Search Results (261)

Immunosenescence refers to the set of immunoendocrinological alterations underlying the progressive decline in innate and adaptive immune function that occurs with aging. It is closely linked to the concept of inflammaging, a state of low-grade chronic systemic inflammation that contributes to age-related diseases. In the elderly, key features of diseases such as rheumatoid arthritis, particularly in its elderly onset form, and senile osteoporosis are characterized by a decline in sex hormones and the immunoregulatory IL-2; an increase in serum autoantibodies and pro-inflammatory mediators such as TNF-α, IL-6; and upregulation of bone-related factors RANKL, DKK1, and sclerostin, including the dysregulation of the IL-33/IL-31 axis. The aim of this review is to examine the key molecular pathways of immunosenescence in osteoimmunology, as well as the potential for therapeutic modulation of inflammaging through biologic and target synthetic disease-modifying antirheumatic drugs, denosumab and romosozumab, with particular attention to their management in elderly patients. Full article

Background: This retrospective study compared the effectiveness and preliminary cost evaluation of denosumab and zoledronic acid (ZA) in patients with bone metastases from breast, prostate, and lung cancer. Methods: Patients treated with ZA or denosumab between January 2016 and August 2023 were analyzed. Outcomes included the incidence of skeletal-related events (SREs), time to first SRE, and cost per prevented SRE. An incremental cost-effectiveness analysis (ICER framework) was also performed, using prevention of SREs as the effectiveness outcome. Results: A total of 192 patients in the denosumab group and 239 in the ZA group were included. Denosumab significantly reduced the incidence of SREs compared with ZA (34.8% vs. 51.8%, p < 0.001). The median time to first SRE was longer with denosumab (34.5 vs. 29.1 months), but the difference was not statistically significant (p = 0.593). Stratified analyses showed significant benefit in breast (29.5% vs. 49.2%, p = 0.002) and prostate cancer (43.9% vs. 66.0%, p = 0.035), but not in lung cancer (39.1% vs. 45.9%, p = 0.484). Denosumab was more costly, with an additional USD 4686 per prevented SRE. Conclusions: Denosumab was more effective than ZA in reducing SREs, particularly in breast and prostate cancer patients, but it was associated with higher costs. These findings should be interpreted as preliminary due to the retrospective design and the absence of QALY-based outcomes. Full article

Background and Objectives: Advanced solid organ tumors, particularly breast, lung, and prostate cancers, frequently metastasize to bone, leading to debilitating skeletal-related events (SREs). Denosumab, a RANKL inhibitor, is crucial in preventing SREs. This study aimed to comparatively evaluate the efficacy and adverse effect profiles of denosumab in patients with bone metastases originating from these three common cancer types. Materials and Methods: This retrospective study included 146 patients treated with denosumab for bone metastases. Data on demographics, SREs before and during denosumab treatment, serum creatinine, calcium, and magnesium levels (at baseline, 3, and 6 months), other adverse effects, and survival were analyzed. Results: Before denosumab, SREs were present in 36.3% of patients (breast: 43.4%, prostate: 28%, lung: 33.8%). During denosumab treatment, SRE rates markedly decreased across all groups (breast: 9.4%, prostate: 16.0%, lung: 8.8%), with no significant intergroup difference in on-treatment SREs. Significant decreases in serum calcium levels were observed at 3 and 6 months post-denosumab initiation in breast (p < 0.0001) and lung cancer patients (p = 0.001). Mean creatinine levels significantly decreased in lung (p < 0.0001) and prostate (p = 0.020) cancer patients at 3 and 6 months. Overall survival significantly differed, with lung cancer patients having the shortest median survival (p < 0.005). Conclusions: Denosumab effectively reduces the incidence of SREs in patients with bone metastases from breast, lung, and prostate cancer. However, clinicians must diligently monitor for hypocalcemia, a notable adverse effect, particularly at 3 and 6 months after starting denosumab, with specific caution warranted in patients with lung cancer. Full article

