[Analysis of the efficacy and safety of bone disease treatment in patients with newly diagnosed multiple myeloma treated with denosumab or zoledronic acid].

Objective: This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma. Methods: The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) . Results: Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration (P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum ß-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type Ⅰ N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups (P>0.05), and the median PFS and OS time were not reached (P>0.05) . Conclusions: In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.

The comparative effect of teriparatide and denosumab on activins, follistatins and inhibins in women with postmenopausal osteoporosis.

The activins-follistatins-inhibins (AFI) hormonal system affects bone metabolism. Treatments that alter bone metabolism may also alter the AFI molecules. In this non-randomized, open-label, head-to-head comparative study, circulating levels of the AFI system were evaluated in postmenopausal women with osteoporosis treated for 12 months with either teriparatide (n = 23) or denosumab (n = 22). Τeriparatide treatment increased activin B (p = 0.01) and activin AB (p = 0.004) and the ratios activin A/follistatin (p = 0.006), activin B/follistatin (p = 0.007), activin AB/follistatin (p < 0.001) and activin AB/FSTL3 (p = 0.034). The significant p for trend in group*time interactions of activins B and AB and of the ratio activin AB/FSTL3 remained robust after adjustment for body mass index (BMI) and lumbar spine bone mineral density (LS BMD) but it was lost for activin B after adjustment for previous antiresorptive treatment. The effect of teriparatide on BMD was attenuated when it was adjusted for baseline activins levels or their 12-month changes. No changes were observed after denosumab treatment. In conclusion, activins B and AB, as well as the ratios of all activins to follistatin and of activin AB to FSTL3 increased with teriparatide treatment, possibly in a compensatory manner. Future studies are needed to study the potentially important role activins may play in bone biology and any associations with the effect of teriparatide on BMD.

Bone and the muscle, comprise two tissues that are considered to interact with each other, not only through mechanical but also through endocrine signals. Several components of the activins-follistatins-inhibins (AFI) hormonal system have been shown to be secreted by the muscle and affect the bone possibly contributing to this interplay. We have previously investigated levels of the AFI molecules in case­control studies and reported differences between osteoporotic versus osteopenic versus postmenopausal and premenopausal women with normal bone mineral density (BMD). In this 12-month, non-randomized, open-labeled, head-to-head comparative study, we prospectively compared the effect of antiosteoporotic agents with opposite effect on bone metabolism, i.e., teriparatide versus denosumab, on the circulating concentrations of all known molecules of the AFI system in postmenopausal women with osteoporosis. We observed increases of activins after teriparatide treatment, but no effect after denosumab treatment on any of the AFI molecules studied. Since activins are mainly acting in an autocrine way and since activin B and AB have not been extensively studied, further studies in the basic research, preclinical and clinical research fields are required to expand these observations and fully elucidate physiology and any therapeutic potential.

Efficacy and safety of denosumab de­escalation in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a locally aggressive intermediate bone tumor. Denosumab has shown effectiveness in GCTB treatment; however, the benefits of denosumab de-escalation for unresectable GCTB have not been well discussed. The present study investigated the efficacy and safety of denosumab de-escalation for GCTB. The medical records of 9 patients with unresectable GCTB or resectable GCTB not eligible for resection, who received de-escalated denosumab treatment at Okayama University Hospital (Okayama, Japan) between April 2014 and December 2021, were retrospectively reviewed. The denosumab treatment interval was gradually extended to every 8, 12 and 24 weeks. The radiographic changes and clinical symptoms during standard and de-escalated denosumab therapy were assessed. The denosumab interval was de-escalated after a median of 12 months of a standard 4-weekly treatment. Imaging showed that the re-ossification of osteolytic lesions obtained with the 4-weekly treatment were sustained with 8- and 12-weekly treatments. The extraskeletal masses reduced significantly with standard treatment, while tumor reduction was sustained during de-escalated treatment. During the 24-weekly treatment, 2 patients remained stable, while 2 patients developed local recurrence. The clinical symptoms improved significantly with standard treatment and remained improved during de-escalated treatment. There were severe adverse events including osteonecrosis of the jaw (2 patients), atypical femoral fracture (1 patient) and malignant transformation of GCTB (1 patient). In conclusion, 12-weekly de-escalated denosumab treatment showed clinical benefits as a maintenance treatment in patients with unresectable GCTB, in addition to sustained stable tumor control and improved clinical symptoms with standard treatment. A 24-weekly treatment can also be administered, with careful attention paid to detecting local recurrence.

