Investigating the Role of Polyunsaturated Fatty Acids in Bone Development Using Animal Models
Investigating the Role of Polyunsaturated Fatty Acids in Bone Development Using Animal Models
Year: 2013
Authors: Lau, B.Y. Cohen, D.J. Ward, W.E. Ma, D.W.
Publication Name: Molecules
Publication Details: Volume 18; Issue 11; Pages 14203-27
Abstract:
Incorporating n 3 polyunsaturated fatty acids (PUFA) in the diet may promote the development of a healthy skeleton and thereby reduce the risk of developing osteoporosis in later life. Studies using developing animal models suggest lowering dietary n 6 PUFA and increasing n 3 PUFA intakes, especially long chain n 3 PUFA, may be beneficial for achieving higher bone mineral content, density and stronger bones. To date, the evidence regarding the effects of α linolenic acid (ALA) remain equivocal, in contrast to evidence from the longer chain products, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This review reports the results of investigations into n 3 PUFA supplementation on bone fatty acid composition, strength and mineral content in developing animal models as well as the mechanistic relationships of PUFA and bone, and identifies critical areas for future research. Overall, this review supports a probable role for essential (ALA) and long chain (EPA and DHA) n 3 PUFA for bone health. Understanding the role of PUFA in optimizing bone health may lead to dietary strategies that promote bone development and maintenance of a healthy skeleton. (Authors abstract)
The purpose of this review is to examine the evidence to date on the effects of n 3 and n 6 PUFA on bone and to critically identify gaps in our understanding. Although much attention is given to the beneficial health effects of longer chain EPA and DHA on bone metabolism, health effects of ALA are much less understood. Only a few studies have investigated how feeding a diet rich in ALA alters bone health in developing animals. Li et al. examined the effects of ALA (0.48 per cent w per w flaxseed oil) and LA (8.5 per cent w per w safflower oil) rich diets on bone fatty acid composition in growing female rats for 12 weeks, with both diets receiving 10 per cent w per w total fat. Compared to the high LA group, the ALA group had a significantly lower ratio of n 6 per n 3 in the femoral cortical bone, specifically enriched in ALA and DHA. Although DHA was enriched with ALA feeding, EPA was only present in trace amounts, suggesting that bone specifically incorporates DHA preferentially over EPA. However, the ALA enriched diet did not have an effect on lowering the AA composition in the bone. Similarly, it was demonstrated that newborn rat pups raised on an n 3 adequate diet with ALA, or an n 3 deficient diet with LA as the main PUFA source for 15 weeks resulted in significantly higher levels of ALA and DHA in the femoral periosteum and bone marrow in the adequate group. It was demonstrated that high fat diets rich in ALA and LA as 20 per cent w per w of diet, resulted in modification of tissue fatty acid composition mirroring the diets in both bone marrow and femur diaphysis. However, there were no discernible changes in the composition of EPA, DHA or AA, suggesting that increasing fat content in the diet may have had a negative impact on the conversion of ALA and LA to their longer chain products. Overall, these studies collectively show that feeding ALA results in selective enrichment of DHA compared to EPA in bone. A number of studies have compared the effects of feeding ALA to EPA and per or DHA to discern if there are differences in fatty acid content in bone. Feeding fish oil to growing male quails resulted in higher levels of EPA and DHA in tibial cortical bone relative to soybean oil (containing 7 per cent of fatty acids as ALA) fed quails. In a rat study, ALA as 0.3 per cent of the diet was needed to achieve the same level of DHA in bone as rats fed DHA as 0.1 per cent of the diet. In another study, female rats were exposed to ALA plus DHA, ALA, LA, or high LA from five weeks before conception, as the corresponding diets were also fed to the dams, to 12 weeks of age. ALA and ALA plus DHA groups had higher ALA and DHA in bone and lower total n 6 PUFA than LA and high LA groups, although AA levels were only lower in the ALA plus DHA group. DHA levels were higher than ALA levels in all the groups, again suggesting that DHA is preferred in bone tissue. The level of DHA achieved by feeding rats ALA alone was not as high as feeding rats both ALA with DHA. Overall, feeding ALA resulted in less DHA incorporation into bone as compared to feeding preformed DHA from fish oil. It is evident from these studies that direct feeding of fish oil or DHASCO containing the preformed fatty acids is more efficient in the incorporation of EPA and DHA into bone. Additionally, in the studies examined, fish oil tends to have the effect of lowering AA content in bone, whereas this effect is blunted or absent in flaxseed or soybean fed animals. These differences in incorporation into tissue with different n 3 sources may explain the discrepancies in the functional outcomes discussed in the next section.
