Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-26T08:12:07.051Z Has data issue: false hasContentIssue false

The effect of polyunsaturated fatty acids on bone health

Published online by Cambridge University Press:  09 February 2011

Marcello Maggio*
Affiliation:
Section of Geriatrics, University of Parma, Parma
Andrea Artoni
Affiliation:
Section of Geriatrics, University of Parma, Parma
Fulvio Lauretani
Affiliation:
Geriatric-Rehabilitation Department, University Hospital, Parma
Carmelinda Ruggiero
Affiliation:
Institute of Gerontology and Geriatrics, University of Perugia, Italy
Tommy Cederholm
Affiliation:
Section of Clinical Nutrition and Metabolism, Uppsala University, Sweden
Antonio Cherubini
Affiliation:
Institute of Gerontology and Geriatrics, University of Perugia, Italy
Gian Paolo Ceda
Affiliation:
Section of Geriatrics, University of Parma, Parma
*
Address for correspondence: Marcello Maggio, Department of Internal Medicine and Biomedical Sciences, Section of Geriatrics, University of Parma, Via Gramsci, 14 43100, Parma, Italy. Email: [email protected]

Summary

The essential polyunsaturated fatty acids (PUFAs) are divided into two classes, n-3 (ω-3) and n-6 (ω-6) and their dietary precursors are α-linolenic (ALA) and linoleic acid (LA), respectively. PUFAs are precursors of a wide range of metabolites, for example eicosanoids like prostaglandins and leukotrienes, which play critical roles in the regulation of a variety of biological processes, including bone metabolism.

A large body of evidence supports an effect of PUFA on bone metabolism which may be mediated by regulation of osteoblastogenesis and osteoclast activity, change of membrane function, decrease in inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor alpha (TNF-α), modulation of peroxisome proliferators-activated receptor γ (PPARγ) and influence in NO secretion and NO synthase.

Animal studies have shown that a higher dietary omega-3/omega-6 fatty acids ratio is associated with beneficial effects on bone health. Human studies conducted in elderly subjects suggest that omega-3 instead of omega-6 has a positive effect on bone metabolism. In spite of increasing evidence, studies conducted in humans do not allow us to draw a definitive conclusion on the usefulness of PUFAs in clinical practice.

Type
Biological gerontology
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Poulsen, RC, Moughan, PJ, Kruger, MC. Long-chain polyunsaturated fatty acids and the regulation of bone metabolism. Exp Biol Med (Maywood) 2007; 232: 1275–88.CrossRefGoogle ScholarPubMed
2Blair, HC, Schlesinger, PH, Ross, FP, Teitelbaum, SL. Recent advances toward understanding osteoclast physiology. Clin Orthop Relat Res 1993; 294: 722CrossRefGoogle Scholar
3Pead, MJ, Skerry, TM, Lanyon, LE. Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading. J Bone Miner Res 1988; 3: 647–56.CrossRefGoogle ScholarPubMed
4Harada, S, Rodan, GA. Control of osteoblast function and regulation of bone mass. Nature 2003; 423: 349–55.CrossRefGoogle ScholarPubMed
5Manolagas, SC. Cell number versus cell vigor – what really matters to a regenerating skeleton? Endocrinology 1999; 140: 4377–81.CrossRefGoogle ScholarPubMed
6Theill, LE, Boyle, WJ, Penninger, JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Ann Rev Immunol 2002; 20: 795823.CrossRefGoogle Scholar
7Theoleyre, S, Wittrant, Y, Tat, SK, Fortun, Y, Redini, F, Heymann, D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 2004; 15: 457–75.CrossRefGoogle ScholarPubMed
