BACKGROUND CONTEXT:Osteoporosis is a significant risk factor for complications after spinal fusion surgery. Romosozumab, a sclerostin inhibitor, is approved for treating osteoporosis in postmenopausal women at high fracture risk. PURPOSE:Here we investigated the theoretical effects of romosozumab on changes in vertebral strength around virtually-implanted pedicle screws, using biomechanical computed tomography (BCT). STUDY DESIGN/SETTING:This retrospective secondary analysis utilized CT scans from 2 randomized clinical trials of osteoporosis drug treatments in postmenopausal women: a phase 2 trial (12-month romosozumab vs placebo vs teriparatide) in women with low bone mineral density (BMD) and a phase 3 trial (12-month romosozumab followed by 12-month alendronate vs 24-month alendronate alone) in women with osteoporosis. PATIENT SAMPLE:Subsets of 82 patients from the phase 2 trial who received subcutaneous romosozumab 210 mg/mo, placebo, or subcutaneous teriparatide 20 μg/d and 90 patients from the phase 3 trial were included in respective imaging substudies. Patients from the substudies in the present analysis had to have baseline and ≥1 postbaseline BCT measurement at Month 12 in the phase 2 trial, and at Months 6, 12, and 24 in the phase 3 trial. OUTCOME MEASURES:The primary endpoints were percent changes (follow-up vs baseline) in shear bone strength and volume of failed tissue compared between treatments; the secondary endpoint was percent change from baseline in periprosthetic BMD. METHODS:For each participant, the baseline CT scan was used to create a finite element model for the L1 vertebra, which was then virtually implanted with pedicle screws and virtually loaded to failure in a "shear pullout" configuration; follow-up CT scans (at 6, 12, or 24 months) were processed in the same way. RESULTS:For the phase 2 trial (N=79), the mean (95% confidence interval) percent change from baseline to Month 12 in shear bone strength was 24.7% (20.8-28.6%) for romosozumab, which was greater (p<.001) than the changes of -2.2% (-5.8 to 1.5%) for placebo and 14.8% (11.3-18.4%) for teriparatide. For the phase 3 trial (N=79), percent change in shear bone strength was greater (p<.001) for romosozumab than alendronate at both Month 6 (21.6% [17.8-25.4%] vs 6.1% [4.2-8.1%]) and Month 12 (26.3% [22.1-30.6%] vs 7.3% [5.0-9.6%]), and also at Month 24 after switching at Month 12 from romosozumab to alendronate (25.2% [19.9-30.5%] vs 5.7% [3.2-8.2%]). Similar trends occurred for volume of failed tissue and periprosthetic BMD. CONCLUSIONS:In BCT-based virtual stress testing of pedicle screws that were virtually implanted in postmenopausal women with low BMD or osteoporosis, shear bone strength, periprosthetic BMD, and amount of failed tissue were significantly improved over time after treatment with romosozumab compared to placebo, teriparatide, and alendronate. Recognizing that these study participants were not candidates for spinal fusion, these findings nevertheless suggest that romosozumab might rapidly and substantially improve the biomechanical integrity of pedicle screw fixation in postmenopausal women with low BMD or osteoporosis.

Context Trabecular bone score (TBS), a gray-level texture index derived from lumbar spine (LS) dual-energy x-ray absorptiometry (DXA) scans, is decreased in patients with diabetes and is associated with increased fracture risk, independent of areal bone mineral density (aBMD), but potentially influenced by abdominal fat tissue.Objective Evaluate effect of romosozumab (210 mg monthly) for 12 months followed by alendronate (70 mg weekly) for 24 months vs alendronate alone (70 mg weekly) for 36 months on LS aBMD and TBS in women with type 2 diabetes (T2D) enrolled in the ARCH study.Methods This post hoc analysis included women from ARCH who had T2D at baseline and LS DXA scans at baseline and >= 1 postbaseline visit (romosozumab-to-alendronate, n = 165; alendronate-to-alendronate, n = 195). aBMD and TBS (determined by an updated tissue thickness-adjusted TBS algorithm [TBSTT]) were assessed on LS DXA scans at baseline and >= 1 postbaseline visit (months 12, 24, and 36).Results Romosozumab led to significantly greater gains in LS aBMD and TBSTT at month 12 vs alendronate, and the greater gains with romosozumab were maintained after transition to alendronate and persisted significantly at months 24 and 36 vs alendronate alone. TBSTT percentage changes weakly correlated to LS aBMD percentage changes from baseline to month 36 (romosozumab-to-alendronate, R2 = 0.1493; alendronate-to-alendronate, R2 = 0.0429).Conclusion In postmenopausal women with osteoporosis and T2D, 12 months of romosozumab followed by 24 months of alendronate vs alendronate alone significantly improved LS aBMD and TBSTT (independently of abdominal fat) and to a greater extent. Hence, romosozumab may improve bone strength in patients with T2D.Trial registration ClinicalTrials.gov-NCT01631214

