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.

We conducted a review of 10 national guidelines from five EU countries to identify similarities or differences in recommendations for the management of patients with osteoporosis. We found general alignment of key recommendations; however, there are notable differences, largely attributed to country-specific approaches to risk assessment and reimbursement conditions.
BACKGROUND: The classification of fracture risk is critical for informing treatment decisions for post-menopausal osteoporosis. The aim of this review was to summarise 10 national guidelines from five European countries, with a focus on identifying similarities or differences in recommendations for the management of patients with osteoporosis.
METHODS: We summarised the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Disease-International Osteoporosis Foundation guidelines and reviewed guidelines from France, Germany, Italy, Spain and the UK.
RESULTS: The approach to risk assessment differed across the guidelines. In France, and Spain, risk assessment was based on DXA scans and presence of prior fractures, whereas UK, German and Italian guidelines recommended use of a validated risk tool. These differences led to distinct definitions of very high and high-risk patients. Guidelines aligned in recommending antiresorptive and anabolic agents as pharmacologic options for the management of osteoporosis, with sequential treatment recommended. There was agreement that patients at high or very high risk of fracture or with severe osteoporosis should receive anabolic agents first, followed by antiresorptive drugs. Variations were identified in recommendations for follow up of patients on anti-osteoporosis therapies. Reimbursement conditions in each country were a key difference identified.
CONCLUSIONS: Criteria for risk assessment of fractures differ across European guidelines which may impact treatment and access to anabolic agents. Harmonisation across EU guidelines may help identify patients eligible for treatment and impact treatment uptake. However, country-specific reimbursement and prescribing processes may present a challenge to achieving a consistent approach across Europe.

Osteoporosis remains incurable. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation, while the anabolic agent, teriparatide, does not inhibit bone resorption, and thus they have limited efficacy in preventing osteoporotic fractures and cause some side effects. Thus, there is an unmet need to develop dual antiresorptive and anabolic agents to prevent and treat osteoporosis. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited marrow fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.

BACKGROUND: Acute-phase reactions (APRs) are common among people treated for the first time with zoledronate (ZOL). The current view is that both the APRs caused by ZOL and its efficacy are related to the mevalonic acid pathway. However, the relationship between APRs and ZOL efficacy remains unclear.
METHODS: This was a prospective observational cohort study involving postmenopausal women with osteoporosis in Shanghai, China, for 1 year. A total of 108 patients with an average age of 67.4 ± 5.8 years were treated with 5 mg intravenous ZOL for the first time. Data on demographic characteristics, APRs, blood counts, bone turnover markers, including C-telopeptide collagen crosslinks (CTX) and N-terminal propeptide of type 1 collagen (PINP), and bone mineral density (BMD) were collected.
RESULTS: (1) The results did not reveal a relationship between APRs and changes in bone turnover markers and BMD but showed that changes in body temperature (T) within 3 days after administration were positively correlated with changes in the BMD of the LS at Month 12 (β = 0.279 P = 0.034). (2) This effect was mediated mainly by changes in serum CTX (b = 0.046, 95% CI [0.0010-0.0091]). (3) The ROC curve revealed that when T increased by 1.95 °C, the sensitivity and specificity of identifying clinically important changes in LS BMD after 1 year were optimized.
CONCLUSIONS: In this study, we tested the hypothesis that people with elevated body T after initial ZOL treatment had greater improvements in BMD and better outcomes.
BACKGROUND: NCT, NCT03158246. Registered 18/05/2017.

BACKGROUND: Zoledronic acid is one of the most commonly used intravenous, highly potent amino diphosphonate salts worldwide and is commonly used in patients with primary or secondary osteoporosis, most of whom are well tolerated. There are currently no reports of severe sepsis induced by zoledronic acid. Here we present the first case of severe sepsis induced by zoledronic acid. We reviewed the literature and found that there is currently a lack of reports on severe sepsis induced by zoledronic acid or other diphosphonates.
METHODS: A 58-year-old woman with severe osteoporosis and Behcet disease developed severe sepsis after treatment with zoledronic acid.
METHODS: Sepsis, septic shock, acute kidney injury, intestinal infection, Behcet disease.
METHODS: The patient was given intensive care immediately after admission, and massive fluid infusion to expand blood volume could not maintain normal blood pressure. Metaraminol was added to maintain circulatory stability, piperacillin-tazobactam was used to strengthen anti-infection, and glucocorticoids were used for anti-inflammatory treatment.
RESULTS: The patient was discharged with improvement and followed up in the outpatient clinic.
CONCLUSIONS: The inducing mechanism of zoledronic acid is not clear, but when the patient has immunosuppression, the use of zoledronic acid should be cautious and monitored. In conclusion, severe sepsis induced by zoledronic acid is a rare but serious complication, and physicians should be aware of this adverse event in time to avoid serious consequences.

BACKGROUND: Osteoporosis, a systemic skeletal disease, seriously affects the quality of life in postmenopausal women. As one type of cathepsin K (CatK) inhibitor, odanacatib (ODN) is a fresh medication for osteoporosis. Considering the potential of ODN, we further examined the effect and safety of ODN for postmenopausal osteoporosis (PMOP) with a meta-analysis.
METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for eligible studies from inception to December 29th, 2023. After that, we conducted a comprehensive meta-analysis following PRISMA guidelines. Risk of bias was meticulously investigated with the Cochrane Collaboration\'s tool. Efficacy was assessed with bone mineral density (BMD) at different sites (lumbar spine, trochanter, radius, femoral neck) and biomarkers of bone turnover (P1NP, uNTx/Cr, s-CTx, BSAP). Safety was evaluated by analyzing total, serious, other, and skin adverse events (AEs).
RESULTS: Four random clinical trials (RCTs) were involved in our research. All trials were rated as having high quality and met the eligibility criteria. In the current research, ODN was found to elevate BMD at lumbar spine, femoral neck, total hip, trochanter and forearm, while it decreased the levels of serum C-telopeptides of type I collagen (s-CTx) as well as urinary N-telopeptide/creatinine ratio (uNTx/Cr). No significant differences were observed in AEs between the ODN group and the control group.
CONCLUSIONS: ODN is a promising alternative for the treatment of PMOP on account of its excellent efficacy and credible safety. Unclear links between ODN and cardiovascular AEs require further research to clarify.

