Three cases of uncommon medication-associated osteonecrosis of temporal bone.

Introduction: Medication-related osteonecrosis of the temporal bone is rare and has been reported to be associated with the use of anti-resorptive and biologic agents. Here, we present the first case of tyrosine-kinase inhibitor-related external auditory canal (EAC) osteonecrosis as well as two cases related to anti-resorptive therapies. Methods: A retrospective case series. Results: Case one: an 84-year-old female presented with chronic otitis externa and osteonecrosis of EACs bilaterally. She had a history of osteoporosis treated with denosumab and risedronic acid. She successfully underwent left EAC reconstruction using an inferiorly-based pedicle periosteal flap while the right ear canal was managed conservatively. Case two: a 69-year-old male presented with osteonecrosis of the right EAC. He had a history of osteoporosis treated with alendronic acid and zoledronic acid. His osteonecrosis is conservatively managed with local debridement and antibiotic application. Case three: a 60-year-old male presented with osteonecrosis of the right inferior EAC. He had a history of chronic myelogenous leukemia treated with a tyrosine-kinase inhibitor, imatinib. After failing conservative therapy, he underwent right ear canal reconstruction using a periosteal vascular pedicle flap without complication and experienced complete resolution to his symptoms. Conclusion: Anti-resorptive agents and/or tyrosine kinase inhibitors may lead to dysregulation of bone remodeling and result in rare cases of temporal bone osteonecrosis. When a local debridement and antibiotic therapy fail, definitive surgical excision of necrotic bone with subsequent reconstruction of the EAC may offer patients a possible resolution in symptoms.

Clinicopathologic and prognostic characteristics of tumor budding-like in giant cell tumor of bone.

BACKGROUND: Currently, tumor budding (TB) is defined as an important factor for a poor prognosis in various types of cancers. The authors identified a significant presence of TB-like structures at the tumor invasive front in giant cell tumor of bone (GCTB), which may have the same biologic function as TB. The objective of this report was to describe the distribution of TB in GCTB and investigate its correlation with clinicopathologic characteristics, the immune microenvironment, survival prognosis, and response to denosumab treatment. METHODS: This multicenter cohort study included 426 patients with GCTB who received treatment between 2012 and 2021 at four centers. Two independent pathologists performed visual assessments of TBL structures in hematoxylin-and-eosin-stained tumor sections. Immunohistochemistry was used to evaluate tumor-infiltrating lymphocyte subtypes (CD3-positive, CD4-positive, CD8-positive, CD20-positive, programmed cell death protein-1-positive, programmed cell death-ligand 1positive, and FoxP3-positive) as well as Ki-67 expression levels in 426 tissue samples. These parameters were then analyzed for associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]), clinicopathologic characteristics, and response to denosumab treatment. RESULTS: High-grade TB was associated with poorer LRFS and OS in both patient groups. In addition, TB was correlated with various clinicopathologic features, tumor-infiltrating lymphocyte expression, and response to denosumab treatment. TB outperformed the traditional Enneking and Campanacci staging systems in predicting patient LRFS and OS. CONCLUSIONS: The current data support the assessment of TBL structures as a reliable prognostic tool in GCTB, potentially aiding in the development of personalized treatment strategies for patients.

Impact of anti-fracture medications on bone material and strength properties: a systematic review and meta-analysis.

