Efficacy Of Denosumab Research Articles

10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension

Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. Denosumab 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. Amgen.

Effect of denosumab on bone mineral density (T-score classification of −1.0 to −2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer.

552 Background: Adjuvant aromatase inhibitor (AI) therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against receptor of nuclear-κB ligand, was previously proven to protect against AI-induced bone loss. In Japan, however, the efficacy of denosumab in the treatment of AI-associated bone loss has not been proven in a prospective study. Methods: This non-randomized prospective study was conducted at four institutions in Japan. we prospectively evaluated the bone mineral density (BMD) of the lumbar spine and bilateral femoral neck in hormone-receptor positive clinical stageⅠ–ⅢA, postoperative postmenopausal breast cancer patients who were scheduled for treatment with AI as adjuvant endocrine therapy or during AI adjuvant therapy. They received supplemental calcium, vitamin D and subcutaneous denosumab 60mg (n=103) every six months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary endpoint was percentage change in lumbar spine BMD from baseline to month 12. The secondary endpoint was percentage change in bilateral femoral neck BMD from baseline to month 12. This is the first trial where the right and left femoral neck BMD are measured separately. Results: We enrolled 103 patients between November, 2014 to October, 2016. At 12 months, lumber spine BMD increased by 4.7 %. The patients who were administered prior AI therapy (n=60) had a 4.8 % increase, and the patients without prior AI therapy (n=40) had a 4.6 % increase. At 12 months, the right and left femoral neck BMD increased by 2.9 % and 2.0 %, respectively. Hypocalcemia ≥ grade2, osteonecrosis of the jaw (ONJ) and non-traumatic clinical fracture were absent in this study. Conclusions: Twice-yearly treatment with denosumab was associated with consistently greater gains in BMD among Japanese women receiving adjuvant AI therapy, regardless of whether prior AI therapy was administered. Clinical trial information: UMIN000013863.

Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study

BackgroundDenosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study.MethodsTo understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study.ResultsExtension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively).ConclusionThe observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects.Trial registrationClincalTrials.gov registration number NCT00523341; registered August 30, 2007

The clinical benefits of denosumab for prophylaxis of steroid-induced osteoporosis in patients with pulmonary disease.

Respiratory physicians are often faced with the dilemma that long-term steroid use will deteriorate bone mineral density and quality. Previous reports demonstrated that bone density decreased 8 to 12% during the initial few months of steroid therapy then continued decreasing at a rate of 2 to 4% annually. Several prospective trials revealed that denosumab increased bone density in patients with osteoporosis [2-4] and decreased the rate of occurrence of fractures. The long-term efficacy of denosumab for glucocorticoid-induced osteoporosis, however, has not yet been proven. This has been an ongoing prospective study since 2014. In our respiratory centre, the first preventative measure used to combat glucocorticoid-induced osteoporosis (GIO) is oral bisphosphonates. Thirty-six patients were enlisted, and their treatment courses were changed from oral bisphosphonate, if administered, to the subcutaneous injection of denosumab 60mg every 6months, combined with a daily oral intake of DENOTAS® chewable combination tablets. The primary efficacy measures were changes in lumbar spine (LS) bone mineral density (BMD) and femoral BMD from baseline at 4, 8, 12 and 28months. At the 12-month follow-up, bone mineral density in the lumbar spine area of these patients increased by 3.2%, while bone mineral density in the hip area showed no significant increase. At the 28-month follow-up, 25 patients were still included in this study. Femoral BMD at 28months increased significantly from the 12-month follow-up (P=0.0259), though the first 12months showed no significant increase. LS BMD continued to increase through the 28-month period. Very little is known regarding the active prevention of GIO. Our data indicates that denosumab can play a promising role in the treatment of GIO.

Impact of denosumab use on the survival of untreated non-squamous non-small cell lung cancer patients with bone metastases.

