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Teriparatide Decreases Bone Density, but Not Strength

Abstract

Changes in trabecular and cortical bone microarchitecture at peripheral sites associated with 18 months of teriparatide therapy in postmenopausal women with osteoporosis.

We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to monitor changes in bone microarchitecture and strength at the distal radius and tibia associated with 18 months of teriparatide therapy in postmenopausal women with osteoporosis. Despite treatment-associated declines in total and cortical BMD, trabecular thinning and reduced trabecular bone volume, bone strength did not change significantly from baseline.
Teriparatide is an established anabolic therapy for osteoporosis; however, treatment effects at the distal radius are unclear. Therefore, we aimed to monitor changes in bone microarchitecture and estimated strength at the distal radius and tibia in osteoporotic postmenopausal women.
We used high-resolution peripheral quantitative computed tomography (Scanco Medical, Switzerland) to perform a standard three-dimensional morphological analysis of the distal radius and tibia in 11 osteoporotic postmenopausal women (mean age, 68.7 ± 12.7 years) at baseline, 6, 12, and 18 months after initiation of 20 μg/day of teriparatide. Ten of the women received bisphosphonate therapy prior to starting on teriparatide. In addition to the standard analysis, we quantified cortical bone mineral density (BMD), porosity, and thickness using an automated segmentation procedure and estimated bone strength (ultimate stress) using finite element analysis.
After 18 months, we observed a decrease in total BMD (p = 0.03) at the distal radius and a decrease in cortical BMD at the distal radius (p = 0.05) and tibia (p = 0.01). The declines in cortical BMD were associated with trends for increased cortical porosity at both sites. At the distal radius, 18 months of teriparatide treatment was also associated with trabecular thinning (p = 0.009) and reduced trabecular bone volume ratio (p = 0.08). We observed similar trends at the distal tibia. Despite these changes in bone quality, bone strength was maintained over the 18-month follow-up.
The observed changes in cortical bone structure are consistent with the effects of parathyroid hormone on intracortical bone remodeling. Controlled trials involving larger sample sizes are required to confirm the effects of teriparatide therapy on trabecular and cortical microarchitecture in the peripheral skeleton.

Macdonald HM, Nishiyama KK, Hanley DA, Boyd SK
Osteoporos Int Jan 2011
PMID: 20458576 | Full Text

Although our sample size was small, our results are consistent with previous reports of declines in cortical BMD at the radius [8, 9, 18] and at the femoral neck [6] with teriparatide therapy. The decrease in cortical BMD in the present study was coupled with increased cortical porosity at both sites; however, cortical porosity was only statistically different from baseline at the distal tibia after 12 months. Despite a more porous cortex, FE analysis indicated that bone strength did not appear to be compro- mised with teriparatide treatment. This finding supports observations from animal models in which treatment with PTH activated intracortical remodeling and lead to in- creased intracortical porosity [19, 20], but did not compro- mise bone strength [20]. This was likely due to localization of the porosity near the endocortical surface where its influence on bone’s mechanical properties is minimal [20], although this spatial distribution needs to be confirmed in future HR-pQCT studies. In the present study, a slightly thicker cortical shell and enlarged cortical area may also have offset the higher cortical porosity at the distal tibia. Similar changes in cortical bone geometry were observed in rabbits [19] and monkeys [20] treated with PTH and were attributed to increased bone formation on the endocortical surface. In addition, postmenopausal women treated with teriparatide for a median of 18 months had significantly larger cortical area at the distal radius compared with untreated women as measured with pQCT, but no pretreatment com- parison was obtained [18]. Whether PTH has an anabolic effect on the periosteal surface remains unclear [19, 20]….

