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Denosumab is a fully human monoclonal antibody that increases BMD, inhibits bone resorption and reduces fracture risk. This double-blind, randomized, parallel group study aimed to demonstrate the pharmacokinetic (PK) equivalence and compare the pharmacodynamic (PD), safety and immunogenicity profiles of the proposed denosumab biosimilar FKS518 vs the originator (reference) denosumab. Healthy males (28-55 yr) were randomized to a single 60 mg s.c. injection of FKS518 or the reference denosumab (Prolia) and were followed for 40 wk after drug injection. The primary endpoints were area under the concentration-time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum observed serum concentration. A total of 213 subjects were injected. Pharmacokinetic equivalence was demonstrated as the 90% CIs for the geometric least squares means ratio FKS518/reference denosumab for the three primary PK parameters were fully contained within the predefined bioequivalence limits. Secondary PK, PD, safety, and local tolerability endpoints also supported the similarity of FKS518 and reference denosumab. No anti-drug antibodies were detected in either treatment group. These results demonstrate that FKS518 is equivalent to originator denosumab with respect to PK profile.

Paget's disease of bone (PDB) is a focal, late-onset, chronic disorder of bone metabolism. Although the prevalence of PDB is stable in Quebec, the incidence and clinical severity of PDB have decreased over time. In this study, we determined the temporal trend of mortality associated with PDB in a large population-based retrospective cohort over 20 yr from the medico-administrative data of the Régie de l'assurance maladie du Québec, compared with the general population. For each fiscal year, the age-standardized rate of all-cause mortality was determined from 2000/2001 to 2020/2021 in individuals aged ≥55 with PDB and in the general population. The population size was 1 706 015 in 2000/2001 and 2 913 820 in 2019/2020. The case definition was based on 1 hospitalization or 2 claims from physicians with the diagnosis code of PDB. We determined the adjusted relative risk (aRR) of mortality in men and women, as well as by age categories. A total of 99% CIs have been calculated. We described the percentage of death for each main cause of death. Between 2000-2001 and 2020/2021, the all-cause age-standardized mortality rate (ASMR) in PDB individuals significantly increased from 47.1/1000 to 54.2/1000, respectively (JoinPoint analysis p < .01). The all-cause ASMR significantly decreased from 27.6/1000 to 22.3/1000 in the general population (JoinPoint analysis p < .01), respectively. Over the study period, compared with the general population, the PDB aRR of mortality rate has increased from 1.06 (0.95-1.19) to 1.16 (1.06-1.27), with a significant increase of mortality observed between 2016/2017 and 2019/2020. We observed an increase in the aRR of mortality in the age category of 65-74 yr from 1.15 (0.84-1.57) to 1.26 (0.97-1.64). The increased mortality in the endocrine and cardiovascular systems may be related to the aging of the pagetic cohort but also to the presence of vascular calcifications.

Elevated levels of AGEs have been implicated in the increased fracture risk of type 2 diabetes (T2D) and CKD patients. AGEs are widely thought to "over-crosslink" bone collagen, making it stiff and less ductile, leading to reduced cortical bone fracture resistance. This idea is primarily based on in vitro studies where predominately pentosidine, an AGE crosslink, has been used as a biomarker for AGEs. However, more recent studies have found that non-crosslinking AGE adducts to be roughly 40-200 times more abundant than pentosidine in human specimens. In addition, ex vivo studies have shown a denatured and less connected collagen network is associated with reduced fracture resistance. This highlights a disconnect in understanding regarding how AGEs impact cortical bone fragility. Specifically, the relationships between AGEs, bone collagen network properties, and cortical bone fracture toughness are poorly understood. Three AGE adducts (carboxy-methyl-lysine, carboxy-ethyl-lysine, 5-hydro-5-methyl-4-imidazolon-2-yl-ornithine 1), pentosidine, collagen network measures, and the fracture toughness of cortical bone specimens from a large heterogenous group of 80 human donors with and without a history of T2D and/or CKD were measured ex vivo. The AGE adducts contents were 57%-63% higher in the T2D/CKD group compared to the controls and were 70-830 times more abundant than pentosidine. The AGE adducts also correlated negatively and strongly with hydroxylysinonorleucine (HLNL), an immature lysyl oxidase-mediated crosslink (r = -0.62 to -0.71, p < .001). From multiple linear regression (MLR) models, interactions between HLNL and collagen network connectivity and cortical bone porosity best explained 2 fracture toughness measures: J-int and Wfx_n (adj-R ² = 47.6% and 40.9%, respectively). From these results, AGE adducts are proposed to disrupt immature crosslink formation during bone remodeling, ultimately leading to a reduction in the cortical bone fracture resistance over time.

