Browsing by Subject "Bone health"

Now showing 1 - 7 of 7
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    Acidic microenvironment and bone pain in cancer-colonized bone
    (SpringerNature, 2015-05-06) Yoneda, Toshiyuki; Hiasa, Masahiro; Nagata, Yuki; Okui, Tatsuo; White, Fletcher A.; Department of Medicine, IU School of Medicine
    Solid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP.
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    Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover
    (SpringerLink, 2015-11) Oesterreich, Steffi; Henry, N. Lynn; Kidwell, Kelley M.; Van Poznak, Catherine H.; Skaar, Todd C.; Dantzer, Jessica; Li, Lang; Hangartner, Thomas N.; Peacock, Munro; Nguyen, Anne T.; Rae, James M.; Desta, Zeruesenay; Philips, Santosh; Storniolo, Anna M.; Stearns, Vered; Hayes, Daniel F.; Flockhart, David A.; Medicine, School of Medicine
    Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2 %) compared to exemestane-treated patients (-1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.
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    Bone Density in Children with Single Ventricle Physiology
    (Springer, 2015-04) Bendaly, Edgard A.; DiMeglio, Linda A.; Fadel, William F.; Hurwitz, Roger A.; Department of Pediatrics, Indiana University School of Medicine
    Background Children with chronic diseases are at risk for low bone mineral density (BMD). There are no studies of BMD in children with congenital heart disease and particularly SV. Children with this defect are often treated with warfarin, suspected to negatively impact BMD in adults. We assessed BMD in patients with single ventricle (SV) physiology and compared the BMD of subjects taking warfarin to those who were not. Methods Subjects 5-12 years with SV were included. BMD z-scores by dual-energy X-ray absorptiometry (DXA) of the spine and total body less head (TBLH) were obtained. Calcium intake, activity level, height, and Tanner stage were assessed. Linear regression models and t-tests were used to investigate differences between participants and normative data as well as between subjects' subgroups. Results Twenty six subjects were included; 16 took warfarin. Mean BMD z-score at the spine was significantly lower than expected at -1.0±0.2 (p<0.0001), as was the BMD z-score for TBLH at - 0.8±0.2 (p<0.0001). Those results remained significant after adjusting for height. Subjects who were on warfarin tended to have lower BMD at both the spine and TBLH than those who were not, with a z-score difference of 0.6±0.46 at the spine (p=0.106) and a difference of 0.4±0.34 at TBLH (p=0.132). Conclusions BMD is significantly reduced in children with SV. Warfarin appears to lower BMD but the effect is less conclusive. Continued evaluation is recommended for these patients at risk for reduced bone density. Evaluation of other cardiac patients on warfarin therapy should also be considered.
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    Effects of estrogen depletion and drug treatment on collagen microstructure: implications
    (SpringerNature, 2015-05-27) Wallace, Joseph M.; Bone, Henry G.; Department of Biomedical Engineering, School of Engineering and Technology
    Commentary on: Cauble MA, Rothman E, Welch K, Fang M, Duong LT, Pennypacker BL, Orr BG, Holl MMB. Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment. BoneKEy 2015; 4: 697. doi:10.1038/ bonekey.2015.66.
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    Exemestane may be less detrimental than letrozole to bone health in women homozygous for the UGT2B17*2 gene deletion
    (Springer, 2019-02-12) Kamdem, Landry K.; Xi, Jingyue; Clark, Brandi L.; Gregory, Bryana J.; Kidwell, Kelley M.; Storniolo, Ana-Maria; Stearns, Vered; Hayes, Daniel F.; Gersch, Christina L.; Rae, James M.; Henry, N. Lynn; Hertz, Daniel L.; Medicine, School of Medicine
    Purpose: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer. Methods: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2. Results: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05). Conclusion: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.
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    Physical Therapist Management of Patients With Suspected or Confirmed Osteoporosis: A Clinical Practice Guideline From the Academy of Geriatric Physical Therapy
    (Wolters Kluwer, 2022) Hartley, Gregory W.; Roach, Kathryn E.; Nithman, Robert W.; Betz, Sherri R.; Lindsey, Carleen; Fuchs, Robyn K.; Avin, Keith G.; Physical Therapy, School of Health and Human Sciences
    A clinical practice guideline on physical therapist management of patients with suspected or confirmed osteoporosis was developed by a volunteer guideline development group (GDG) that was appointed by the Academy of Geriatric Physical Therapy (APTA Geriatrics). The GDG consisted of an exercise physiologist and 6 physical therapists with clinical and methodological expertise. The guideline was based on a systematic review of existing clinical practice guidelines, followed by application of the ADAPTE methodological process described by Guidelines International Network for adapting guidelines for cultural and professional utility. The recommendations contained in this guideline are derived from the 2021 Scottish Intercollegiate Guideline Network (SIGN) document: Management of Osteoporosis and the Prevention of Fragility Fractures. These guidelines are intended to assist physical therapists practicing in the United States, and implementation in the context of the US health care system is discussed.
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    TGFβ-Mediated induction of SphK1 as a potential determinant in human MDA-MB-231 breast cancer cell bone metastasis
    (SpringerNature, 2015-07-08) Stayrook, Keith R.; Mack, Justin K.; Cerabona, Donna; Edwards, Daniel F.; Bui, Hai H.; Niewolna, Maria; Fournier, Pierrick G.J.; Mohamma, Khalid S.; Waning, David L.; Guise, Theresa A.; Department of Pharmacology and Toxicology, IU School of Medicine
    Mechanistic understanding of the preferential homing of circulating tumor cells to bone and their perturbation on bone metabolism within the tumor-bone microenvironment remains poorly understood. Alteration in both transforming growth factor β (TGFβ) signaling and sphingolipid metabolism results in the promotion of tumor growth and metastasis. Previous studies using MDA-MB-231 human breast cancer-derived cell lines of variable metastatic potential were queried for changes in sphingolipid metabolism genes to explore correlations between TGFβ dependence and bone metastatic behavior. Of these genes, only sphingosine kinase-1 (SPHK1) was identified to be significantly increased following TGFβ treatment. Induction of SPHK1 expression correlated to the degree of metastatic capacity in these MDA-MB-231-derived cell lines. We demonstrate that TGFβ mediates the regulation of SPHK1 gene expression, protein kinase activity and is critical to MDA-MB-231 cell viability. Furthermore, a bioinformatic analysis of human breast cancer gene expression supports SPHK1 as a hallmark TGFβ target gene that also bears the genetic fingerprint of the basal-like/triple-negative breast cancer molecular subtype. These data suggest a potential new signaling axis between TGFβ/SphK1 that may have a role in the development, prognosis or the clinical phenotype associated with tumor-bone metastasis.