We acknowledge limitations of our study including the small sample size and the fact that all but one of the women had received prior therapy with bisphosphonates. The degree to which prior bisphosphonate therapy blunts the bone response to teriparatide remains unclear, as in some instances, it does not appear to do so [4, 23]. Since distal radius fractures are recognized indicators of osteoporosis [24], there is an obvious need for larger clinical trials that employ HR-pQCT to monitor and compare the treatment- related effects of teriparatide on bone microarchitecture and strength in treatment-naïve subjects and subjects with a history of bisphosphonate therapy.

Teriparatide Stimulates Bone Formation and Resorption, and Decreases Fracture Risk

Abstract

Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown.
We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry.
New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache).
Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Neer RM, Arnaud CD, Zanchetta JR, Prince R…
N. Engl. J. Med. May 2001
PMID: 11346808 | Free Full Text

Parathyroid hormone stimulates bone formation and resorption and can increase or decrease bone mass, depending on the mode of administration. Continuous infusions and daily subcutaneous injections of parathyroid hormone stimulate bone formation similarly but have different effects on bone resorption and bone mass.1,2 Continuous infusions, which result in a persistent elevation of the serum parathyroid hormone concentration, lead to greater bone resorption than do daily injections, which cause only transient increases in the serum parathyroid hormone concentration.3

Coconut Oil Reduces Oxidative Stress of Bone in Rats

Abstract

The effects of virgin coconut oil on bone oxidative status in ovariectomised rat.

Virgin coconut oil (VCO) was found to have antioxidant property due to its high polyphenol content. The aim of this study was to investigate the effect of the virgin coconut oil on lipid peroxidation in the bone of an osteoporotic rat model. Normal female Sprague-Dawley rats aged 3 months old were randomly divided into 4 groups, with 8 rats in each group: baseline, sham, ovariectomised (OVX) control group, and OVX given 8% VCO in the diet for six weeks. The oxidative status of the bone was assessed by measuring the index of lipid peroxidation, which is malondialdehyde (MDA) concentration, as well as the endogenous antioxidant enzymes glutathione peroxidase (GPX) and superoxide dismutase (SOD) in the tibia at the end of the study. The results showed that there was a significant decrease in MDA levels in the OVX-VCO group compared to control group. Ovariectomised rats treated with VCO also had significantly higher GPX concentration. The SOD level seemed to be increased in the OVX-VCO group compared to OVX-control group. In conclusion, VCO prevented lipid peroxidation and increased the antioxidant enzymes in the osteoporotic rat model.

Abujazia MA, Muhammad N, Shuid AN, Soelaiman IN
Evid Based Complement Alternat Med 2012
PMID: 22927879 | Free Full Text

This is significant for bone strength because:

Increased activity of reactive oxygen species (ROS) leads to overexpressions of TNF-α, RANKL, and M-CSF which enhance osteoclasts function and induce bone loss [7, 8]. Oxidative stress also suppresses bone formation by inhibiting osteoblast differentiation and decreasing the survival of these cells [9, 10].

Review: Nutrients for Bone Health

Abstract

Essential Nutrients for Bone Health and a Review of their Availability in the Average North American Diet.

Osteoporosis and low bone mineral density affect millions of Americans. The majority of adults in North America have insufficient intake of vitamin D and calcium along with inadequate exercise. Physicians are aware that vitamin D, calcium and exercise are essential for maintenance of bone health. Physicians are less likely to be aware that dietary insufficiencies of magnesium, silicon, Vitamin K, and boron are also widely prevalent, and each of these essential nutrients is an important contributor to bone health. In addition, specific nutritional factors may improve calcium metabolism and bone formation. It is the authors’ opinion that nutritional supplements should attempt to provide ample, but not excessive, amounts of factors that are frequently insufficient in the typical American diet. In contrast to dietary insufficiencies, several nutrients that support bone health are readily available in the average American diet. These include zinc, manganese, and copper which may have adverse effects at higher levels of intake. Some multivitamins and bone support products provide additional quantities of nutrients that may be unnecessary or potentially harmful. The purpose of this paper is to identify specific nutritional components of bone health, the effects on bone, the level of availability in the average American diet, and the implications of supplementation for each nutritional component. A summary of recommended dietary supplementation is included.