Background/Objectives: The efficacy of zoledronic acid (ZOL) compared to denosumab (DMAB) after teriparatide (TPTD) is largely unknown. We compared the effect of ZOL or DMAB treatment after TPTD on BMD changes and fracture (FX) occurrence. Methods: We retrospectively revised data from 77 patients treated at Fondazione IRCCS Ca’Granda Milan, Italy, with TPTD (≥18 months), given at withdrawal (T0), single ZOL 5 mg (Group A, N = 56) or DMAB 60 mg/6 months (Group B, N = 21). BMD changes and incident FX were assessed after 24 months (T1) in all patients and after 48 months (T2) in 46 patients (Group A1, N = 15, treated with a single ZOL at T0; Group A2, N = 17, treated with ZOL at T0 and T1; Group B, N = 14, treated with DMAB since T0 to T2). Results: During the T0–T1 period, in all groups, both spine (LS) and total hip (TH) T-scores improved (mean ± SD, T0 vs. T1): Group A (LS −2.5 ± 1.2 vs. −2.3 ± 1.3, p = 0.006; TH −2.2 ± 1.0 vs. −2.0 ± 1.1, p = 0.002) and Group B (LS −2.4 ± 1.4 vs. −1.8 ± 1.4, p < 0.001; TH −2.4 ± 1.0 vs. −2.2 ± 1.0, p = 0.003). At T2 vs. T0, all groups showed an increase in TH-BMD (A1 −1.8 ± 0.9 vs. −1.4 ± 1.0, p = 0.008; A2: −1.8 ± 0.8 vs. −1.6 ± 0.9, p = 0.032; B: −2.6 ± 0.7 vs. −2.2 ± 0.7, p < 0.001), while LS-BMD increased only in Group B (−2.7 ± 1.4 vs. −2.0 ± 1.2, p = 0.002), with stability in A1 and A2. No significant differences in incident FX between groups were observed. Conclusions: At 24 months after TPTD withdrawal, both ZOL and DMAB improved BMD at all sites; after 48 months, both ZOL (1 or 2 infusions) and DMAB led to BMD improvement at TH, whereas only DMAB led to an increase in LS-BMD. Full article

Background/Objectives: MB09 is a denosumab biosimilar to the reference products (RPs) Xgeva and Prolia. A population pharmacokinetic (popPK) meta-analysis was conducted to characterize the denosumab PK profile and to support MB09 biosimilarity. Methods: Pooled denosumab PK data from one phase I study [255 healthy adult men receiving a single 35 mg subcutaneous (SC) dose] and one phase III study (555 postmenopausal women with osteoporosis receiving two 60 mg SC doses, one every six months) were used. A one-compartment model with first-order absorption and elimination and parallel non-linear saturable clearance was used. Body weight was included on clearance as a structural covariate and treatment was tested as a covariate on all PK parameters. PK biosimilarity was assessed at 35 mg dose. Results: For a 70 kg subject, the apparent clearance and central volume of distribution for denosumab were 0.123 L/day [95% confidence interval (CI): 0.114, 0.132] and 9.33 L (95% CI: 9.11, 9.55), respectively. The Michaelis constant was 0.124 ng/mL and the maximum rate for the non-linear clearance was 0.139 ng/day. Model-based bioequivalence criteria were met for RP Xgeva, European and US-sourced, versus MB09 for a dose of 60 mg SC. The mean area under the plasma concentration curve (AUC) resultant from the simulation of MB09 120 mg SC was similar to the published mean AUC observed for Xgeva 120 mg SC every four weeks. Conclusions: This analysis provides a valuable assessment of denosumab PK characteristics and elucidates in more detail how the MB09 PK profile compares to the denosumab RPs, supporting the totality of evidence on MB09 biosimilarity. Full article

Background/Objectives: The combination of denosumab treatment with biological disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) in patients with inflammatory rheumatic diseases (IRD) may raise safety concerns for clinicians, particularly regarding infections. In this study, we investigated whether the risk of infection increases in patients who receive bDMARDs or tsDMARDs for IRD and are simultaneously treated with denosumab for osteoporosis (OP). Methods: As a control group, we evaluated patients receiving bDMARDs or tsDMARDs concomitantly with zoledronic acid (ZA), which is not clearly associated with infections. A total of 88 patients—including 30 patients receiving bDMARDs or tsDMARDs with ZA and 58 patients receiving bDMARDs or tsDMARDs with denosumab—met the criteria and were included in this study. The groups were compared in terms of the ratio/risk of serious infections requiring hospitalisation and infections requiring outpatient treatment after applying the inverse probability of treatment weighting (IPTW) to the control for confounding factors. The Cox proportional hazards regression model was used to compare the risks of infection, taking confounding factors into account. Results: The mean age of patients in the ZA group was 59.07 years (±SD: 13.65), while that of patients in the denosumab group was 69.93 years (±SD: 11.72). Comorbidities occurred more frequently in the denosumab group (n = 44, 75.86%) than in the ZA group (n = 14, 46.66%). The median duration of medication use in the denosumab group was 24 months (minimum: 6 months; maximum: 72 months). The median duration of medication use in the ZA group was 24 months (minimum: 12 months; maximum: 60 months). When comparing the groups regarding the risk of infection, denosumab was not associated with an increased risk of either a serious infection requiring hospitalisation (Hazard Ratio (HR): 0.37; 95% Confidence Interval (CI): 0.14–0.94) or an infection requiring outpatient treatment (HR: 0.29; 95% CI: 0.12–0.71). Conclusions: In conclusion, the combination of denosumab treatment with bDMARD or tsDMARD treatments is safe for short-term use. Full article

