From The March 2001 Issue of Nutrition Science News
by C. Leigh Broadhurst, Ph.D
The omega-3 polyunsaturated fatty acids linoleic acid and alpha-linolenic acid can help increase bone formation and reduce bone resorption
Bone strength is not normally associated with conditions such as osteo- and rheumatoid arthritis, inflammatory bowel diseases, severe food allergies, Lyme disease or the autoimmune condition known as ankylosing spondylitis. However, these conditions are known to interfere with the absorption and utilization of nutrients needed to construct healthy bone and cartilage.  Moreover, some biochemical messengers associated with these chronic inflammatory conditions directly interfere with bone growth and repair. 
In addition, all nonsteroidal anti-inflammatory drugs (NSAIDs) as well as scores of medicinal plants used to relieve the pain and inflammation associated with conditions such as arthritis, headaches, sports injuries and tendinitis work wholly or partly by inhibiting cycloxygenases such as prostaglandin E2 (PGE2). And high levels of PGE2 may do more than simply aggravate aching joints. Evidence exists that lowering PGE2 levels can actually help increase bone formation and reduce bone resorption rates. 
Investigation into this aspect of inflammation has revealed that balancing essential fatty acids in the body can prevent abnormalities in bone protein matrix growth and/or mineralization.
In the case of mammals, essential fatty acids are conventionally defined as the polyunsaturated fatty acids (PUFA) linoleic acid and alpha-linolenic acid. Both have 18 carbons in the fatty acid chain. Linoleic acid is the head of the n-6 PUFA family, and alpha-linolenic is the head of the n-3 PUFA family. These two families are not interchangeable. They are like men and womenboth sexes are humans, but one sex can never replace the other, and both are needed to continue the species.
When ingested and metabolized in the body, linoleic and alpha-linolenic acids are converted with enzymes to the more biochemically active long-chain polyunsaturated fats (LC-PUFAs). After years of laboratory studies, however, researchers have found that in humans this conversion is often slow or incomplete. Presumably this is because we are omnivores and evolved eating diets containing LC-PUFAs, thus we did not have to create them. Hence, some researchers now consider some LC-PUFAs as essential or conditionally essential. 
The 20-carbon n-6 LC-PUFA arachidonic acid (AA) is one such fatty acid that could be considered essential. Arachidonic acid is found in cell membranes throughout the body because it is necessary for numerous body processes. It also makes up about half of the PUFAs in our brains and nervous systems. The placenta and sperm are rich in AA. Infants, growing children, and pregnant and nursing women in particular appear to require arachidonic acid in the diet in order to achieve optimal growth and health.
Arachidonic acid is best known as the substrate for the series-2 eicosanoids. Eicosanoids are hormonelike biochemicals that control activities locally where they are produced. There are three series of eicosanoids, which all function in virtually the same manner.
The biochemical reactions required to make series-2 eicosanoids from arachidonic acid are controlled by the sister enzyme systems cycloxygenase and lipoxygenase. Cycloxygenases are well known for their ability to change arachidonic acid into eicosanoids such as prostaglandin E2 (PGE2). PGE2 production is an important reaction to trauma and injury, which increases inflammatory mediators as the body tries to react to the damage. Unfortunately, in many chronic conditions this process becomes unbalanced and an overproduction of PGE2 results in a chronic inflammatory response. Such a response can have long-term effects on bone health.
Bone Modeling and Remodeling
The human skeleton is not static. Bone is a highly active metabolic tissue, continually changing throughout life. The process of bone modeling is associated with body growth in children, teenagers, and young adults, when 100 percent of their bone surface is active. Modeling adds length, width, and weight to bones and increases overall skeletal mass. Bone remodeling, on the other hand, is the process of bone growth associated with maintaining a fixed adult bone mass. In remodeling, only about 20 percent of the bone surface is active. Older bone tissue is destroyed (resorption) and replaced by new bone tissue (formation) in a cyclical process.  In the case of osteoporosis, the basic problem is that resorption gets ahead of formation, resulting in a net bone loss.
Bone supports and protects, manufactures various immune and blood cells, and is a "metabolic reservoir" for calcium, magnesium, and phosphorus. While minerals such as calcium and magnesium are necessary for bone formation, they do not supply enough to produce bone. For example, calcium intake beyond dietary requirements does not stimulate bone formation. Instead, bone metabolism is under the control of many hormones and growth factors, including activated vitamin D, estrogen, growth hormone, insulin, insulinlike growth factor, parathyroid hormone, and various eicosanoidswith PGE2 playing a major role. 
