Denosumab and sclerotherapy for recurrent spinal aneurysmal bone cyst in a child.

Aneurysmal bone cyst (ABC) is a non-malignant, locally destructive, blood-filled lesion in the bone that tends to grow aggressively. A young girl presented with a rapid recurrence after aggressive surgery of a large symptomatic sacral-spinal ABC. After a multidisciplinary tumour board, she was successfully treated with sclerotherapy and monthly intravenous denosumab. The patient has maintained asymptomatic for over 36 months now and has returned to full activity and strength. She never required surgery and has had radiologic resolution of the lesions. Treatment of recurrent ABC requires a multidisciplinary team approach. We believe this to be the first report to use this combined therapy to provide an alternative to morbid surgery for children with ABCs.

Bone loss after discontinuation of denosumab: the devil is in the details.

A 47-year-old postmenopausal woman with osteoporosis was treated with denosumab, which was discontinued due to side effects. She was therefore transitioned to a yearly intravenous infusion of zoledronic acid. An increase in bone turnover markers together with bone loss at the lumbar spine was observed before the second infusion, suggesting an overshooting of bone resorption due to denosumab discontinuation. On physical examination, the patient was restless and reported having lost about 10 kg since the last visit. A solitary left inferior thyroid nodule was noted on neck palpation. Circulating thyroid hormone levels were elevated, with suppressed thyroid-stimulating hormone. A thyroid scan showed increased uptake in the left inferior nodule with suppression of the remainder of the thyroid gland. A diagnosis of hyperthyroidism due to toxic adenoma was made. The patient was treated with radioactive iodine ablation, with consequent complete normalization of thyroid function. She continued yearly treatment with zoledronic acid. She remained clinically well with no further fractures. Bone turnover markers were appropriately suppressed and bone mineral density increased in the spine and hip. This case illustrates how the overshooting phenomenon following denosumab discontinuation may be compounded by the development of secondary conditions, which can result in suboptimal response to antiresorptive osteoporosis medications.

Treatment of bone metastases from solid tumors with bone-modifying agents: a web survey of Italian oncologists investigating patterns of practice drug prescription and prevention of side effects.

PURPOSE: Optimal use of bone-modifying agents (BMAs) in patients with bone metastases from solid tumors is uncertain in some aspects: the drug choice; the planned treatment duration and long-term therapy; the prevention and management of possible side effects, including renal toxicity, hypocalcaemia, and medication-related osteonecrosis of the jaw (MRONJ). METHODS: Italian oncologists were invited to fulfil a 24-question web survey about prescription of BMAs for bone metastases of breast cancer, prostate cancer, and other solid tumors. Prevention and management of side effects were also investigated. RESULTS: Answers of 191 oncologists were collected. BMAs are usually prescribed at the time of diagnosis of bone metastases by 87.0% (breast cancer) and 76.1% (solid tumors except breast and prostate cancers) of oncologists; the decision is more articulated for prostate cancer (endocrine-sensitive versus castration-resistant). The creatinine level (32.3%), the availability of patient venous access (15.8%), and the type of primary neoplasm (13.6%) are the most reported factors involved in choice between bisphosphonates and denosumab. Zoledronic acid every 3 months was considered as a valid alternative to monthly administration by 94% of Italian oncologists. Oncologists reported a good confidence with measures aimed to prevent MRONJ, whereas uncertainness about prevention and management of hypocalcemia was registered. CONCLUSION: Italian oncologists showed a high attitude in prescribing bisphosphonates or denosumab at the time of diagnosis of bone metastases, with a large application of preventive measures of side effects. Further studies are needed to investigate some controversial aspects, such as optimal drug treatment duration and long-term drug schedules.

Assessing EGFR-mutated NSCLC with bone metastasis: Clinical features and optimal treatment strategy.

BACKGROUND: This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non-small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR-tyrosine kinase inhibitors (TKIs). METHODS: The study included patients with stage IV EGFR-mutated NSCLC who were receiving first-line treatment with EGFR-TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. RESULTS: The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression-free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM. CONCLUSIONS: The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes.

Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients With Breast Cancer With Bone Metastasis in India.

PURPOSE: Denosumab is clinically superior to zoledronic acid (ZA) for preventing and delaying time to first and subsequent skeletal-related events (SREs) among patients with breast cancer (BC) with bone metastases. We evaluated the cost and health benefits of denosumab and ZA (once every 4 weeks and once every 12 weeks) among four different molecular subtypes of BC with bone metastases in India. MATERIALS AND METHODS: A Markov model was developed in Microsoft Excel to estimate lifetime health consequences and resulting costs among cohort of 1,000 patients with BC with bone metastasis, for three intervention scenarios, namely denosumab (once every 4 weeks), ZA (once every 4 weeks), and ZA (once every 12 weeks). The health outcomes were measured in terms of SREs averted and quality-adjusted life-years (QALYs) gained. The cost of each intervention scenario was measured using both the health system and the patient's perspectives. Indirect costs because of lost productivity were not included. The future costs and outcomes were discounted at the standard rate of 3%. RESULTS: Over a lifetime, the incremental number of SREs averted with use of denosumab once every 4 weeks (compared with ZA once every 4 weeks and once every 12 weeks) among patients with luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and triple negative breast cancer were estimated as 0.39, 0.26, 0.25, and 0.19, respectively. The number of QALYs lived were slightly higher in the denosumab arm (1.45-2.80) compared with ZA once every 4 weeks and once every 12 weeks arms (1.44-2.78). However, denosumab once every 4 weeks was not found to be a cost-effective alternative for either of the four molecular subtypes of breast cancer. ZA once every 12 weeks was found to be a cost-effective option with an average cost-effectiveness ratio ranging between ₹68,254 and ₹73,636. CONCLUSION: ZA once every 12 weeks is the cost-effective treatment option for BC with bone metastases in India. The present study findings hold significance for standard treatment guidelines under India's government-funded health insurance program.

Association between pharmacotherapy and secondary vertebral fracture managed with a brace in a real-world setting: A nationwide database study in Japan.

AIM: This retrospective cohort study assessed the association between the incidence of secondary vertebral fracture managed with a brace (SVF) and pharmacotherapy. METHODS: The association between the incidence of SVF and the presence, type, and medication possession ratio (MPR) of pharmacotherapy was investigated using medical insurance data acquired from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. RESULTS: The data of female patients (n = 637 303) were analyzed. The 2-year incidence of SVF was 73.5 per 10 000 patients (n = 4687). Approximately 0.73% of patients without medications and 0.74% with medications had SVF. Patients taking bisphosphonates (0.87), denosumab (0.77), and selective estrogen receptor modulators (0.88) had significantly lower standardized incidence ratios (SIRs) than patients not taking medications after the occurrence of primary fracture; meanwhile, patients taking parathyroid hormone medications had considerably higher SIRs than those not taking medications. The non-SVF group (59.1%) had a significantly higher mean MPR than the SVF group (55.5%). Patients taking denosumab in the non-SVF group (68.2%) had the highest mean MPR. The proportion of patients taking denosumab with an MPR of ≥80% in the non-SVF group was significantly higher than that in the SVF group. CONCLUSION: Patients taking medications were at a lower risk of developing SVF than those not taking medications. Although this study did not compare the medications' SVF prevention effects, patients taking denosumab had a 0.77 SIR of SVF in Japan. The effect of pharmacotherapy on SVF prevention might be affected by the MPR of each medication. Geriatr Gerontol Int 2024; 24: 390-397.

Using Denosumab as a Nonsurgical Management of Aneurysmal Bone Cysts in the Pelvis.