Denosumab reduces the incidence of skeletal-related events (SREs) in solid tumor patients with bone metastases (BM). However, there have been no detailed reports of the efficacy of denosumab in untreated non-squamous non-small cell lung cancer (NSCLC) patients with BM. The medical records of patients with untreated non-squamous NSCLC and BM at diagnosis at our institution were reviewed retrospectively. The overall survival (OS) and the time to SREs were analyzed according to the treatment for the BM. Of the total of 149 patients who were eligible, 52 had received denosumab (Dmab group), 51 had received zoledronic acid (ZA group), and 46 had received no treatment (No-Tx group) for the BM. The frequencies of prior SREs were higher in the Dmab group and ZA group than in the No-Tx group (44, 41 and 22%, respectively); however, there were no significant differences in any of the other clinicopathological characteristics examined among the three groups. The median OS in the Dmab group, ZA group and No-Tx group were 21.4 months, 12.7 months and 10.5 months, respectively; the OS was significantly longer in the Dmab group than in the ZA group (P < 0.01). Results of multivariate analysis revealed that denosumab treatment was significantly associated with a more favorable survival [hazard ratio, 0.500; 95% CI 0.332-0.741; P < 0.01]. No significant difference in the time to SREs was observed among the three groups. Our results suggest that treatment with denosumab may improve the overall survival of non-squamous NSCLC patients with BM.

Efficacy and Safety of Denosumab for the Treatment of Osteoporosis in Patients with Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and may lead to metabolic abnormalities that accelerate bone loss. Bisphosphonates, the most widely used treatment for osteoporosis, are contraindicated in patients with severe renal impairment. In the present study, we assessed whether denosumab is a safe and effective treatment for osteoporosis in patients with CKD. Methods and Findings: A total of 143 patients with osteoporosis who were treated with denosumab were analyzed retrospectively. Of these patients, 40 had been previously treated with bisphosphonates. All patients received supplemental vitamin D. Effectiveness was assessed by analyzing changes in bone mineral density (BMD) and serum tartrate-resistant acid phosphatase (TRACP)-5b as a marker for serum bone resorption. More than fifty percent of the patients treated with bisphosphonates showed low BMD at the time their therapy was changed to denosumab. Denosumab was associated with a larger increase in both lumbar and femur neck BMD than were bisphosphonates (+4.8% and +5.5%, respectively). Denosumab decreased serum TRACP-5b while increasing BMD (P<0.001), and was well tolerated. Serum calcium levels decreased shortly after the injection of denosumab, but recovered within 14 days. Supplemental vitamin D (0.5 to 1.0 μg/day) appeared to prevent hypocalcemia and to support efficacy of denosumab. Conclusions: Denosumab increases BMD in the lumbar vertebra and femur neck in patients with CKD. The effect of denosumab on BMD is greater than that of bisphosphonates in these patients.

Denosumab treatment of inoperable or locally advanced giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is an osteolytic, locally aggressive tumor that rarely metastasizes and typically occurs in the bones. At present, the primary treatment for GCTB is curettage with local adjuvants. Giant cells express receptor activator of nuclear factor-κB ligand (RANKL). Denosumab, a RANKL inhibitor appears to present an effective therapeutic option in advanced cases of GCTB. The aim of the present study was to confirm the efficacy of denosumab in large group of patients with locally advanced GCTB. A total of 35 patients with histologically confirmed GCTB that were treated with denosumab with no participation in clinical trials between May 2013 and September 2015 were included in the present study. Denosumab treatment was administered until complete tumor resection was feasible or tumor progression or unacceptable toxicity had occurred. The mean denosumab treatment duration was 7.4 months. A total of 17 patients received surgery following denosumab treatment: 11 patients underwent wide en bloc resection with prosthesis implantation in 10 cases and 6 patients were treated with intralesional curettage. Tumor progression was observed in 2 patients that underwent intralesional curettage without prosthesis implantation. In addition, tumor progression was observed during denosumab treatment in 2 patients that had previously undergone radiotherapy. The overall 1-year progression-free survival rate was 92.8%. Thus, for patients with advanced, unresectable, progressive or symptomatic pretreated GCTB, denosumab provides a therapeutic option not previously available, which has become the standard therapy in multidisciplinary management of GCTB.