Malignant giant cell tumor of bone (GCTB) is a rare malignant bone tumor. This analysis was conducted on patients with malignant GCTB at our center. The clinical, demographic, and prognostic characteristics were evaluated and compared. During 1 January 2015 to 31 December 2022, fifty patients were included in the study, which made up 3.3% of the contemporary GCTB patients. The clinical characteristics were comparable between the 24 patients with primary malignant GCTB (PMGCTB) and 26 patients with secondary malignant GCTB (SMGTCB). The tumor location was mainly at the axial and pelvic region (70%) and differed between the two types (p = 0.040). H3F3A pathogenic variant presented frequently in SMGCTB (p = 0.020). Cox regression analysis showed the prognostic outcomes were poor in those with a tumor located in the axial bone and sacrum with invasion of other places. H3F3A mutation status is also a risk factor, while chemotherapy and denosumab failed to demonstrate prognostic benefits. Malignant GCTB is a rare condition with a poor prognosis, especially in SMGTCB. The location and H3F3A mutation status had an influence on prognosis, and systemic therapy should be taken into consideration for patients with unfavorable prognostic features. Full article

Aortic stenosis (AS) and atherosclerosis are progressive cardiovascular conditions that frequently coexist and share multiple clinical and molecular features. Medical therapies have shown effectiveness in preventing and treating atherosclerosis and its consequences. For AS, effective pharmacological therapies remain limited. Understanding the shared risk factors and mechanisms between the two conditions may provide opportunities for therapeutic repositioning in AS. We performed a narrative review focusing on studies published from 2005 to 2025. Inclusion criteria encompassed clinical trials, experimental models, and molecular studies addressing overlapping risk factors, pathological pathways, and treatment approaches for AS and atherosclerosis. AS and atherosclerosis share key risk factors, including age, hypertension, hyperlipidemia, and diabetes. Molecular mechanisms, such as chronic inflammation, endothelial dysfunction, oxidative stress, lipid accumulation, and calcific remodeling, are common to both. Pathways involving the renin-angiotensin system, Notch signaling, and osteogenic mediators contribute to disease progression. Several drug classes, notably proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipoprotein(a) (Lp(a)) lowering therapies, anti-inflammatory agents, and immunomodulators, show potential for repositioning in AS management. The substantial overlap in risk factors and molecular mechanisms between AS and atherosclerosis supports a rationale for therapeutic repositioning. Targeting shared pathways could lead to innovative strategies for slowing AS progression and improving patient outcomes. Full article

Aromatase inhibitors (AIs), with or without gonadotropin-releasing hormone analogs, are the cornerstone of adjuvant endocrine therapy for women with hormone receptor-positive early-stage breast cancer, offering significant reductions in recurrence risk and improving long-term survival. Their use is frequently accompanied by treatment-related toxicities that can adversely affect patients’ quality of life (QoL) and adherence to therapy. Commonly reported side effects include vasomotor symptoms, such as hot flashes; musculoskeletal disorders, such as arthralgia and myalgia; mood disorders; and genitourinary discomfort, such as vaginal dryness and dyspareunia. Additionally, AIs are associated with a heightened risk of bone loss, leading to osteoporosis and fractures, and may have implications for cardiovascular health. Effective management of these adverse events is pivotal in maintaining treatment adherence and preserving QoL. Evidence-based strategies to address these toxicities include pharmacological interventions, such as analgesics for joint pain, bisphosphonates or denosumab for bone health, and hormonal or non-hormonal approaches for vasomotor and genitourinary symptoms. Non-pharmacological measures, including physical activity, dietary adjustments, and complementary therapies, can also help mitigate symptoms. This review examines the broad spectrum of AI-associated toxicities, discusses their clinical implications, and provides an overview of evidence-based management strategies. These insights aim to support clinicians in optimizing patient care while minimizing the toxicities of therapy. Full article