8Schoppet, M, Preissner, KT, Hofbauer, LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol 2002; 22: 549–53.CrossRefGoogle ScholarPubMed
9Walsh, MC, Kim, N, Kadono, Y, Rho, J, Lee, SY, Lorenzo, J, Choi, Y. Osteoimmunology: interplay between the immune system and bone metabolism. Ann Rev Immunol 2006; 24: 3363.CrossRefGoogle ScholarPubMed
10Asagiri, M, Takayanagi, H. The molecular understanding of osteoclast differentiation. Bone 2007; 40: 251–64.CrossRefGoogle ScholarPubMed
11Quinn, JM, Gillespie, MT. Modulation of osteoclast formation. Biochem Biophys Res Commun 2005; 328: 739–45.CrossRefGoogle ScholarPubMed
12Bonewald, LF. Mechanosensation and transduction in osteocytes. Bonekey Osteovision 2006; 3: 715.CrossRefGoogle ScholarPubMed
13Kanaan, RA, Kanaan, LA. Transforming growth factor beta1, bone connection. Med Sci Monit 2006; 12: RA16469.Google ScholarPubMed
14Cherian, PP, Siller-Jackson, AJ, Gu, S, Wang, X, Bonewald, LF, Sprague, E, Jiang, JX. Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell 2005; 16: 3100–6.CrossRefGoogle ScholarPubMed
15Smith, EL, Clark, WD. Cellular control of bone response to physical activity. Top Geriatr Rehab 2005; 21: 7787.CrossRefGoogle Scholar
16Yoshida, K, Oida, H, Kobayashi, T, Maruyama, T, Tanaka, M, Katayama, T, Yamaguchi, K, Segi, E, Tsuboyama, T, Matsushita, M, Ito, K, Ito, Y, Sugimoto, Y, Ushikubi, F, Ohuchida, S, Kondo, K, Nakamura, T, Narumiya, S. Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc Natl Acad Sci USA 2002; 99: 4580–85.CrossRefGoogle ScholarPubMed
17Watkins, BA, Li, Y, Lippman, HE, Feng, S. Modulatory effect of omega-3 polyunsaturated fatty acids on osteoblast function and bone metabolism. Prostaglandins Leukot Essent Fatty Acids 2003; 68: 387–98.CrossRefGoogle ScholarPubMed
18Celil, AB, Campbell, PG. BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. J Biol Chem 2005; 280: 31353–59.CrossRefGoogle ScholarPubMed
19Cashman, KD. Diet, nutrition, and bone health. J Nutr 2007; 137 (11 suppl): 250712SCrossRefGoogle ScholarPubMed
20Cashman, KD. Diet and control of osteoporosis. In Remacle, C, Reusens, B (eds). Functional Foods, Ageing and Degenerative Disease. Cambridge, UK: Woodhead Publishing Limited; 2004. pp. 83114.CrossRefGoogle Scholar
21European Commission. Report on osteoporosis in the European Community: action for prevention. Luxembourg: Office for Official Publications for the European Commission; 1998.Google Scholar
22US Department of Health and Human Services. The 2004 Surgeon General's report on bone health and osteoporosis. Washington, DC: US Department of Health and Human Services, Office of the Surgeon General; 2004.Google Scholar
23Prentice, A. Is nutrition important in osteoporosis? Proc Nutr Soc 1997; 56: 357–67.CrossRefGoogle ScholarPubMed
24World Health Organisation. Diet, nutrition and the prevention of chronic disease. Report of a joint WHO/FAO expert consulation. Technical Report Series 619. Geneva: World Health Organization; 2003.Google Scholar
25Weaver, CM. The growing years and prevention of osteoporosis in later life. Proc Nutr Soc 2000; 59: 303–6.CrossRefGoogle ScholarPubMed
26Weaver, CM. Calcium requirements of physically active people. J Clin Nutr 2000; 72 (2 suppl): 57984S.CrossRefGoogle ScholarPubMed
27Oeffinger, KC. Scurvy: more than historical relevance. Am Fam Physician 1993; 48: 609–13.Google ScholarPubMed
