The Regulation of Marrow Fat by Vitamin D: Molecular Mechanisms and Clinical Implications

  • Hanel Sadie-Van GijsenEmail author
Bone Marrow and Adipose Tissue (G Duque and B Lecka-Czernik, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Bone Marrow and Adipose Tissue


Purpose of Review

To review the available literature regarding a possible relationship between vitamin D and bone marrow adipose tissue (BMAT), and to identify future avenues of research that warrant attention.

Recent Findings

Results from in vivo animal and human studies all support the hypothesis that vitamin D can suppress BMAT expansion. This is achieved by antagonizing adipogenesis in bone marrow stromal cells, through inhibition of PPARγ2 activity and stimulation of pro-osteogenic Wnt signalling. However, our understanding of the functions of BMAT is still evolving, and studies on the role of vitamin D in modulating BMAT function are lacking. In addition, many diseases and chronic conditions are associated with low vitamin D status and low bone mineral density (BMD), but BMAT expansion has not been studied in these patient populations.


Vitamin D suppresses BMAT expansion, but its role in modulating BMAT function is poorly understood.


Vitamin D Bone marrow fat Bone mineral density PPARγ2 Marrow fat unsaturation 


Compliance with Ethical Standards

Conflict of Interest

Hanel Sadie-Van Gijsen declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Hardouin P, Rharass T, Lucas S. Bone marrow adipose tissue: tTo be or not to be a typical adipose tissue? Front Endocrinol (Lausanne). 2016;7:85 This is the first formal description of bone marrow adipose tissue (BMAT) as a distinct adipose depot. CrossRefGoogle Scholar
  2. 2.
    Ambrosi TH, Schulz TJ. The emerging role of bone marrow adipose tissue in bone health and dysfunction. J Mol Med (Berl). 2017;95:1291–301.CrossRefGoogle Scholar
  3. 3.
    •• Craft CS, Li Z, MacDougald OA, Scheller EL. Molecular differences between subtypes of bone marrow adipocytes. Curr Mol Biol Rep. 2018;4:16–23 This paper provides a comprehensive description of the two subtypes of bone marrow adipocytes identified in animal models, and highlights future research questions. PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Sebo ZL, Rendina-Ruedy E, Ables GP, Lindskog DM, Rodeheffer MS, Fazeli PK, et al. Bone marrow adiposity: basic and clinical implications. Endocr Rev. 2019. Scholar
  5. 5.
    Suchacki KJ, Cawthorn WP. Molecular interaction of bone marrow adipose tissue with energy metabolism. Curr Mol Biol Rep. 2018;4:41–9.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Veldhuis-Vlug AG, Rosen CJ. Clinical implications of bone marrow adiposity. J Intern Med. 2018;283:121–39.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Scheller EL, Khandaker S, Learman BS, Cawthorn WP, Anderson LM, Pham HA, et al. Bone marrow adipocytes resist lipolysis and remodeling in response to β-adrenergic stimulation. Bone. 2019;118:32–41.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Horowitz MC, Berry R, Holtrup B, Sebo Z, Nelson T, Fretz JA, et al. Bone marrow adipocytes. Adipocyte. 2017;6:193–204.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Li Y, Meng Y, Yu X. The unique metabolic characteristics of bone marrow adipose tissue. Front Endocrinol (Lausanne). 2019;10:69.CrossRefGoogle Scholar
  10. 10.
    Wang H, Leng Y, Gong Y. Bone marrow fat and hematopoiesis. Front Endocrinol (Lausanne). 2018;9:694.CrossRefGoogle Scholar
  11. 11.
    Luo G, He Y, Yu X. Bone marrow adipocyte: an intimate partner with tumor cells in bone metastasis. Front Endocrinol (Lausanne). 2018;9:339.CrossRefGoogle Scholar
  12. 12.
    Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME. Playing with bone and fat. J Cell Biochem. 2006;98:251–66.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Sadie-Van Gijsen H, Crowther NJ, Hough FS, Ferris WF. The interrelationship between bone and fat: from cellular see-saw to endocrine reciprocity. Cell Mol Life Sci. 2013;70:2331–49.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Sadie-Van Gijsen H, Hough FS, Ferris WF. Determinants of bone marrow adiposity: the modulation of peroxisome proliferator-activated receptor-γ2 activity as a central mechanism. Bone. 2013;56:255–65.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    • Tencerova M, Kassem M. The bone marrow-derived stromal cells: commitment and regulation of adipogenesis. Front Endocrinol (Lausanne). 2016;7:127 This review provides an update on the cellular and molecular mechanisms involved in regulating the competitive selection between adipogenesis and osteoblastogenesis in BMSCs.CrossRefGoogle Scholar
  16. 16.
    Justesen J, Stenderup K, Ebbesen EN, Mosekilde L, Steiniche T, Kassem M. Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology. 2001;2:165–71.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    He J, Fang H, Li X. Vertebral bone marrow fat content in normal adults with varying bone densities at 3T magnetic resonance imaging. Acta Radiol. 2019;60:509–15.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Cortes ARG, Cohen O, Zhao M, Aoki EM, Ribeiro RA, Abu Nada L, et al. Assessment of alveolar bone marrow fat content using 15 T MRI. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125:244–9.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Bani Hassan E, Demontiero O, Vogrin S, Ng A, Duque G. Marrow adipose tissue in older men: association with visceral and subcutaneous fat, bone volume, metabolism, and inflammation. Calcif Tissue Int. 2018;103:164–74.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Zhu L, Xu Z, Li G, Wang Y, Li X, Shi X, et al. Marrow adiposity as an indicator for insulin resistance in postmenopausal women with newly diagnosed type 2 diabetes—an investigation by chemical shift-encoded water-fat MRI. Eur J Radiol. 2019;113:158–64.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Lips P, van Schoor NM. The effect of vitamin D on bone and osteoporosis. Best Pract Res Clin Endocrinol Metab. 2011;25:585–91.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Topor LS, Melvin P, Giancaterino C, Gordon CM. Factors associated with low bone density in patients referred for assessment of bone health. Int J Pediatr Endocrinol. 2013;2013(1):4.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Swanson CM, Srikanth P, Lee CG, Cummings SR, Jans I, Cauley JA, et al. Associations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with bone mineral density, bone mineral density change, and incident nonvertebral fracture. J Bone Miner Res. 2015;30:1403–13.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Arunabh S, Pollack S, Yeh J, Aloia JF. Body fat content and 25-hydroxyvitamin D levels in healthy women. J Clin Endocrinol Metab. 2003;88:157–61.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, et al. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 2004;89:1196–9.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    •• Pino AM, Miranda M, Figueroa C, Rodríguez JP, Rosen CJ. Qualitative aspects of bone marrow adiposity in osteoporosis. Front Endocrinol (Lausanne). 2016;7:139 This review discusses the emerging concept of the impact of marrow fat lipid composition, rather than marrow fat volume per se, on bone fragility. CrossRefGoogle Scholar
  27. 27.
    • Cordes C, Baum T, Dieckmeyer M, Ruschke S, Diefenbach MN, Hauner H, et al. MR-based assessment of bone marrow fat in osteoporosis, diabetes, and obesity. Front Endocrinol (Lausanne). 2016;7:74 This paper describes how MR-based methods can be applied to quantify BMAT lipid composition. CrossRefGoogle Scholar
  28. 28.