Background and aims: Reduced bone mineral density (BMD) and microarchitectural deterioration contribute to increased fracture risk. Although the effects of anti-fracture medications (AFMs) on BMD are well-documented, their impact on bone material properties (BMPs) remains poorly characterized. Accordingly, we conducted a systematic review and meta-analysis to evaluate the effects of AFMs on BMPs. Based on data availability, we further categorized AFMs into anti-resorptives, bisphosphonates alone, and strontium ranelate subgroups to perform additional analyses of BMPs in osteoporotic patients. Methods: We did a comprehensive search of three databases, namely, PubMed, Web of Science, and Google Scholar, using various permutation combinations, and used Comprehensive Meta-Analysis software to analyze the extracted data. Results: The 15 eligible studies (randomized and non-randomized) compared the following: (1) 301 AFM-treated patients with 225 on placebo; (2) 191 patients treated with anti-resorptives with 131 on placebo; (3) 86 bisphosphonate-treated patients with 66 on placebo; and (4) 84 strontium ranelate-treated patients with 70 on placebo. Pooled analysis showed that AFMs significantly decreased cortical bone crystallinity [standardized difference in means (SDM) -1.394] and collagen maturity [SDM -0.855], and collagen maturity in cancellous bone [SDM -0.631]. Additionally, anti-resorptives (bisphosphonates and denosumab) significantly increased crystallinity [SDM 0.387], mineral-matrix ratio [SDM 0.771], microhardness [SDM 0.858], and contact hardness [SDM 0.952] of cortical bone. Anti-resorptives increased mineral-matrix ratio [SDM 0.543] and microhardness [SDM 0.864] and decreased collagen maturity [SDM -0.539] in cancellous bone. Restricted analysis of only bisphosphonate-treated studies showed a significant decrease in collagen maturity [SDM -0.650] in cancellous bone and an increase in true hardness [SDM 1.277] in cortical bone. In strontium ranelate-treated patients, there was no difference in BMPs compared to placebo. Conclusion: Collectively, our study suggests that AFMs improve bone quality, which explains their anti-fracture ability that is not fully accounted for by increased BMD in osteoporosis patients.

Unusual Histopathological Challenges in Diagnosis of Giant Cell Tumor Cases Treated with Neoadjuvant Denosumab Chemotherapy: A Rare Case Report.

Introduction: Giant cell tumor of bone (GCTB) is a rare yet locally aggressive neoplasm primarily affecting young adults. Its hallmark features include multinucleated osteoclast-type giant cells and mononuclear tumor cells. Treatment with denosumab, an anti-RANK ligand antibody, has shown efficacy, but it alters histomorphology, posing diagnostic challenges. Co-occurrence with achondroplasia, though rare, warrants consideration in bone lesion evaluations. Case Report: A 30-year-old male with achondroplasia presented with a proximal femur GCT, a rare association. Neoadjuvant denosumab was administered due to thin tumor cortex and cortical breech. Surgical excision with bone cement filling and Philo's plate supplementation was performed. Histopathological examination post-treatment revealed the absence of osteoclast-type giant cells, extensive necrosis, hyalinization, and mononuclear infiltrates. Discussion: Denosumab induces a reduction in osteoclast numbers, causing tumor shrinkage and sclerosis, while altering typical GCT histology. Similar findings were noted in the literature, including stromal changes like spindle-shaped cells, inflammation, vascular proliferation, and hemosiderin-laden foamy macrophages. Recognition of these alterations is crucial for accurate diagnosis. Conclusion: GCT, though rare, presents distinct histopathological features aiding diagnosis. Denosumab treatment modifies tumor morphology, necessitating thorough clinical evaluation for accurate diagnosis post-treatment. Understanding, these challenges is essential for optimal management of GCT cases.

Functional Outcomes of Limb Salvage Surgery in Patients with Giant Cell Tumor of Bone of the Lower Extremities: A Cross-sectional Comparative Study.

