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Romosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation: A case report.

ABSTRACT: Discontinuation of denosumab is associated with the increase of bone turnover markers to above-baseline levels (so-called rebound in bone turnover) and rapid bone loss. Several studies have reported vertebral fractures (VFs), particularly multiple spontaneous clinical VFs (MSCVFs), occurring after discontinuation of denosumab. There is currently no recommendation for the management of VFs including MSCVFs. Presently, romosozumab is the strongest anti-osteoporotic agent that inhibits sclerostin and rapidly increases bone mass, but it is uncertain that romosozumab is an effective treatment choice to treat VFs occurring after discontinuation of denosumab. Herein we reported a novel case of a 60-year-old woman who was treated with romosozumab after discontinuation of denosumab and subsequently suffered MSCVFs under romosozumab treatment. She had a history of two osteoporotic VFs (T6 and T8) and received five doses of 60 mg denosumab every 6 months following the osteoporosis diagnosis. As per the patient's convenience, the sixth denosumab injection was postponed. To improve the persistent low bone mass in the lumbar spine (T-score -3.8), 210 mg romosozumab was administered monthly after 9 months following the last denosumab injection. At the first romosozumab injection, she had no clinical symptoms such as low back pain, but her bone formation and resorption marker levels elevated compared with those treated with denosumab. After three doses of romosozumab, spontaneous severe low back pain occurred, and time-course radiographs revealed five new VFs (T12, L2, L3, L4, and L5). Romosozumab administration had no suppressive effect on bone resorption during the rebound in bone turnover after discontinuation of denosumab. This case suggests that romosozumab is not effective in preventing VFs or MSCVFs after denosumab discontinuation.

SUBMITTER: Kashii M

PROVIDER: S-EPMC7284126 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Romosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation: A case report.

Kashii Masafumi M Ebina Kosuke K Kitaguchi Kazuma K Yoshikawa Hideki H

Bone reports 20200605

Discontinuation of denosumab is associated with the increase of bone turnover markers to above-baseline levels (so-called rebound in bone turnover) and rapid bone loss. Several studies have reported vertebral fractures (VFs), particularly multiple spontaneous clinical VFs (MSCVFs), occurring after discontinuation of denosumab. There is currently no recommendation for the management of VFs including MSCVFs. Presently, romosozumab is the strongest anti-osteoporotic agent that inhibits sclerostin a ...[more]

PMID: 32548215

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Project description:Background: Denosumab is approved to prevent fragility fractures in patients with osteoporosis at high risk for fracture and to prevent bone loss in patients with breast and prostate cancer who receive endocrine therapy. The antiresorptive effect of denosumab rapidly dissipates when it is delayed or discontinued, but the risk for, and incidence of, multiple clinical vertebral fractures in patients with breast cancer after stopping denosumab is currently unclear. Question/Purposes: We sought to identify the incidence of clinical vertebral fractures in patients with breast cancer who received at least 2 doses of denosumab (60 mg) and then discontinued the medication. Methods: We conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010, and July 18, 2018, at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal women and 1 man with nonmetastatic breast cancer who received their final denosumab injection at least 6.5 months earlier. Data recorded included baseline bone density and the incidence of vertebral fractures after denosumab discontinuation. Results: The median age of patients was 62 years. Patients received between 2 and 13 denosumab doses before drug discontinuation. Most of the patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months. We identified 1 case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. Most of the patients (88%) had a gap in denosumab dosing. Conclusions: Clinicians treating patients with breast cancer-especially those continuing to take aromatase inhibitors-should be aware of the possible risks of delaying doses of or discontinuing denosumab and should educate their patients accordingly. Prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab.

Project description: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.

Project description: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.

Project description:Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a -0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (-4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 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).

Project description: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.IntroductionThis 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.MethodsDuring 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.ResultsOf 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.ConclusionsConsistent 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.

Project description:Radiographic vertebral fractures (VFxs) are the most common fractures in osteoporosis and are associated with increased morbidity, mortality, and costs. A subset of VFxs manifest clinically, usually with a sudden onset of severe back pain. Romosozumab is a monoclonal antibody that binds and inhibits sclerostin, increasing bone formation and decreasing bone resorption, leading to rapid and large increases in bone density and strength and reduction in fracture risk. The FRAME (Fracture Study in Postmenopausal Women with Osteoporosis) study of postmenopausal women with osteoporosis demonstrated a significant reduction in new VFxs with romosozumab versus placebo. Here, we report the effect of romosozumab versus placebo on clinical VFx incidence over 12 months in women reporting back pain suggestive of VFxs. FRAME enrolled 7180 postmenopausal women with osteoporosis, mean age 70.9 years (hip T-score -2.5 to -3.5). In the first year of the study, women received monthly romosozumab 210?mg (n?=?3589) or placebo (n?=?3591). At regular monthly visits, women reporting back pain suggestive of a clinical VFx had a confirmatory spine X-ray. Clinical VFx risk in the romosozumab group versus the placebo group was calculated by Cox-proportional hazards model. Of 119 women in FRAME with back pain suggestive of a clinical VFx over 12 months, 20 were confirmed to have experienced a new/worsening VFx. Three women receiving romosozumab had a clinical VFx (<0.1% of 3589 women) versus 17 (0.5% of 3591 women) receiving placebo resulting in a reduction in clinical VFx risk of 83% in the romosozumab group versus placebo through 12 months (HR 0.17; 95% CI, 0.05 to 0.58; p?=?0.001). In the three romosozumab-treated women, clinical VFxs occurred within the first 2 months of the study with no further clinical VFxs throughout the year. Romosozumab treatment for 12 months was associated with rapid and large reductions in clinical VFx risk versus placebo. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Dataset Information

Romosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation: A case report.

Publications

Romosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation: A case report.

Similar Datasets

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