28Peterkofsky, B. Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy. Am J Clin Nutr 1991; 54 (6 suppl): 113540S.CrossRefGoogle ScholarPubMed
29Sugimoto, T, Nakada, M, Fukase, M, Imai, Y, Kinoshita, Y, Fujita, T. Effects of ascorbic acid on alkaline phosphatase activity and hormone responsiveness in the osteoblastic osteosarcoma cell line UMR-106. Calcif Tissue Int 1986; 39: 171–74.CrossRefGoogle ScholarPubMed
30Franceschi, RT, Young, J. Regulation of alkaline phosphatase by 1,25-dihydroxyvitamin D3 and ascorbic acid in bone-derived cells. J Bone Miner Res 1990; 5: 1157–67.CrossRefGoogle ScholarPubMed
31Hall, SL, Greendale, GA. The relation of dietary vitamin C intake to bone mineral density: results from the PEPI study. Calcif Tissue Int 1998; 63: 183–89.CrossRefGoogle ScholarPubMed
32Wang, MC, Luz Villa, M, Marcus, R, Kelsey, JL. Associations of vitamin C, calcium and protein with bone mass in postmenopausal Mexican American women. Osteoporos Int 1997; 7: 533–38.CrossRefGoogle ScholarPubMed
33Melhus, H, Michaëlsson, K, Holmberg, L, Wolk, A, Ljunghall, S. Smoking, antioxidant vitamins, and the risk of hip fracture. J Bone Miner Res 1999; 14: 129–35.CrossRefGoogle ScholarPubMed
34Maggio, D, Barabani, M, Pierandrei, M, Polidori, MC, Catani, M, Mecocci, P, Senin, U, Pacifici, R, Cherubini, A. Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. J Clin Endocrinol Metab 2003; 88: 1523–27.CrossRefGoogle ScholarPubMed
35Kruger, MC, Horrobin, DF. Calcium metabolism, osteoporosis and essential fatty acids: a review. Prog Lipid Res 1997; 36: 131–51.CrossRefGoogle ScholarPubMed
36Watkins, BA, Li, Y, Lippman, HE, Seifert, MF. Omega-3 polyunsaturated fatty acids and skeletal health. Exp Biol Med (Maywood) 2001; 226: 485–97.CrossRefGoogle ScholarPubMed
37Watkins, BA, Li, Y, Seifert, MF. Lipids as modulators of bone remodelling. Curr Opin Clin Nutr Metab Care 2001; 4: 105–10.CrossRefGoogle ScholarPubMed
38Das, UN. Essential fatty acids and osteoporosis. Nutrition 2000; 16: 386–90.CrossRefGoogle ScholarPubMed
39Lewis, RA, Austen, KF, Soberman, RJ. Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med 1990; 323: 645–55.Google ScholarPubMed
40Endres, S, Ghorbani, R, Kelley, VE, Georgilis, K, Lonnemann, G, Van Der Meer, JW, Cannon, JG, Rogers, TS, Klempner, MS, Weber, PC et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320: 265–71.CrossRefGoogle ScholarPubMed
41Fernandes, G, Lawrence, R, Sun, D. Protective role of n-3 lipids and soy protein in osteoporosis. Prostaglandins Leukot Essent Fatty Acids 2003; 68: 361–72.CrossRefGoogle ScholarPubMed
42Schlemmer, CK, Coetzer, H, Claassen, N, Kruger, MC. Oestrogen and essential fatty acid supplementation corrects bone loss due to ovariectomy in the female Sprague Dawley rat. Prostaglandins Leukot Essent Fatty Acids 1999; 61: 381–90.CrossRefGoogle ScholarPubMed
43Claassen, N, Coetzer, H, Steinmann, CM, Kruger, MC. The effect of different n-6/n-3 essential fatty acid ratios on calcium balance and bone in rats. Prostaglandins Leukot Essent Fatty Acids 1995; 53: 1319.CrossRefGoogle ScholarPubMed
44Haag, M, Magada, ON, Claassen, N, Bohmer, LH, Kruger, MC. Omega-3 fatty acids modulate ATPases involved in duodenal Ca absorption. Prostaglandins Leukot Essent Fatty Acids 2003; 68: 423–29.CrossRefGoogle ScholarPubMed
45Coetzer, H, Claassen, N, van Papendorp, DH, Kruger, MC. Calcium transport by isolated brush border and basolateral membrane vesicles: role of essential fatty acid supplementation. Prostaglandins Leukot Essent Fatty Acids 1994; 50: 257–66.CrossRefGoogle ScholarPubMed