Background and Objectives: Giant cell tumor of bone (GCTB) is a benign aggressive tumor primarily treated with surgery. Neoadjuvant treatment with denosumab or zoledronic acid is a common adjunct given to down-stage tumors and facilitate limb sparing surgery. This study sought to determine the characteristics, outcomes, and occurrence of complications following resection (RS) or extended curettage (EC) for GCTB of the lower extremities. Correlation of neoadjuvant therapy with the occurrence of complications was also investigated. Methods: This is an analytical cross-sectional study of 30 patients diagnosed with GCTB of the lower extremity treated between 2015 to 2022 in a single tertiary hospital. Functional outcomes were determined using the 1993 version of the Musculoskeletal Tumor Society (MSTS) score. Mean follow-up for all patients was 2.6 years (SD 1.8). Twenty-two patients (73%) underwent resection, while eight (27%) patients underwent extended curettage. Of the 30 patients, 26 (87%) patients received neoadjuvant therapy, with 21 (81%) given denosumab and five (19%) given zoledronic acid. Results: Functional outcomes were excellent for 23 patients (77%), with no significant difference between RS and EC groups. Nine complications occurred in the RS group, including dehiscence (n=3), superficial infection (n=2), implant failure (n=1), nonunion (n=1), palsy (n=1), and implant irritation (n=1). Five complications occurred in the EC group, four of which were noted to be recurrences, with one case of deep infection. Recurrence was noted to be significantly higher (p=0.0004) in the EC group. Separate correlation analysis showed no significant difference in incidence of complications but found that duration of surgery was significantly longer (p=0.0001), and intraoperative blood loss was significantly higher (p=0.0072) in the RS group. No significant difference (p=0.78) was noted in complication rate between patients given denosumab versus zoledronic acid. Conclusions: Functional outcomes of EC and RS appear to be comparable, including the incidence of complications. However, recurrence was noted to be significantly higher in EC. There appears to be no clear advantage between denosumab or zoledronic acid for GCTB. As a neoadjuvant medication and/or to control tumor progression, zoledronic acid may be the more economic option especially for patients in developing countries.

Bisphosphonate- and disumab-related gingival disorders: case analysis from the U.S. Food and Drug Administration Adverse Event Reporting System.

Prior research has indicated that bisphosphonates (BPs) can improve periodontal disease because of their anti-osteoporosis properties. In vitro studies have shown that BPs induce cytotoxicity, inhibit wound healing, and thus affect periodontal disease. Denosumab and BPs have alternative indications. BP and denosumab are not known to correlate with gingival disorders. We assessed such a relationship by applying Bayesian and nonproportional analyses to data in the US FDA Adverse Event Reporting System (FAERS) database. The study analyzed BPs and denosumab-reported incidents with preferred terms found in the narrow Standardized MedDRA Queries for gingival disorders. A total of 5863 reported cases of gingival disorders were associated with five BPs (alendronate, pamidronate, ibandronate, risedronate, and zoledronate) and denosumab. More than 15% of patients with gingival disorders related to BPs and denosumab other than denosumab were hospitalized over short- or long-term periods. Our findings indicated BPs and denosumab had significant reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) with respect to gingival disorders. Pamidronate had the highest association (ROR = 64.58, PRR = 57.99, IC = 5.71), while the weakest association was found with denosumab (ROR = 3.61, PRR = 3.60, IC = 1.77). Significant associations were found between the six drugs and gingival pain, gingival recession, gingivitis, periodontal disease, and periodontitis. In conclusion, our comprehensive overview of the correlations, clinical characteristics, and prognoses of BPs and denosumab-related gingival disorders suggests that these issues deserve continued surveillance and appropriate management.

The use of denosumab in osteoporosis - an update on efficacy and drug safety.

INTRODUCTION: Denosumab (Prolia) is a fully human monoclonal antibody against the receptor activator of the nuclear factor kappaB ligand. It is a potent antiresorptive agent that reduces osteoclastogenesis. AREAS COVERED: Denosumab has been shown to improve bone mineral density and reduce the incidence of new fractures in postmenopausal women and men. It is also used in the treatment of glucocorticoid-induced osteoporosis, as well as for the prevention of bone loss and reduction of fracture risk in men receiving androgen deprivation therapy for non-metastatic prostate cancer and women receiving adjuvant aromatase inhibitor therapy for breast cancer. Initial safety concerns included infections, cancer, skin reactions, cardiovascular disease, hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures; however, further study and experience provide reassurance on these issues. Anecdotal reports have raised concerns about an increased risk of multiple vertebral fractures following discontinuation of denosumab. EXPERT OPINION: Although bisphosphonates are often selected as initial therapy for osteoporosis, denosumab may be an appropriate initial therapy in patients at high risk for fracture, including older patients who have difficulty with the dosing requirements of oral bisphosphonates, as well as patients who are intolerant of, unresponsive to, or have contraindications to other therapies. Additional data is needed to address questions regarding treatment duration and discontinuation.

Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial.

