Weiss LA, Barrett-Connor E & von Mn D. Ratio of n6 to n3 fatty acids and bone mineral density in older adults: the Rancho Bernardo Study
Am J Clin Nut, 2005;81(4):934-938

Background: Several lines of evidence suggest that n3 fatty acids reduce the risk of some chronic diseases, including heart disease, diabetes, and cancer. Other research, mainly in animals, also suggests a role in bone health.

Objective: We aimed to investigate the association between the ratio of dietary n6 to n3 fatty acids and bone mineral density (BMD) in 1532 community-dwelling men and women aged 45 90 y.

Design: Between 1988 and 1992, dietary data were obtained through self-administered food-frequency questionnaires, and BMD was measured at the hip and spine with the use of dual-energy X-ray absorptiometry. A medical history was obtained and current medication use was validated. Age- and multiple-adjusted linear regression analyses were performed.

Results: There was a significant inverse association between the ratio of dietary linoleic acid to -linolenic acid and BMD at the hip in 642 men, 564 women not using hormone therapy, and 326 women using hormone therapy; these results were independent of age, body mass index, and lifestyle factors.
An increasing ratio of total dietary n6 to n3 fatty acids was also significantly and independently associated with lower BMD at the hip in all women and at the spine in women not using hormone therapy.

Conclusions: A higher ratio of n6 to n3 fatty acids is associated with lower BMD at the hip in both sexes.
These findings suggest that the relative amounts of dietary polyunsaturated fatty acids may play a vital role in preserving skeletal integrity in older age.

Watkins B, Li Y, Lippman H,and Seifert M. Experimental Biology and Medicine 2001,226:485-497

Omega-3 Polyunsaturated Fatty Acids and Skeletal Health

This minireview on skeletal biology describes the actions of prostaglandins and cytokines involved in the local regulation of bone metabolism, it documents the role of lipids in bone biology, and it presents relationships between fatty acids and other factors that impact skeletal metabolism. The data presented herein show consistent and reproducible beneficial effects of omega-3 (n-3) fatty acids on bone metabolism and bone/joint diseases. Polyunsaturated fatty acids modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression. These effects have not been explored in the skeletal system. Future research on n-3 fatty acids in bone biology should focus on the following two aspects. First, the further elucidation of how n-3 fatty acids alter biochemical and molecular processes involved in bone modeling and bone cell differentiation, and second, the evaluation of the potential pharmaceutical applications of these nutraceutical fatty acids in maintaining bone mineral status and controlling inflammatory bone/joint diseases.

Bhattacharya A, Rahman M, et al. Inhibition of Osteoporosis in Autoimmune Disease Prone MRL/Mpj-Faslpr Mice by N-3 Fatty Acids. J Am Coll Nut, 2005; 24(3)200-209

Objective: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease involving the breakdown of cartilage and juxta-articular bone, which is often accompanied by decreased bone mineral density (BMD) and increased risk of fracture.
Anti-inflammatory omega-3 fatty acids may prevent arthritis and bone loss in MRL/lpr mice model of arthritis and in humans.

Methods: In this study, the effect of long term feeding of 10% dietary n-3 (fish oil (FO)) and n-6 (corn oil (CO)) fatty acids begun at 6 weeks of age on bone mineral density (BMD) in different bone regions in an MRL/lpr female mouse model of RA was measured at 6, 9, and 12 months of age by dual energy x-ray absorptiometry (DEXA).

After sacrificing the mice at 12 months of age, antioxidant enzyme activities were measured in spleen, mRNA for receptor activator of NF-B ligand (RANKL) and osteoprotegerin (OPG) was measured by RT-PCR in lymph nodes, and synovitis was measured in leg joints.

Results: At 6, 9 and 12 months of age, BMD was significantly higher (p < 0.05) in distal femur, proximal tibia, and lumbar spine of FO fed mice than those of CO fed mice.
Spleen catalase (CAT) and superoxide dismutase (SOD) activities were also significantly higher (p < 0.01) in FO fed mice than in CO fed mice.

Histology of knee joints revealed mild synovitis in CO fed mice, which was not present in FO fed mice. RT-PCR analysis of lymph nodes revealed decreased RANKL mRNA (p < 0.001) expression and enhanced OPG mRNA expression (p < 0.01) in FO fed mice compared to CO fed mice.