46Claassen, N, Potgieter, HC, Seppa, M, Vermaak, WJH, Coetzer, H, Vanpapendorp, DH, Kruger, MC. Supplemented gamma-linolenic acid and eicosapentaenoic acid influence bone status in young male rats: effects on free urinary collagen cross-links, total urinary hydroxyproline, and bone calcium content. Bone 1995; 16: S38592.CrossRefGoogle Scholar
47Kruger, M, Coetzer, H, de Winter, R, Claassen, N. Eicosapentaenoic acid and docosahexaenoic acid supplementation increases calcium balance. Nutr Res 1995; 15: 211–19.CrossRefGoogle Scholar
48Stillwell, W, Wassall, SR. Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids 2003; 126: 127.CrossRefGoogle ScholarPubMed
49Simons, K, Ehehalt, R. Cholesterol, lipid rafts, and disease. J Clin Invest 2002; 110: 597603.CrossRefGoogle ScholarPubMed
50Sepulveda, MR, Berrocal-Carrillo, MB, Gasset, M, Mata, AM. The plasma membrane Ca2+-ATPase isoform 4 is localized in lipid rafts of cerebellum synaptic plasma membranes. J Biol Chem 2006; 281: 447453.CrossRefGoogle ScholarPubMed
51Tu, X, Huang, A, Bae, D, Slaughter, N, Whitelegge, J, Crother, T, Bickel, P, Nel, A. Proteome analysis of lipid rafts in jurkat cells characterizes a raft subset that is involved in NF-kappaB activation. J Proteome Res 2004; 3: 445–54.CrossRefGoogle ScholarPubMed
52Valentine, R, Valentine, D. Omega-3 fatty acids in cellular membranes: a unified concept. Prog Lipid Res 2004; 43: 383402.CrossRefGoogle ScholarPubMed
53Armstrong, VT, Brzustowicz, MR, Wassall, SR, Jenski, LJ, Stillwell, W. Rapid flip-flop in polyunsaturated (docosahexaenoate) phospholipid membranes. Arch Biochem Biophys 2003; 414: 7482.CrossRefGoogle ScholarPubMed
54Priante, G, Bordin, L, Musacchio, E, Clari, G, Baggio, B. Fatty acids and cytokine mRNA expression in human osteoblastic cells: a specific effect of arachidonic acid. Clin Sci 2002; 102: 403–9.CrossRefGoogle Scholar
55Bordin, L, Priante, G, Musacchio, E, Giunco, S, Tibaldi, E, Clari, G. Arachidonic acid-induced IL-6 expression is mediated by PKC alpha activation in osteoblastic cells. Biochemistry 2003; 42: 4485–91.CrossRefGoogle ScholarPubMed
56Chandrasekar, B, Fernandes, G. Decreased pro-inflammatory cytokines and increased antioxidant enzyme gene expression by omega-3 lipids in murine lupus nephritis. Biochem Biophys Res Commun 1994; 200: 893–98.CrossRefGoogle ScholarPubMed
57Ferrucci, L, Cherubini, A, Bandinelli, S, Bartali, B, Corsi, A, Lauretani, F, Martin, A, Andres-Lacueva, C, Senin, U, Guralnik, JM. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 2006; 91: 439–46.CrossRefGoogle ScholarPubMed
58Gheorghiade, H. Effects of n3 polynsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomiophaty. Heart Failure Society of America, Scientific Meeting, Sept 15; 2010.Google Scholar
59Kehn, P, Fernandes, G. The importance of omega-3 fatty acids in the attenuation of immune-mediated diseases. J Clin Immunol 2001; 21: 99101.CrossRefGoogle ScholarPubMed
60Akune, T, Ohba, S, Kamekura, S, Yamaguchi, M, Chung, UI, Kubota, N, Terauchi, Y, Harada, Y, Azuma, Y, Nakamura, K, Kadowaki, T, Kawaguchi, H. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 2004; 113: 846–55.CrossRefGoogle ScholarPubMed
61Ali, AA, Weinstein, RS, Stewart, SA, Parfitt, AM, Manolagas, SC, Jilka, RL. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 2005; 146: 1226–35.CrossRefGoogle ScholarPubMed