    Singhal V, Bredella MA. Marrow adipose tissue imaging in humans. Bone. 2019;118:69–76.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Xu K, Sigurdsson S, Gudnason V, Hue T, Schwartz A, Li X. Reliable quantification of marrow fat content and unsaturation level using in vivo MR spectroscopy. Magn Reson Med. 2018;79:1722–9.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Martel D, Leporq B, Bruno M, Regatte RR, Honig S, Chang G. Chemical shift-encoded MRI for assessment of bone marrow adipose tissue fat composition: pilot study in premenopausal versus postmenopausal women. Magn Reson Imaging. 2018;53:148–55.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Martel D, Leporq B, Saxena A, Belmont HM, Turyan G, Honig S, et al. 3T chemical shift-encoded MRI: detection of altered proximal femur marrow adipose tissue composition in glucocorticoid users and validation with magnetic resonance spectroscopy. J Magn Reson Imaging. 2019;50:490–6.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Zhu M, Hao G, Xing J, Hu S, Geng D, Zhang W, et al. Bone marrow adipose amount influences vertebral bone strength. Exp Ther Med. 2019;17:689–94.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Scheller EL, Troiano N, Vanhoutan JN, Bouxsein MA, Fretz JA, Xi Y, et al. Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. Methods Enzymol. 2014;537:123–39.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689S–96S.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Geng S, Zhou S, Bi Z, Glowacki J. Vitamin D metabolism in human bone marrow stromal (mesenchymal stem) cells. Metabolism. 2013;62:768–77.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011;96:E447–52.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Romagnoli E, Pepe J, Piemonte S, Cipriani C, Minisola S. Management of endocrine disease: value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation. Eur J Endocrinol. 2013;169:R59–69.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Christakos S, Dhawan P, Liu Y, Peng X, Porta A. New insights into the mechanisms of vitamin D action. J Cell Biochem. 2003;88:695–705.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Norman AW. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology. 2006;147:5542–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Langub MC, Reinhardt TA, Horst RL, Malluche HH, Koszewski NJ. Characterization of vitamin D receptor immunoreactivity in human bone cells. Bone. 2000;27:383–7.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Geng S, Zhou S, Glowacki J. Effects of 25-hydroxyvitamin D(3) on proliferation and osteoblast differentiation of human marrow stromal cells require CYP27B1/1α-hydroxylase. J Bone Miner Res. 2011;26:1145–53.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Whitfield GK, Hsieh JC, Nakajima S, MacDonald PN, Thompson PD, Jurutka PW, et al. A highly conserved region in the hormone-binding domain of the human vitamin D receptor contains residues vital for heterodimerization with retinoid X receptor and for transcriptional activation. Mol Endocrinol. 1995;9:1166–79.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Suda T, Ueno Y, Fujii K, Shinki T. Vitamin D and bone. J Cell Biochem. 2003;88:259–66.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Atkins GJ, Anderson PH, Findlay DM, Welldon KJ, Vincent C, Zannettino AC, et al. Metabolism of vitamin D3 in human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25-dihydroxyvitamin D3. Bone. 2007;40:1517–28.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    • Zhou S, LeBoff MS, Glowacki J. Vitamin D metabolism and action in human bone marrow stromal cells. Endocrinology. 2010;151:14–22 This article first demonstrated that BMSCs possess all of the molecular machinery required to produce and respond to calcitriol.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Beresford JN, Joyner CJ, Devlin C, Triffitt JT. The effects of dexamethasone and 1,25-dihydroxyvitamin D3 on osteogenic differentiation of human marrow stromal cells in vitro. Arch Oral Biol. 1994;39:941–7.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Piek E, Sleumer LS, van Someren EP, Heuver L, de Haan JR, de Grijs I, et al. Osteo-transcriptomics of human mesenchymal stem cells: accelerated gene expression and osteoblast differentiation induced by vitamin D reveals c-MYC as an enhancer of BMP2-induced osteogenesis. Bone. 2010;46:613–27.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Kelly KA, Gimble JM. 1,25-Dihydroxy vitamin D3 inhibits adipocyte differentiation and gene expression in murine bone marrow stromal cell clones and primary cultures. Endocrinology. 1998;139:2622–8.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Ding J, Nagai K, Woo JT. Insulin-dependent adipogenesis in stromal ST2 cells derived from murine bone marrow. Biosci Biotechnol Biochem. 2003;67:314–21.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Kong J, Li YC. Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. Am J Physiol Endocrinol Metab. 2006;290:E916–24.