BACKGROUND: Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. METHODS AND RESULTS: In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. CONCLUSIONS: Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. REGISTRATION: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Incidence and prevention of skeletal-related events in multiple myeloma patients: A population-based real-world experience.

Novel treatments in multiple myeloma (MM) could influence the incidence of skeletal-related events (SREs). We aimed to examine the incidence of SRE and the preventive use of osteoclast inhibitors (OIs) in a cohort of MM patients in the era of modern treatment. In this real-world retrospective study, we included 199 patients with a diagnosis of MM between January 1, 2010, and December 31, 2019, with follow-up at St. Olavs University Hospital. Data was extracted from The Myeloma Registry of Central Norway. SREs occurred in 46% of patients at baseline and 55.8% during follow-up. Excluding baseline SREs, the incidence rate was 29 (95% confidence interval: 26-33) per 100 person years. 48% experienced > 1 SRE. The incidence of SREs was highest at baseline followed by a gradual increase in each subsequent line of treatment. The first two years after diagnosis 80% received bisphosphonates (BPs). The proportion of recommended dosage was 46%. Only two cases (1.2%) of symptomatic hypocalcemia and one case (0.6%) of osteonecrosis of the jaw were identified. SREs are still a common problem in an era of novel treatment. Cumulative dosage of BPs was lower than recommended, and treatment with BPs was safe in this population.

One versus 2 years of alendronate following denosumab: the CARD extension.

When denosumab is discontinued, antiresorptive therapy is critical to reduce high-turnover bone loss. The ideal duration of antiresorptive therapy after denosumab is uncertain. This study demonstrates that both 1 and 2 years of alendronate maintained bone density gains achieved with 1 year of denosumab. BACKGROUND: When denosumab is discontinued, antiresorptive therapy is critical to attenuate high-turnover bone loss. The ideal choice and duration of antiresorptive therapy are not yet defined, however. In the Comparison of Alendronate or Raloxifene following Denosumab (CARD) study, we demonstrated that 12 months of alendronate was better able to maintain the bone mineral density (BMD) gains achieved with 12 months of denosumab versus 12 months of raloxifene. In this extension, we wished to determine if 12 months of alendronate would be sufficient in maintaining these denosumab-induced BMD gains. METHODS: In the CARD study, postmenopausal osteoporotic women aged 60-79 at high fracture risk received 12 months of denosumab 60-mg SC every 6 months followed by 12 months of either alendronate 70 mg weekly (N = 26) or raloxifene (N = 25). All subjects in the alendronate arm were then offered participation in a 1-year extension in which they were randomized to continue alendronate for an additional 12 months (N = 10) or to receive calcium and vitamin D alone (N = 8). The primary outcome was change in spine BMD between months 24 and 36. Exploratory endpoints included changes in areal BMD (aBMD) at other anatomic sites as well as changes in serum bone turnover markers. RESULTS: The CARD study demonstrated the effectiveness of 12 months alendronate in preserving denosumab-induced BMD gains. In the extension, aBMD was maintained at the spine, total hip, and femoral neck in both those randomized to an additional year of alendronate and those randomized to calcium/vitamin D alone. We did, however, observe a transient comparative decrease between months 24-30 in the calcium/vitamin D group at the total hip (P = 0.008) and femoral neck (P = 0.040). At the end of 24 months of the CARD study, bone turnover markers serum c-telopeptide (CTX) and procollagen N-propeptide of type I collagen (PINP) were suppressed in both groups and then increased more between months 24-36 in the calcium/vitamin D group than the alendronate group (P = 0.051 for CTX, P = 0.030 for P1NP). Both CTX and PINP remained below the month 0 baseline in both groups (P < 0.05 for all comparisons). CONCLUSIONS: With the limitations of our small sample size, these data suggest that both 1 and 2 years of alendronate effectively maintain BMD gains achieved with 1 year of denosumab and prevented any rebound in bone turnover marker levels above pre-denosumab baseline. This is the first randomized trial to assess minimum duration of bisphosphonate after short-term denosumab and may be helpful to guide clinical care. Similar studies performed after longer durations of denosumab would be helpful to further define optimal management. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT03623633.