62Schwartz, AV, Sellmeyer, DE, Vittinghoff, E, Palermo, L, Lecka-Czernik, B, Feingold, KR, Strotmeyer, ES, Resnick, HE, Carbone, L, Beamer, BA, Park, SW, Lane, NE, Harris, TB, Cummings, SR. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 2006; 91: 3349–54.CrossRefGoogle ScholarPubMed
63Vanek, C, Connor, WE. Do n-3 fatty acids prevent osteoporosis? Am J Clin Nutr 2007; 85: 647–48.CrossRefGoogle ScholarPubMed
64Collins, DA, Chambers, TJ. Effect of prostaglandins E1, E2 and F2a on osteoclast formation in mouse bone marrow cultures. J Bone Miner Res 1991; 6: 157–64.CrossRefGoogle Scholar
65Jee, WSS, Ma, YF. The in vivo anabolic actions of prostaglandins in bone. Bone 1997; 21: 297304.CrossRefGoogle ScholarPubMed
66Corwin, RL. Effects of dietary fats on bone health in advanced age. Prostaglandin Leukot Essent Fatty Acids 2003; 68: 379–86.CrossRefGoogle Scholar
67Evans, DB, Bunning, RA, Russell, RG. The effects of recombinant human interleukin-1 beta on cellular proliferation and the production of prostaglandin E2, plasminogen activator, osteocalcin and alkaline phosphatase by osteoblast-like cells derived from human bone. Biochem Biophys Res Commun 1990; 166: 208–16.CrossRefGoogle ScholarPubMed
68Evans, DB, Thavarajah, M, Kanis, JA. Involvement of prostaglandin E2 in the inhibition of osteocalcin synthesis by human osteoblast-like cells in response to cytokines and systemic hormones. Biochem Biophys Res Commun 1990; 167: 194202.CrossRefGoogle ScholarPubMed
69Igarashi, K, Hirafuji, M, Adachi, H. Role of endogenous PGE2 in osteoblastic functions of a clonal osteoblast-like cell, MC3T3-E1. Prostaglandins Leukot Essent Fatty Acids 1994; 50: 169–72.CrossRefGoogle ScholarPubMed
70Igarashi, K, Hirafuji, M, Adachi, H. Effects of bisphosphonates on alkaline phosphatase activity, mineralization, and prostaglandin E2 synthesis in the clonal osteoblast-like cell line MC3T3-E1. Prostaglandins Leukot Essent Fatty Acids 1997; 56: 121–25.CrossRefGoogle ScholarPubMed
71Kajii, T, Suzuki, K, Yoshikawa, M. Long-term effects of prostaglandin PGE2 on the mineralization of a clonal osteoblastic cell line (MC3T3-E1). Arch Oral Biol 1999; 44: 233–41.CrossRefGoogle ScholarPubMed
72Raisz, LG, Alander, CB, Simmons, HA. Effects of prostaglandin E3 and eicosapentaenoic acid on rat bone in organ culture. Prostaglandins 1989; 37: 615–25.CrossRefGoogle ScholarPubMed
73Laneuville, O, Breuer, DK, Xu, N, Huang, ZH, Gage, DA, Watson, JT. Fatty acid substrate specificities of human prostaglandin-endoperoxide H synthase-1 and -2. J Biol Chem 1995; 270: 19330–36.CrossRefGoogle ScholarPubMed
74Watkins, BA, Li, Y, Allen, KGD, Hoffman, WE, Seifert, MF. Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats. J Nutr 2000; 130: 2274–84.CrossRefGoogle Scholar
75Li, Y, Seifert, MF, Ney, DM, Grahn, M, Grant, AL, Allen, KGD. Dietary conjugated linoleic acids alter serum IGF-I and IGF binding protein concentrations and reduce bone formation in rats fed (n-6) or (n-3) fatty acids. J Bone Miner Res 1999; 14: 1153–62.CrossRefGoogle ScholarPubMed
76Shen, CL, Peterson, J, Tatum, OL, Dunn, DM. Effect of long-chain n-3 polyunsaturated fatty acid on inflammation mediators during osteoblastogenesis. J Med Food 2008; 11: 105–10.CrossRefGoogle ScholarPubMed
77Tian, XY, Zhang, Q, Setterberg, RB, Zeng, QQ, Iturria, SJ, Ma, YF. Continuous PGE2 leads to net bone loss while intermittent PGE2 leads to net bone gain in lumbar vertebral bodies of adult female rats. Bone 2008; 42: 914–20.CrossRefGoogle ScholarPubMed
