Faculty Bibliography

In the pivotal Fracture Study in Postmenopausal Women with Osteoporosis (FRAME; NCT01575834), 1 year of the bone-forming agent romosozumab significantly reduced new vertebral and clinical fracture risk versus placebo. Nonvertebral fracture risk was not significantly reduced in the overall population, influenced by a low placebo-group fracture rate, observed particularly in the highest-enrolling region of Latin America. In year 1 of FRAME, postmenopausal women with a T-score of -2.5 to -3.5 at the total hip or femoral neck were randomized to subcutaneous romosozumab 210 mg or placebo once monthly for 12 months. Of 7180 randomized women, 43% were from Latin America, largely Colombia and Brazil. Prespecified analyses assessed fracture risk reductions by geographic regions. A significant treatment-by-geographic region interaction for the clinical (p = 0.029) and nonvertebral fracture (p = 0.042) endpoints led to further characterization of the Latin American population and comparison with the remaining study population, grouped post hoc as rest-of-world. Nonvertebral fracture efficacy in the overall population was also assessed by baseline fracture risk using the Fracture Risk Assessment Tool (FRAX). Romosozumab significantly and consistently reduced new vertebral fracture risk in Latin America (70% reduction; p = 0.014) and rest-of-world (74% reduction; p < 0.001). For nonvertebral fracture, risk reductions were observed in rest-of-world (42% reduction; p = 0.012), with no treatment effect observed in Latin America, where background nonvertebral fracture risk was low (1.2% in the placebo group). Consistent with this finding, in the overall population, greater reductions in nonvertebral fracture risk were observed among women with higher FRAX scores. These findings suggest that fracture risk assessment should consider regional factors in addition to classical risk factors, such as bone mineral density. In women at high risk for fracture, romosozumab reduced nonvertebral fracture risk within 1 year. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Romosozumab is a bone-forming agent with a dual effect of increasing bone formation and decreasing bone resorption. In the FRAME study, postmenopausal women with osteoporosis received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. One year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Here, we further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T-score changes from baseline over the 2-year study and contrast these results with the long-term BMD gains seen with denosumab during FREEDOM and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (N = 3591 placebo, N = 3589 romosozumab), most romosozumab-treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T-score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo-to-denosumab: 0.38 and 0.17), with the 2-year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p < 0.001), with fewer fractures consistently observed across other fracture categories. The data support the clinical benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive therapy.

BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

BACKGROUND: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. METHODS: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. FINDINGS/RESULTS: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. INTERPRETATION/CONCLUSIONS: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. FUNDING/BACKGROUND:Amgen, Astellas, and UCB Pharma.

Tophaceous gout is painful and impairs quality of life. The optimal modality for assessing tophus resolution in response to urate-lowering treatment remains poorly defined. Using pegloticase as a model system for resolving tophi, we compared multiple imaging and physical diagnostic strategies for assessing tophus resolution. A 32-year-old subject with chronic refractory tophaceous gout was enrolled and received 6 months of pegloticase treatment. Measurements of tophi using vernier calipers (monthly), photographs and musculoskeletal ultrasound (MSK-US; every 3 months), and dual-energy CT (DECT) were compared. Pegloticase persistently lowered the patient's sUA to <0.5 mg/dl. After 6 months, caliper measurements revealed 73, 60, and 61% reductions of three index tophi, while MSK-US revealed 47, 65, and 48% reductions. In contrast, DECT revealed 100% resolution of monosodium urate deposition in all three index tophi, and resolution or improvement of all other tophi identified. On caliper and MSK-US measurement, index tophus size fluctuated, with some lesions enlarging before ultimately contracting. Correlation between assessment modalities during tophus resolution may be poor. DECT identifies urate deposits invisible to physical exam and reveals that some urate deposits completely resolve even as their physically/sonographically measurable lesions persist. Recognition of urate resorption during the urate-lowering process may be confounded by fluctuating lesion volumes during initial tophus breakdown. While DECT was superior for identifying total (including occult) urate deposition, and assessing volume of deposits, other modalities may permit better assessment of non-urate tophus components.

Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naïve postmenopausal women with low bone mass, romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L₁ vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p < 0.0001); changes in femoral strength for romosozumab showed similar but smaller changes, increasing more with romosozumab versus teriparatide (3.6% versus -0.7%; p = 0.027), and trending higher versus placebo (3.6% versus -0.1%; p = 0.059). Compartmental analysis revealed that the bone-strengthening effects for romosozumab were associated with positive contributions from both the cortical and trabecular bone compartments at both the lumbar spine and hip. Taken together, these findings suggest that romosozumab may offer patients with osteoporosis a new bone-forming therapeutic option that increases both vertebral and femoral strength within 12 months. © 2017 American Society for Bone and Mineral Research.

OBJECTIVES/OBJECTIVE:To identify women's beliefs and other factors associated with lack of osteoporosis (OP) pharmacotherapy (OP-RX) during the 6 months after a fragility fracture, including the woman's perspective on fracture risk, OP, and treatment. DESIGN/METHODS:Cross-sectional. SETTING/METHODS:Group Health Cooperative, a mixed-model delivery system. PARTICIPANTS/METHODS:Female Group Health Cooperative enrollees aged 55 and older with an OP-related fracture according to diagnostic and procedure codes from January 1, 2013, to March 30, 2014 (N = 985). MEASUREMENTS/METHODS:OP-RX and participant characteristics were ascertained from electronic health records including medications dispensed. A mailed survey was used to obtain data on health behaviors; OP-related history; concern about, knowledge of, and perceived risk of future fracture; beliefs about OP-RX; sources of information on OP; postfracture discussions with providers; and provider recommendations. RESULTS:The response rate was 73%. Of 634 eligible respondents, 84% did not undergo OP-RX during the 6 months after fracture. Fewer than 20% of women thought that OP caused their fracture, 52% did not think they were at risk of future fracture, and 75% did not think or know whether OP-RX reduces risk of fracture. Knowledge about OP and the benefits of treatment was higher in the 16% of women who underwent OP-RX after their fracture. Women reported low levels of engagement with their healthcare providers regarding OP and fracture risk management. CONCLUSION/CONCLUSIONS:These findings suggest low awareness about OP and its contribution to fracture risk, lack of understanding about the benefits of pharmacotherapy, and limited discussion about OP with primary care physicians. Information about individual's beliefs and knowledge gaps can help design targeted patient and provider education to improve treatment rates.

PURPOSE/OBJECTIVE:The goal of this study was to assess and compare the potential clinical and economic value of emerging bone-forming agents using the only currently available agent, teriparatide, as a reference case in patients at high, near-term (imminent, 1- to 2-year) risk of osteoporotic fractures, extending to a lifetime horizon with sequenced antiresorptive agents for maintenance treatment. METHODS:Analyses were performed by using a Markov cohort model accounting for time-specific fracture protection effects of bone-forming agents followed by antiresorptive treatment with denosumab. The alternative bone-forming agent profiles were defined by using assumptions regarding the onset and total magnitude of protection against fractures with teriparatide. The model cohort comprised 70-year-old female patients with T scores below -2.5 and a previous vertebral fracture. Outcomes included clinical fractures, direct costs, and quality-adjusted life years. The simulated treatment strategies were compared by calculating their incremental "value" (net monetary benefit). FINDINGS/RESULTS:Improvements in the onset and magnitude of fracture protection (vs the teriparatide reference case) produced a net monetary benefit of $17,000,000 per 10,000 treated patients during the (1.5-year) bone-forming agent treatment period and $80,000,000 over a lifetime horizon that included 3.5 years of maintenance treatment with denosumab. IMPLICATIONS/CONCLUSIONS:Incorporating time-specific fracture effects in the Markov cohort model allowed for estimation of a range of cost savings, quality-adjusted life years gained, and clinical fractures avoided at different levels of fracture protection onset and magnitude. Results provide a first estimate of the potential "value" new bone-forming agents (romosozumab and abaloparatide) may confer relative to teriparatide.

BACKGROUND:Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. METHODS:We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures. RESULTS:At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. CONCLUSIONS:In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).