Background: Aneurysmal bone cysts (ABCs) are infrequent, benign, and locally destructive lesions that most commonly occur during the first two decades of life. They usually affect the metaphysis of the long bones, but the pelvis is involved in 8%-12% of the cases. The management of pelvic ABCs is a challenging issue due to difficulties in choosing the appropriate approach, adjacent neurovascular bundles, the risk of intraoperative bleeding with difficulty achieving good hemostasis, and the risk of injury to the hip or sacroiliac joints. Limited data exist concerning the use of denosumab as a non-surgical treatment for pelvic ABCs. Our hypothesis was that denosumab might be an effective and safe solo treatment of cases with ABCs in the pelvis. Methods: We retrospectively assessed 20 patients with ABCs in the pelvis, who were treated by denosumab as a solo agent without surgery. Patients were assessed regarding disease control, the incidence of recurrence and non-oncological complications, and functional outcome. Results: The mean follow-up period was 38.5 months. Disease control was achieved in 16 patients (80%), with no local recurrence. Tolerable drug-related complications occurred in 15% of cases. The mean Musculoskeletal Tumor Society score was 92.3%. Conclusions: Denosumab may provide a reliable option in the nonsurgical treatment of ABCs of pelvic origin with expected lower morbidity than the surgical solution and tolerable complications. Further studies on the safety profile and long-term effects of denosumab especially in skeletally immature patients are required.

[Metabolic bone diseases : what's new in 2023]. / Maladies osseuses : ce qui a changé en 2023.

The sequential effects of romosozumab and denosumab in osteoporosis are shown in real-life, while the mechanisms of post-denosumab rebound are reviewed extensively. A network meta-analysis confirms the superiority of anabolics vs anti-resorptives on fracture reduction, while the latter shown a reduction of mortality in a large population-based study. Fracture risk prediction by FRAXPlus is improved. New meta-analyses confirm the benefits of Vitamin D on fractures and falls. Finally, multiples trials with new molecules for the treatment of rare bone diseases, including osteogenesis imperfecta, fibrous dysplasia and hypoparathyroidism, shown promising results.

Dans l'ostéoporose, les effets séquentiels du romosozumab et du dénosumab se précisent et les mécanismes du rebond à l'arrêt de ce dernier font l'objet d'une revue détaillée. Une méta-analyse en réseau confirme la supériorité des traitements anaboliques sur les antirésorbtifs, alors que l'effet de ces derniers sur la réduction de la mortalité est démontré dans une large étude populationnelle. La prédiction du risque fracturaire est améliorée par l'outil FRAXPlus. De nouvelles méta-analyses des bénéfices de la vitamine D sur le risque de fractures et de chutes sont également disponibles. Enfin, de nombreuses études encourageantes sur l'efficacité de nouveaux traitements dans de multiples maladies osseuse rares, telles l'ostéogenèse imparfaite, la dysplasie fibreuse et l'hypoparathyroïdie, ont été publiées.

Denosumab and the Risk of Diabetes in Patients Treated for Osteoporosis.

