Long-term Denosumab Therapy Research Articles

Long-Term Effect of Denosumab on Bone Disease in Patients with CKD.

The effect of long-term denosumab therapy and of denosumab discontinuation on the cortical bone of the hip regions in dialysis patients has not been studied. This retrospective study investigated the cortical and trabecular compartments and estimated strength indices of the hip region, obtained using 3D-SHAPER software, after a maximum of 5 years of denosumab therapy in 124 dialysis patients. A Wilcoxon signed-rank test was used to identify the differences in each parameter before and after denosumab initiation. Similarly, we investigated the changes in these parameters after denosumab discontinuation in 11 dialysis patients. Integral and trabecular volumetric bone mineral densities (BMD) were significantly lower at the start of denosumab therapy than those in 1 year before denosumab initiation. After starting denosumab, areal BMD (median change +7.7% [interquartile range (IQR), +4.6 to +10.6]), cortical volumetric BMD (median change +3.4% [IQR, +1.0 to +4.7]), cortical surface BMD (median change +7.1% [IQR, +3.4 to +9.4]), and cortical thickness (median change +3.2% [IQR, +1.8 to +4.9]) showed a significantly higher trend for 3.5 years, which then stabilized at a higher value compared with baseline. A similar trend in the trabecular volumetric BMD (median change +9.8% [IQR, +3.8 to +15.7]) was observed over 2.5 years, with a higher value maintained thereafter. The whole area of the hip region improved after denosumab therapy. Similar trajectories were also found in the estimated strength indices. Conversely, at 1 year after denosumab discontinuation, these 3D parameters and estimated strength indices tended to largely worsen. The lateral aspect of the greater trochanter was the most pronounced location showing volumetric BMD loss. The BMD of both cortical and trabecular components in the hip region was significantly higher after starting denosumab therapy. However, these measurements exhibited a trend of declining substantially after the discontinuation of denosumab.

Denosumab treatment and infection risks in patients with osteoporosis: propensity score matching analysis of a national-wide population-based cohort study.

Denosumab demonstrates efficacy in reducing the incidence of hip, vertebral, and nonvertebral fractures in postmenopausal women with osteoporosis. We present a population-based national cohort study to evaluate the infection risks in patients with osteoporosis after long-term denosumab therapy. We used the Taiwan National Health Insurance Research Database (NHIRD) to identify patients with osteoporosis. The case cohort comprised patients treated with denosumab. Propensity score (PS) matching was used to select denosumab nonusers for the control cohort. The study period was between August 2011 and December 2017. Our study comprised 30,106 pairs of case and control patients. Patients receiving denosumab therapy had high risks of the following infections: pneumonia and influenza (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI]: 1.27 -1.39), urinary tract infection (aHR: 1.36; 95% CI:1.32 -1.40), tuberculosis (aHR: 1.60; 95% CI: 1.36 -1.87), fungal infection (aHR: 1.67; 95% CI:1.46 -1.90), candidiasis (aHR: 1.68; 95% CI: 1.47 -1.93), herpes zoster infection (aHR: 1.27; 95% CI: 1.19 -1.35), sepsis (aHR: 1.54; 95% CI:1.43 -1.66), and death (aHR: 1.26; 95% CI: 1.20 -1.32). However, the longer the duration of denosumab treatment, the lower the risk patients had of developing infections. Denosumab therapy is associated with a higher infection risk at the early periods of treatment. Nevertheless, the risk attenuates significantly after the 2nd year of therapy. Clinicians should closely monitor infection status in patients with osteoporosis during the initial stages of denosumab therapy.

Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: Observations in a real-world setting.