Change in spinal bone mineral density as estimated by Hounsfield units following osteoporosis treatment with romosozumab, teriparatide, denosumab, and alendronate: an analysis of 318 patients.

OBJECTIVE: The purpose of this study was to determine the effect of osteoporosis medications on opportunistic CT-based Hounsfield units (HU). METHODS: Spine and nonspine surgery patients were retrospectively identified who had been treated with romosozumab for 3 to 12 months, teriparatide for 3 to 12 months, teriparatide for > 12 months, denosumab for > 12 months, or alendronate for > 12 months. HU were measured in the L1-4 vertebral bodies. One-way ANOVA was used to compare the mean change in HU among the five treatment regimens. RESULTS: In total, 318 patients (70% women) were included, with a mean age of 69 years and mean BMI of 27 kg/m2. There was a significant difference in mean HU improvement (p < 0.001) following treatment with romosozumab for 3 to 12 months (n = 32), teriparatide for 3 to 12 months (n = 30), teriparatide for > 12 months (n = 44), denosumab for > 12 months (n = 123), and alendronate for > 12 months (n = 100). Treatment with romosozumab for a mean of 10.5 months significantly increased the mean HU by 26%, from a baseline of 85 to 107 (p = 0.012). Patients treated with teriparatide for > 12 months (mean 23 months) experienced a mean HU improvement of 25%, from 106 to 132 (p = 0.039). Compared with the mean baseline HU, there was no significant difference after treatment with teriparatide for 3 to 12 months (110 to 119, p = 0.48), denosumab for > 12 months (105 to 107, p = 0.68), or alendronate for > 12 months (111 to 113, p = 0.80). CONCLUSIONS: Patients treated with romosozumab for a mean of 10.5 months and teriparatide for a mean of 23 months experienced improved spinal bone mineral density as estimated by CT-based opportunistic HU. Given the shorter duration of effective treatment, romosozumab may be the preferred medication for optimization of osteoporotic patients in preparation for elective spine fusion surgery.

Effect of anti-resorptive therapy on implant failure: a systematic review and meta-analysis.

PURPOSE: This review was conducted to systematically assess the impact of bisphosphonates (BPs) and denosumab, used as anti-resorptive therapies, on the incidence of dental implant failure. METHODS: Electronic and manual searches were performed in accordance with the described search protocol. Only articles that met the inclusion criteria were selected. The primary outcome was implant failure, while secondary outcomes included biological complications and comorbidities. Following data extraction, a quality assessment and meta-analysis were conducted. RESULTS: Fourteen eligible studies were included in the analysis following a qualitative evaluation. BP administration, regardless of the timing of anti-resorptive therapy, did not significantly increase the risk of implant failure (odds ratio [OR], 1.40; 95% confidence interval, 0.83-2.34). Subgroup analysis revealed a slightly higher, although statistically insignificant, risk of failure in patients with a follow-up period of 3 years or more compared to those with a follow-up duration of less than 3 years (with ORs of 2.82 and 1.53, respectively). Due to a lack of eligible studies, a meta-analysis for denosumab could not be conducted. CONCLUSIONS: Our findings suggest that BP treatment does not compromise the survival of dental implants. Specifically, in patients with osteoporosis, implant failure rates were not significantly influenced by the administration of BPs before the placement of dental implants, suggesting that low-dose BP therapy may not contraindicate implant placement. Nevertheless, regular check-ups and maintenance periodontal treatment must not be neglected, and concomitant biological factors should be considered to ensure the long-term success of implant rehabilitation.

MASCC/ISOO Clinical Practice Statement: Adjuvant bone-modifying agents in primary breast cancer patients - prevention of medication-related osteonecrosis of the jaw.

