The Efficacy of Denosumab in Patients With Rheumatoid Arthritis: A Systematic Review and Pooled Analysis of Randomized or Matched Data

ObjectiveThe purpose of this study was to evaluate the efficacy of denosumab treatment in patients with rheumatoid arthritis (RA).MethodsThe Medline, Embase and Cochrane Library databases were searched for relevant clinical studies. Studies that assessed the efficacy of denosumab in patients with RA were identified. The primary endpoints were the percent changes in bone mineral density (BMD), and the changes in modified total Sharp score (mTSS), modified Sharp erosion score and joint space narrowing (JSN) score. Pooled analyses were calculated using random-effect models.ResultsAfter searching the literature and performing further detailed assessments, 10 studies with a total of 1758 patients were included in the quantitative analysis. Pooled analyses showed that denosumab treatment significantly increased the percent changes in lumbar spine BMD [mean difference (MD): 5.12, confidence intervals (CI): 4.15 to 6.09], total hip BMD (MD: 2.72, 95% CI: 1.80 to 3.64) and femoral neck BMD (MD: 2.20, 95% CI: 0.94 to 3.46) compared with controls. Moreover, denosumab treatment significantly decreased the changes in mTSS (MD: -0.63, 95% CI: -0.86 to -0.41) and modified Sharp erosion score (MD: -0.62, 95% CI: -0.88 to -0.35). Subgroup analysis indicated that denosumab was superior to bisphosphonates for the improvement of BMD and the mitigation of joint destruction.ConclusionDenosumab treatment was associated with increased BMD and alleviated progression of joint destruction in RA patients, even when compared with bisphosphonates.

Therapeutic efficacy of denosumab for rheumatoid arthritis: a systematic review and meta-analysis

Objectives Denosumab is used for osteoporosis, as it inhibits osteoclast maturation and suppresses bone resorption. Although denosumab is expected to inhibit the bone erosion in rheumatoid arthritis (RA), its therapeutic efficacy is not well established. The aim of this study was to estimate the effects of denosumab on RA through a meta-analysis. Methods A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Web of Science and Scopus were searched for original studies providing information on bone mineral density (BMD), joint destruction and disease activity in denosumab-treated RA. A random-effects model was used in the meta-analysis. Results Of the 367 studies identified, 18 met the selection criteria. The BMDs of the lumbar spine, total hip and femoral neck at 12 months after denosumab treatment increased by 5.27% (95% confidence interval: 4.37–6.18), 2.82% (2.46–3.18) and 3.07% (2.66–3.48), respectively. In the sensitivity analysis, age and gender tended to influence the effect of denosumab therapy on the variation rate of BMD, but not glucocorticoid use. The changes in the modified total sharp, erosion and joint space narrowing scores at 12 months after denosumab treatment were significantly smaller with denosumab than with placebo, although the disease activity score did not change after denosumab treatment. Conclusion Although denosumab has an inhibitory effect on the bone resorption in RA, its effects may be influenced by age and gender of RA, but not glucocorticoid use.

Efficacy of denosumab therapy for a 12-year-old female patient with Williams syndrome with osteoporosis and history of fractures: a case report

Background A decrease in bone mineral density is common in patients with Williams syndrome. However, appropriate management for osteoporosis in Williams syndrome patients has not been established. We report the case of a 12-year-old female patient with Williams syndrome, who underwent denosumab treatment for osteoporosis. Case presentation A 12-year-old Japanese female patient with Williams syndrome was shown to have very low bone mineral density. Bone mineral density was evaluated before treatment and at 5, 9, 17, 23, and 29 months of treatment by dual-energy X-ray absorptiometry. After denosumab therapy for 29 months, lumbar and total hip bone mineral density values had increased by 51.6% and 37.6%, respectively. No new fractures occurred during the observation period. Conclusions To the best of our knowledge, this is the first experience with denosumab treatment in Williams syndrome patients with osteoporosis. Based on our findings, denosumab may be an effective treatment option for Williams syndrome patients with osteoporosis.