Denosumab combined with chemotherapy followed by anlotinib in the treatment of multiple metastases of malignant peripheral nerve sheath tumor: a case report and literature review.

Primary intraosseous malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive neoplasms originating from peripheral nerves. Typically manifesting as soft tissue masses accompanied by pain or functional impairment, these tumors pose significant challenges in management. Surgical intervention remains the cornerstone of treatment for patients with MPNST lacking distant metastasis, with generally modest success rates. In cases of recurrence and metastasis, the pursuit of effective systemic therapies has been a focus of clinical investigation. Herein, we present a case study involving an elderly female patient with refractory MPNST. In light of surgical limitations, a multimodal therapeutic approach combining chemotherapy, denosumab, and subsequent administration of anlotinib was pursued following collaborative consultation. This regimen yielded noteworthy clinical benefits, exemplifying a promising avenue in the management of challenging MPNST cases.

Denosumab Re-Challenge and Long-Term Efficacy for Aneurysmal Bone Cyst of the Spine: Enhanced Treatment Algorithm.

Background/Objective: Surgical treatment of aneurysmal bone cysts (ABCs) can be challenging, especially in the spine. Non-surgical treatments such as with denosumab have shown promising results in different osteolytic pathologies. This retrospective observational study aimed to evaluate the long-term clinical and radiologic response of patients with ABCs of the mobile spine treated with denosumab and propose an updated treatment algorithm. Methods: Six patients with relapsed and symptomatic ABCs of the mobile spine were treated with denosumab (120 mg subcutaneously on days 1, 8, 15, 29, and every 4 weeks thereafter) between 2012 and 2023. Disease assessments were conducted using CT and MRI at 3, 6, 9, and 12 months post-treatment. Clinical data, including pain levels, symptoms, and adverse events, were documented from patients' charts. Results: Patients underwent an initial phase of treatment with denosumab, receiving a mean of 22 administrations (range 13-42) over a median follow-up period of 41 months (range 15-98 months). Clinical improvement was observed in all patients after 4 weeks of treatment, and all patients demonstrated a radiological response after 12-24 weeks on denosumab. Three patients were progression-free after discontinuing denosumab following 13, 15, and 42 administrations, respectively. At the last follow-up, after 38, 43, and 98 months, these patients remained stable without relapse of the disease. Three patients had a relapse of disease after denosumab; two of them underwent denosumab re-challenge, while one patient received one mesenchymal stem cells (MSCs) injection. All patients showed clinical and radiological improvement and were resulted to be disease-free at the last follow-up. Conclusions: This study demonstrates the long-term efficacy and safety of denosumab in treating ABCs of the mobile spine, as well as the potential of re-challenge in managing recurrence. A treatment algorithm is proposed, positioning denosumab as a viable therapeutic option after other local treatments. Careful patient selection, monitoring, and further research are necessary to optimize denosumab use for ABCs.

Effect of bisphosphonate and denosumab treatment on TBS in Japanese breast cancer patients with AIBL.

INTRODUCTION: Bisphosphonates and denosumab increase bone mineral density (BMD) for osteoporosis treatment in patients with aromatase inhibitor-associated bone loss (AIBL). This study aimed to directly compare bisphosphonates with denosumab in treating patients with AIBL and to determine the effect of denosumab on the trabecular bone score (TBS). MATERIALS AND METHODS: Thirty-nine patients with AIBL receiving osteoporosis treatment (21 in the bisphosphonates group and 18 in the denosumab group) were retrospectively evaluated for changes in lumbar spine and femoral BMD, lumbar spine bone quality (assessed by TBS), and blood bone metabolic markers. The Mann-Whitney and Wilcoxon tests were used for statistical evaluation. RESULTS: After 24 months of treatment, the lumbar spine BMD change rate was 5.82 ± 1.10% with bisphosphonates and 10.49 ± 1.20% with denosumab, with the change rate of denosumab significantly increasing over that of bisphosphonates. The change rate in femoral BMD was 2.69 ± 1.16% with bisphosphonates and 2.95 ± 1.26% with denosumab, with no significant difference between the two groups. The rate of decrease in tartrate-resistant acid phosphatase isoform 5b was significantly higher in the denosumab group. The change rate in TBS at 24 months of treatment was 0.53 ± 1.26% in the bisphosphonates group and 1.08 ± 1.33% in the denosumab group, with no significant difference between the two groups. After 24 months, TBS remained stable. CONCLUSION: Both bisphosphonates and denosumab may increase BMD, improve bone metabolism, and inhibit bone quality loss in patients with AIBL.