Comparison of the efficacy of denosumab and bisphosphonates for treating secondary osteoporosis in patients with rheumatoid arthritis

Objectives: This study aimed to investigate the efficacy of denosumab (compared with that of bisphosphonates) for preventing secondary osteoporosis and inflammation caused by excessive bone resorption in Japanese rheumatoid arthritis (RA) patients never previously treated for osteoporosis.Methods: Ninety-eight patients with coexisting RA and osteoporosis were enrolled. The patients were subdivided by whether they were treated with denosumab (n = 49) or traditional bisphosphonates (n = 49). RA disease activity, bone turnover markers, and bone mineral density (BMD) were compared between the two groups before treatment, and after 6 and 12 months of treatment.Results: There was no significant difference between the groups in any of the disease activity indices and BMD at any of the measured time points. With regard to bone metabolism, denosumab significantly reduced bone-specific alkaline phosphatase at 6 and 12 months compared with pretreatment, but had no effect on tartrate-resistant acid phosphatase 5b levels, suggesting an effect on the bone formation rate, but not on the bone resorption rate.Conclusions: Neither denosumab nor bisphosphonates could suppress inflammation or RA disease activity, but denosumab significantly suppressed a marker of bone metabolism in Japanese RA patients never previously treated for osteoporosis.

Safety and efficacy of denosumab in osteoporotic hemodialysed patients.

In elderly subjects, renal insufficiency and osteoporosis often coexist with high risk of fracture and elevated socio-economic burden. Today a large number of effective anti-osteoporotic drugs are available but generally they are contraindicated in patients with chronic kidney disease (CKD) because of their progressive accumulation. Denosumab, instead, does not require dose adjustments for different degrees of renal impairment so it can be a valid treatment in osteoporotic patients with CKD. Limited data are available in the literature concerning the use of denosumab in hemodialysis (HD). The aim of our study was, therefore, to study the efficacy and tolerability of this drug in this particular subset of patients. We retrospectively reviewed the charts of 12 osteoporotic HD patients who received a single 60-mg subcutaneous dose of denosumab every 6months for an observation period of 24months. Serum electrolyte, markers of bone turnover and quantitative ultrasound (QUS) were evaluated. Over 24months, we observed a gradual improvement of bone metabolism: β-CrossLaps from 2567.08±1264 to 1492.5±1182.5pg/ml; bone alkaline phosphatase (BALP) from 33.5±28.8 to 11.8±3.7 mcg/l, and of QUS index (T-score from -5.33±1.58 to -4.84±1.2; risk of fracture from 13.9±4.7 to 11.07±5.3%). Few cases of hypocalcemia were detected, more significant after the first and second injection, but with careful monitoring of serum calcium and rapid therapy adjustment we could easily manage serum Ca levels. Our pilot experience highlights the safety and efficacy of denosumab in the treatment of osteoporosis in HD patients, potentially supporting its use to reduce the burden of fractures in this patient population.

Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: a systematic review and meta-analysis.