Conclusions: These results suggest beneficial effects of long-term FO feeding in maintaining higher BMD and lower synovitis in this mouse model.
These beneficial effects may be due, in part, to increased activity of antioxidant enzymes, decreased expression of RANKL, and increased expression of OPG in FO fed mice thereby altering the RANKL/OPG ratio.

These significant beneficial effects on BMD suggest that FO may serve as an effective dietary supplement to prevent BMD loss in patients with RA.

Hamazaki K, Itomura M, et al. Fish oil reduces tooth loss mainly through its anti-inflammatory effects? Med Hypotheses, 2006;67(4):868-870.

Competing at several steps of arachidonic acid metabolism, n-3 fatty acids reduce production of highly active prostaglandins and leukotrienes and exert anti-inflammatory effects. They are also experimentally shown to be anti-osteoporotic.

Periodontitis is responsible for most tooth loss in adult populations. If enough n-3 fatty acids are provided, periodontitis with alveolar bone resorption may be controlled, and tooth loss may be prevented.

In fact, n-3 fatty acid administration lowered prostaglandin E(2) production, tooth movement and alveolar bone resorption in animal experiments. Aggression, which may be related with tooth loss, was also controlled with fish oil.

Our cross-sectional data supported our hypothesis. We recruited 256 men (22-59 y of age) and 95 women (22-66 y), counted the numbers of their remaining teeth, and analyzed the fatty acid composition of the total phospholipid fraction of RBCs. The beta-coefficient of the numbers of remaining teeth and EPA concentrations in the fraction was 0.89 (per 1% EPA, p=0.007) after adjustment for 9 possible confounding factors.

Long-term intervention studies with fish oil planned in the future should be able to test our hypothesis by just adding another very simple endpoint in those studies: tooth loss during the intervention period.

This hypothesis may explain the linkage between periodontitis/tooth loss and coronary heart disease.

Essential fats may prevent bone loss. USA Today. Vol. 134, No. 2725, pp 15(1)

Maintaining a proper balance of dietary fats may ward off much of the bone loss associated with postmenopausal osteoporosis, states a study by scientists at the Indiana University School of Medicine, Bloomington, and Purdue University, West Lafayette, Ind.

The researchers found that diets with a low ratio of omega-6 fatty acids to omega-3 fatty acids minimizes the bone loss typically brought on by estrogen deficiency, which is common in post-menopausal females.
Omega-6 is found in foods such as grains and beef, while omega-3 is contained in products like walnuts and salmon.

"Many people don't realize it, but our bones are not static structures," explains Mark Seifert, professor of anatomy and cell biology at Indiana University.
Bones undergo a process called "remodeling," in which they continuously are broken down and rebuilt.
Two types of cells govern this process--bone resorption cells, which remove small portions of bone, and bone building cells, which fill in the gaps.
Estrogen blocks some of the inflammatory compounds associated with bone resorption, which may explain why osteoporosis typically progresses after estrogen levels fall with the onset of menopause.

"Our lab and others have shown that omega-3 fatty acids help promote bone formation," reports Bruce Watkins, professor and director of Purdue's Center for Enhancing Foods to Protect Health. "We also have shown that higher intakes of omega-6 fatty acids lead to an increased production of compounds associated with bone loss."

While both types of fats are essential for human health, diets with a high ratio of omega-6 to omega-3 fatty acids often are associated with cardiovascular disease, cancer, and inflammatory and autoimmune diseases.

A low ratio, however, is believed to promote cardiovascular health, improve memory and, as the study demonstrates, protect bone health.

"We saw in this study that omega-3 fatty acids are associated with a better blood profile of bone health, and with higher bone mineral density, in the absence of estrogen," Watkins notes. "A five-to-one dietary ratio of omega-6 to omega-3 fatty acids led to a conservation of bone mineral content that we didn't see with a 10-to-one ratio."

The average American's dietary ratio is approximately 10 to one, which is inflated by the types of foods people eat and the methods used to produce those foods, especially those containing vegetable oils. "Our foods are different today than they were yesterday," he says. "Omega-6 fatty acids have been an important part of our diet but, over the past 80 years, the human diet has shifted in a way that increased the ratio of omega-6 to omega-3 fatty acids."