Anti-RANKL Antibody For Active Charcot Foot Neuro-Osteoarthropathy in Patients with Diabetes and Chronic Kidney Disease.

BACKGROUND: Charcot neuroosteoarthropathy (CNO) is characterized with increased osteoclastic activity that can be curbed with antiresorptive agents. Chronic kidney disease (CKD) precludes bisphosphonates but anti-receptor activator of nuclear factor-B ligand (anti-RANKL) antibody, denosumab, can be contemplated in CKD. We investigated denosumab for active CNO of foot in CKD for CNO remission. METHODS: During the study period, 446 persons of diabetes with unilateral, active CNO of foot and CKD were identified and 78 were finally enrolled. Patients received either 60 mg denosumab (single-dose, subcutaneous) along with standard of care (SoC) as total contact cast (TCC) (group A; n = 26) or SoC (group B; n = 52) only. Patients were followed every 4 weeks until CNO remission and subsequently every 8 weeks until 48 weeks following remission. Remission was defined as temperature difference <2 °C between 2 feet confirmed twice (4 weeks apart) with clinical resolution of signs of inflammation. The primary outcome studied was proportion of patients achieving remission within 48 weeks and the time to remission. RESULTS: Median age was 56.5 (48.8-65) and 57 (48.5-61.2) years, P = .57; duration of diabetes 16 (10-25.3) and 14.9 (10-19) years, P = .151; and estimated glomerular filtration rate 44.8 (21.1-65.6) and 45.7 (32.9-55.7) mL/min/1.73 m2, P = .771, in group A and B, respectively. Median temperature difference at presentation between the affected and opposite foot was 3.4 °C (2.7-6.9) and 3.2 °C (2.2-4.0), P = .119, respectively. All patients achieved remission in group A (100%) compared with 42 (80.8%) in group B (P = .006) (hazard ratio 0.52, 95% CI: 0.32-0.87; P = .012). The median time to remission was similar in the 2 groups (15 [11-25] and 17.5 [14-31.5] weeks, P = .229, respectively). 25-Hydroxyvitamin D3 >14 ng/mL was significantly associated (OR 9.5, 95% CI 1.04-87.5, P = .045) with remission. CONCLUSION: Anti-RANKL antibody added to SoC (TCC) induces remission of active foot CNO in greater proportions of patients with diabetes and CKD.

Bone Health Optimization in Adult Spinal Deformity Patients: A Narrative Review.

Osteoporosis and low bone mineral density (BMD) pose significant challenges in adult spinal deformity surgery, increasing the risks of complications such as vertebral compression fractures, hardware failure, proximal junctional kyphosis/failure, and pseudoarthrosis. This narrative review examines the current evidence on bone health optimization strategies for spinal deformity patients. Preoperative screening and medical optimization are crucial, with vitamin D supplementation showing particular benefit. Among the pharmacologic agents, bisphosphonates demonstrate efficacy in improving fusion rates and reducing hardware-related complications, though the effects may be delayed. Teriparatide, a parathyroid hormone analog, shows promise in accelerating fusion and enhancing pedicle screw fixation. Newer anabolic agents like abaloparatide and romosozumab require further study but show potential. Romosozumab, in particular, has demonstrated significant improvements in lumbar spine BMD over a shorter duration compared to other treatments. Surgical techniques like cement augmentation and the use of larger interbody cages can mitigate the risks in osteoporotic patients. Overall, a multifaceted approach incorporating medical optimization, appropriate pharmacologic treatment, and tailored surgical techniques is recommended to improve outcomes in adult spinal deformity patients with compromised bone quality. Future research should focus on optimizing the treatment protocols, assessing the long-term outcomes of newer agents in the spine surgery population, and developing cost-effective strategies to improve access to these promising therapies.