PURPOSE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS raises awareness to the prevention of medication-related osteonecrosis of the jaw (MRONJ) in patients with breast cancer treated with adjuvant bone-modifying agents (BMA). METHODS: This CPS was developed based on a critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and tables to generate a short manual about the best standard of care. RESULTS: In patients treated with adjuvant BMA, dento-alveolar surgery poses a moderate risk for MRONJ that ranges between the high risk for MRONJ in patients with metastatic breast cancer and the low risk for MRONJ in patients with osteoporosis. Existing MRONJ guidelines serve as a starting point for adjuvant BMA use. Urgent procedures should be delivered without delay using the accepted precautions to prevent MRONJ. If elective surgery is considered, the individual risk for MRONJ following surgery should be assessed according to common risk factors. CONCLUSION: Prevention of MRONJ in primary breast cancer patients treated with adjuvant BMA requires risk-benefit assessment; collaboration between the medical team, dental professional, and patient; and patient-specific tailored dental treatment planning. The patient should be informed about this risk. Additional research is needed to define optimal MRONJ care for this population.

A Real-world Study of Denosumab For Reducing Refracture Risk after Percutaneous Vertebral Augmentation.

OBJECTIVE: To investigate the use of anti-osteoporotic agents and refracture incidence in patients with osteoporotic vertebral compression fracture (OVCF) following percutaneous vertebral augmentation (PVA) and to evaluate the real-world treatment of patients using denosumab following PVA. This study aims to provide spine surgeons with empirical insights derived from real-world scenarios to enhance the management of bone health in OVCF patients. METHODS: This retrospective cohort study was based on data from the MarketScan and Optum databases from the USA. Female patients aged 55-90 years who underwent PVA for OVCF between January 2013 and March 2020 were included and followed up from the day after surgery. Patients who received at least one dose of denosumab were included in the denosumab cohort and were further divided into the on-treatment and off-treatment groups according to whether they received a second dose of denosumab, with follow-up beginning on the index day (225 days after the first denosumab dose). In this study, the off-treatment group was considered as the control group. Refracture incidence after PVA, the proportion of patients using anti-osteoporotic agents in the total study population, and refracture incidence after the index day in the denosumab cohort were analyzed. RESULTS: A total of 13,451 and 21,420 patients from the MarketScan and Optum databases, respectively, were included. In the denosumab cohort, the cumulative incidence of clinical osteoporotic fractures within 3 years after the index day was significantly lower in the on-treatment group than in the off-treatment group (MarketScan database: 23.0% vs 39.0%, p = 0.002; Optum database: 28.2% vs 40.0%, p = 0.023). The cumulative incidence of clinical vertebral fractures was also lower in the on-treatment group than in the off-treatment group, with a significant difference in the MarketScan database (14.4% vs 25.5%, p = 0.002) and a numerical difference was found in the Optum database (20.2% vs 27.5%, p = 0.084).The proportion of patients using anti-osteoporotic agents was low at 6 months postoperatively, with only approximately 7% using denosumab and 13%-15% taking oral bisphosphonates. CONCLUSION: Postmenopausal women have a high refracture rate and a low proportion of anti-osteoporotic drug use after PVA. Continued denosumab treatment after PVA is associated with a lower risk of osteoporotic and clinical vertebral fractures. Therefore, denosumab may be a treatment option for patients with osteoporosis after PVA.

Exploring the Clinical Impact of RANK Pathway Inhibition in Advanced Breast Cancer: Insights From a Retrospective Study on CDK4/6 Inhibitors and Antiresorptive Therapy.