Bone mineral density (BMD) is only one of several bone strength determinants affected by osteoporosis therapies. Trabecular Bone Score (TBS), a gray-level texture index determined from lumbar spine (LS) dual-X-ray absorptiometry scans, is an indirect measure of bone microarchitecture independent of and complementary to BMD and clinical risk factors. In the Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH), monthly subcutaneous romosozumab 210 mg for 12 mo followed by 24-mo open-label weekly oral alendronate 70 mg (romosozumab-to-alendronate) significantly reduced fracture risk compared to 36-mo alendronate alone in postmenopausal women with osteoporosis and prior fracture. This analysis evaluated tissue thickness-adjusted TBS (TBSTT) in a subgroup of patients from ARCH who had post-hoc TBS measurements at baseline and at least one post-baseline visit at months 12, 24, and 36. Baseline characteristics were similar between romosozumab-to-alendronate (n = 190) and alendronate alone (n = 188). Romosozumab led to significantly greater gains in TBSTT vs alendronate at month 12 (least squares mean difference, 3.6%), with greater gains maintained after transition to alendronate and persisting at months 24 (2.9%) and 36 (2.3%; all p<.001). Romosozumab-to-alendronate increased the percentage of individual patients with "normal" TBSTT from 28.9% at baseline to 48.1%, 43.9%, and 45.4% at months 12, 24, and 36, respectively, and decreased the percentage of individual patients with degraded TBSTT from 52.6% to 33.3%, 36.0%, and 33.5%, respectively (all p<.001). A similar but smaller trend was observed with alendronate alone from baseline through month 36 (p <=.012). Changes in TBSTT and LS BMD were largely unrelated from baseline to month 12 (romosozumab-to-alendronate, r(2) = 0.065; alendronate alone, r(2) = 0.021) and month 36 (r(2) = 0.058; r(2) = 0.057, respectively). In postmenopausal women with osteoporosis and prior fracture, 12-mo romosozumab followed by 24-mo alendronate significantly improved bone microarchitecture estimated by TBSTT more than 36-mo alendronate alone.

Osteoanabolic-first treatment sequences are superior to oral bisphosphonates for fracture reduction and bone mineral density (BMD) gain. However, data comparing osteoanabolic medications, with the more potent antiresorptive, denosumab (DMAb), are limited. We analyzed FRAME and FRAME Extension data to assess BMD and fracture incidence in patients treated with romosozumab (Romo) followed by DMAb (Romo/DMAb) versus DMAb (DMAb/DMAb) for 24 months. In FRAME, women aged ≥55 years (total hip [TH] or femoral neck [FN] T-score: -2.5 to -3.5) were randomized to Romo or placebo for 12 months followed by DMAb for 12 months. In FRAME Extension, both cohorts received DMAb for another 12 months. This post hoc analysis compared BMD change and fracture incidence in patients on Romo/DMAb (months 0-24) versus DMAb/DMAb (months 12-36). Patient characteristics were balanced by propensity score weighting (PSW) and sensitivity analyses were conducted using PSW with multiple imputation (PSW-MI) and propensity score matching (PSM). Unmeasured confounding was addressed using E-values. After PSW, over 24 months, compared with DMAb/DMAb, treatment with Romo/DMAb produced significantly greater BMD increases at the lumbar spine [LS], TH, and FN (mean differences: 9.3%, 4.4%, and 4.1%, respectively; all p<0.001). At month 24, in women with a baseline T-score of -3.0, the probability of achieving a T-score > -2.5 was higher with Romo/DMAb versus DMAb/DMAb (LS: 92% versus 47%; TH: 50% versus 5%). In the Romo/DMAb versus DMAb/DMAb cohorts, new vertebral fractures were significantly reduced (0.62% versus 1.26% [odds ratio = 0.45; p=0.003]) and rates of clinical, nonvertebral, and hip fractures were lower (differences not significant). Similar BMD and fracture outcomes were observed with PSW-MI and PSM sensitivity analyses. The sequence of Romo/DMAb resulted in greater BMD gains and higher probability of achieving T-scores > -2.5, significantly reduced new vertebral fracture incidence, and numerically lowered the incidence (not significant) of clinical, nonvertebral, and hip fractures versus DMAb only through 24 months.