Importance: Denosumab, a humanized monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), is a widely used antiresorptive medication for osteoporosis treatment. Recent preclinical studies indicate that inhibition of RANKL signaling improves insulin sensitivity, glucose tolerance, and ß-cell proliferation, suggesting that denosumab may improve glucose homeostasis; however, whether denosumab reduces the risk of incident diabetes remains unclear. Objective: To evaluate whether denosumab use is associated with a lower risk of developing diabetes in patients with osteoporosis. Design, Setting, and Participants: This nationwide, propensity score-matched cohort study used administrative data from Taiwan's National Health Insurance Research Database. Adult patients who received denosumab for osteoporosis therapy in Taiwan between 2012 and 2019 were included. To eliminate the inherent bias from confounding by indication, the patients were categorized into a treatment group (34 255 patients who initiated denosumab treatment and adhered to it) and a comparison group (34 255 patients who initiated denosumab treatment but discontinued it after the initial dose) according to the administration status of the second dose of denosumab. Propensity score matching was performed to balance patient characteristics and to control for confounders. Exposure: Treatment with denosumab. Main Outcomes and Measures: The primary outcome was incident diabetes requiring treatment with antidiabetic drugs. A Cox proportional hazards model was used to estimate the hazard ratio (HR) for incident diabetes. Data were analyzed from January 1 to November 30, 2023. Results: After propensity score matching, 68 510 patients were included (mean [SD] age, 77.7 [9.8] years; 57 762 [84.3%] female). During a mean (SD) follow-up of 1.9 (1.6) years, 2016 patients developed diabetes in the treatment group and 3220 developed diabetes in the comparison group (incidence rate, 35.9 vs 43.6 per 1000 person-years). Compared with the comparison group, denosumab treatment was associated with a lower risk of incident diabetes (HR, 0.84; 95% CI, 0.78-0.90). Several sensitivity analyses also demonstrated similar results of lower diabetes risk associated with denosumab treatment. Conclusions and relevance: The results from this cohort study indicating that denosumab treatment was associated with lower risk of incident diabetes may help physicians choose an appropriate antiosteoporosis medication for patients with osteoporosis while also considering the risk of diabetes.

The efficacy of Denosumab in the treatment of femoral head osteonecrosis: a retrospective comparative study.

The present study aimed to compare clinical and radiological differences of ONFH patients who were treated with denosumab, and a control group. A total of 178 patients (272 hips) with symptomatic, nontraumatic ONFH were divided into a denosumab group (98 patients, 146 hips) and a control group (80 patients, 126 hips). Patients in the denosumab group received a 60 mg subcutaneous dose of denosumab every 6 months. For the clinical assessments, Harris hip scores (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were evaluated. Plain radiographs and MRI were performed before and a minimum of 1 year after administration of denosumab, which were evaluated for radiological results including femoral head collapse (≥ 2 mm) and volume change of necrotic lesion. Femoral head collapse occurred in 36 hips (24.7%) in the denosumab group, and 48 hips (38.1%) in the control group, which was statistically significant (P = 0.012). Twenty-three hips (15.8%) in the denosumab group and 29 hips (23%) in the control group required THA, which showed no significant difference (P = 0.086). At the final follow-up, 71.9% of hips in the denosumab group had a good or excellent HHS compared with 48.9% in the control group, showing a significant difference (P = 0.012). The denosumab group showed a significantly higher rate of necrotic lesion volume reductions compared with the control group (P < 0.001). Denosumab can significantly reduce the volume of necrotic lesions and prevent femoral head collapse in patients with ARCO stage I or II ONFH.

Immunomodulatory Effects of RANK/RANKL Blockade in Patients with Cancer.

In cancer, multiple factors converge upon receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) signaling to promote the development of bone metastases; agents that inhibit RANKL signaling reduce skeletal-related events (SRE) in patients with cancer. In addition, RANKL signaling is important in augmenting the ability of dendritic cells (DC) to stimulate both naïve T-cell proliferation and the survival of RANK+ T cells. In this issue, Chang and colleagues using high-dimensional cytometry to evaluate immunomodulatory effects of denosumab in patients with advanced solid, observe early on treatment changes in multiple compartments, and greater effects in patients receiving concurrent chemotherapy or steroids. See related article by Chang et al., p. 453 (4).

Clinical application of bone turnover markers in osteoporosis.

Bone turnover markers (BTM) are highly responsive to initiation and changes in anti-osteoporotic therapy. In contrast to the slow treatment-induced changes in bone mineral density, the fast changes in BTM enable the clinician to adjust treatment management within a short timeframe. This review describes how BTM can be used for treatment monitoring, including monitoring during discontinuation of alendronate and denosumab therapy. In addition, sources of errors and pitfalls when using BTM monitoring will be described.

Treatment Patterns of Bone-targeting Agents Among Solid Tumor Patients With Bone Metastases: An Analysis of Electronic Health Record Data in the United States From 2014 to 2018.