BACKGROUND AND OBJECTIVE: Breast cancer (BC) remains a significant health concern, particularly in advanced stages where the prognosis is poor. The combination of endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has improved outcomes for advanced BC (aBC) patients. However, resistance to CDK4/6i remains a challenge, with no validated biomarkers to predict response. The receptor activator of the nuclear factor-kB (RANK) pathway has emerged as a key player in aBC, particularly in luminal BC. RANK overexpression has been associated with aggressive phenotypes and resistance to therapy. In view of these findings, we proceeded to investigate the potential involvement of the RANK pathway in luminal BC resistance to CDK4/6i. The objective was to evaluate the effectiveness of denosumab in increasing overall survival (OS) and progression-free survival (PFS). METHODS: In this retrospective analysis, 158 BC patients with bone metastases were included. Patients with human epidermal growth factor receptor-2 (HER2)-negative and hormone receptor-positive BC who received palbociclib or ribociclib in addition to antiresorptive medication were included. Patients received either denosumab or zoledronic acid (ZA) therapy. The primary endpoint was OS, with PFS as a secondary endpoint. RESULTS: Although the PFS and OS of denosumab were better than ZA in this study, it did not show a significant difference between the two drugs. Meanwhile, mOS was not achievable in patients in the denosumab group, while it was 34.1 months in patients in the ZA group. The hazard ratio (HR) showed a significant improvement for the denosumab group in patients under 60 of age (HR: 0.33, p<0.01), patients with a score of 1 HER2 overexpression (HR: 0.09, p=0.01), and patients with resistant endocrine (HR: 0.42, p=0.02) compared to ZA. CONCLUSION: This study highlights the potential clinical relevance of the RANK pathway in BC treatment, and our findings suggest that denosumab may offer significant benefits in terms of PFS and OS for certain subgroups, particularly those with HER2 scores of 1, patients under 60, and those with endocrine-resistant BC. In conclusion, considering that RANK pathway status may be a predictive biomarker for CDK4/6i treatment and may cause treatment resistance, our results demonstrate the clinical relevance of the combination of CDK4/6i + ET with RANKL inhibition.

Bone-active drugs in premenopausal women with breast cancer under hormone-deprivation therapies.

BACKGROUND: Bone health management in premenopausal women with breast cancer (BC) under hormone-deprivation therapies (HDTs) is often challenging, and the effectiveness of bone-active drugs is still unknown. METHODS: This retrospective multicenter study included 306 premenopausal women with early BC undergoing HDTs. Bone mineral density (BMD) and morphometric vertebral fractures (VFs) were assessed 12 months after HDT initiation and then after at least 24 months. RESULTS: After initial assessment, bone-active drugs were prescribed in 77.5% of women (151 denosumab 60 mg/6 months, 86 bisphosphonates). After 47.0 ± 20.1 months, new VFs were found in 16 women (5.2%). Vertebral fracture risk was significantly associated with obesity (odds ratio [OR] 3.87, P = .028), family history of hip fractures or VFs (OR 3.21, P = .040], chemotherapy-induced menopause (OR 6.48, P < .001), preexisting VFs (OR 25.36, P < .001), baseline T-score less than or equal to -2.5 standard deviation (SD) at any skeletal site (OR 4.14, P = .036), and changes at lumbar and total hip BMD (OR 0.94, P = .038 and OR 0.88, P < .001, respectively). New VFs occurred more frequently in women untreated compared to those treated with bone-active drugs (14/69, 20.8% vs 2/237, 0.8%; P < .001) and the anti-fracture effectiveness remained significant after correction for BMI (OR 0.03; P < .001), family history of fractures (OR 0.03; P < .001), chemotherapy-induced menopause (OR 0.04; P < .001), and preexisting VFs (OR 0.01; P < .001). CONCLUSIONS: Premenopausal women under HDTs are at high risk of VFs in relationship with high BMI, densitometric diagnosis of osteoporosis, preexisting VFs, and family history of osteoporotic fractures. Vertebral fractures in this setting might be effectively prevented by bisphosphonates or denosumab.

Monoclonal antibodies in patients with osteoporosis and renal insufficiency: An updated systematic review and meta-analysis.