In this single-center, randomized, placebo-controlled, single-blinded, crossover trial (Clinical Trial Registry-India: CTRI/2024/08/090041), we evaluated the efficacy and safety of low-dose hydrochlorothiazide (HCTZ) in adults with nonsurgical hypoparathyroidism (excluding autoimmune and obvious syndromic forms). After stabilization on fixed doses of calcium carbonate and calcitriol under a controlled low-sodium diet, 26 participants received HCTZ (12.5-25 mg/d) or placebo for 7 d, with a 15-d washout before crossover, followed by an optional 4-wk open-label HCTZ extension. The primary outcome was change in serum calcium; secondary outcomes included change in 24-h urinary calcium (UCa), fractional calcium excretion, urinary sodium, and bone turnover markers (β-CTX and P1NP). Compared to baseline (8.61 ± 0.32 mg/dL), serum calcium increased significantly with HCTZ at day 5 (9.01 ± 0.46 mg/dL) and day 8 (9.04 ± 0.52 mg/dL; p < .001), while no significant change occurred with placebo. Hydrochlorothiazide reduced 24-h UCa by -26.3% at day 8 (vs +4.7% with placebo; p < .001). These effects remained robust in sensitivity analyses adjusting for urinary sodium and when expressed per kg body weight. Fractional calcium excretion fell by 29.9% with HCTZ (p < .001). A small but statistically significant decline in serum potassium was observed at day 8 (from 4.18 to 3.95 mEq/L; p < .001), though values remained within the normal range, no participants developed hypokalemia; renal function and intact PTH (iPTH) were stable. During the extension phase, serum calcium levels rose while UCa excretion declined significantly, without any reported adverse effects. These findings indicate that low-dose HCTZ with sodium restriction safely improves calcium homeostasis in nonsurgical hypoparathyroidism-raising serum calcium and reducing calciuria-with good tolerability. Hydrochlorothiazide offers a cost-effective adjunct to standard therapy and warrants further investigation for long-term outcomes.

In patients with postmenopausal osteoporosis, the accumulation of bone microdamage further increases fracture risk. Exosomes derived from the circulatory system of young individuals can reverse age-related defects during bone repair. Therefore, the present study aimed to elucidate the mechanisms underlying the protective effects of exosomes against structural degradation under fatigue-induced damage. To this end, a rat tibial fatigue injury model was established to investigate the protective effects of serum-derived exosomes (SDEs) isolated from young rats on bone after fatigue damage. SDEs were administered via intramedullary injection for 3 wk. The results demonstrated that treatment with SDEs significantly alleviated bone microdamage in ovariectomized rats. Specifically, it decreased cortical bone microcrack density and increased the mineral apposition rate significantly. In the distal trabecular bone region, treatment with SDEs increased bone volumetric bone mineral density (vBMD) and decreased trabecular spacing (Tb.Sp) significantly, with no significant changes in the structure model index. This study revealed that SDEs can rapidly repair fatigue-damaged bone microstructure, improving microstructural parameters in non-weight-bearing (distal tibial) cancellous bone (increased vBMD and decreased Tb.Sp). These findings provide a potential novel strategy for early intervention of microdamage in postmenopausal osteoporosis.