Despite the increasing number of novel therapies to treat newly diagnosed multiple myeloma (NDMM), preventing skeletal-related events (SREs) remains a challenge. This review summarizes the mechanistic causes of myeloma bone disease, data supporting the use of bisphosphonates and RANKL inhibitors, and the optimal management of preventing SREs in NDMM patients. Both zoledronic acid (ZA) and denosumab are acceptable treatment options with comparable safety and efficacy profiles. However, in patients who are candidates for autologous stem cell transplant (ASCT), denosumab may be preferred over ZA due to a progression-free survival (PFS) benefit observed in post hoc analyses when used with proteasome inhibitor-based regimens. The optimal duration of bone-directed therapy is unclear, but it is typically given for two years. Supportive care should include dental evaluation at baseline, annually, and if symptoms appear, given the risk for jaw osteonecrosis with both ZA and denosumab. Both drugs should be held in the setting of dental work. Patients should receive adequate calcium and vitamin D supplementation. Supportive procedures such as cement augmentation, radiation, and orthopedic surgery can also help treat compression fractures, uncontrolled pain, cord compression, and pathologic fractures. We conclude with our approach for managing SREs and a review of novel therapies and targets. Full article

Adjuvant endocrine therapy for early breast cancer significantly reduces recurrence but increases bone fragility. Given limited data on denosumab (60 mg every 6 months) in premenopausal patients receiving endocrine therapy for early breast cancer, we conducted a retrospective real-world study at the Gemelli Hospital (September 2018–January 2025). A descriptive analysis was performed. The primary endpoint was to assess efficacy, evaluated by changes in bone mineral density via dual-energy X-ray absorptiometry and by monitoring bone turnover markers, particularly serum C-terminal telopeptide of type I collagen. Safety was evaluated based on adverse endocrine therapy events (osteoporotic fractures) and adverse denosumab events (osteonecrosis of the jaw). Sixty-nine patients were eligible for the study. Endocrine therapy included ovarian function suppression with exemestane (89.8%) or tamoxifen (10.1%). Baseline spinal osteoporosis decreased from 20.3% to 5.8%, osteopenia from 39.1% to 34.8%, with normal T-scores rising from 17.4% to 34.8%. Femoral improvements were similar. Serum C-terminal telopeptide of type I collagen levels (evaluated in 35.8%) showed stable reduction in 97%. Denosumab adherence was 89.9%. One osteonecrosis of the jaw case occurred (1.4%); no fractures were reported. Denosumab demonstrated efficacy in improving bone density and reducing bone turnover, with excellent adherence and favorable safety. Longer follow-up is needed to assess post-discontinuation effects. Full article

Background and Objectives: We wished to evaluate the effect of antiresorptive agents (ARAs) on peri-implant tissues and to examine the risk factors for peri-implant medication-related osteonecrosis of the jaw (MRONJ). Materials and Methods: The study cohort consisted of patients who underwent implant surgery or maintenance treatment between March 2012 and December 2024. The patients were divided into two groups: those in whom bisphosphonates (BPs) or denosumab (Dmab) was used to treat osteoporosis after implant treatment (the ARA group) and a control group. Peri-implant clinical parameters (implant probing depth (iPPD), implant bleeding on probing (iBoP), marginal bone loss (MBL), and mandibular cortical index (MCI)) measured at the baseline and at the final visit were statistically evaluated and compared in both groups. Risk factors were examined using a multivariate analysis of adjusted odds ratios (aORs). Results: A total of 192 implants in 61 patients (52 female, 9 male) were included in this study. The ARA group consisted of 89 implants (22 patients). A comparison of the clinical parameters showed that the ARA group had significantly higher variations in their maximum iPPD and iBoP values over time than those in the control group. Risk factors for peri-implantitis as objective variables were the use of ARAs (aOR: 3.91; 95% confidence interval [CI]: 1.29–11.9) and the change in the maximum iPPD over time (aOR: 1.86; 95% CI: 0.754–4.58). Conclusions: During long-term implant maintenance treatment, patients’ health and medication status change. Monitoring peri-implantitis, the presumed cause of peri-implant MRONJ, is essential, especially in patients who started ARA treatment after implant placement, and special attention should be paid to changes in implant pocket depth. Full article