At low levels, PGE2 apparently stimulates bone formation. The mechanism for this may be that PGE2 increases the production of insulinlike growth factor, a powerful "master" growth stimulator for bone, cartilage, and muscle. Surprisingly, high or excessive levels of PGE2 swamp this effect, and bone formation is reduced and resorption is increased.  In bone modeling, this pattern leads to reduced skeletal growth. In bone remodeling, this pattern leads to osteoporosis. Growth opportunity lost in childhood can never be fully compensated for in adulthood and may put an individual at greater risk for osteoporosis later in life. Therefore, it is important to maintain low levels of PGE2 throughout one's lifetime.
Nutritional Strategy for Lowering PGE2
Just as the n-6 LC-PUFA arachidonic acid gives rise to series-2 eicosanoids, eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA) serve as substrates for the series-1 and -3 eicosanoids, respectively. DGLA and EPA compete with arachidonic acid for the cycloxygenase and lipoxygenase enzymes, thereby reducingbut not eliminatingthe production of series-2 eicosanoids. High intakes of fish, black currant, evening primrose, and borage oils have been shown to moderately increase production of series-1 and -3 prostaglandins at the expense of PGE2; therefore, specialized PUFA supplementation may help optimize bone modeling and remodeling. 
In a 2000 study conducted at Purdue University in West Lafayette, Ind., this nutritional approach was tested on bone modeling in growing rats.  For 42 days, groups of 15 rats were fed identical diets except that the n-6 to n-3 PUFA ratios differed. Fish oil and safflower oil were mixed to produce n-6 to n-3 ratios of 23:8, 9:8, 2:6, and 1:2. Rat liver and bone tissue samples showed both PGE2 levels and serum alkaline phosphatase decreased as the proportion of n-6 to n-3 decreased. High levels of alkaline phosphatase indicate bone is being resorbed. Moreover, rats fed the 1:2 ratio diet had slightly higher rates of bone formation.
Only a single 1995 South African human study has specifically examined the effects of LC-PUFA supplementation on osteoporosis.  Forty elderly women with age-related osteoporosis were divided into four groups. They received one of four treatments daily for 16 weeks: 4 g evening primrose oil; 4 g fish oil; 4 g of a fish and evening primrose oil mixture; or 4 g olive oil placebo. The women took no other medications, supplements, or special foods. In this study fish oil increased serum calcium, osteocalcin and collagen, and decreased alkaline phosphatase. Evening primrose oil alone had no significant effects, but the positive results from the fish oil group were also seen in the fish oil plus evening primrose oil group. According to the research team, evening primrose oil may have potentiated the effects of fish oil.
Mood and Bone
Clinical depression in both women and men has been correlated with reduced bone density. In a 1997 National Institutes of Health study, 24 women with a history of major depression were compared to 24 controls. Subjects were matched for age, race, body-mass index, and menopausal status. Upon testing, various bone sites showed densities 6.5 to 13.6 percent lower in the depressed women.  Clinical depression is known to be associated with strongly reduced levels of n-3 LC-PUFAs, and clinically depressed people have been found to respond to fish oil supplementation. Deficiencies of n-3 PUFA may be a common link between depression and reduced bone density, both prevalent in older people. 
Bone is a complex tissue whose health and maintainence needs a great deal of nutritional support. Yet many postmenopausal women still take excessive amounts (1.5 to 2 g) of calcium per dayoften at their doctor's recommendationwithout any complementary supplements such as magnesium, silicon, boron, protein and vitamin D. Even in the natural products industry we actively push menopausal women toward soy milks and cheeses that do not naturally contain vitamin D and are not necessarily fortified with vitamin D like their dairy counterparts are. With the insights that the n-3 to n-6 PUFA ratio directly affects bone modeling, and that fish oil may increase the rate of bone formation, perhaps we can broaden our thinking beyond single "bone health" products and toward an integrated protocol approach.
Doses of 2 g per day of fish oil, evening primrose, or black currant or borage oil are reasonable and safe, and may enhance bone formation, especially when used on a long-term, preventive basis.  We can expect that those in the medical community interested in bone health will embrace these nutrients in the next five years, as was calcium in the 1990s. For those who create and dispense such supplements, the time is now.
PUFAs and Cartilage
C. Leigh Broadhurst, Ph.D., heads 22nd CenturyNutrition, a nutritional/scientific consulting firm, and is the author of Diabetes: Prevention and Cure (Kensington, 1999)
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