X-linked hypophosphatemia (XLH) is caused by inactivating mutations in PHEX, leading to disturbed mineral metabolism, rickets, and osteomalacia. Dentoalveolar defects affecting dentin, cementum, and alveolar bone, contribute to dental abscesses and periodontal breakdown. Limited efficacy of current therapies for ameliorating XLH-associated dentoalveolar effects suggests mechanisms of disease that remain unchecked. Increased production and abnormal distribution of osteopontin (OPN) is thought to contribute to XLH-associated mineralization defects. Osteopontin is a secreted phosphoprotein and mineralization inhibitor, and a substrate of PHEX. To investigate the potential role of OPN in the pathology of XLH-associated dentoalveolar defects, a genetic approach was used to ablate or diminish Spp1/OPN in the Hyp mouse model of XLH. One or both Spp1 alleles in Hyp mice were deleted and tissues were analyzed at 60 d postnatally (dpn). Micro-CT showed no differences in volumes or densities of dentin and alveolar bone in Hyp mice lacking one or both Spp1 alleles, as compared to control Hyp mice. Histological assessment showed no improvements in cementum or periodontal ligament attachment, and dynamic mechanical analysis revealed no normalization of periodontal mechanical properties. While OPN may play a role in regulating dentoalveolar mineralization, diminishing OPN alone was not sufficient to substantially ameliorate XLH-associated defects.

Opioid drugs, prescribed for pain management or opioid use disorder, have been associated with decreased BMD and increased fracture risk. Changes in circulating microRNA (miRNA) levels have been observed in opioid-treated patients, and miRNAs are crucial regulators of bone metabolism, but the effects of circulating miRNAs on BMD in the context of opioid use remains unexplored. This study aims to identify circulating miRNAs differentially expressed with opioid use that may explain opioid use effects on BMD. We conducted a cross-sectional analysis of 5692 participants from the Framingham Heart Study Offspring and Third Generation cohorts for which 412 miRNA profiles were obtained via qRT-PCR. BMD measurements were obtained using DXA for most participants, among whom opioid use was reported in 62 (1.1%). We modeled miRNA as a function of opioid use and/or BMD, adjusting for age, sex, and BMI, in linear or logistic regression models. Significant miRNAs associated with both opioid use and BMD were then analyzed using a novel strategy for pathway enrichment to identify biological functions impacted by these miRNAs. We found a significant inverse association between opioid use and BMD after adjusting for covariates (β = -.042, 95% CI = -0.075, -0.007, p = .017). We identified 64 miRNAs associated with BMD and 28 miRNAs associated with opioid use (p < .05). Ten miRNAs were significantly (p < .05) associated with both opioid use and BMD, 9 with opposing effects. Pathway enrichment analysis revealed the involvement of thyrotropin-releasing hormones, phosphatidylserine, vascular endothelial growth factors, integrins, and modulation of calcium and potassium ions. Our study has found preliminary evidence for miRNA-mediated mechanisms by which opioid use impacts bone health, which may guide future translational applications to prevent bone loss in opioid users.