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Atmani H, Chappard D, Basle MF. Proliferation and differentiation of osteoblasts and adipocytes in rat bone marrow stromal cell cultures: effects of dexamethasone and calcitriol. J Cell Biochem. 2003;89:364–72.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Mahajan A, Stahl CH. Dihydroxy-cholecalciferol stimulates adipocytic differentiation of porcine mesenchymal stem cells. J Nutr Biochem. 2009;20:512–20.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Zarei A, Hulley PA, Sabokbar A, Javaid MK, Morovat A. 25-hydroxy- and 1α,25-dihydroxycholecalciferol have greater potencies than 25-hydroxy- and 1α,25-dihydroxyergocalciferol in modulating cultured human and mouse osteoblast activities. PLoS One. 2016;11(11):e0165462.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Duque G, Rivas D. Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J Bone Miner Res. 2007;22:1603–11.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Duque G, Li W, Vidal C, Bermeo S, Rivas D, Henderson J. Pharmacological inhibition of PPARγ increases osteoblastogenesis and bone mass in male C57BL/6 mice. J Bone Miner Res. 2013;28:639–48.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    • Cianferotti L, Demay MB. VDR-mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells. J Cell Biochem. 2007;101:80–8 This article identified stimulation of Wnt signalling as a mechanism whereby calcitriol could inhibit marrow adipogenesis. PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Nicolas V, Prewett A, Bettica P, Mohan S, Finkelman RD, Baylink DJ, et al. Age-related decreases in insulin-like growth factor-I and transforming growth factor-beta in femoral cortical bone from both men and women: implications for bone loss with aging. J Clin Endocrinol Metab. 1994;78:1011–6.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Gómez JM. The role of insulin-like growth factor I components in the regulation of vitamin D. Curr Pharm Biotechnol. 2006;7:125–32.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Wei S, Tanaka H, Seino Y. Local action of exogenous growth hormone and insulin-like growth factor-I on dihydroxyvitamin D production in LLC-PK1 cells. Eur J Endocrinol. 1998;139:454–60.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Ameri P, Giusti A, Boschetti M, Bovio M, Teti C, Leoncini G, et al. Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency. Eur J Endocrinol. 2013;169:767–72.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Bredella MA, Gerweck AV, Barber LA, Breggia A, Rosen CJ, Torriani M, et al. Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women. Bone. 2014;62:29–35.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Duque G, Macoritto M, Kremer R. 1,25(OH)2D3 inhibits bone marrow adipogenesis in senescence accelerated mice (SAM-P/6) by decreasing the expression of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2). Exp Gerontol. 2004;39:333–8.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Duque G, Rivas D, Li W, Li A, Henderson JE, Ferland G, et al. Age-related bone loss in the LOU/c rat model of healthy ageing. Exp Gerontol. 2009;44:183–9.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20:771–84.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Holick MF, Smith E, Pincus S. Skin as the site of vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol (1,25-dihydroxyvitamin D3) for treatment of psoriasis. Arch Dermatol. 1987;123:1677–83a.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Montero-Odasso M, Duque G. Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone. Mol Asp Med. 2005;26:203–19.CrossRefGoogle Scholar
  67. 67.
    Geng S, Zhou S, Glowacki J. Age-related decline in osteoblastogenesis and 1α-hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone. Aging Cell. 2011;10:962–71.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Skversky AL, Kumar J, Abramowitz MK, Kaskel FJ, Melamed ML. Association of glucocorticoid use and low 25-hydroxyvitamin D levels: results from the National Health and Nutrition Examination Survey (NHANES): 2001-2006. J Clin Endocrinol Metab. 2011;96:3838–45.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Mazziotti G, Formenti AM, Adler RA, Bilezikian JP, Grossman A, Sbardella E, et al. Glucocorticoid-induced osteoporosis: pathophysiological role of GH/IGF-I and PTH/VITAMIN D axes, treatment options and guidelines. Endocrine. 2016;54:603–11.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Ghali O, Al Rassy N, Hardouin P, Chauveau C. Increased bone marrow adiposity in a context of energy deficit: the tip of the iceberg? Front Endocrinol (Lausanne). 2016;7:125.CrossRefGoogle Scholar
  71. 71.
    Veronese N, Solmi M, Rizza W, Manzato E, Sergi G, Santonastaso P, et al. Vitamin D status in anorexia nervosa: a meta-analysis. Int J Eat Disord. 2015;48:803–13.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Pereira-Santos M, Costa PR, Assis AM, Santos CA, Santos DB. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes Rev. 2015;16:341–9.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Greco EA, Lenzi A, Migliaccio S. Role of hypovitaminosis D in the pathogenesis of obesity-induced insulin resistance. Nutrients. 2019:11(7).Google Scholar
  74. 74.