Objectives: There are challenges for the treatment of osteoporosis in patients with kidney failure and monoclonal antibodies (MAb) might be a suitable therapy. However, the efficacy and safety of MAb among patients with osteoporosis and renal insufficiency remains unclear. Methods: We systematically searched PubMed, Embase, and Cochrane Central for studies evaluating the efficacy and safety of the use of MAb in patients with osteoporosis and renal insufficiency. We pooled risk ratios (RR) and 95% confidence intervals (CI) for binary outcomes. Mean difference (MD) was used for continuous outcomes. Results: We included 5 studies with 33,550 patients. MAb therapy decreased the risk of vertebral fractures (RR 0.32; 95% CI 0.26-0.40; P < 0.01) when compared to placebo and no statistical difference was found when comparing to bisphosphonate (RR 0.71; 95% CI 0.49-1.03; P = 0.07). MAb therapy also decreased the risk of nonvertebral fractures (RR 0.79; 95% CI 0.69-0.91; P = 0.0009). Lumbar spine bone mineral density (BMD) was higher in the MAb therapy when compared to both placebo (MD 10.90; 95% CI 8.00-13.80; P < 0.01) and bisphosphonate (MD 7.66; 95% CI 6.19-9.14; P < 0.01). There was no statistically significant difference in the change of estimated glomerular filtration rate and in the incidence of hypocalcemia and serious adverse events between groups. Conclusions: There were reductions in both vertebral and nonvertebral fracture risks, alongside improvements in BMD among patients with renal insufficiency treated with MAb.

Denosumab: A Useful Addition to the Armamentarium for the Management of Male Osteoporosis.

Bone is a dynamic tissue. It remodels, preserving serum calcium, repairing microdamage, and maintaining strength. Osteoporosis is caused by a decrease in bone strength, which manifests clinically as low-energy vertebral and non-vertebral fractures. Osteoporosis poses a significant public health challenge. While it's often portrayed as primarily impacting postmenopausal women, there's been growing recognition among researchers and clinicians regarding its prevalence in men. Major fracture in men has higher mortality rates than in women. Denosumab is a fully human monoclonal immunoglobulin G2 (IgG2) antibody that binds to RANKL, the principal regulator of osteoclastic bone resorption. Multiple studies suggest that denosumab is both effective and safe, exhibiting higher adherence rates and greater patient satisfaction. In this narrative review, we highlighted the effects of denosumab in men with osteoporosis, subsequent changes in bone mineral density, and bone turnover markers outlining the literature and guideline support.

Differences Between Medication-Related Osteonecrosis of the Jaw Caused by Bisphosphonates and Denosumab: Histological, Molecular Biological, and Clinical Studies.

Purpose Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of antiresorptive agents such as bisphosphonates (BPs) and denosumab (DMB). We investigated whether a difference exists between BP- and DMB-related osteonecrosis of the jaw (ONJ). Patients and methods Histological images of 30 patients with BP-related ONJ and 13 patients with DMB-related ONJ were observed using hematoxylin-eosin and cathepsin K staining. Moreover, bone metabolism markers in the blood and bone mineral density were measured in 18 patients with BP-related ONJ and five patients with DMB-related ONJ. Furthermore, we conducted a quantitative analysis of local bone metabolism-related genes using surgical specimens through real-time reverse transcription polymerase chain reaction. Additionally, a retrospective study of 298 patients with MRONJ examined the differences in the characteristics of BP- and DMB-related ONJ and the factors associated with treatment outcomes. Results Histological examination revealed that patients treated with DMB had more severe osteoclast suppression than those treated with BP. No significant difference was observed in blood-bone metabolism markers between the two drugs; however, the suppression of local bone metabolism-related genes was stronger in patients treated with DMB. Clinical studies indicate that DMB-related ONJ is more frequently observed without osteolysis. Conclusion BP-associated ONJ and DMB-associated ONJ were shown to differ slightly. Clinical studies indicate that osteolysis is often unclear in DMB-related ONJ, and methods of bone resection during surgery need to be established.

Type 2 diabetes incidence in patients initiating denosumab or alendronate treatment: a primary care cohort study.