The aim of this review is to compare the efficacy and safety of denosumab over other treatments for osteoporosis. The results of this study suggest that the safety of denosumab and its efficacy in reducing fractures is not significantly different from bisphosphonates. Denosumab was, however, more effective in increasing bone mineral density. This study was conducted to compare the efficacy and safety of denosumab over other pharmacological treatments for osteoporosis in individuals at risk of fracture. Randomised controlled trials comparing denosumab with another pharmacological treatment for osteoporosis were searched in MEDLINE, EMBASE and CENTRAL. Identified articles were screened by two independent reviewers and assessed for inclusion. Data from included studies were extracted and meta-analyses were conducted using random effects models. Nine studies including a total of 4890 postmenopausal women were identified. The follow-up period varied from 12 to 24months. In all studies except one, the comparator treatment was a bisphosphonate. There was no statistically significant difference between patients receiving denosumab and those receiving a bisphosphonate in terms of fracture risk (RR[95% CI] = 1.15 [0.84-1.58]), adverse events (RR[95% CI] = 0.99 [0.96-1.02]) or deaths (OR[95% CI] = 0.58 [0.12-2.71]). Withdrawals due to adverse events were less frequent in denosumab than in other treatment groups but the difference did not reach statistical significance (OR[95% CI] = 0.68 [0.45-1.04]). The percent change in bone mineral density at the total hip, lumbar spine, femoral neck and one-third radius was significantly higher in participants who received denosumab (e.g. mean difference [95% CI] at the total hip: 1.06 [0.86-1.25]). These results suggest that, after 12 to 24months, the safety and efficacy of denosumab for reducing fracture risk is not significantly different from bisphosphonates despite higher gains in bone mineral density. In a clinical setting, denosumab may demonstrate greater effectiveness.

Efficacy of denosumab in joint preservation for patients with giant cell tumour of the bone

BackgroundGiant cell tumour of the bone (GCTB) is an aggressive osteolytic primary tumour. GCTB is rich in osteoclast-like giant cells and contains mononuclear cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. The potential therapeutic effect of denosumab was investigated with special reference to its role in joint preservation. MethodsIn this prospective non-randomised study patients with GCTB received denosumab for 6–11 months preoperatively. Serial radiographs and biopsy and resection tumour specimens were used to monitor response to denosumab. ResultsAll 20 patients experienced pain relief in the first month of treatment. All patients demonstrated a positive radiographic response with improved subchondral and cortical bone which allowed intralesional tumour resection and preservation of the joint and articular surface in 18 cases. Histological examination following denosumab revealed rarely detectable osteoclast-like giant cells. There was an obvious increase in osteoid matrix and woven bone which showed rare RANK staining amongst the mononuclear cells and only focal RANKL positivity. At median 30 months follow-up after resection, local tumour recurrence occurred in three patients. ConclusionDenosumab provides favourable and consistent clinical, radiographic and pathologic responses which facilitates less aggressive surgical treatment, especially joint preservation. However, the local recurrence rate for GCTB following resection does not seem to be affected by denosumab and remains a concern.

Safety and efficacy of denosumab in patients with multiple myeloma

Safety and efficacy of denosumab in patients with multiple myeloma

Case Report: Prolonged Disease Stability in Giant Cell Tumor of the Bone in the Cervical Spine Treated with Denosumab

We present a case of locally recurring giant cell tumor (GCT) of the bone in the cervical spine of a 12-year-old girl. After three surgeries with two resulting in negative margins, adjuvant chemotherapy with Doxorubicin and Ifosfamide, and two local recurrences of the GCT of the bone within the cervical spine, she was started on a Denosumab clinical trial at the age of 13 years. The patient’s pain and neurologic symptoms decreased significantly within a few weeks and disappeared after 5 months. She has been receiving monthly Denosumab for over five years, totaling 68 doses to date, and will continue this regimen for the forseeable future. GCT of the bone is rarely seen in adolescents or in the cervical spine and effective treatment options are limited. Denosumab is an excellent treatment for non-resectable and recurrent GCT of the bone, it only eliminates giant cells, leaving the stromal cells to reactivate the GCT of the bone after a period of halting Denosumab. While this patient has maintained tumor stability over five years, the effects of receiving life-long Denosumab supplementation are currently unknown. This case demonstrates the efficacy of Denosumab in stabilizing the progression of giant cell tumor of bone but also highlights the need for further investigation into cumulative dose-related side effects and long term treatment planning as patients currently have no other treatment options once stability is achieved.

Denosumab increases sublesional bone mass in osteoporotic individuals with recent spinal cord injury.

