Sclerostin antibody improves phosphate metabolism hormones, bone formation rates, and bone mass in adult Hyp mice.

X-linked hypophosphatemia (XLH) is caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX). Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23), impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily by osteocytes, suppresses bone formation by antagonizing canonical Wnt-signaling and is reported to be elevated in XLH patients. Our previous study reported that a monoclonal antibody to sclerostin (Scl-Ab) decreases FGF23 and increases phosphate and bone mass in growing Hyp mice (XLH murine model). In the current study, we investigated the efficacy of Scl-Ab in treating XLH pathophysiology in adult Hyp mice that are past the period of rapid skeletal growth (12 and 20-weeks old). We hypothesized that Scl-Ab would not only increase bone formation, bone strength and bone mass, but would also normalize phosphate regulating hormones, FGF23, parathyroid hormone (PTH), and vitamin 1,25(OH)2D. Scl-Ab treatment increased cortical area, trabecular bone volume fraction, trabecular bone formation rate, and the bending moment in both sexes of both age groups. Scl-Ab treatment suppressed circulating levels of intact FGF23 and c-term FGF23 in treated male and female wild-type and Hyp mice of both age groups and improved both vitamin 1,25(OH)2D and PTH. Scl-Ab treated Hyp mice also showed evidence of increased renal expression of the sodium-phosphate co-transporter, NPT2a, specifically in the female Hyp mice. Our study suggests that Scl-Ab treatment can improve several skeletal and metabolic pathologies associated with XLH, further establishes the role of sclerostin in the regulation of FGF23 and provides evidence that Scl-Ab can improve phosphate regulation by targeting the bone-renal axis.

Depression Following Operative Treatments for Achilles Ruptures and Ankle Fractures.

BACKGROUND: The sudden and debilitating nature of lower extremity injuries can trigger mood disturbances, including major depressive disorder. METHODS: This prospective study enrolled patients undergoing operative repair of ankle fractures and Achilles ruptures and followed them for 1 year postoperatively. The validated Patient Health Questionnaire (PHQ-9) for depressive symptoms was administered at the preoperative visit and at postoperative weeks 1, 2, 4, 8, 16, 24, 32, 40, and 52. PHQ-9 is scored 0 to 27, with higher values indicating greater depression symptoms. RESULTS: Fifty-eight patients completed 1 year of follow-up. The mean PHQ-9 score was 2.7 (range, 0-20) at the preoperative visit, peaked at postoperative week 1 (4.9; range, 0-16), and reached its low at postoperative week 52 (0.8; range, 0-7). Cumulative incidences of depressive symptoms during the first year following surgery were 51.7% for at least mild depression, 22.4% for at least moderate depression, and 6.9% for severe depression. A history of mental health disorder and the inability to work during the period of postoperative immobilization were independently associated with greater depressive symptoms. CONCLUSION: The majority of patients undergoing operative treatment of Achilles ruptures and ankle fractures develop postoperative symptoms of mild to moderate depression that normalize after several months. Patients with a history of mental health disorder or who cannot work while immobilized postoperatively are at greatest risk. LEVEL OF EVIDENCE: Level II, prospective cohort study.

What Effect Do Pulmonary Micronodules Detected at Presentation in Patients with Osteosarcoma Have on 5-Year Overall Survival?

For osteosarcoma, staging criteria, prognosis estimates, and surgical recommendations have not yet changed to reflect increasingly sensitive computed tomography (CT) imaging. However, the frequent identification of micronodules (<5 mm) on presentation leaves clinicians in a difficult position regarding the need to biopsy, resect, or follow the lesions and whether to consider the patient metastatic or non-metastatic. Our objective was to compare the 5-year overall survival rates of patients with osteosarcoma with non-surgically resected lung micronodules on presentation to patients without micronodules to guide community oncologists faced with this common dilemma. We collected data retrospectively on all newly diagnosed osteosarcoma patients, aged less than 50, treated at Rush University Hospital over 25 years without pulmonary nodules >10 mm or pulmonary surgical intervention. Kaplan-Meier curves showed there was no difference in 5-year overall survival in patients with any size nodule <5 mm compared to patients with no nodules. Additionally, our study showed a survival advantage for those who presented with 0 or 1 nodule (90%) compared to ≥2 nodules (53%). Our data suggest surgery may not be necessary for singular nodules <5 mm identified on presentation, and that these patients behave more like "localized" patients than metastatic patients.

Osteoporosis Treatments Affect Bone Matrix Maturation in a Rat Model of Induced Cortical Remodeling.

To test how osteoporosis drugs affect bone matrix maturation during cortical bone remodeling, 72 pregnant rats were switched from a 0.4% to a 0.01% calcium diet at parturition for a 23-day lactation period. At weaning, eight dams were sacrificed to establish baseline values, while the remaining dams were returned to 0.4% calcium and treated with vehicle (saline), sodium fluoride (NaF), zoledronic acid (ZA), or sclerostin antibody (Scl-Ab) for either 7 or 28 days (eight animals per group per time point). Femora were examined by µCT, dynamic histomorphometry, Fourier transform infrared imaging, and three-point bending of notched specimens. Cortical porosity decreased in all groups from baseline to day 28. Intracortical mineralizing surface (MS/BS) and mineral apposition rate (MAR), as well as the mineral-to-matrix ratio were unaffected by treatment, but intracortical crystallinity was increased in the ZA group at day 10 compared with vehicle. Cortical area increased in all groups over 28 days mainly because of an addition of bone at the endocortical surface. Endocortical MS/BS did not vary among the groups, but endocortical MAR was suppressed in the NaF group at day 2 and elevated in the Scl-Ab group at day 4 compared with vehicle. Endocortical mineral-to-matrix ratio was increased at days 5 and 10 following NaF treatment and endocortical crystallinity was increased at day 5 following ZA treatment compared with vehicle. Fracture toughness did not differ among the groups. Thus, the treatments affected matrix maturation more strongly at the endocortical then intracortical envelope. In this model of induced remodeling, the bone formation phase is synchronized at multiple sites, facilitating study of the effects of drugs or other bone-targeting agents on matrix maturation independent of their effects on the initiation of remodeling. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.