BACKGROUND: Patients undergoing hemodialysis are at an elevated risk of fractures; however, substantial evidence for osteoporosis treatment in this population is lacking. We explored the efficacy of denosumab, an anti-IgG2 antibody that targets the receptor activator of nuclear factor-kappa B ligand, in reducing fracture incidence and all-cause mortality in patients undergoing hemodialysis.
METHODS: This retrospective cohort study-conducted from December 2013 to December 2022-evaluated the effects of denosumab on fracture incidence and all-cause mortality. Patients who initiated denosumab treatment during the study period were defined as the denosumab group, while those without a history of denosumab administration were defined as the non-denosumab group. Kaplan-Meier curves and log-rank tests were used to assess survival and fracture/mortality risks, respectively. Cox proportional hazards models were used to analyze both fractures and all-cause mortality.
RESULTS: Among 214 patients undergoing hemodialysis, 52 (24.3%) received denosumab. The median age was 73.0 ± 11.5 years, with 92 (43.0%) females, and the median dialysis duration was 59 months (interquartile range, 6-126). During the study, thirty-seven non-denosumab-treated patients had fractures compared to eight in the denosumab group. No significant differences were observed in the unadjusted model (HR, 0.53; 95% confidence interval (CI), 0.24-1.14). Adjusting for competing mortality and clinical factors, the HR remained at 0.64 (95% CI, 0.27-1.51). Regarding all-cause mortality, we found a statistically significant difference in the unadjusted model (HR, 0.61 [95% CI, 0.38-0.98]). A significant reduction in mortality was observed in the adjusted model (HR, 0.46 [95% CI, 0.26-0.80]). Notably, the denosumab group showed a significant decrease in mortality, particularly in cardiovascular disease-related cases (HR, 0.33 [95% CI, 0.14-0.78]).
CONCLUSIONS: Denosumab may reduce all-cause mortality in patients undergoing hemodialysis, particularly in those with cardiovascular complications. This finding offers a promising direction for osteoporosis treatment in patients undergoing hemodialysis.

This was a Phase I, randomized, double-blinded, three-arm, single-dose, parallel study aimed to demonstrate pharmacokinetic (PK) similarity between MB09 (a denosumab biosimilar candidate) and reference denosumab (XGEVA® from European Union [EU-reference] and United States [US-reference]) in a healthy male population. The primary PK endpoints included: Area under the serum concentration versus time curve from time 0 to the last quantifiable concentration timepoint (AUC0-last); and maximum observed serum concentration (Cmax). Secondary endpoints included: AUC from time 0 extrapolated to infinity (AUC0-∞), time to reach maximum observed concentration, clearance, terminal phase half-life, pharmacodynamic, safety, and immunogenicity assessments. A total of 255 subjects were randomized (1:1:1) to receive a subcutaneous 35 mg dose of MB09 or reference denosumab. Cmax was reached after denosumab administration, followed by a decline in the concentration with similar terminal phase half-live across treatment arms. Systemic exposure of MB09 (AUC0-last and Cmax) was equivalent to the reference denosumab, as the 90% confidence intervals around the geometric least square mean ratios laid within the predefined acceptance limits (80.00%, 125.00%) across all comparisons. Pharmacodynamic parameters, based on the percent of change from baseline in serum C-terminal telopeptide of Type 1 collagen levels, were similar across the three arms. The treatments were considered safe and generally well tolerated, with 92 treatment-emergent adverse events reported (most Grade 2 and 3) and similarly distributed. Immunogenicity was low and similarly distributed. These results provide strong evidence that supports the biosimilarity between MB09 and denosumab reference products.

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.

Bisphosphonates are widely used for the treatment of postmenopausal osteoporosis; however, they cause several long-term side effects, necessitating the investigation of local ways to improve osseointegration in compromised bone tissue. The purpose of this study was to evaluate peri-implant bone repair using implants functionalized with zoledronic acid alone (OVX ZOL group, n = 11), zoledronic acid + teriparatide (OVX ZOL + TERI group, n = 11), and zoledronic acid + ruterpy (OVX ZOL + TERPY group, n = 11) compared to the control group (OVX CONV, n = 11). Analyses included computer-assisted microtomography, qualitative histologic analysis, and real-time PCR analysis. Histologically, all functionalized surfaces improved peri-implant repair, with the OVX ZOL + TERI group standing out. Similar results were found in computerized microtomography analysis. In real-time PCR analysis, however, the OVX ZOL and OVX ZOL + TERPY groups showed better results for bone formation, with the OVX ZOL + TERPY group standing out, while there were no statistical differences between the OVX CONV and OVX ZOL + TERI groups for the genes studied at 28 postoperative days. Nevertheless, all functionalized groups showed a reduced rate of bone resorption. In short, all surface functionalization groups outperformed the control group, with overall better results for the OVX ZOL + TERI group.