Osteoporosis is a frequent complication related to spinal cord injury (SCI), and data on osteoporosis treatment after SCI is scarce. Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis. Osteoporosis development is a frequent complication related to SCI, especially at the sublesional level. Nevertheless, data on osteoporosis treatment after SCI is scarce, particularly short term after injury, when the highest bone loss is produced. The aim of this study was to analyze the efficacy of denosumab in the treatment of SCI-related osteoporosis. Fourteen individuals aged 39 ± 15 years with osteoporosis secondary to recent SCI (mean injury duration 15 ± 4 months) were treated with denosumab for 12 months. Bone turnover markers (BTMs) (PINP, bone ALP, sCTx), 25-hydroxyvitamin D (25OHD) levels and bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were assessed at baseline and at 12 months. All participants received calcium and vitamin D supplementation. At 12 months, SCI denosumab-treated participants showed a significant increase in BMD at TH (+2.4 ± 3.6 %, p = 0.042), FN (+3 ± 3.6 %, p = 0.006), and LS (+7.8 ± 3.7 %, p < 0.001) compared to baseline values. Denosumab treatment was associated with significant decreases in BTMs (bone ALP -42 %, p < 0.001; PINP -58 %, p < 0.001, sCTx -57 %, p = 0.002) at 12 months. BMD evolution was not related to BTM changes or 25OHD serum levels. No skeletal fractures or serious adverse events were observed during follow-up. Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis.

Treatment with denosumab reduces secondary fracture risk in women with postmenopausal osteoporosis

Objectives A history of prior fracture is one of the strongest predictors of a future fragility fracture. In FREEDOM, denosumab significantly reduced the risk of new vertebral, non-vertebral, and hip fractures. We carried out a post-hoc analysis of FREEDOM to characterize the efficacy of denosumab in preventing secondary fragility fractures in subjects with a prior fracture.Methods A total of 7808 women aged 60–90 years with a bone mineral density T-score of less than − 2.5 but not less than − 4.0 at either the lumbar spine or total hip were randomized to subcutaneous denosumab 60 mg or placebo every 6 months for 36 months. The anti-fracture efficacy of denosumab was analyzed by prior fracture status, to assess secondary fragility fracture, and by subject age, prior fracture site and history of prior osteoporosis medication use.Results A prior fragility fracture was reported for 45% of the overall study population. Compared with placebo, denosumab significantly reduced the risk of a secondary fragility fracture by 39% (incidence, 17.3% vs. 10.5%; p < 0.0001). Similar results were observed regardless of age or prior fracture site. In the overall population, denosumab significantly reduced the risk of a fragility fracture by 40% (13.3% vs. 8.0%; p < 0.0001), with similar results observed regardless of history of prior osteoporotic medication use.Conclusions Denosumab reduced the risk of fragility fractures to a similar degree in all risk subgroups examined, including those with prior fragility fractures. Identifying and treating high-risk individuals could help to close the current care gap in secondary fracture prevention.

Clinical efficacy of denosumab versus bisphosphonates for the prevention of bone complications: implications for nursing.

Antiresorptive therapies are used for the prevention of skeletal-related events (SREs) associated with metastatic bone disease related to breast cancer, prostate cancer, and other solid tumors. This review highlights the central role of nurses in supporting and educating advanced cancer patients regarding the consequences of bone metastases and SREs, including therapy management options. Contemporary clinical journals reporting evidence-based studies were reviewed. SREs associated with bone metastases can significantly impact the quality of life of advanced cancer patients. Denosumab therapy, an advancement in antiresorptive treatments, significantly prevents and delays the time to develop SREs. In the multifaceted approach required for successful and consistent management of SREs associated with bone metastases, antiresorptive therapies can play a central role in maintaining the functional independence of patients through the prevention of debilitating SREs, thereby preserving quality of life.