In addition to studies demonstrating that changes in dietary fatty acid composition are reflected in bone tissue, studies have examined the effects of ALA alone on bone development, which have yielded mixed results. Overall, due to the limited number of studies showing a weak or absent effect of ALA, it is not possible yet to conclude a definitive role for ALA in bone health. However, despite these conflicting results, these studies demonstrate no adverse effects of ALA. Comparing the results of studies involving ALA with studies using EPA and DHA, ALA appears to have a lesser effect than their long chain products. Although it is possible that ALA indirectly exerts its effects through its conversion into EPA and or DHA, the likelihood or the effectiveness of this mechanism relies on the rate of conversion, which is known to be low in humans. However, the conversion of PUFA is also known to be species and tissue specific, with rodents possessing a higher capacity to convert ALA and LA to their long chain products. In the studies using ALA, there are differences in the methodology that may explain the conflicting findings. Feeding rats an ALA rich diet in utero demonstrated positive results, whereas feeding similar ALA rich diets postnatally did not confer any positive benefits. Therefore, it is possible that any action of ALA on bone health may be programmed as early as during gestation, and ALA may exert its potentially favourable effects during a limited developmental window. While further research is needed, the available data indicates a potentially beneficial effect of n 3 PUFA, especially DHA. Moreover, the potential benefit of ALA rich diets vs. traditionally termed “unhealthy” fats should be studied.
The evidence presented in this review provides a probable role for EPA and DHA in bone health during development, while the function of ALA remains poorly understood. Although generally regarded as pro and anti inflammatory, n 6 and n 3 PUFA, respectively, appear to have effects in bone metabolism that exist outside these stereotypical roles. In general, there remains much to be understood about the individual effects of specific n 6 and n 3 PUFA. To further refine our understanding of fatty acids and bone development, there are a number of knowledge gaps needing further study including dose and type of PUFA; timing of exposure; gender differences. There is a probable role for n 3 PUFA in the development of stronger bones, with EPA and DHA intervention being more efficacious than ALA. Whether this translates to reduced fracture risk in humans remains to be determined. Both n 3 and n 6 PUFA play a role in bone development. Future research should be aimed at determining the dose, duration, and timing of exposure to individual n 3 and n 6 PUFA throughout the lifecycle. n3 PUFA may improve bone health by increasing calcium absorption in the gut, and increasing osteoblast differentiation and activity, reducing osteoclast activity and promoting deposition of mineral in developing bones. These mechanisms require further study. (Editors comments)
The purpose of this review is to examine the evidence to date on the effects of n 3 and n 6 PUFA on bone and to critically identify gaps in our understanding. Although much attention is given to the beneficial health effects of longer chain EPA and DHA on bone metabolism, health effects of ALA are much less understood. Only a few studies have investigated how feeding a diet rich in ALA alters bone health in developing animals. Li et al. examined the effects of ALA (0.48 per cent w per w flaxseed oil) and LA (8.5 per cent w per w safflower oil) rich diets on bone fatty acid composition in growing female rats for 12 weeks, with both diets receiving 10 per cent w per w total fat. Compared to the high LA group, the ALA group had a significantly lower ratio of n 6 per n 3 in the femoral cortical bone, specifically enriched in ALA and DHA. Although DHA was enriched with ALA feeding, EPA was only present in trace amounts, suggesting that bone specifically incorporates DHA preferentially over EPA. However, the ALA enriched diet did not have an effect on lowering the AA composition in the bone. Similarly, it was demonstrated that newborn rat pups raised on an n 3 adequate diet with ALA, or an n 3 deficient diet with LA as the main PUFA source for 15 weeks resulted in significantly higher levels of ALA and DHA in the femoral periosteum and bone marrow in the adequate group. It was demonstrated that high fat diets rich in ALA and LA as 20 per cent w per w of diet, resulted in modification of tissue fatty acid composition mirroring the diets in both bone marrow and femur diaphysis. However, there were no discernible changes in the composition of EPA, DHA or AA, suggesting that increasing fat content in the diet may have had a negative impact on the conversion of ALA and LA to their longer chain