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Item A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation(Wiley, 2021-03-03) Coffman, Abigail A.; Basta-Pljakic, Jelena; Guerra, Rosa M.; Ebetino, Frank H.; Lundy, Mark W.; Majeska, Robert J.; Schaffler, Mitchell B.; Anatomy, Cell Biology and Physiology, School of MedicineBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment.Item Bone health effects of androgen-deprivation therapy and androgen receptor inhibitors in patients with nonmetastatic castration-resistant prostate cancer(Springer Nature, 2021) Hussain, Arif; Tripathi, Abhishek; Pieczonka, Christopher; Cope, Diane; McNatty, Andrea; Logothetis, Christopher; Guise, Theresa; Medicine, School of MedicineBackground: Osteoporosis is a skeletal disorder characterized by compromised bone strength, resulting in increased fracture risk. Patients with prostate cancer may have multiple risk factors contributing to bone fragility: advanced age, hypogonadism, and long-term use of androgen-deprivation therapy. Despite absence of metastatic disease, patients with nonmetastatic castrate-resistant prostate cancer receiving newer androgen receptor inhibitors can experience decreased bone mineral density. A systematic approach to bone health care has been hampered by a simplistic view that does not account for heterogeneity among prostate cancer patients or treatments they receive. This review aims to raise awareness in oncology and urology communities regarding the complexity of bone health, and to provide a framework for management strategies for patients with nonmetastatic castrate-resistant prostate cancer receiving androgen receptor inhibitor treatment. Methods: We searched peer-reviewed literature on the PubMed database using key words "androgen-deprivation therapy," "androgen receptor inhibitors," "bone," "bone complications," and "nonmetastatic prostate cancer" from 2000 to present. Results: We discuss how androgen inhibition affects bone health in patients with nonmetastatic castrate-resistant prostate cancer. We present data from phase 3 trials on the three approved androgen receptor inhibitors with regard to effects on bone. Finally, we present management strategies for maintenance of bone health. Conclusions: In patients with nonmetastatic castrate-resistant prostate cancer, aging, and antiandrogen therapy contribute to bone fragility. Newer androgen receptor inhibitors were associated with falls or fractures in a small subset of patients. Management guidelines include regular assessment of bone density, nutritional guidance, and use of antiresorptive bone health agents when warranted.Item Doubling Down on Wnt Signaling to Overcome Myeloma Bone Disease(Oxford University Press, 2023) Delgado-Calle, Jesus; Roodman, G. David; Medicine, School of MedicineItem Editorial Peer Reviewers as Shepherds, Rather Than Gatekeepers(Wiley, 2021) Boerckel, Joel D.; Plotkin, Lilian I.; Sims, Natalie A.; Anatomy, Cell Biology and Physiology, School of MedicineThe journals of the American Society for Bone and Mineral Research (the Journal of Bone and Mineral Research [JBMR] and its sister journal JBMR Plus) recognize peer review, whether pre- or post-publication, as an essential guard of scientific integrity and rigor that shapes academic discourse in our field. In this Perspective, we present a vision and philosophy of peer review in a rapidly changing publishing landscape. We emphasize the importance of journal peer reviewers as active players in shaping collegial behavior in the musculoskeletal research community and provide information about benefits and resources available for reviewers and reviewers-in-training. Publishing is becoming increasingly transparent, bringing benefits to authors, to reviewers, and to the scientific community at large. We discuss new initiatives such as transparent peer review and preprint servers, the ways they are changing scientific publishing, and how JBMR is responding to broaden the impact of musculoskeletal research. We emphasize the need to change any perception of peer reviewers as gatekeepers to viewing them as shepherds, who partner with authors and editors in the publishing endeavor. Promoting access, transparency, and collegiality in the way we assess science in our community will elevate its quality, clarify its communication, and increase its societal impact. © 2021 American Society for Bone and Mineral Research (ASBMR).Item Editorial: Rare musculoskeletal disorders: disease mechanisms and therapies(Frontiers Media, 2023-05-24) Seefried, Lothar; Bravenboer, Nathalie; Imel, Erik A.; Medicine, School of MedicineItem Genome-Wide Mapping and Interrogation of the Nmp4 Antianabolic Bone Axis(Oxford University Press, 2015-09) Childress, Paul; Stayrook, Keith R.; Alvarez, Marta B.; Wang, Zhiping; Shao, Yu; Hernandez-Buquer, Selene; Mack, Justin K.; Grese, Zachary R.; He, Yongzheng; Horan, Daniel; Pavalko, Fredrick M.; Warden, Stuart J.; Robling, Alexander G.; Yang, Feng-Chun; Allen, Matthew R.; Krishnan, Venkatesh; Liu, Yunlong; Bidwell, Joseph P.; Department of Anatomy & Cell Biology, IU School of MedicinePTH is an osteoanabolic for treating osteoporosis but its potency wanes. Disabling the transcription factor nuclear