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1 From the Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, OR
2 Address reprint requests to WE Connor, Department of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L465, Portland, OR 97239. E-mail: connorw{at}ohsu.edu.
See corresponding article on page 803.
The essential polyunsaturated fatty acids (PUFAs) comprise 2 main classes: n–6 and n–3 fatty acids. The most common source of n–6 fatty acids is linoleic acid (LA), which is found in high concentrations in various vegetable oils. Arachidonic acid (AA), the 20-carbon n–6 fatty acid, is obtained largely by synthesis from LA in the body. The n–3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in fish and fish oils. The beneficial health effects of these two n–3 fatty acids were first described in the Greenland Eskimos, who consumed a high-seafood diet and had low rates of coronary heart disease, asthma, type 1 diabetes mellitus, and multiple sclerosis. Since that observation, the positive health attributes of n–3 fatty acids have been extended to include benefits related to cancer, inflammatory bowel disease, rheumatoid arthritis, and psoriasis (1, 2).
Both n–3 and n–6 fatty acids are incorporated into cellular phospholipid membranes, where they serve as precursors to the production of eicosanoids, such as prostaglandins, leukotrienes, and thromboxanes. Eicosanoid metabolites of n–3 fatty acids are less atherogenic, proinflammatory, and vasocontrictive than are the eicosanoids from n–6 fatty acids. For example, prostaglandin E2, thromboxane A2, and leukotriene B4 are derived from AA by cyclooxygenase and lipoxygenase enzymes and are well-described mediators of platelet aggregation, immune response, and vasoreactivity. Conversely, EPA is metabolized by cyclooxygenase and lipoxygenase to prostaglandin E3 and leukotriene B5, which are lesser promoters of platelet aggregation and immune reactivity (1). Dietary supplementation with n–3 fatty acids also reduces the production of interleukin 1 and tumor necrosis factor in response to an endotoxin stimuli (3). Therefore, a diet high in n–3 fatty acids favorably modulates the production of eicosanoids and cytokines that play a deleterious role in heart disease, cancer, and autoimmune diseases.
The study by Högström et al (4) in this issue of the Journal nicely adds to a growing body of evidence that n–3 fatty acids are also beneficial to bone health. Högström et al determined the fatty acid composition of the serum phospholipid fraction of 78 healthy young men and found a positive correlation between the n–3 fatty acid content and bone mineral density (BMD). BMD at the spine at age 22 y and changes in spinal BMD between the ages of 16 and 22 y were significantly correlated with higher serum concentrations of total n–3 fatty acids and DHA. Also, a negative association was found between higher ratios of n–6 to n–3 fatty acids and spinal BMD accrual between ages 16 and 22 y. A negative association between higher ratios of n–6 to n–3 fatty acids and BMD was also found in an earlier study of elderly men and women (5). However, the study by Högström et al is unique in that it measured serum fatty acid concentrations rather than use a dietary-recall questionnaire to determine fatty acid intakes.
Animal models have suggested that n–3 fatty acids may attenuate postmenopausal bone loss. Ovariectomized mice fed a diet high in fish oil had significantly less bone loss at the femur and lumbar vertebrae than did ovariectomized mice fed a diet high in n–6 fatty acids (6). In vitro models using a preosteoblastic cell line, MC3T3-E1, indicated a greater production of the bone-formation markers alkaline phosphatase and osteocalcin after 48 h of treatment with EPA than after treatment with AA (7).
An additional mechanism of postmenopausal bone loss involves the findings that 1) increased marrow adiposity accompanies osteoporosis in aging populations (8) and 2) osteoblasts are derived from pluripotent mesenchymal stem cells that can differentiate into mature osteoblasts or adipocytes (9). An important regulatory mechanism controlling this differentiation is the peroxisome proliferator–activated receptor (PPAR) nuclear transcription factor. PPAR is a member of the nuclear receptor superfamily of proteins that mediates ligand-dependent transcriptional activation and repression. This protein governs genes that regulate metabolic functions, such as lipogenesis, fatty acid oxidation, and glucose uptake. PPAR is expressed in adipose tissue and bone marrow.
Heterozygous PPAR-deficient mice created by gene targeting exhibited enhanced osteoblastogenesis, increased bone volume, and decreased adipogenesis in femoral histology, radiology, and bone marrow stem cell cultures (10). Mice fed rosiglitazone, the PPAR agonist, showed reduced bone mass, decreased osteoblasts, and increased marrow adiposity (11). Elderly women with type 2 diabetes who were taking PPAR agonist (eg, troglitazone, pioglitazone, and rosiglitazone) antidiabetic medication had greater bone loss at the lumbar spine than did those who were not taking this class of medication (12). Importantly, the n–6 polyunsaturated fatty acids can also activate PPAR (13).
LA and AA are oxidized by lipoxygenases to form 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE), respectively. 13-HODE and 15-HETE are known activators of PPAR (13). In contrast, lipoxygenases convert EPA and DHA into 15-hydroxyeicosapentaenoic acid and 17-hydroxydocosahexanoic acid, which are not known activators of PPAR. Overexpression of the Alox15 gene in mice, a lipoxygenase that converts LA and AA into 13-HODE and 15-HETE, results in decreased femoral BMD and femoral failure load (14). Allelic variations in the human lipoxygenase homologue, ALOX12 and ALOX15 on chromosome 17, are linked to variations in spinal BMD (15, 16).
Lowering the dietary ratio of n–6 to n–3 fatty acids may diminish PPAR activation and thereby promote osteoblastogenesis at the expense of bone marrow adiposity. Unfortunately, the few studies that have been conducted to determine the effects of PUFAs on the prevention or treatment of osteoporosis have been contradictory (17). Sixty-five postmenopausal women receiving PUFA supplements (60% LA, 8% -linolenic acid, 4% EPA, and 3% DHA) had statistically significant increases in lumbar spine and femoral neck BMD compared with placebo. However, a study of 42 postmenopausal women receiving a similar mixture of PUFA supplements showed no significant increases in BMD compared with women receiving placebo. Both studies used high amounts of n–6 fatty acids (LA and -linolenic), which may have interfered with the outcomes.
n–3 Fatty acids play an important role in health and disease (2) and are thought to favorably affect skeletal health as well. The diseases prevented or ameliorated by n–3 fatty acids are as follows: coronary heart disease, stroke, autoimmune disorders, inflammatory bowel disease, osteoporosis, and cancers of the breast, colon, and prostate. The attainment of peak bone mass in adolescence and the prevention of age-related osteoporosis are potential positive effects of n–3 fatty acids. Further elucidation of the physiologic effects of n–3 fatty acids on bone health, along with clinical trials of EPA and DHA to prevent or treat osteoporosis, is needed.
ACKNOWLEDGMENTS
The authors had no conflicts of interest to disclose.
REFERENCES
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