    Bouillon R, Bex M, Van Herck E, Laureys J, Dooms L, Lesaffre E, et al. Influence of age, sex, and insulin on osteoblast function: osteoblast dysfunction in diabetes mellitus. J Clin Endocrinol Metab. 1995;80:1194–202.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Reichrath J. Dermatologic management, sun avoidance and vitamin D status in organ transplant recipients (OTR). J Photochem Photobiol B. 2010;101:150–9.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Lai CY, Yang JY, Rayalam S, Della-Fera MA, Ambati S, Lewis RD, et al. Preventing bone loss and weight gain with combinations of vitamin D and phytochemicals. J Med Food. 2011;14:1352–62.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    • Duque G, Macoritto M, Kremer R. Vitamin D treatment of senescence accelerated mice (SAM-P/6) induces several regulators of stromal cell plasticity. Biogerontology. 2004;5:421–9 Combined, references 65 and 66 demonstrate that vitamin D suppress BMAT formation through upregulation of IGF-1 and downregulation of pro-adipogenic genes, including PPARγ2. PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Yang YJ, Zhu Z, Wang DT, Zhang XL, Liu YY, Lai WX, et al. Tanshinol alleviates impaired bone formation by inhibiting adipogenesis via KLF15/PPARγ2 signaling in GIO rats. Acta Pharmacol Sin. 2018;39:633–41.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Maurice F, Dutour A, Vincentelli C, Abdesselam I, Bernard M, Dufour H, et al. Active Cushing syndrome patients have increased ectopic fat deposition and bone marrow fat content compared to cured patients and healthy subjects: a pilot 1H-MRS study. Eur J Endocrinol. 2018;179:307–17.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Pereira RC, Delany AM, Canalis E. Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation: correlation with CCAAT-enhancer binding protein expression. Bone. 2002;30:685–91.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018;61:7–16.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Badr S, Legroux-Gérot I, Vignau J, Chauveau C, Ruschke S, Karampinos DC, et al. Comparison of regional bone marrow adiposity characteristics at the hip of underweight and weight-recovered women with anorexia nervosa using magnetic resonance spectroscopy. Bone. 2019;127:135–45.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, et al. Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women. Obesity (Silver Spring). 2011;19:49–53.CrossRefGoogle Scholar
  84. 84.
    Baum T, Yap SP, Karampinos DC, Nardo L, Kuo D, Burghardt AJ, et al. Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus? J Magn Reson Imaging. 2012;35:117–24.CrossRefGoogle Scholar
  85. 85.
    Yu EW, Greenblatt L, Eajazi A, Torriani M, Bredella MA. Marrow adipose tissue composition in adults with morbid obesity. Bone. 2017;97:38–42.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    De Araújo IM, Salmon CE, Nahas AK, Nogueira-Barbosa MH, Elias J Jr, de Paula FJ. Marrow adipose tissue spectrum in obesity and type 2 diabetes mellitus. Eur J Endocrinol. 2017;176:21–30.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Tencerova M, Figeac F, Ditzel N, Taipaleenmäki H, Nielsen TK, Kassem M. High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice. J Bone Miner Res. 2018;33:1154–65.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Tencerova M, Frost M, Figeac F, Nielsen TK, Ali D, Lauterlein JL, et al. Obesity-associated hypermetabolism and accelerated senescence of bone marrow stromal stem cells suggest a potential mechanism for bone fragility. Cell Rep. 2019;27:2050–62.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    • Mangan A, Le Roux CW, Miller NG, Docherty NG. Iron and vitamin D/calcium deficiency after gastric bypass: mechanisms involved and strategies to improve oral supplement disposition. Curr Drug Metab. 2019;20:244–52 This article provides evidence for increased prevalence of vitamin D deficiency after gastric bypass surgery, which is of clinical concern in an era where such surgery is increasingly used to treat morbid obesity. PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Kim TY, Schwartz AV, Li X, Xu K, Black DM, Petrenko DM, et al. Bone marrow fat changes after gastric bypass surgery are associated with loss of bone mass. J Bone Miner Res. 2017;32:2239–47.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Bredella MA, Greenblatt LB, Eajazi A, Torriani M, Yu EW. Effects of Roux-en-Y gastric bypass and sleeve gastrectomy on bone mineral density and marrow adipose tissue. Bone. 2017;95:85–90.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Patsch JM, Li X, Baum T, Yap SP, Karampinos DC, Schwartz AV, et al. Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures. J Bone Miner Res. 2013;28:1721–8.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Woods GN, Ewing SK, Sigurdsson S, Kado DM, Ix JH, Hue TF, et al. Chronic kidney disease is associated with greater bone marrow adiposity. J Bone Miner Res. 2018;33:2158–64.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Hernandez MJ, Dos Reis LM, Marques ID, Araujo MJ, Truyts CAM, Oliveira IB, et al. The effect of vitamin D and zoledronic acid in bone marrow adiposity in kidney transplant patients: a post hoc analysis. PLoS One. 2018;13(5):e0197994.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Stein EM, Cohen A, Freeby M, Rogers H, Kokolus S, Scott V, et al. Severe vitamin D deficiency among heart and liver transplant recipients. Clin Transpl. 2009;23:861–5.CrossRefGoogle Scholar
  96. 96.