OBJECTIVES: This study evaluated real-world treatment patterns of approved bone-targeting agents (BTAs) with various mechanisms of action-pamidronate, zoledronic acid, and denosumab-for the prevention of skeletal-related events in patients with bone metastases (BM) from solid tumors. METHODS: Adult patients with BM secondary to solid tumors between January 1, 2014, and December 31, 2018, were identified from the Flatiron Health Oncology Services Comprehensive Electronic Records database and categorized by BTA use and therapy type. Time from diagnosis to initiation, persistence (mean time on treatment), and compliance (≥12 administrations/year) with BTA with up to 4 years of follow-up were examined. RESULTS: This study included 27,268 patients with BM (breast cancer, 32.7%; lung cancer, 16.5%; prostate cancer, 17.2%; and other solid tumors, 33.6%); of these, 41.4% initiated denosumab after BM diagnosis; 21.3%, zoledronic acid; 0.6%, pamidronate; and 36.7% had no treatment record. Mean (SD) time to initiation for denosumab or zoledronic acid was 68.6 (157.0) days (denosumab, 70.3 (160.4) days; zoledronic acid, 65.2 [150.2] days). Mean persistence and compliance (first year of treatment) were significantly higher for denosumab than for zoledronic acid (22.0 vs. 14.9 mo [ P <0.0001] and 42.3% vs. 34.8% [ P <0.0001], respectively). Treatment compliance was the highest in patients with breast cancer (denosumab, 48.2%; zoledronic acid, 39.1%). CONCLUSION: Real-world BTA treatment patterns in the United States suggest that over one-third of patients with BM secondary to solid tumors remain untreated and less than 50% of the patients received ≥12 administrations/year of BTA therapy.

Changes in mandibular radiomorphometric indices in osteoporosis patients treated with denosumab: a retrospective case-control study.

BACKGROUND: Radiomorphometric indices measured on Dental Panoramic Radiography (DPR) can reflect Bone Mineral Density (BMD). The aim of our study is to evaluate changes in DPR radiographic markers in patients undergoing antiresorptive therapy with denosumab and correlate them to BMD and serum bone turnover markers (BTM). METHODS: We evaluated two radiomorphometric indices: Mandibular Cortical Width (MCW) and Panoramic Mandibular Index (PMI), in patients undergoing antiresorptive therapy with denosumab at T0 (before starting the therapy) and at T1 (after 12 months), comparing results with a control group of healthy patients who performed two DPRs at a one-year time distance. Correlation analysis was performed in the denosumab group, as well as ROC curves were obtained for both indices. RESULTS: The study included 18 patients and 21 controls according to specific inclusion and exclusion criteria, matched by gender and age. Both MCW and PMI were significantly lower at T0 in the denosumab group, consistently with lower BMD. MCW showed significant correlation with femoral and lumbar DEXA and was significantly lower in patients with osteoporosis compared to osteopenia. Only PMI index increased significantly in the denosumab group from T0 to T1. After one year (T1), there weren't any differences between patients and controls for both indices. No significant correlations were found with BTMs. Sensitivity and specificity for MCW and PMI were also calculated. CONCLUSIONS: Our results show how CMW shows sufficient sensitivity and specificity to be used as a radiographic marker to screen and intercept patients with osteoporosis. PMI seems to be able to reflect changes in response to antiresorptive therapy with denosumab. Further studies are needed to confirm our hypothesis.

Cost-consequence analysis of continuous denosumab therapy for osteoporosis treatment in South Korea.