The omega-6 fatty acids in today's animal feed incorporate right into the animals' tissues where they become part of the eggs, poultry, meats, and pork served in households and restaurants across the country.

Kruger MC, Schollum LM.Is docosahexaenoic acid more effective than eicosapentaenoic acid for increasing calcium bioavailability? Prosta, Leukot Essent Fatty Acids,2005;73(5):327-334.

Experimental animal and human studies have indicated that long chain polyunsaturated fatty acids (LCPUFA) may enhance calcium absorption, reduce urinary calcium excretion, and increase bone calcium content.

In the present study, the effect of LCPUFA, as provided in evening primrose oil, fish and tuna oils, on calcium bioavailability was investigated. Growing male rats were fed a semi-synthetic diet for 6 weeks, after which calcium absorption, bone mineral density (ex vivo), bone calcium content, and bone biomechanics were measured.

Calcium absorption, ex vivo bone mineral density, and bone calcium content were significantly higher in the animals fed tuna oil compared with those of a control group fed corn oil.

Significant correlations were found between the docosahexaenoic acid (DHA) (22:6n-3) content of the red cell membranes and bone density and bone calcium content.

DHA increased accretion of calcium in bone significantly more so than eicosapentaenoic acid (EPA) (20:5n-3).

Watkins BA, Li Y, Lippman HE, Feng S. Modulatory effect of omega-3 polyunsaturated fatty acids on osteoblast function and bone metabolism. Prosta Leukot Essent Fatty Acids, 2003 Jun;68(6):387-98.

Recent investigations indicate that the type and amount of polyunsaturated fatty acids (PUFA) influence bone formation in animal models and osteoblastic cell functions in culture.

In growing rats, supplementing the diet with omega-3 PUFA results in greater bone formation rates and moderates ex vivo prostaglandin E(2) production in bone organ cultures.

A protective effect of omega-3 PUFA on minimizing bone mineral loss in ovariectomized rats has also been reported. The actions of omega-3 fatty acids on bone formation appear to be linked to altering osteoblast functions.

Herein we describe experiments with MC3T3-E1 osteoblast-like cells that support findings in vivo where omega-3 PUFA modulated COX-2 protein expression, reduced prostaglandin E(2) production, and increased alkaline phosphatase activity.

Other studies indicate that the dietary source of PUFA may affect protein expression of Cbfa1 and nodule formation in fetal rat calvarial cells.

PMID: 12798659

Claassen N, Coetzer H, et al. The effect of different n-6/n-3 essential fatty acid ratios on calcium balance and bone in rats. Prosta Leukot Essent Fatty Acids,1995;53(1):13-19

Prostaglandins (PGs) are known to have various effects on bone metabolism.

The supplementation of essential fatty acids (EFAs), the precursors of PGs, leads to increased intestinal calcium absorption and calcium balance.

It is, however, not known whether increased calcium absorption and calcium balance will enhance the calcium content in bone.

Male Sprague-Dawley rats (n = 40) aged 5-12 weeks were supplemented with EFAs. The main dietary EFAs, linoleic acid (LA) and alpha-linolenic acid (ALA) were administered in a ratio of 3:1 as a control group.

The conversion of LA ans ALA to the PG precursors is slow, with the first step, delta-6-desaturation being rate limiting.

Fatty acids beyond this rate-limiting step, gamma-linolenic acid (GLA, n-6) and eicoapentaenioc acid (EPA, n-3), were administered to different groups in the ratios 3:1, 1:1 and 1:3 to explore the impact of different ratios of n-6 and n-3 EFAs.

Intestinal calcium absorption (mg/24 h) increased by 41.5% in the 3:1 supplemented group, compared with the control group. The decrease in urinary calcium (mg/24 h) correlated with the increase in n-3 level.

The calcium balance (mg/24 h) and bone calcium (mg/g bone ash) increased significantly in the 3:1 (41.5% and 24.7%) group, compared with the control.

The increase in bone calcium might be attributed to an EFA-induced increase in circulating PGs.

An increased synthesis of PGs acting on target bone cells, as well as changes in membrane fluidity, may underlie these observations.