    Anastasilakis AD, Tsourdi E, Makras P, Polyzos SA, Meier C, McCloskey EV, et al. Bone disease following solid organ transplantation: a narrative review and recommendations for management from The European Calcified Tissue Society. Bone. 2019;127:401–18.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Kühne CA, Heufelder AE, Hofbauer LC. Bone and mineral metabolism in human immunodeficiency virus infection. J Bone Miner Res. 2001;16:2–9.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Ahmad AN, Ahmad SN, Ahmad N. HIV infection and bone abnormalities. Open Orthop J. 2017;11:777–84.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Cotter EJ, Ip HS, Powderly WG, Doran PP. Mechanism of HIV protein induced modulation of mesenchymal stem cell osteogenic differentiation. BMC Musculoskelet Disord. 2008;9:33.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Butler JS, Dunning EC, Murray DW, Doran PP, O'Byrne JM. HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism. J Orthop Res. 2013;31:218–26.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Noe S, Moeckel CI, Schwerdtfeger C, Oldenbuettel C, Jaeger H, Wolf E, et al. Monthly or weekly supplementation with cholecalciferol 20,000 IU in people living with HIV: results from a nested cohort study. Interdiscip Perspect Infect Dis. 2018;2018:7502127.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Haug CJ, Aukrust P, Haug E, Mørkrid L, Müller F, Frøland SS. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab. 1998;83:3832–8.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Mayur N, Lewis S, Catherwood BD, Nanes MS. Tumor necrosis factor alpha decreases 1,25-dihydroxyvitamin D3 receptors in osteoblastic ROS 17/2.8 cells. J Bone Miner Res. 1993;8:997–1003.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Fernandez-Martin JL, Kurian S, Farmer P, Nanes MS. Tumor necrosis factor activates a nuclear inhibitor of vitamin D and retinoid-X receptors. Mol Cell Endocrinol. 1998;141:65–72.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    • Nylén H, Habtewold A, Makonnen E, Yimer G, Bertilsson L, Burhenne J, et al. Prevalence and risk factors for efavirenz-based antiretroviral treatment-associated severe vitamin D deficiency: a prospective cohort study. Medicine (Baltimore). 2016;95(34):e4631 This article discusses the risk of vitamin D deficiency associated with efavirenz and TDF use, which is of clinical concern in a population that already presents with an infection-related burden of vitamin D deficiency. PubMedCentralCrossRefGoogle Scholar
  106. 106.
    •• Conradie MM, van de Vyver M, Andrag E, Conradie M, Ferris WF. A direct comparison of the effects of the antiretroviral drugs Stavudine, Tenofovir and the combination Lopinavir/Ritonavir on bone metabolism in a rat model. Calcif Tissue Int. 2017;101:422–32 This article is the only study to date to provide evidence that certain ARVs may cause BMAT expansion in vivo.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Hernandez-Vallejo SJ, Beaupere C, Larghero J, Capeau J, Lagathu C. HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin. Aging Cell. 2013;12:955–65.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Gaudio A, Morabito N, Catalano A, Rapisarda R, Xourafa A, Lasco A. Pathogenesis of thalassemia major-associated osteoporosis: a review with insights from clinical experience. J Clin Res Pediatr Endocrinol. 2019;11:110–7.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab. 2003;88:4623–32.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Klein GL. The interaction between burn injury and vitamin D metabolism and consequences for the patient. Curr Clin Pharmacol. 2008;3:204–10.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Murdaca G, Tonacci A, Negrini S, Greco M, Borro M, Puppo F, et al. Emerging role of vitamin D in autoimmune diseases: an update on evidence and therapeutic implications. Autoimmun Rev. 2019;102350.Google Scholar
  112. 112.
