 12 months, and then received romosozumab for 12 months. In women who were randomized to placebo followed by denosumab, romosozumab treatment for 12 months maintained BMD gained during denosumab treatment at the total hip (mean change from end of denosumab treatment of 0.9%) and further increased BMD gains at the lumbar spine (mean change from end of denosumab treatment of 5.3%). Upon transition to romosozumab (months 36–48), P1NP and β‐CTX levels gradually returned to baseline from their reduced values during denosumab administration. Transitioning to romosozumab after 12 months of denosumab appears to improve lumbar spine BMD and maintain total hip BMD while possibly preventing the rapid increase in levels of bone turnover markers above baseline expected upon denosumab discontinuation. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. This study in postmenopausal women with low bone mineral density shows that denosumab, a fully human monoclonal antibody inhibiting RANKL, increased bone mineral density and decreased bone resorption in a manner similar to alendronate and more than placebo. Thus, denosumab may deserve further study for the treatment of osteoporosis. This study in postmenopausal women with low bone mineral density shows that denosumab, a fully human monoclonal antibody inhibiting RANKL, increased bone mineral density and decreased bone resorption in a manner similar to alendronate and more than placebo. Osteoporosis is a well-established risk factor for fracture. 1 Despite treatment options that reduce the risk of fracture in patients with osteoporosis, few patients fully adhere to current therapies. A recent study reported one-year adherence rates of less than 25 percent for all osteoporosis therapies examined. 2 This adherence rate is substantially lower than that for therapies for other asymptomatic conditions, such as hypertension (50 to 70 percent adherence). 3 Thus, new treatment approaches that engender high adherence are needed. Receptor activator of nuclear factor-κB ligand (RANKL), a protein expressed by osteoblastic stromal cells, binds to receptor activator of nuclear factor-κB (RANK) and . . .

Romosozumab, a sclerostin inhibitor, exerts a dual effect of increasing bone formation while decreasing bone resorption to rapidly increase bone mineral density (BMD) and reduce fracture risk in postmenopausal women. Iterative Convolution OptimizatioN (ICON) allows accurate calculation of deconvolved cortical thickness from high-resolution quantitative computed tomography (HR-QCT) scanning. This study employed HR-QCT to evaluate compartmental (including endosteal and periosteal) changes in the vertebral cortical shell in postmenopausal women who received romosozumab, teriparatide, or placebo. In a subset of a phase 2, randomized study (NCT00896532), women (55-85 yr) with low BMD (T-score ≤ −2.0, but not <−3.5, at the lumbar spine, total hip, or femoral neck) treated with subcutaneous (SC) romosozumab monthly (210 mg; n = 11), SC teriparatide daily (20 μg; n = 12), or SC placebo (n = 8) had spine HR-QCT scans at baseline and Month 12 to assess treatment effects on cortical and cancellous compartments of the T12 vertebra. HR-QCT was obtained at 120 kVp and 360 mAs. Cortical changes were evaluated using ICON software. At Month 12, compared to teriparatide and placebo, romosozumab treatment was associated with greater gains in all cortical parameters. Changes in cancellous bone parameters were similar with romosozumab and teriparatide. Romosozumab significantly increased cortical thickness (mean ± SD; 53 ± 18%) and the magnitude of this change was greater than that of teriparatide (20 ± 13%) and placebo (3 ± 6%); all p < .001. With romosozumab, cortical BMC and apparent cortical BMD were also significantly increased from baseline, and compared to teriparatide and placebo (all p < .001). These changes occurred through endosteal and periosteal bone matrix apposition, with greatest changes seen at the endosteal surface. The location and magnitude of these changes likely form the basis of the rapid improvement in bone mass, structure, and strength that contribute to romosozumab’s rapid vertebral fracture risk reduction efficacy; however, conclusions are limited by the small sample size.

Bone loss with aging places postmenopausal women at a higher risk for osteoporosis and its consequences such as fractures, pain, disability, and increased morbidity and mortality. Approximately 200 million patients worldwide are affected. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that up to 18% of US women aged 50 and older have osteoporosis and up to 50% have osteopenia. Greater than 2 million osteoporotic related fractures occurred in the United States with direct healthcare costs exceeding $17 billion. Hormone Replacement Therapy (HRT) was a popular option for postmenopausal women before the Women’s Health Initiative (WHI). Several agents are available in the U.S., including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone and the selective estrogen receptor modulator (SERM) raloxifene. There are concerns about long term safety and compliance. Therefore, other agents are under investigation. SERMs are a diverse group of agents that bind to the estrogen receptor and each SERM appears to have a unique set of clinical responses, which are not always consistent with the typical responses seen with other SERMs. This article will discuss the SERMs approved in the United States, tamoxifene and raloxifene, and investigational SERMs. The ideal SERM would include the beneficial effects of estrogen in bone, heart and the central nervous system, with neutral or antagonistic effects in tissues where estrogen effects are undesirable(breast and endometrium). A new target in treating postmenopausal osteoporosis is the tissue estrogen complex or the pairing of a SERM with a conjugated estrogen known as a tissue selective estrogen complex (TSEC). This novel approach is currently being evaluated with bazodoxifene which could yield the beneficial effects of estrogens and SERMS, while potentially being more tolerable and safer than either therapy alone.

Background Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study. Methods To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study. Results Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX ® ) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively). Conclusion The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects. Trial registration ClincalTrials.gov registration number NCT00523341 ; registered August 30, 2007

Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly. To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued. Double-blind, placebo-controlled discontinuation trial. 18 U.S. centers. 244 postmenopausal, hysterectomized women 44 to 77 years of age. 2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo. Bone mineral density and biochemical markers of bone turnover. Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, -5.0% to -4.0%) and a 2.4% decrease at the trochanter (CI, -2.7% to -2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment. Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.