PROJECT SUMMARY/ABSTRACT Osteonecrosis of the femoral head (ONFH) is a serious skeletal complication that affects 30% of people living with sickle cell disease (SCD). ONFH causes severe chronic pain and permanent disability. ONFH symptoms persist even after curative hematopoietic stem cell transplant therapy, with post-transplant patients reporting poorer quality of life due to their skeletal limitations. There is an urgent need to explore effective therapies for ONFH to relieve pain and improve the health-related quality of life for people with SCD. Alendronate, an oral bisphosphonate that is FDA-approved for treatment of osteoporosis, decreased bone pain and delayed the time to femoral head collapse in people with steroid-induced and traumatic ONFH. The therapeutic potential of alendronate to alleviate bone pain in adults with SCD-related ONFH is an important gap in knowledge with far-reaching public health implications. My colleagues and I recently showed that low bone density, another prevalent skeletal complication of SCD, associates with ONFH and chronic pain in children and adolescents with SCD. I speculate that the association between low bone density, ONFH and sickle cell pain will be even more significant in adults since many SCD complications worsen with age. In this K23 resubmission, I plan to study the pain phenotype of adults with SCD and low bone density using a validated patient-reported outcome measure. I will also conduct a single-arm 6- month feasibility study of alendronate in a prospective cohort of 24 adults with SCD-related ONFH. The primary endpoints are predetermined recruitment and retention rates. Secondary endpoints include preliminary safety and efficacy, as measured by adverse events reporting, medication adherence, opioid use, change in pain scores and other surrogate markers. Lastly, I will collect serum and urine specimens from a subset of non-transfused study subjects to better understand how bone biomarkers can be used a proxy for alendronate adherence and to study how bone biomarker concentrations correlate with underlying SCD bone pathobiology. Repurposing alendronate as targeted therapy for SCD-related ONFH can reduce opioid use and improve health-related quality of life for people with SCD. This revised K23 proposal will lay the groundwork for a subsequent R01 application for a Phase 2 multicenter, randomized, placebo-controlled trial of alendronate in adults with SCD complicated by ONFH. My work will significantly add to ongoing clinical-translational studies to reduce the burden of chronic pain in people living with SCD. The research and training program detailed in my K23 application will provide me with the critical skills I need to build my career as an independent, clinical investigator engaged in developing safe and effective therapies for people with SCD.