Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models.

Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and µCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.

Cost comparison between surgical and conservative management for pediatric sinogenic subperiosteal abscesses.

BACKGROUND: There remains variation in management of orbital complications of acute bacterial rhinosinusitis (ABRS); specifically, those subperiosteal abscesses that present without immediate surgical indication. Recent systematic reviews on management and proposed treatment algorithms are helpful but do not consider the financial implications for healthcare systems and patients. METHODS: A retrospective chart review of pediatric patients from a tertiary care children's hospital between 2002 and 2020 was performed, identifying patients via ICD coding corresponding to acute bacterial sinusitis and orbital involvement classified as Chandler 3 confirmed by contrasted computed tomography (CT). Two groups of patients were identified: intravenous (IV) antibiotics alone and IV antibiotics plus surgery. Billing records of total hospital charges and physician fees were recorded for financial analysis. Demographic, length of stay, and charges were analyzed. RESULTS: 58 patients with ABRS and Chandler 3 orbital involvement were confirmed by CT imaging. Twenty-nine (50%) were treated with IV antibiotics alone, and twenty-nine (50%) underwent surgery in addition to IV antibiotics. There were no significant differences in patient demographics. The average total hospital charges for the medically managed group were $9262 ± 4831 compared to $30,830 ± 11,397 for the surgical group (p < 0.0001). In the medically managed group, the average hospital fees were $7305 ± 4048 and the average physician fees were $1543 ± 799. In the surgical group, the average hospital and physician fees were also significantly higher at $23,071 ± 7305 (p < 0.0001) and $7763 ± 3335 (p < 0.0001), respectively. Patients who were treated medically and had a longer than average LOS still had significantly fewer charges than those treated with antibiotics plus surgery and a shorter than average length of stay [$15,311 and $27,723, respectively (p = 0.02)]. CONCLUSION: Pediatric ABRS with orbital involvement requires prompt attention and management. Controversy persists over subperiosteal abscess management that present without overt surgical indications. Surgical intervention is expensive. Our subgroup analysis demonstrates the magnitude of this cost difference. Specifically, longer inpatient stays with IV antibiotics alone appear to be significantly cheaper than shorter ones that include surgery. Not all Chandler 3 patients are candidates for non-surgical management; however, clinicians are encouraged to keep these data in mind for those patients where further medical management is safe and may yield less expensive clinical resolution.