Glial cells missing 2 (GCM2) is an essential transcription factor for the development of parathyroid glands. Germline GCM2 variants that repress or enhance transcriptional activity predispose a subset of patients to hypoparathyroidism or hyperparathyroidism, respectively. A recurrent germline heterozygous activating missense variant of GCM2, p.Y394S has been identified in some patients with primary hyperparathyroidism. A genetically engineered knock-in mouse model of this variant corresponding to p.Y392S in the mouse Gcm2 gene (Gcm2 ^+/Y392S) did not show obvious parathyroid tumors. However, in GCM2-binding site mediated luciferase reporter assays in HEK293 cells, the mouse and the human variant both exhibited enhanced transcriptional activity. Therefore, we assessed the effect of this variant on gene expression in vivo in parathyroid glands from Gcm2 ^+/Y392S and WT mice. Using the 10x Genomics Visium platform, spatially resolved transcriptomic analysis was performed on formalin-fixed and paraffin-embedded (FFPE) tracheal tissue sections of Gcm2 ^+/Y392S and WT mice to capture RNA from parathyroid glands together with other cell types in the tissue sections. Transcriptome sequence data analysis detected 8 different clusters in the tissue sections based on similarity of gene expression profiles. Cluster-1, which contained parathyroid gland cells expressing Pth and Gcm2, was further evaluated for transcripts that were differentially expressed more than 2-fold in Gcm2 ^+/Y392S compared to WT. Increased transcript level of Lgals3 (galectin-3) was seen in Gcm2 ^+/Y392S parathyroid gland cells which is among markers of parathyroid carcinoma. Galectin-3 protein was detected in available FFPE human parathyroid samples of patients with germline heterozygous activating GCM2 variants, p.Y394S (n = 4/10) or p.L379Q (n = 2/2). These results indicate a potential for growth and malignancy of parathyroid glands expressing GCM2 variants. The transcriptomic data of mouse parathyroid gland cells generated in this study can serve as a valuable resource for investigating genes and pathways in normal or abnormal parathyroid gland growth and physiology.

Cherubism is a rare autosomal dominant bone disease of the maxilla and mandible with variable severity. Most patients harbor a mutation in SH3 domain-binding protein 2 (SH3BP2), yet factors influencing genetic penetrance and clinical severity remain unclear. In mice, this mutation induces tumor necrosis factor alpha (TNF-α)-mediated systemic inflammation, though its role in human cherubism is debated. Multinucleated osteoclasts (OCs), rather than macrophages, are linked to symptom severity, but whether this results from progenitor differentiation or environmental factors is unknown. To elucidate this, OC differentiation and resorption were compared in PBMCs from two symptomatic and one asymptomatic carrier of the same cherubism mutation. All carriers exhibited larger OCs than healthy controls when cultured with RANKL or TNF-α. On bone slices, OCs from carriers resorbed more bone than controls, with TNF-α exerting a weaker effect than RANKL. No significant differences were observed between symptomatic and asymptomatic carriers, suggesting that symptom severity is influenced by microenvironmental factors external to OCs. Additionally, while TNF-α promotes giant cell formation in cherubism OCs, its impact on resorption is limited. These findings may explain why TNF-α inhibition reduces giant cell numbers in cherubism lesions without improving clinical outcomes.

Glucocorticoids, such as dexamethasone, are essential for treating severe childhood conditions, including cancer, organ transplantation, and inflammatory disorders. However, their long-term use can impair bone development, posing risks to pediatric bone health, which is vital for lifelong skeletal integrity. A mechanistic insight into how glucocorticoids negatively impact bone could improve decision-making in patient care, thereby improving the quality of life for pediatric cancer patients and survivors. In this study, we aimed to elucidate the molecular mechanisms underlying dexamethasone-induced bone toxicity in developing bones using single-cell transcriptomics. We treated skeletally immature C57BL/6JRj male mice with dexamethasone for 28 days, and assessed the bone architecture with micro-computed tomography, and characterized bone and bone marrow cells from the femurs using single-cell RNA sequencing. Our findings revealed a marked reduction in osteoblast and chondrocyte cell populations and impaired function of pre-osteoblasts. Additionally, dexamethasone adversely affected B cell subsets, significantly depleting early B cell progenitors while allowing some further developed immature B cells to persist. These cellular changes were accompanied by reduced longitudinal bone growth, compromised bone architecture, and increased bone fragility at the highest doses of dexamethasone. Interestingly, unlike observations in adults, dexamethasone did not enhance osteoclast activity in our model. Overall, our study suggests that the adverse effects of dexamethasone on bone development are primarily due to its impact on osteoblastic, chondroblastic, and B cell lineages. This disruption affects the critical signaling crosstalk between the cells necessary for both bone development and hematopoiesis.