Objective Romosozumab is a bone‐forming agent approved for osteoporosis treatment. Here we report results of the protocol‐specified, noninferiority osteoarthritis substudy of the fracture study in postmenopausal women with osteoporosis (FRAME), which evaluated the effect of romosozumab versus placebo on knee osteoarthritis in patients with a clinical history of osteoarthritis. Methods Women in FRAME with a history of knee osteoarthritis were eligible for enrollment in the osteoarthritis substudy; key inclusion criteria were osteoarthritis‐related signal knee pain, morning stiffness lasting less than 30 minutes, knee crepitus, and knee osteoarthritis confirmed by x‐ray within 12 months. The protocol‐specified outcomes were change from baseline through month 12 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, incidence of worsening knee osteoarthritis, and treatment‐emergent adverse events (TEAEs) with romosozumab versus placebo. In a post hoc analysis, percentage change from baseline to month 12 in bone mineral density (BMD) was assessed. Results Of 7180 women in FRAME, 347 participated in the osteoarthritis substudy (placebo, 177; romosozumab, 170). At month 12, no significant difference in progression of knee osteoarthritis was observed with romosozumab versus placebo (least squares mean total WOMAC score: –2.2 vs. –1.3; P = 0.71). Incidence of worsening symptoms of knee osteoarthritis was comparable between romosozumab (17.1%) and placebo (20.5%) (odds ratio 0.9 [95% confidence interval: 0.5, 1.7]; P = 0.69). Incidence of TEAEs of osteoarthritis was numerically lower with romosozumab (13 [7.7%]) versus placebo (21 [12.0%]). BMD gains were higher with romosozumab. Conclusion Romosozumab treatment did not impact knee pain or function in postmenopausal women with osteoporosis and knee osteoarthritis and resulted in significant BMD gains in these women.

Objective: We evaluated the efficacy of romosozumab in women from FRAME who had no prior fracture but met other criteria for very high fracture risk (VHFR). Methods: In FRAME, postmenopausal women received romosozumab or placebo for 12 months (year 1) followed by denosumab for 12 months (year 2). In this post hoc analysis, we applied the following criteria from the American Association of Clinical Endocrinology to define VHFR: lumbar spine or total hip T-score <-3.0 and/or Fracture Risk Assessment Tool probability of major osteo-porotic fracture >30% or hip fracture >4.5% to women with no fracture history at baseline (no fracture-VHFR [NF-VHFR]). Incidence of new vertebral, clinical, and nonvertebral fractures and mean bone mineral density (BMD) percentage change from baseline were assessed at years 1 and 2. Results: Of the 7180 women in FRAME, 2825 were included in the NF-VHFR subgroup analysis. At year 1, romosozumab versus placebo reduced the incidence of new vertebral fracture (relative risk reduction [RRR]: 76%), clinical fracture (RRR: 60%), and nonvertebral fracture (RRR: 54%) (all P <.05). This fracture reduction was maintained through year 2 in women receiving the romosozumab-to-denosumab sequence versus the placebo-to-denosumab sequence for new vertebral, clinical, and nonvertebral fractures (RRR: 77%, 54%, and 46%, respectively; all P <.05). The mean BMD changes in both treatment groups were similar to those in the overall FRAME population at years 1 and 2. Conclusion: Romosozumab significantly reduced vertebral, clinical, and nonvertebral fracture risk and increased the BMD more than placebo in women at VHFR. (c) 2023 AACE. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

In this post hoc analysis, we assessed romosozumab efficacy and safety in European patients enrolled in FRAME. Romosozumab treatment through 12 months, followed by denosumab for a further 24 months, resulted in early and sustained risk reduction for major fracture categories, associated with large gains in bone mineral density. In the multinational FRAME phase 3 trial of romosozumab in postmenopausal women with osteoporosis, marked differences between clinical and non-vertebral fracture outcomes were observed among patients from Central and Southern America versus rest of world. This post hoc analysis assessed romosozumab efficacy and safety in European patients enrolled in the FRAME trial and extension study. In FRAME (NCT01575834), patients were randomised 1:1 to romosozumab 210 mg or placebo monthly (QM) for 12 months, followed by open-label denosumab 60 mg Q6M to month 36, including a 12-month extension study. We report incidence of major fracture outcomes, bone mineral density (BMD) change from baseline and safety for European patients enrolled in FRAME. In FRAME, 3013/7180 (41.96%) patients were European; 1494 received romosozumab and 1519 received placebo. Through 12 months, romosozumab reduced fracture risk versus placebo for non-vertebral fracture (1.4% versus 3.0%; p = 0.004), clinical fracture (1.4% versus 3.6%; p < 0.001), new vertebral fracture (0.4% versus 2.1%; p < 0.001) and major osteoporotic fracture (0.9% versus 2.8%; p < 0.001), with results sustained through 36 months following transition to denosumab. Hip fractures were numerically reduced with romosozumab at month 12 (0.2% versus 0.6%; p = 0.092). Romosozumab increased BMD versus placebo at month 12; all patients in the romosozumab and placebo groups experienced further increases by month 36 after transition to denosumab. Adverse events were balanced between groups. Among European patients in FRAME, romosozumab resulted in early and sustained risk reduction for all major fracture categories, associated with large BMD gains that continued after transition to denosumab.