    Peterson CA, Heffernan ME. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J Inflamm (Lond). 2008;5:10.CrossRefGoogle Scholar
  113. 113.
    Fletcher J, Cooper SC, Ghosh S, Hewison M. The role of vitamin D in inflammatory bowel disease: mechanism to management. Nutrients 2019;11(5).PubMedCentralCrossRefGoogle Scholar
  114. 114.
    Szafors P, Che H, Barnetche T, Morel J, Gaujoux-Viala C, Combe B, et al. Risk of fracture and low bone mineral density in adults with inflammatory bowel diseases. A systematic literature review with meta-analysis. Osteoporos Int. 2018;29:2389–97.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Choi ST, Kwon SR, Jung JY, Kim HA, Kim SS, Kim SH, Kim JM, Park JH, Suh CH. Prevalence and fracture risk of osteoporosis in patients with rheumatoid arthritis: a multicenter comparative study of the FRAX and WHO criteria. J Clin Med. 2018;7(12).PubMedCentralCrossRefGoogle Scholar
  116. 116.
    Xia J, Luo R, Guo S, Yang Y, Ge S, Xu G, et al. Prevalence and risk factors of reduced bone mineral density in systemic lupus erythematosus patients: a meta-analysis. Biomed Res Int. 2019;2019:3731648.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Mutt SJ, Karhu T, Lehtonen S, Lehenkari P, Carlberg C, Saarnio J, et al. Inhibition of cytokine secretion from adipocytes by 1,25-dihydroxyvitamin D3 via the NF-κB pathway. FASEB J. 2012;26:4400–7.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    •• Jacobs FA, Sadie-Van Gijsen H, van de Vyver M, Ferris WF. Vanadate impedes adipogenesis in mesenchymal stem cells derived from different depots within bone. Front Endocrinol (Lausanne). 2016;7:108 In this article, we identified two separate MSC populations in the rat femur, with different adipogenic potential, which may have distinct contributions to BMAT expansion. CrossRefGoogle Scholar
  119. 119.
    Li Y, Bäckesjö CM, Haldosén LA, Lindgren U. Species difference exists in the effects of 1alpha,25(OH)(2)D(3) and its analogue 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D(3) (2MD) on osteoblastic cells. J Steroid Biochem Mol Biol. 2008;112:110–6.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Wiberg K, Ljunghall S, Binderup L, Ljunggren O. Studies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitro. Bone. 1995;17:391–5.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Hou QK, Huang YQ, Luo YW, Wang B, Liu YM, Deng RD, et al. (+)-Cholesten-3-one induces osteogenic differentiation of bone marrow mesenchymal stem cells by activating vitamin D receptor. Exp Ther Med. 2017;13:1841–9.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Peräkylä M, Malinen M, Herzig KH, Carlberg C. Gene regulatory potential of nonsteroidal vitamin D receptor ligands. Mol Endocrinol. 2005;19:2060–73.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    • Montazeri-Najafabady N, Ghasemi Y, Dabbaghmanesh MH, Talezadeh P, Koohpeyma F, Gholami A. Supportive role of probiotic strains in protecting rats from ovariectomy-induced cortical bone loss. Probiotics Antimicrob Proteins. 2018. findings suggest that specific gut microbiota populations may provide support in maintaining or correcting vitamin D status.
  124. 124.
    • Fairfield H, Falank C, Harris E, Demambro V, McDonald M, Pettitt JA, et al. The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis. J Cell Physiol. 2018;233:1156–67 This article identifies sclerostin, another Wnt inhibitor, as a driver of BMAT expansion, similar to the Wnt inhibitors identified in reference 56. CrossRefGoogle Scholar
  125. 125.
    •• Fairfield H, Falank C, Farrell M, Vary C, Boucher JM, Driscoll H, et al. Development of a 3D bone marrow adipose tissue model. Bone. 2019;118:77–88 This model may fundamentally change the way that we study BMAT function in vitro. PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health SciencesStellenbosch University Tygerberg CampusParowSouth Africa

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