Osteoporosis and Bone Fragility in Children: Diagnostic and Treatment Strategies.

The incidence of osteoporosis in children is increasing because of the increased survival rate of children with chronic diseases and the increased use of bone-damaging drugs. As childhood bone fragility has several etiologies, its management requires a thorough evaluation of all potentially contributing pathogenetic mechanisms. This review focuses on the main causes of primary and secondary osteoporosis and on the benefits and limits of the different radiological methods currently used in clinical practice for the study of bone quality. The therapeutic and preventive strategies currently available and the most novel diagnostic and treatment strategies are also presented. Optimal management of underlying systemic conditions is key for the treatment of bone fragility in childhood. DXA still represents the gold standard for the radiologic evaluation of bone health in children, although other imaging techniques such as computed tomography and ultrasound evaluations, as well as REMS, are increasingly studied and used. Bisphosphonate therapy is the gold standard for pharmacological treatment in both primary and secondary pediatric osteoporosis. Evidence and experience are building up relative to the use of monoclonal antibodies such as denosumab in cases of poor response to bisphosphonates in specific conditions such as osteogenesis imperfecta, juvenile Paget's disease and in some cases of secondary osteoporosis. Lifestyle interventions including adequate nutrition with adequate calcium and vitamin D intake, as well as physical activity, are recommended for prevention.

Combined preoperative denosumab and adjuvant microwave ablation for high-risk giant cell tumor of bone: a retrospective study in a single center.

BACKGROUND: Giant cell tumor of bone (GCTB) is a locally aggressive neoplasm with a high propensity for recurrence following intralesional curettage. The introduction of denosumab, a RANKL inhibitor, has shown potential in facilitating joint-sparing surgery. However, concerns exist regarding its impact on local recurrence rates. This study aimed to evaluate the efficacy and safety of combined preoperative denosumab with adjuvant microwave ablation (MWA) for the treatment of high-risk GCTB. METHODS: We conducted a retrospective review of 19 patients with high-risk GCTB who underwent preoperative denosumab treatment followed by curettage and adjuvant MWA. The primary outcome measure was the local recurrence rate, with secondary outcomes including functional status assessed by the Musculoskeletal Tumor Society (MSTS) score and safety profile of the treatment. RESULTS: In this retrospective analysis, we evaluated the outcomes of 19 patients with high-risk GCTB treated with preoperative denosumab and adjuvant MWA. The median follow-up duration was 33.1 months, 3 patients (15.8%) experienced local recurrence at a median of 21.6 months postoperatively and the local recurrence-free survival was 81.2% at two years. Notably, no patient developed lung metastasis, and all recurrences were successfully managed with repeat curettage and MWA, with a mean MSTS score of 27.3. No patient required joint replacement due to tumor recurrence, resulting in a 100% joint preservation rate. CONCLUSION: The combination of preoperative denosumab and adjuvant MWA is a feasible and effective strategy for the management of high-risk GCTB, providing effective local control with preserved joint function. This approach may offer a surgical alternative for young patients where joint preservation is paramount.

Impact of Teriparatide and Denosumab on Clinical and Radiographic Outcomes in Osteoporotic Vertebral Compression Fractures.

Background and Objectives: Osteoporotic vertebral compression fractures (OVCFs) are prevalent among the elderly, often leading to significant pain, morbidity, and mortality. Effective management of underlying osteoporosis is essential to prevent subsequent fractures. This study aimed to compare the clinical and radiographic outcomes of teriparatide and denosumab treatments in patients with OVCFs to determine their relative effectiveness in improving patient outcomes. Materials and Methods: This retrospective study included 78 patients diagnosed with an acute thoracolumbar OVCF who received either teriparatide (35 patients) or denosumab (43 patients) within three months of a fracture. Clinical outcomes were assessed using the visual analog scale (VAS) for back pain, Oswestry disability index (ODI), and EQ-5D quality of life scores at baseline, 6 months, and 12 months. Bone mineral density (BMD) and radiographic outcomes were evaluated initially and at 12 months post-treatment. Results: Both treatment groups demonstrated significant improvements in VAS, ODI, and EQ-5D scores over 12 months. No significant differences were observed between the teriparatide and denosumab groups in terms of clinical outcomes or radiographic measurements at any time point. Fracture union and BMD improvements were similarly observed in both groups. The teriparatide group had a lower baseline BMD, but this did not affect the overall outcomes. Conclusions: Both teriparatide and denosumab are effective in improving clinical and radiographic outcomes in patients with OVCFs. Despite concerns about denosumab's potential to hinder fracture healing, our study found no significant differences between the two treatments. These findings support the use of denosumab for early treatment of OVCFs to prevent subsequent fractures without compromising fracture healing. Further prospective studies are needed to confirm these results.