products. Overall, these studies collectively show that feeding ALA results in selective enrichment of DHA compared to EPA in bone. A number of studies have compared the effects of feeding ALA to EPA and per or DHA to discern if there are differences in fatty acid content in bone. Feeding fish oil to growing male quails resulted in higher levels of EPA and DHA in tibial cortical bone relative to soybean oil (containing 7 per cent of fatty acids as ALA) fed quails. In a rat study, ALA as 0.3 per cent of the diet was needed to achieve the same level of DHA in bone as rats fed DHA as 0.1 per cent of the diet. In another study, female rats were exposed to ALA plus DHA, ALA, LA, or high LA from five weeks before conception, as the corresponding diets were also fed to the dams, to 12 weeks of age. ALA and ALA plus DHA groups had higher ALA and DHA in bone and lower total n 6 PUFA than LA and high LA groups, although AA levels were only lower in the ALA plus DHA group. DHA levels were higher than ALA levels in all the groups, again suggesting that DHA is preferred in bone tissue. The level of DHA achieved by feeding rats ALA alone was not as high as feeding rats both ALA with DHA. Overall, feeding ALA resulted in less DHA incorporation into bone as compared to feeding preformed DHA from fish oil. It is evident from these studies that direct feeding of fish oil or DHASCO containing the preformed fatty acids is more efficient in the incorporation of EPA and DHA into bone. Additionally, in the studies examined, fish oil tends to have the effect of lowering AA content in bone, whereas this effect is blunted or absent in flaxseed or soybean fed animals. These differences in incorporation into tissue with different n 3 sources may explain the discrepancies in the functional outcomes discussed in the next section.
In addition to studies demonstrating that changes in dietary fatty acid composition are reflected in bone tissue, studies have examined the effects of ALA alone on bone development, which have yielded mixed results. Overall, due to the limited number of studies showing a weak or absent effect of ALA, it is not possible yet to conclude a definitive role for ALA in bone health. However, despite these conflicting results, these studies demonstrate no adverse effects of ALA. Comparing the results of studies involving ALA with studies using EPA and DHA, ALA appears to have a lesser effect than their long chain products. Although it is possible that ALA indirectly exerts its effects through its conversion into EPA and or DHA, the likelihood or the effectiveness of this mechanism relies on the rate of conversion, which is known to be low in humans. However, the conversion of PUFA is also known to be species and tissue specific, with rodents possessing a higher capacity to convert ALA and LA to their long chain products. In the studies using ALA, there are differences in the methodology that may explain the conflicting findings. Feeding rats an ALA rich diet in utero demonstrated positive results, whereas feeding similar ALA rich diets postnatally did not confer any positive benefits. Therefore, it is possible that any action of ALA on bone health may be programmed as early as during gestation, and ALA may exert its potentially favourable effects during a limited developmental window. While further research is needed, the available data indicates a potentially beneficial effect of n 3 PUFA, especially DHA. Moreover, the potential benefit of ALA rich diets vs. traditionally termed “unhealthy” fats should be studied.
The evidence presented in this review provides a probable role for EPA and DHA in bone health during development, while the function of ALA remains poorly understood. Although generally regarded as pro and anti inflammatory, n 6 and n 3 PUFA, respectively, appear to have effects in bone metabolism that exist outside these stereotypical roles. In general, there remains much to be understood about the individual effects of specific n 6 and n 3 PUFA. To further refine our understanding of fatty acids and bone development, there are a number of knowledge gaps needing further study including dose and type of PUFA; timing of exposure; gender differences. There is a probable role for n 3 PUFA in the development of stronger bones, with EPA and DHA intervention being more efficacious than ALA. Whether this translates to reduced fracture risk in humans remains to be determined. Both n 3 and n 6 PUFA play a role in bone development. Future research should be aimed at determining the dose, duration, and timing of exposure to individual n 3 and n 6 PUFA throughout the lifecycle. n3 PUFA may improve bone health by increasing calcium absorption in the gut, and increasing osteoblast differentiation and activity, reducing osteoclast activity and promoting deposition of mineral in developing bones. These mechanisms require further study. (Editors comments)