BACKGROUND: Insurance reimbursement provisions in South Korea limit osteoporosis medication availability for patients with T-scores exceeding - 2.5. This study aimed to evaluate the financial impact and fracture prevention of continuous denosumab therapy until a T-score>-2.0 (Dmab-C strategy), versus discontinuation of denosumab after reaching T-score>-2.5 (Dmab-D strategy) in osteoporosis patients. METHODS: A cost-consequence analysis from a Korean healthcare system perspective was performed using a newly developed Markov model. The incidence of vertebral and non-vertebral fracture, fracture-related deaths, drug costs, and fracture-treatment costs were estimated and compared between Dmab-C and Dmab-D strategy over a lifetime in eligible patients aged 55 years. RESULTS: Base-case analysis revealed that Dmab-C prevented 32.21 vertebral fracture (VF) and 12.43 non-VF events per 100 patients over a lifetime, while reducing 1.29 fracture-related deaths. Lifetime direct healthcare cost saving per patient was KRW 1,354,655 if Dmab-C replaces Dmab-D. When productivity losses were considered, Dmab-C saved KRW 29,025,949 per patient compared to Dmab-D. The additional treatment costs of Dmab-C could be offset by the higher subsequent treatment costs and fracture treatment costs of Dmab-D. The sensitivity analysis showed consistent patterns with results of the base-case analysis. CONCLUSION: Continuous treatment using denosumab until osteoporosis patients achieve and maintain a T-score of -2.0 would provide greater clinical and economic benefits in terms of fracture prevention and reduced mortality risks compared to outcomes from discontinuing treatment at a T-score of -2.5 or above. This new treatment strategy would effectively lower the risk of fractures and fracture-related mortality, ultimately leading to lower medical expenses.

Fat Body Mass and Vertebral Fracture Progression in Women With Breast Cancer.

Importance: Women with early breast cancer (EBC) exposed to aromatase inhibitors (AIs) may experience fragility fractures despite treatment with bone-active drugs. Risk factors for fractures in patients receiving AIs and denosumab have not been explored to date. Objectives: To evaluate whether an association exists between dual x-ray absorptiometry (DXA)-measured fat body mass (FBM) and vertebral fracture (VF) progression in postmenopausal women with EBC undergoing adjuvant therapy with AIs in combination with denosumab and to examine whether VF was associated with common risk factors for bone fracture and parameters of body composition other than FBM. Design, Setting, and Participants: For this prospective, single-center, cohort study, 237 patients with EBC who were undergoing adjuvant treatment with AIs and denosumab (60 mg every 6 months) were enrolled at the Breast Unit of the ASST Spedali Civili of Brescia from September 2014 to June 2018. Data analysis was conducted in June 2022. Exposure: Body composition parameters, bone mineral density, and morphometric VFs were assessed by DXA at study entry and after 18 months of therapy. Main Outcomes and Measures: VF progression, defined as either new or worsening of preexisting VFs, between the 2 time points. Results: Of the 237 patients enrolled (median [range] age, 61 [28-84] years), 17 (4.4%) reported VF progression. Univariable analysis found an association between VF progression and a history of clinical fractures (odds ratio [OR], 3.22; 95% CI, 1.19-8.74; P = .02), Fracture Risk Assessment Tool (FRAX) score for major fractures (OR, 4.42; 95% CI, 1.23-13.79; P = .04), percentage of FBM (OR, 6.04; 95% CI, 1.69-21.63; P = .006), and android fat (OR, 9.58; 95% CI, 1.17-78.21; P = .04) and an inverse association with appendicular lean mass index-FBM ratio (OR, 0.25, 95% CI, 0.08-0.82; P = .02). Multivariable analysis revealed percentage of FBM (OR, 5.41; 95% CI, 1.49-19.59; P = .01) and FRAX score (OR, 3.95; 95% CI, 1.09-14.39; P = .04) as independent variables associated with VF progression. Conclusions and Relevance: The findings of this study suggest that baseline FBM is an independent factor for VF progression in patients with EBC treated with adjuvant AIs and denosumab. This observation is new and indicates that diet and exercise may synergize with denosumab in the management of bone health in this patient setting.

Histological and immunohistochemical analyses of osteoclast maturation in giant cell tumor of bone.