A total of 38% of Americans do not meet the Recommended Dietary Allowance (RDA) for calcium including those at risk for osteoporosis. To increase the percentage of patients at risk for osteoporosis who achieve goal calcium RDA intake, a collaborative specialty pharmacy-registered dietitian-nutritionist (RDN) quality improvement program was developed. Patients aged 18 to 90 years old receiving osteoporosis therapy (denosumab, teriparatide, zoledronic acid) or medications that increase bone loss (elagolix, oral prednisone) were provided with a structured assessment and educational intervention. Daily calcium intake included patient self-reported dietary intake plus supplement use. Written and verbal education on increasing dietary intake based on patient preferences was provided with 5 calcium-rich food-source store coupons. Recommendations for supplement selection (citrate vs. carbonate) and/or medication-related problem resolution were provided. Follow-up occurred at 3–6 months. Fifty patients enrolled [94% female, mean age 66.6 years (SD 15.3)] were taking denosumab (36), teriparatide (1), zoledronic acid (1), elagolix (7) and prednisone (5). The mean baseline daily dietary calcium intake was 500 mg (SD 247) with none achieving goal intake with diet alone. Average calcium supplement use in 22 (44%) patients was 686 mg daily (SD 284). At baseline, 17 (34%) met goal daily calcium intake compared to 30 (60%) at post intervention follow-up (p = 0.009). Over half of the store coupons were redeemed. A specialty pharmacy-RDN customized intervention program provides a model for aiding patients to modify calcium intake. Full article

Diabetes is a risk factor for periodontitis. Increasing evidence suggests that a central player in this link is the vacuolar H+-ATPase (V-ATPase), which provides a physical and functional core for regulation by the catabolic lysosomal AMP-activated protein kinase complex (L-AMPK) and the anabolic mammalian target of rapamycin complex 1 (mTORC1). These complexes detect levels of various cellular nutrients, including glucose at the lysosome, and promote cellular responses to restore homeostasis. The high-glucose conditions of diabetes foster anabolic mTORC1 signaling that increases inflammation and inflammatory bone resorption in response to periodontal infections. Here, we review the structure and composition of V-ATPase, L-AMPK, mTORC1, and other elements of the energy-sensing platform. Mechanisms by which V-ATPase passes signals to the complexes are examined and recent data are reviewed. Current anti-bone resorptive therapeutics, bisphosphonates and denosumab, enhance the risk of medicine-related osteonecrosis of the jaw (MRONJ) and are not used to treat periodontal bone loss. Accumulating data suggest that it may be possible to target inflammatory bone resorption through agents that stimulate L-AMPK, including metformin and glucagon-like peptide-1 agonists. This approach may reduce inflammatory bone resorption without major effects on overall bone remodeling or increased risk of MRONJ. Full article

Fracture risk is a serious yet underrecognized complication among patients with chronic kidney disease (CKD), especially in those with stages G3-G5D. The overlap between CKD-Mineral and Bone Disorder (CKD-MBD) and osteoporosis leads to complex bone changes that increase the likelihood of fragility fractures. Studies show that 18% to 32% of CKD patients also have osteoporosis, and these individuals are more than 2.5 times as likely to suffer from fractures compared to those without CKD. In the advanced stages of the disease, fracture risk is up to four times higher than in the general population, with the femur, forearm, and humerus being the most commonly affected sites. Hip fractures are of particular concern as they are linked to longer hospital stays and higher rates of morbidity and mortality. Furthermore, dialysis patients who experience hip fractures have a mortality rate 2.4 times higher than those in the general population with similar fractures. This increased risk underscores the need for proactive bone health maintenance in CKD patients to prevent fractures and related complications. This review explores the underlying pathophysiological mechanisms, diagnostic challenges, and treatment options related to bone fragility in CKD. Diagnostic tools, such as bone mineral density (BMD) assessments, the trabecular bone score (TBS), and biochemical markers, remain underused, especially in advanced CKD stages. Recent treatment strategies emphasize a multidisciplinary, stage-specific approach, incorporating calcium and vitamin D supplements, anti-resorptive agents like denosumab, and anabolic therapies such as teriparatide and romosozumab. Effective management needs to be tailored to the patient’s bone turnover status and stage of CKD. Despite progress in understanding bone fragility in CKD, significant gaps remain in both diagnosis and treatment. Personalized care, guided by updated KDIGO recommendations and based on an interdisciplinary approach, is essential to reduce fracture risk and improve outcomes in this vulnerable population. Further research is needed to validate risk assessment tools and refine therapeutic protocols. Full article