The rebound effect after denosumab discontinuation is lessened with subsequent zoledronate therapy. However, it is unclear whether this mitigation is sufficient after long-term denosumab treatment. This retrospective observational study analysed bone mineral density (BMD) and bone turnover marker (BTM) changes after denosumab therapy according to treatment duration and subsequent zoledronate regimen. We measured the outcomes of 282 women with postmenopausal osteoporosis who discontinued denosumab and received zoledronate 6months later. In patients with longer denosumab therapy (≥5years), BTMs were measured every 3months and a second zoledronate infusion was administered if BTM levels increased by ≥2-fold. The BMD of all women was measured before denosumab therapy, at the last injection and 1 to 2years after the first zoledronate. Bone loss after switching from denosumab to zoledronate was higher in patients with 10±2 denosumab injections (n=84) compared to 5±2 injections (n=144, p<0.001 for lumbar spine and femoral neck), but there was no further increase with treatment durations of ≥15±2 injections (n=54, p=0.35 and p=0.20, respectively). BTMs in patients with ≥10 denosumab injections were elevated 6months after zoledronate in some patients, but not all. Twenty-four women received a second zoledronate dose 6months after the first one. BTMs in these patients were subsequently lower, but bone loss at both the lumbar spine and hip was comparable to that in patients with only one zoledronate dose (p=0.37 for lumbar spine and p=0.97 for femoral neck). Rebound-associated bone loss reached a plateau after denosumab treatment durations of 4-6years, irrespective of the frequency of subsequent zoledronate therapy.

Effects of Zoledronate on Bone Mineral Density and Bone Turnover after Long-Term Denosumab Therapy: Observations in a Real-World Setting

Effects of Zoledronate on Bone Mineral Density and Bone Turnover after Long-Term Denosumab Therapy: Observations in a Real-World Setting

The role of denosumab in the complex treatment of giant cell tumor of the spine: reducing of local recurrence rate, surgery time and blood loss

Objective. To assess the effect of the combined treatment method including preoperative denosumab therapy on the results of treatment of patients with giant cell tumors of the spine.Material and Methods. A single-center retrospective-prospective study of a series of clinical cases included 15 patients with giant cell tumors of vertebrae. The average follow-up period was 56 months. A total of 11 patients received denosumab therapy according to the following scheme: 120 mg subcutaneously on the 1st, 8th, 15th and 28th days of the first month and then once every 28 days. Surgical options included marginal resection, segmental resection, or en-bloc resection with or without spinal reconstruction/stabilization. In the case of locally advanced and inoperable disease, long-term therapy with denosumab was carried out until the disease progressed or serious adverse events appeared.Results. Thoracic vertebrae were involved in 7 (46.6 %) of 15 cases, lumbar in 4 (26.7 %) and cervical in 4 (26.7 %). Local recurrence rate after surgery alone was 40 % (2/5), average time to recurrence onset was 4.5 months. No relapses were observed after combined treatment performed in four patients. Disease progression during long-term denosumab therapy for inoperable disease recurrence was not recorded (0/7). The average number of denosumab injections before surgery and during long-term therapy was 15 and 24 injections, respectively. Denosumab therapy allows reducing the duration of surgery and the volume of blood loss.Conclusion. Combined therapy of giant cell vertebral tumor allows to reduce the risk of recurrence of the disease, as well as to reduce surgery duration and blood loss. Long-term continuous therapy for inoperable cases allows achieving long-term stabilization of the effect. Due to the rarity of giant cell tumors of the spine, a further prospective recruitment of patients is required to study the efficacy and safety of combined therapies.

Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed.

Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791, NCT00523341.

Safety of long-term denosumab therapy for osteoporosis

Osteoporosis, characterised by progressive age-related increases in bone fragility and fracture risk, is a chronic condition that often requires many years of treatment. Data on safety and efficacy of drugs are provided by pivotal clinical trials, which are generally limited to 3 years duration; results of such studies cannot necessarily be extrapolated to longer treatment periods. Adverse effects might increase as a result of both ageing and cumulative drug exposure. Likewise, beneficial skeletal effects of the drug might not be maintained indefinitely. Furthermore, continued long-term suppression of bone turnover with potent antiresorptive agents could potentially result in weakened bone. Extension studies can provide useful information about effects of long-term treatment, although the absence of a placebo control group beyond the initial trial period, mandated by ethical considerations, and attenuation of the size of the treated population can reduce the robustness of the findings. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extensionDenosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Full-Text PDF

Observations following discontinuation of long-term denosumab therapy

SummaryStopping 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.

Erratum to: Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.

Erratum to: Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.

Long-term denosumab therapy further reduces the rate of non-vertebral fractures in women with persisting low hip BMD after 3 years

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)