Denosumab After Teriparatide in Premenopausal Women with Idiopathic Osteoporosis

Context We have previously reported that teriparatide is associated with substantial increases in bone mineral density (BMD) at the lumbar spine (LS), total hip (TH) and femoral neck (FN) and small declines at the distal radius (DR) in 41 premenopausal women with idiopathic osteoporosis (IOP), all severely affected with low trauma fractures and/or very low BMD. Effects of teriparatide dissipate if not followed by antiresorptives. Objectives To assess the effects of 12 and 24 months (M) of denosumab in premenopausal women with IOP completing 24M of teriparatide. Design Preplanned phase 2B extension study Setting Tertiary referral centers Patients Premenopausal women with IOP Interventions Denosumab 60mg every 6 months for 12 and 24M Main Outcome Measures Within-group change in BMD at the LS at 12M. Secondary outcomes include change in 12M BMD at other sites, 24M BMD at all sites, trabecular bone score (TBS) and bone turnover markers (BTM). Findings After completing teriparatide, 32 participants took denosumab for 12M and 29 for 24M, with statistically significant increases in BMD at the LS (5.2±2.6% and 6.9±2.6%), TH (2.9±2.4% and 4.6±2.8%) and FN (3.0±3.8% and 4.7±4.9%). Over the entire 24M teriparatide and 24M denosumab treatment period, BMD increased by 21.9±7.8% at the LS, 9.8±4.6% at the TH and 9.5±4.7% at the FN (all p<0.0001). TBS increased by 5.8±5.6% (p<0.001). Serum BTM decreased by 75%-85% by 3M and remained suppressed through 12M of denosumab. Denosumab was generally well-tolerated. Conclusions These data support the use of sequential teriparatide and denosumab to increase BMD in premenopausal women with severe osteoporosis.

Real-world cost-effectiveness of denosumab for the treatment of postmenopausal osteoporosis in Taiwan

Summary This study assessed the cost-effectiveness of continued denosumab treatment, compared with discontinuation of denosumab after one dose, for the treatment of postmenopausal osteoporosis in Taiwan, using real-world fracture reduction effectiveness and cost data. Outcomes indicate that continued denosumab treatment produces an incremental cost-effectiveness ratio of USD $16,743 per QALY. Purpose To evaluate the cost-effectiveness of continued denosumab use versus discontinuation after one dose, for the treatment of postmenopausal osteoporosis in Taiwan, using real-world fracture reduction effectiveness and cost data. Methods A Markov cohort model was used to evaluate the lifetime costs and QALYs associated with continued denosumab treatment versus discontinuation of treatment after one dose. The evaluation was conducted from the perspective of Taiwan’s healthcare system and used a discount rate of 3% per annum. The patient population consisted of postmenopausal women with osteoporosis with a mean age of 77 years who initiated denosumab treatment. Fracture reduction effectiveness data, baseline fracture rates, mortality data, and costs of fracture were informed by Taiwan’s National Health Insurance Research Database. Results Model outcomes showed that continued treatment with denosumab produced an expected gain of 0.042 QALYs and an incremental cost of USD $704, compared with discontinuation of denosumab after one dose. This corresponds to an incremental cost-effectiveness ratio of USD $16,743 per QALY gained. Probabilistic and scenario analysis showed that results are stable to variations in model assumptions and parameters. Conclusion In a real-world setting, at a cost per QALY threshold equivalent to gross domestic product per capita in 2020 in Taiwan (USD $30,038), continued treatment with denosumab in postmenopausal women with osteoporosis is cost-effective compared with treatment discontinuation.

The Essential Role of Nuclear β-Catenin Translocation in the Osteoblastic Differentiation of GCTB: Prediction of Tumor Ossification After Denosumab Treatment

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/β-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear β-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear β-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear β-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear β-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear β-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

A single-center experience with giant cell tumors of sphenoid bone and clivus

Objective: To present pathologic, clinical, and treatment findings for giant cell tumors (GCTs) of sphenoid bone and clivus. Methods: We describe the optimal treatment algorithm in patients with a histopathologic diagnosis of bone GCT by presenting the effects of denosumab treatment in both pediatric and adult patients with GCT undergoing endoscopic transnasal surgery. Clinicopathologic correlation is crucial for the differential diagnosis of GCT and the choice of treatment modality. Conclusion: GCT of bone is a local aggressive tumor that accounts for about 3%–7% of all bone tumors. GCTs located in the cranium are extremely uncommon neoplasms. There are no defined guidelines for the treatment of GCTs in skull base. Following surgical resection of the tumor, the addition of denosumab treatments to radiotherapy has a significant role in preventing the recurrence of GCT and in promoting regression of residual tumor size.