INTRODUCTION: Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor characterized by the occurrence of multinucleated osteoclast-like giant cells that play a key role in GCTB pathogenesis. However, little is known about the molecular mechanisms underlying osteoclast differentiation in GCTB. Denosumab, a human monoclonal antibody against RANKL, is used for GCTB treatment. Here, we performed morphological and immunohistochemical examinations of pre- and post-denosumab treatment changes by analyzing each stage of osteoclast differentiation. METHODS: We retrieved 15 archival cases of GCTB with tumor samples from both pre- and post-denosumab treatment. We selected three immunohistochemical markers from the expression data from a previous single-cell RNA study: FOS, a progenitor osteoclast marker, and JDP2 and NFATc1, mature osteoclast markers. RESULTS: The mean positivity of the markers decreased after denosumab treatment from 11.1% to 8.9% for FOS, from 10.6% to 7.2% for JDP2, and from 10.0% to 0.2% for NFATc1. Only NFATc1 positivity decreased significantly (P < 0.001) after denosumab treatment. CONCLUSIONS: We identified a new differentiation stage of osteoclast maturation, intermediate cell, by comparing histological findings before and after denosumab treatment. We demonstrated that discrepancies exist between histological and molecular data and highlight the need for establishing an integrated definition of osteoclasts considering morphology and marker expression.

Comparison of radiological and functional outcomes of conservative treatment with teriparatide and denosumab in thoracolumbar osteoporotic vertebral fracture.

Teriparatide and denosumab, anti-osteoporosis medications with different mechanisms, have been widely used in the patients with osteoporotic vertebral fracture (OVF) considered as advanced osteoporosis. Teriparatide has been shown to enhance bone formation and fracture healing in OVF, but there are still no sufficient evidences discussing about the role of denosumab in newly developed OVF. In this study, we found the similar radiological deformation and functional outcomes of conservative treatment with teriparatide and denosumab in thoracolumbar (TL) OVF, and teriparatide showed a more frequent incidence of fracture union with paravertebral bone bridge formation compared to denosumab. INTRODUCTION: Teriparatide and denosumab have been widely used to treat advanced osteoporosis and prevent subsequent fractures in patients with OVCF. Unlike teriparatide, which is considered to be effective in fracture healing, there is still no clear role and evidence for the effect of denosumab in acute OVCF. This study compared the radiological and functional outcomes of conservative treatment with teriparatide and denosumab in TL-OVF. METHODS: This retrospective study enrolled 78 women with mean age of 74.69 ± 7.66 (60-92) years diagnosed as a TL-OVF with no neurological deficits. All patients were treated conservatively with teriparatide (34 of group T, once-daily 20 µg) or denosumab (44 of group D, once-6 months 60 mg) for 6 months. We evaluated the radiological deformation (kyphotic angle, segmental vertebral kyphotic angle, and compression ratio) and the incidence of fracture union with paravertebral bone bridge formation (FUPB) and functional outcomes using the visual analog scale (VAS) and Oswestry Disability Index (ODI) at 0, 3, and 6 months. RESULTS: In the radiological deformation and functional outcomes, there were no significant differences at 0, 3, and 6 months between the two groups (P > 0.05). However, the incidence of FUPB at 6 months was higher in group T (20/34, 58.8%) compared to group D (11/44, 25.0%) (P = 0.004), and teriparatide was the most statistically significant factor for achieving FUPB (OR 4.486, P = 0.012) in multivariable logistic analysis. CONCLUSIONS: Teriparatide and denosumab, despite of their different pharmacological mechanisms, showed similar radiological deformation and functional outcomes in the conservative treatment of TL-OVF. However, teriparatide showed a significantly higher incidence of fracture union with paravertebral bone bridge formation.

Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer.

Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK-RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic cells and medullary thymic epithelial cells. Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in patients with cancer. Blood was collected from 23 patients with prostate cancer and 3 patients with renal cell carcinoma, all of whom had advanced disease and were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T-cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of natural killer cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatments, can lead to the induction of immunologic checkpoints. See related Spotlight by Nasrollahi and Davar, p. 383.