A novel approach to the management of a central giant cell granuloma with denosumab: A case report and review of current treatments

PurposeTo describe the efficacy of denosumab in the treatment of an aggressive giant cell granuloma of the mandible. MethodsDenosumab was administered to a patient with a large aggressive giant cell granuloma of the mandible resistant to standard medical therapy. The effectiveness and response was measured on the basis of patient symptoms and radiological parameters. ResultsA significant reduction in patient symptoms was reported in association with tumour regression on follow up radiographs. ConclusionThis report demonstrates potential use of denosumab in aggressive giant cell granulomas of the jaws that have been resistant to medical therapy.

Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events

In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point. Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form. Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66-0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65-0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE. In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.

A randomized placebo-controlled trial of the efficacy of denosumab in Indian postmenopausal women with osteoporosis.

Introduction:Osteoporosis is a serious condition affecting up to 50% of Indian postmenopausal women. Denosumab reduces bone resorption by targeting the receptor activator of nuclear factor-κB ligand. This study assessed the efficacy and safety of denosumab in Indian postmenopausal women with osteoporosis.Materials and Methods:In this double-blind, multicenter, phase 3 study, 250 Indian postmenopausal women aged 55 to 75 years (T-score <-2.5 and >-4.0 at the lumbar spine or total hip; serum 25(OH) D levels ≥20 ng/mL) were randomized to receive one subcutaneous dose of denosumab 60 mg or placebo. All subjects received oral calcium ≥1000 mg and vitamin D3 ≥ 400 IU daily. The primary end point was mean percent change in bone mineral density (BMD) at the lumbar spine from baseline to Month 6. Secondary end points included mean percent change from baseline in BMD at total hip, femoral neck, and trochanter at Month 6 and median percent change from baseline in bone turnover markers at Months 1, 3, and 6.Results:Total 225 subjects (denosumab = 111, placebo = 114) completed the six-month study. Baseline demographics were similar between groups. A 3.1% (95% confidence interval, 1.9%, 4.2%) increase favoring denosumab versus placebo was seen for the primary end point (P < 0.0001). Denosumab demonstrated a significant treatment benefit over placebo for the secondary end points. There were no fractures or withdrawals due to adverse events.Conclusions:Consistent with results from studies conducted in other parts of the world, denosumab was well tolerated and effective in increasing BMD and decreasing bone turnover markers over a six-month period in Indian postmenopausal women.

Denosumab improves bone mineral density and microarchitecture and reduces bone pain in women with osteoporosis with and without glucocorticoid treatment

Osteoporosis is a key health problem in postmenopausal women with high social and economic impact. Decreased bone mineral density (BMD) and deterioration of bone microarchitecture may occur also as a result of long-term glucocorticoid treatment (GCT) of autoimmune or inflammatory conditions. Denosumab specifically inhibits the binding of the receptor activator of nuclear factor-κB to its ligand, thus preventing osteoclast activation and bone resorption. The efficacy and safety of denosumab, administered subcutaneously as 60 mg, once every six months for 12 months, were evaluated in 60 patients with postmenopausal osteoporosis (PMO) divided into two groups. The GCT group included 30 patients receiving concomitant glucocorticoid therapy and the non-GCT group included 30 patients that did not receive GCT. In the non-GCT group, the 12-month treatment with denosumab resulted in BMD increase of 6.1% and 2.8% in lumbar spine and hip, respectively. T-score increased by 13.1% and 5.6% in both, the lumbar spine and hip. A slight rise in the Trabecular Bone Score (TBS) of 0.3% was observed. Bone pain was markedly reduced by 56.2%. In the GCT group, denosumab therapy increased BMD with 5.8% and 2.3% in lumbar spine and hip, respectively. T-score of lumbar spine and hip significantly increased by 14.0% and 4.4%, and the TBS rose by 5%. Bone pain was reduced by 53.6%. These data confirm the available knowledge on denosumab efficacy and safety in women with PMO and also provide new insights into its therapeutic potential in patients with osteoporosis related to a long-term corticosteroid treatment.