Denosumab initiation is related to a lower risk of type 2 diabetes than alendronate in anti-osteoporotic treatment-naïve users in primary care practices. PURPOSE: Links have been suggested between bone metabolism and glucose tolerance. Downregulation of the receptor activator of nuclear factor κ B ligand (RANKL) signaling improves glucose metabolism. Denosumab, a human monoclonal antibody against RANKL, may be associated with a lower risk of type 2 diabetes (T2D). The aim was to compare incidence rates of T2DM in primary care patients initiating denosumab or alendronate, which is a first-line therapy of osteoporosis. Alendronate as comparator enhances comparability of the two cohorts. METHOD: The IQVIA Disease Analyzer comprises a representative panel of general and specialist practices (Germany). A new-user comparative study was conducted among patients with denosumab or alendronate treatment (2010-2021) without history of diabetes and age ≥ 45 years. Incidence rates (per 1,000 person-years) and Cox proportional hazard ratios (HR; 95%CI) for T2DM were estimated. RESULTS: The cohorts consisted of 3,354 denosumab (age: 75 years; women: 87%) and 27,068 alendronate (76 years; 86%) users. Overall, 1,038 persons developed T2D during 54,916 person-years. T2DM incidence rates per 1,000 person-years were 11.9 (9.5-14.4) for denosumab and 20.1 (18.8-21.3) for alendronate users, respectively. Denosumab was associated with a reduced risk of T2DM compared to alendronate, adjusting for age, sex, index year, visits, obesity, comorbidities and statins (HR: 0.73; 0.58-0.89). CONCLUSION: In this comparative study of older patients seen in routine practices, denosumab was associated with a lower risk of developing T2DM than alendronate.

Efficacy and safety of candidate biosimilar CT-P41 versus reference denosumab: a double-blind, randomized, active-controlled, Phase 3 trial in postmenopausal women with osteoporosis.

This 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles. PURPOSE: To demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis. METHODS: This 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80-125% (for 95% CIs associated with geometric LS mean ratios). RESULTS: Equivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: - 0.139 [- 0.826, 0.548] in the full analysis set and - 0.280 [- 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab. CONCLUSIONS: CT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints.

Hypercalcemia in children induced by denosumab: a case report and an analysis of the FDA adverse event reporting system database.

BACKGROUND: The potential risks of denosumab on pediatric patients have raised concerns about its safety. This article aims to analyze the adverse effects of denosumab in minors, with a specific focus on hypercalcemia. RESEARCH DESIGN AND METHODS: A case study involving a child was analyzed. The OpenVigil 2.1 was utilized to extract adverse event data from the FAERS database, focusing on denosumab as the primary suspect drug in pediatric patients. The study also reviewed published cases of children developing hypercalcemia after discontinuing denosumab. RESULTS: The incidence of denosumab induced hypercalcemia in individuals under 18 years old is significantly higher than the overall incidence. The signal value for hypercalcemia was higher in the male group and was highest in the adolescent group. Hypercalcemia usually appeared approximately 4 months after denosumab discontinuation. Males had a higher peak blood calcium level. Patients aged 0-11 years had a higher average peak serum calcium compared to aged 12-17 years. CONCLUSIONS: This study highlights the risk of hypercalcemia after discontinuation of denosumab in minors, with young age and male gender identified as potential high-risk factors. These findings offer valuable safety warnings and preventative measures for the secure administration of this drug in pediatric populations.

The tumor-stroma ratio in giant cell tumor of bone: associations with the immune microenvironment and responsiveness to denosumab treatment.

BACKGROUND: Currently, there is limited understanding regarding the clinical significance of the tumor-stroma ratio (TSR) in giant cell tumor of bone (GCTB). Hence, we aimed to investigate the distribution of TSR in GCTB and explore its correlation with various clinicopathologic factors, immune microenvironment, survival prognosis, and denosumab treatment responsiveness. METHODS: We conducted a multicenter cohort study comprising 426 GCTB patients treated at four centers. TSR was evaluated on hematoxylin and eosin-stained and immunofluorescent sections of tumor specimens. Immunohistochemistry was performed to assess CD3+, CD4+, CD8+, CD20+, PD-1+, PD-L1+, and FoxP3+ TIL subtypes as well as Ki-67 expression levels in 426 tissue specimens. These parameters were then analyzed for their correlations with patient outcomes [local recurrence-free survival (LRFS) and overall survival (OS)], clinicopathological features, and denosumab treatment responsiveness. RESULTS: Low TSR was significantly associated with poor LRFS and OS in both cohorts. Furthermore, TSR was also correlated with multiple clinicopathological features, TIL subtype expression, and denosumab treatment responsiveness. TSR demonstrated similar predictive capabilities as the conventional Campanacci staging system for predicting patients' LRFS and OS. CONCLUSION: The results of this study provide evidence supporting the use of TSR as a reliable prognostic tool in GCTB and as a predictor of denosumab treatment responsiveness. These findings may aid in developing individualized treatment strategies for GCTB patients in the future.

