In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11 . Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas control mice lost cortical bone between 8 and 24 months of age, mice lacking RANKL in osteocytes gained cortical bone during this period. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Overexpression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Finally, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone.

Hospital readmissions can negatively impact cost and patient outcomes. Predictors of 30-day readmissions have been primarily identified using medical claims data. Reported here are results of a patient survey developed as part of regular hospital quality assurance activities. Two-thirds of patients reported good discharge experiences but were still readmitted. One-third of patients discharged had a post-discharge doctor appointment scheduled; half were readmitted before that scheduled appointment. Results suggest post-discharge experiences could be improved, especially the timing of follow up doctor appointments. Identified weaknesses in the survey process highlight need for engagement of survey methodologists in efforts to understand patient experiences.

Denosumab is an anti-RANKL Ab that potently suppresses bone resorption, increases bone mass, and reduces fracture risk. Discontinuation of denosumab causes rapid rebound bone resorption and bone loss, but the molecular mechanisms are unclear. We generated humanized RANKL mice and treated them with denosumab to examine the cellular and molecular conditions associated with rebound resorption. Denosumab potently suppressed both osteoclast and osteoblast numbers in cancellous bone in humanized RANKL mice. The decrease in osteoclast number was not associated with changes in osteoclast progenitors in bone marrow. Long-term, but not short-term, denosumab administration reduced osteoprotegerin (OPG) mRNA in bone. Localization of OPG expression revealed that OPG mRNA is produced by a subpopulation of osteocytes. Long-term denosumab administration reduced osteocyte OPG mRNA, suggesting that OPG expression declines as osteocytes age. Consistent with this, osteocyte expression of OPG was more prevalent near the surface of cortical bone in humans and mice. These results suggest that new osteocytes are an important source of OPG in remodeling bone and that suppression of remodeling reduces OPG abundance by reducing new osteocyte formation. The lack of new osteocytes and the OPG they produce may contribute to rebound resorption after denosumab discontinuation.

In this study, we aim to identify predictors of a no-show in neurology clinics at our institution. We conducted a retrospective review of neurology clinics from July 2013 through September 2018. We compared odds ratio of patients who missed appointments (no-show) to those who were present at appointments (show) in terms of age, lead-time, subspecialty, race, gender, quarter of the year, insurance type, and distance from hospital. There were 60,012 (84%) show and 11,166 (16%) no-show patients. With each day increase in lead time, odds of no-show increased by a factor of 1.0019 (p < 0.0001). Odds of no-show were higher in younger (p ≤ 0.0001, OR = 0.49) compared to older (age ≥ 60) patients and in women (p < 0.001, OR = 1.1352) compared to men. They were higher in Black/African American (p < 0.0001, OR = 1.4712) and lower in Asian (p = 0.03, OR = 0.6871) and American Indian/Alaskan Native (p = 0.055, OR = 0.6318) as compared to White/Caucasian. Patients with Medicare (p < 0.0001, OR = 1.5127) and Medicaid (p < 0.0001, OR = 1.3354) had higher odds of no-show compared to other insurance. Young age, female, Black/African American, long lead time to clinic appointments, Medicaid/Medicare insurance, and certain subspecialties (resident and stroke clinics) are associated with high odds of no show. Possible suggested interventions include better communication and flexible appointments for the high-risk groups as well as utilizing telemedicine.

Autophagy is a recycling pathway in which damaged proteins, protein aggregates, and organelles are delivered to lysosomes for degradation. Autophagy insufficiency is thought to contribute to osteoporosis. Accordingly, autophagy elimination from the osteoblast lineage reduces bone formation and bone mass. However, whether increasing autophagy would benefit bone health is unknown. Here, we increased expression of endogenous transcription factor EB gene (Tfeb) in osteoblast lineage cells in vivo via CRISPR activation (Tfeb^CRa mice). Elevated Tfeb stimulated autophagy and lysosomal biogenesis in osteoblasts. Tfeb^CRa mice displayed a robust increase in femoral and vertebral cortical thickness at 4.5 months of age. Increases in cortical thickness was due to increased periosteal bone formation. Tfeb elevation also increased femoral trabecular bone volume. These changes increased bone strength of Tfeb^CRa mice. Female Tfeb^CRa mice displayed a progressive increase in bone mass and at 12 months of age had high cortical thickness and trabecular bone volume. Increased vertebral trabecular bone volume was due to elevated bone formation. Osteoblastic cultures showed that Tfeb elevation increased proliferation and mineral deposition. Overall, these results demonstrate TFEB-driven stimulation of autophagy in osteoblast lineage cells is associated with increased bone formation and strength and may represent an effective approach to combat osteoporosis.