78Ono, K, Kaneko, H, Choudhary, S, Pilbeam, CC, Lorenzo, JA, Akatsu, T. Biphasic effect of prostaglandin E2 on osteoclast formation in spleen cell cultures: role of the EP2 receptor. J Bone Miner Res 2005; 20: 2329.CrossRefGoogle ScholarPubMed
79Tsutsumi, R, Xie, C, Wei, X, Zhang, M, Zhang, X, Flick, LM. PGE2 signaling through the EP4 receptor on fibroblasts upregulates RANKL and stimulates autolysis. J Bone Miner Res 2009; 24: 1753–62.CrossRefGoogle Scholar
80Calder, PC. N-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 2006; 83: 1505–19S.CrossRefGoogle ScholarPubMed
81Liu, XH, Kirschenbaum, A, Yao, S, Levine, AC. Interactive effect of interleukin-6 and prostaglandin E2 on osteoclastogenesis via the OPG/RANKL/RANK system. Ann NY Acad Sci 2006; 1068: 225–33.CrossRefGoogle ScholarPubMed
82Watkins, B, Lippman, H, Le Boutellier, L, Li, Y, Seifert, M. Bioactive fatty acids: role in bone biology and bone cell function. Prog Lipid Res 2001; 40:125–48.CrossRefGoogle ScholarPubMed
83Hamid, R, Singh, J, Reddy, BS, Cohen, LA. Inhibition by dietary menhaden oil of cyclooxygenase-1 and 2 in N-nitrosomethylurea-induced rat mammary tumors. Int J Oncol 1999; 14: 523–28.Google ScholarPubMed
84Shen, RF, Tai, HH. Thromboxanes: synthase and receptors. J Biomed Sci 1998; 5: 153–72.CrossRefGoogle ScholarPubMed
85Ramirez-Yanez, GO, Hamlet, S, Jonarta, A, Seymour, GJ, Symons, AL. Prostaglandin E2 enhances transforming growth factor-beta 1 and TGF-beta receptor synthesis: an in vivo and in vitro study. Prostaglandin Leukot Essent Fatty Acids 2006; 74: 183.CrossRefGoogle ScholarPubMed
86Martinez-Ramirez, MJ, Palma, S, Martinez-Gonzalez, MA, Delgado-Martinez, AD, De la Fuente, C, Delgado-Rodriques, M. Dietary fat intake and the risk of osteoporotic fractures in the elderly. Eur J Clin Nutr 2007; 61: 1114–20.CrossRefGoogle ScholarPubMed
87Watkins, BA, Seifert, MF. Conjugated linoleic acid and bone biology. J Am Coll Nutr 2000; 19: 478–86S.CrossRefGoogle ScholarPubMed
88Wang, Y, Nishida, S, Elalieh, HZ, Long, RK, Halloran, BP, Bikle, DD. Role of IGF-1 signalling in regulating osteoclastogenesis. J Bone Miner Res 2006; 21: 1350–58.CrossRefGoogle ScholarPubMed
89Weiler, HA, Fitzpatrick-Wong, SC. Dietary long-chain polyunsaturated fatty acids minimize dexamethasone-induced reductions in arachidonic acid status but not bone mineral content in piglets. Pediatr Res 2002; 51: 282–89.CrossRefGoogle Scholar
90Delany, AM, Pash, JM, Canalis, E. Cellular and clinical perspectives on skeletal insulin-like growth factor I. J Cell Biochem 1994; 55: 328–33.CrossRefGoogle ScholarPubMed
91Das, UN. Nitric oxide as the mediator of the antiosteoporotic actions of estrogen, statins, and essential fatty acids. Exp Biol Med 2002; 227: 8893.CrossRefGoogle ScholarPubMed
92Armour, KE, van't Hof, RJ, Grabowski, PS. Evidence for a pathogenic role of nitric oxide in inflammation-induced osteoporosis. J Bone Miner Res 1999; 14: 2137–42.CrossRefGoogle ScholarPubMed
93Fan, X, Roy, E, Zhu, L, Murphy, TC, Ackert-Bicknell, C, Hart, CM. Nitric oxide regulates receptor activator of nuclear factor-kB ligand and osteoprotegerin expression in bone marrow stromal cells. Endocrinology 2004; 145: 751–59.CrossRefGoogle Scholar
94Priante, G, Musacchio, E, Pagnin, E, Calo, LABaggio, B. Specific effect of arachidonic acid on inducible nitric oxide synthase (iNOS) mRNA expression in human osteoblastic cells. Clin Sci 2005; 109: 177182.CrossRefGoogle ScholarPubMed