ABSTRACT 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.

ABSTRACT Bone mineral density (BMD) is an established measure used to diagnose patients with osteoporosis. In clinical trials, change in BMD has been shown to provide a reliable estimate of fracture risk reduction, and achieved BMD T-score has been shown to reflect the near-term risk of fracture. We aimed to test the association between BMD T-score and fracture risk in patients treated for osteoporosis in a real-world setting. This retrospective, observational cohort study included Swedish females aged ≥55 years who had a total hip BMD measurement at one of three participating clinics. Patients were separated into two cohorts: bisphosphonate-treated and bisphosphonate-naïve prior to BMD measurement, stratified by age and prior nonvertebral fracture status. The primary outcome was cumulative incidence of clinical fractures within 24 months of BMD measurement, with other fracture types included as secondary outcomes. Associations between T-score and fracture risk were estimated using proportional hazards regression and restricted cubic splines. A total of 15,395 patients were analyzed: 11,973 bisphosphonate-naïve and 3422 bisphosphonate-treated. In the 24 months following BMD measurement, 6.3% (95% confidence interval [CI], 5.9–6.7) of bisphosphonate-naïve and 8.4% (95% CI, 7.5–9.4) of bisphosphonate-treated patients experienced a clinical fracture. Strong inverse relationships between BMD T-score and fracture incidence were observed in both cohorts. Among bisphosphonate-naïve patients, this relationship appeared to plateau around T-score −1.5, indicating smaller marginal reductions in fracture risk above this value; bisphosphonate-treated patients showed a more consistent marginal change in fracture risk across the evaluated T-scores (−3.0 to –0.5). Trends remained robust regardless of age and prior fracture status. This real-world demonstration of a BMD–fracture risk association in both bisphosphonate-naïve and bisphosphonate-treated patients extends evidence from clinical trials and recent meta-regressions supporting the suitability of total hip BMD as a meaningful outcome for the clinical management of patients with osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

BackgroundFragility fractures (FF) are common in women >50 years (yrs), with 1 in 3 experiencing a fracture (Fx).1 However, the cause of these Fx is poorly recognised and measures taken to prevent future Fx are often inadequate. Recent US patient (pt) survey data suggest that awareness of osteoporosis (OP) and its contribution to Fx risk, appreciation of the benefits of OP pharmacotherapy (Rx), and discussion about OP with healthcare professionals (HCPs) are limited.2ObjectivesThis study gained insight into the attitudes and experiences of post-FF women in Europe regarding future Fx risk management.MethodsWomen ≥51 yrs from Germany (DE), Spain (ES), UK, France (FR) and Italy (IT) (EU5) with self-reported experience of a FF completed a 30–min online survey (AplusA; 13–20 Feb 2018). Data are reported for EU5 pts who had their first Fx at ≥50 yrs; pts whose first Fx was a hand/finger or ankle/foot/toe Fx were excluded.Results199 women participated (DE: 38; ES: 36; UK: 41; FR: 34; IT:50). The most commonly experienced Fx was of the lower arm/wrist (43%). 43% reported >1 Fx (any type). Most women discussed bone health with an HCP within 6 months (mo) (70%; 42% with a GP) and HCPs were their primary source of information on OP (85%). Around a third reported taking a DEXA test within 6 mo of their first FF (37%). Advice from HCPs to prevent Fx focused on calcium/vitamin D supplements (74%) and diet/exercise changes (54%); 46% were prescribed OP-Rx. After having a FF, around half worried about future Fx (51%) and 39% voiced concerns about their general health (Figure). A third of pts thought that OP had caused their Fx (33%), most were likely to attribute it to a fall (67%). Only 18% felt empowered to manage their bone health; 61% did not think OP-Rx reduces risk of Fx or were unsure. 97% had never joined a support group.ConclusionThese results indicate that pts discuss future Fx risk with an HCP soon after having a FF and are concerned about future Fx. However, low levels of DEXA testing and OP-Rx, and poor awareness of the link between OP and Fx risk remain. Better education to empower women at risk of FF is critical.Reference[1] Hernlund E. Arch Osteoporos2013;8:136; 2. Boudreau D. J Am Geriatr Soc2017;65:1829–35.AcknowledgementThe study was funded by UCB Pharma and Amgen, conducted by AplusA, medical writing by Arianna Psichas, Costello Medical, UKDisclosure of InterestsCharles Chaine: None declared, Peter Ray: None declared, Jen Timoshanko Employee of: UCB Pharma