Rankl genetic deficiency and functional blockade undermine skeletal stem and progenitor cell differentiation.

BACKGROUND: Skeletal Stem Cells (SSCs) are required for skeletal development, homeostasis, and repair. The perspective of their wide application in regenerative medicine approaches has supported research in this field, even though so far results in the clinic have not reached expectations, possibly due also to partial knowledge of intrinsic, potentially actionable SSC regulatory factors. Among them, the pleiotropic cytokine RANKL, with essential roles also in bone biology, is a candidate deserving deep investigation. METHODS: To dissect the role of the RANKL cytokine in SSC biology, we performed ex vivo characterization of SSCs and downstream progenitors (SSPCs) in mice lacking Rankl (Rankl-/-) by means of cytofluorimetric sorting and analysis of SSC populations from different skeletal compartments, gene expression analysis, and in vitro osteogenic differentiation. In addition, we assessed the effect of the pharmacological treatment with the anti-RANKL blocking antibody Denosumab (approved for therapy in patients with pathological bone loss) on the osteogenic potential of bone marrow-derived stromal cells from human healthy subjects (hBMSCs). RESULTS: We found that, regardless of the ossification type of bone, osteochondral SSCs had a higher frequency and impaired differentiation along the osteochondrogenic lineage in Rankl-/- mice as compared to wild-type. Rankl-/- mice also had increased frequency of committed osteochondrogenic and adipogenic progenitor cells deriving from perivascular SSCs. These changes were not due to the peculiar bone phenotype of increased density caused by lack of osteoclast resorption (defined osteopetrosis); indeed, they were not found in another osteopetrotic mouse model, i.e., the oc/oc mouse, and were therefore not due to osteopetrosis per se. In addition, Rankl-/- SSCs and primary osteoblasts showed reduced mineralization capacity. Of note, hBMSCs treated in vitro with Denosumab had reduced osteogenic capacity compared to control cultures. CONCLUSIONS: We provide for the first time the characterization of SSPCs from mouse models of severe recessive osteopetrosis. We demonstrate that Rankl genetic deficiency in murine SSCs and functional blockade in hBMSCs reduce their osteogenic potential. Therefore, we propose that RANKL is an important regulatory factor of SSC features with translational relevance.

Case Report: Development of medication-related osteonecrosis of the jaw in a patient on long-term infliximab therapy.

Medication-Related Osteonecrosis of the Jaw (MRONJ) is a challenging and evolving aspect of Oral and Maxillofacial Surgery. In recent years, several medications apart from those traditionally associated with MRONJ such as bisphosphates (BPs) and Denosumab (DMB) have been implicated in bony necrosis of the jaw. This aim of this report is to demonstrate a significant case of bone necrosis following dental extractions on a patient being treated with infliximab therapy for Crohn's disease. Several cases in literature have reported MRONJ associated with infliximab but very few patients have developed as significant a form of the disease as seen in this report. Previous investigators have proposed pathophysiological pathways via which TNF-α inhibitors such as infliximab have a causative mechanism for MRONJ. When osteoclastic activity is restricted via these pathways, bone healing is impaired and MRONJ can occur. However, it remains a diagnostic challenge to differentiate between antiresorptive MRONJ and chronic osteomyelitis with bone necrosis in patients with acquired immunodeficiency. This case aims to illustrate why the antiresorptive effects of TNF-α inhibitors need to be considered as a possible primary driver of bone necrosis in such patients.