Real world clinical outcomes when discontinuing denosumab or bisphosphonates in patients with surgically managed osteoporotic vertebral compression fractures: a population-based cohort study.

BACKGROUND CONTEXT: Osteoporotic vertebral compression fractures (OVCFs) are common fragility fractures. Patients who undergo surgical treatment for their initial OVCFs warrant particular attention because there is an elevated risk of subsequent vertebral fractures and other types of fragility fractures. However, the optimal osteoporosis treatment for this specific patient group is less investigated. PURPOSE: This study compares the risk of subsequent osteoporotic fractures and mortality rate for patients who are initiated with denosumab and bisphosphonates and determines the effect of adherence to treatment. STUDY DESIGN: Retrospective nationwide cohort study PATIENT SAMPLE: A total of 2,858 patients who had surgically-managed osteoporotic vertebral compression fractures. OUTCOME MEASURES: The risk of osteoporotic fractures, vertebral fractures, nonvertebral fractures and death. METHODS: This is a retrospective nationwide cohort study that uses the National Health Insurance Research Database. Patients aged ≥50 years who were admitted for surgical interventions for OVCF between 2012 and 2016 and subsequently received denosumab or bisphosphonates for one year were included. Patients were stratified according to their antiosteoporosis medications and adherence to treatment. A multivariable, time-varying Cox proportional hazards model was used to determine the risk of osteoporotic fractures, vertebral fractures, nonvertebral fractures and death. RESULTS: A total of 2,858 patients were included in this study: 1,123 patients in the denosumab group and 1,735 patients in the bisphosphonates group. Compared to persistent denosumab users, the nonpersistent denosumab users, persistent bisphosphonate users and nonpersistent bisphosphonate users had a greater risk of osteoporotic fractures, with respective hazard ratios of 1.64 (95% confidence interval [CI], 1.16-2.32), 1.74 (95% CI, 1.25-2.42) and 1.53 (95% CI, 1.14-2.06). If osteoporotic fractures were divided into nonvertebral and vertebral fractures, none of the groups exhibited an increased risk of vertebral fractures compared to persistent denosumab users, with an HR of 1.00 (95% CI: 0.54-1.88) for nonpersistent denosumab users, 1.64 (95% CI: 0.96-2.81) for persistent bisphosphonate users and 1.52 (95% CI: 0.95-2.43) for nonpersistent bisphosphonate users. However, there was a significantly greater risk of nonvertebral fracture, with respective hazard ratios of 2.04 (95% CI, 1.33-3.11), 1.80 (95% CI, 1.18-2.76) and 1.56 (95% CI, 1.06-2.27) for nonpersistent denosumab users, persistent bisphosphonate users and nonpersistent users. Noteworthy, nonpersistent denosumab users exhibited a significantly greater risk of mortality than persistent denosumab users, with a hazard ratio of 3.12 (95% CI, 2.22-4.38). CONCLUSIONS: In terms of patients with OVCFs who require hospitalization and surgical intervention, those who receive ongoing denosumab treatment exhibit less risk of developing subsequent osteoporotic fractures than those who receive bisphosphonates or nonpersistent denosumab treatment. However, discontinuation of denosumab is associated with a significantly increased risk of subsequent fractures and mortality. Therefore, adherence to the treatment is crucial for patients who are initiated with denosumab.

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.