95Sakaguchi, K, Morita, I, Murota, S. Eicosapentaenoic acid inhibits bone loss due to ovariectomy in rats. Prostaglandins Leukot Essent Fatty Acids 1994; 50: 8184.CrossRefGoogle ScholarPubMed
96Sun, D, Krishnan, A, Zaman, K, Lawrence, R, Bhattacharya, A, Fernandes, G. Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice. J Bone Miner Res 2003; 18: 1206–16.CrossRefGoogle ScholarPubMed
97Shen, CL, Yeh, JK, Rasty, J, Li, Y, Watkins, BA. Protective effect of dietary long-chain n-3 polyunsaturated fatty acids on bone loss in gonad-intact middle-aged male rats. Br J Nutr 2006; 95: 462–68.CrossRefGoogle Scholar
98Shen, CL, Yeh, JK, Rasty, J, Chyu, MC, Dunn, DM, Li, Y, Watkins, BA. Improvement of bone quality in gonad-intact middle-aged male rats by long-chain n-3 polyunsaturated fatty acid. Calcif Tissue Int 2007; 80: 286–93.CrossRefGoogle ScholarPubMed
99Michaëlsson, K, Holmberg, L, Mallmin, H, Wolk, A, Bergström, R, Ljunghall, S. Diet, bone mass, and osteocalcin: a cross-sectional study. Calcif Tissue Int 1995; 57: 8693.CrossRefGoogle ScholarPubMed
100Kruger, MC, Coetzer, H, de Winter, R, Gericke, G, van Papendorp, DH. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano) 1998; 10: 385–94.Google ScholarPubMed
101Terano, T. Effect of omega 3 polyunsaturated fatty acid ingestion on bone metabolism and osteoporosis. World Rev Nutr Diet 2001; 88: 141–47.CrossRefGoogle Scholar
102Van Papendorp, DH, Coetzer, H, Kruger, MG; Biochemical profile of osteoporotic patients on essential fatty acid supplementation. Nutrition Res 1995; 15: 325–34.CrossRefGoogle Scholar
103Macdonald, HM, New, SA, Golden, MH, Campbell, MK, Reid, DM. Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids. Am J Clin Nutr 2004; 79: 45.CrossRefGoogle ScholarPubMed
104Weiss, LA, Barrett-Connor, E, von Mühlen, D. Ratio of n-6 to n-3 fatty acids and bone mineral density in older adults: the Rancho Bernardo Study. Am J Clin Nutr 2005; 81: 934–38.CrossRefGoogle ScholarPubMed
105Griel, AE, Kris-Etherton, PM, Hilpert, KF, Zhao, G, West, SG, Corwin, RL. An increase in dietary n-3 fatty acids decreases a marker of bone resorption in humans. Nutr J 2007; 6: 2.CrossRefGoogle ScholarPubMed
106Corwin, RL, Hartman, TJ, Maczuga, SA, Graubard, BI. Dietary saturated fat intake is inversely associated with bone density in humans: analysis of NHANES III. J Nutr 2006; 136: 159–65.CrossRefGoogle ScholarPubMed
107Högström, M, Nordström, P, Nordström, A. n-3 Fatty acids are positively associated with peak bone mineral density and bone accrual in healthy men: the NO2 Study. Am J Clin Nutr 2007; 85: 803–7.CrossRefGoogle ScholarPubMed
108Bassey, E, Littlewood, J, Rothwell, M, Pye, D. Lack of effect of supplementation with essential fatty acids on bone mineral density in healthy pre- and post-menopausal women: two randomized controlled trials of Efacal® v. calcium alone. Br J Nutr 2000; 83: 629–35.CrossRefGoogle Scholar
109Dodin, S, Lemay, A, Jacques, H, Legare, F, Forest, JC, Masse, B. The effects of flaxseed dietary supplement on lipid profile, bone mineral density, and symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial. J Clin Endocrinol Metab 2005; 90: 1390–97.CrossRefGoogle ScholarPubMed
110Salari, P, Rezaie, A, Larijani, B, Abdollahi, M. A systematic review of the impact of n-3 fatty acids in bone health and osteoporosis. Med Sci Monit 2008; 14: RA3744.Google ScholarPubMed
111Kruger, MC, Coetzee, M, Haag, M, Weiler, H. Long chain polynsaturated fatty acids: selected mechanism of action on bone. Prog Lipid Res 2010; 49: 438–49.CrossRefGoogle Scholar