matrix protein 4 (Nmp4) in healthy, ovary-intact mice enhances bone response to PTH and bone morphogenetic protein 2 and protects from unloading-induced osteopenia. These Nmp4(-/-) mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8(+) T cells. To determine whether the Nmp4(-/-) phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4(-/-) mice. To identify potential Nmp4 target genes, we performed bioinformatic/pathway profiling on Nmp4 chromatin immunoprecipitation sequencing (ChIP-seq) data. Mice (12 w) were ovx or sham operated 4 weeks before the initiation of PTH therapy. Skeletal phenotype analysis included microcomputed tomography, histomorphometry, serum profiles, fluorescence-activated cell sorting and the growth/mineralization of cultured WT and Nmp4(-/-) bone marrow mesenchymal stem progenitor cells (MSPCs). ChIP-seq data were derived using MC3T3-E1 preosteoblasts, murine embryonic stem cells, and 2 blood cell lines. Ovx Nmp4(-/-) mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8(+) T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4(-/-) MSPCs displayed enhanced proliferation and accelerated mineralization. ChIP-seq/gene ontology analyses identified target genes likely under Nmp4 control as enriched for negative regulators of biosynthetic processes. Interrogation of mRNA transcripts in nondifferentiating and osteogenic differentiating WT and Nmp4(-/-) MSPCs was performed on 90 Nmp4 target genes and differentiation markers. These data suggest that Nmp4 suppresses bone anabolism, in part, by regulating IGF-binding protein expression. Changes in Nmp4 status may lead to improvements in osteoprogenitor response to therapeutic cues.Item Pathophysiology of Medication‐Related Osteonecrosis of the Jaw—A Minireview(Wiley, 2023-06-22) Tetradis, Sotirios; Allen, Matthew R.; Ruggiero, Salvatore L.; Anatomy, Cell Biology and Physiology, School of MedicineMedication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive medications administered for control of osseous malignancy, osteoporosis, or other bone metabolic diseases. Despite being reported in the literature two decades ago, MRONJ etiology, pathophysiology, and progression remain largely unknown, and current nonoperative or operative treatment strategies are mostly empirical. Several hypotheses that attempt to explain the mechanisms of MRONJ pathogenesis have been proposed. However, none of these hypotheses alone is able to capture the complex mechanistic underpinnings of the disease. In this minireview, we aim to highlight key findings from clinical and translational studies and propose a unifying model for the pathogenesis and progression of MRONJ. We also identify aspects of the disease process that require further investigation and suggest areas for future research efforts toward calibrating methodologic approaches and validating experimental findings.Item Skeletal Fluorosis: A Case of Inhalant Abuse Leading to a Diagnosis of Colon Cancer(Sage, 2022) Mohideen, Haseeb; Dahiya, Dushyant Singh; Parsons, Dustin; Hussain, Hafsa; Ahmed, Rizwan Syed; Medicine, School of MedicineSkeletal fluorosis is a long-term bone disease that develops when prolonged fluoride toxicity leads to osteosclerosis and bone deformities that result in crippling pain and debility. The disease is endemic to many countries due to environmental or industrial exposures. However, rare cases in the United States have been reported from various causes including heavy toothpaste ingestion, excessive tea consumption, voriconazole use, and inhalant abuse. Here, we present a case of a 41-year-old man who presented for weight loss and severe joint pains due to bony sclerotic lesions found on X-rays. Social history revealed that he had been recreationally inhaling compressed air dusters used for cleaning electronics. Owing to concern for malignancy, he underwent an extensive work-up which led to a diagnosis of colon cancer, but positron emission tomography/computed tomography (PET/CT) and bone biopsy were unexpectedly negative for metastatic bone disease. Further characterization of his lesions by skeletal survey led to a diagnosis of skeletal fluorosis secondary to inhalant abuse. As in this patient, the disease can be difficult for clinicians to recognize as it can be mistaken for various boney diseases such as metastatic cancer. However, once there is clinical suspicion for skeletal fluorosis, various tests to help confirm the diagnosis can include serum and urine fluoride levels, skeletal survey, and bone ash fluoride concentration. Treatment of skeletal fluorosis primarily involves cessation of fluoride exposure, and recovery can take years. Ultimately, further study is required to develop recommendations and guidelines for diagnosis, management, and prognosis of the disease in the United States.Item X-Linked Hypophosphatemia Caused by the Prevailing North American PHEX Variant c.*231A>G; Exon 13-15 Duplication Is Often Misdiagnosed as Ankylosing Spondylitis and Manifests in Both Men and Women(Wiley, 2022-11-02) McCrystal Dahir, Kathryn; Black, Margo; Gottesman, Gary S.; Imel, Erik A.; Mumm, Steven; Nichols, Cindy M.; Whyte, Michael P.; Medicine, School of MedicineInactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH.