Do n-3 fatty acids prevent osteoporosis?

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 welldescribed 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 Hogstrom 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. Hogstrom 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 Hogstrom 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 13hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE), respectively. 13-HODE and 15-HETE