Price CT, Langford JR, Liporace FA
Open Orthop J 2012
PMID: 22523525 | Free Full Text

Oral intake of 2 gm/day of strontium ranelate have improved bone strength and reduced fracture rates in women with osteoporosis, but there are reports of increased risks of venous blood clots and memory loss [82, 87].

Arginine May Increase Bone Formation by Increasing Silicon Absorption in Rats

Abstract

Dietary silicon and arginine affect mineral element composition of rat femur and vertebra.

Both arginine and silicon affect collagen formation and bone mineralization. Thus, an experiment was designed to determine if dietary arginine would alter the effect of dietary silicon on bone mineralization and vice versa. Male weanling Sprague-Dawley rats were assigned to groups of 12 in a 2 x 2 factorially arranged experiment. Supplemented to a ground corn/casein basal diet containing 2.3 microg Si/g and adequate arginine were silicon as sodium metasilicate at 0 or 35 microg/g diet and arginine at 0 or 5 mg/g diet. The rats were fed ad libitum deionized water and their respective diets for 8 wk. Body weight, liver weight/body weight ratio, and plasma silicon were decreased, and plasma alkaline phosphatase activity was increased by silicon deprivation. Silicon deprivation also decreased femoral calcium, copper, potassium, and zinc concentrations, but increased the femoral manganese concentration. Arginine supplementation decreased femoral molybdenum concentration but increased the femoral manganese concentration. Vertebral concentrations of phosphorus, sodium, potassium, copper, manganese, and zinc were decreased by silicon deprivation. Arginine supplementation increased vertebral concentrations of sodium, potassium, manganese, zinc, and iron. The arginine effects were more marked in the silicon-deprived animals, especially in the vertebra. Germanium concentrations of the femur and vertebra were affected by an interaction between silicon and arginine; the concentrations were decreased by silicon deprivation in those animals not fed supplemental arginine. The change in germanium is consistent with a previous finding by us suggesting that this element may be physiologically important, especially as related to bone DNA concentrations. The femoral and vertebral mineral findings support the contention that silicon has a physiological role in bone formation and that arginine intake can affect that role.

Seaborn CD, Nielsen FH
Biol Trace Elem Res Dec 2002
PMID: 12462747

Arginine is an essential amino acid for the rat. In animals L-arginine apparently induces growth hormone and insulin-like growth factor-1 responses and stimulates nitric oxide synthase. Growth hormone and insulin-like growth factor-1 are important mediators of bone turnover and osteoblastic bone formation, whereas nitric oxide is a potent inhibitor of osteoclastic bone resorption (1). By affecting these physiological regulators of bone remodeling, L-arginine could potentially increase bone formation over bone resorption and, consequently, increase bone mass.

There is experimental evidence suggesting that arginine supplementation promotes bone formation. A mixture of lactose, L-arginine, and L-lysine improved fracture healing of rabbits subjected to an osteotomy of the left fibula (2). These authors suggested that arginine was involved not only in the increase of intestinal calcium absorption but also in collagen synthesis. Although there is evidence that L-arginine affects bone maintenance minimal attention has been given to the possible interaction between arginine and other macro and/or trace minerals, including silicon associated with mineralized bone formation and remodeling.

Silicon can affect bone formation and remodeling (3). The basic amino acids such as arginine can increase silicon absorption (4). Therefore the effects of silicon on bone mineralization may be modified by the amount of arginine in the diet….

Low Dose MK-4 May Benefit Bones in Postmenopausal Japanese Women

Abstract

Effect of low dose vitamin K2 (MK-4) supplementation on bio-indices in postmenopausal Japanese women.

It has been reported that treatment with a pharmacological dose (45 mg/d) of menaquinone-4 (MK-4) prevents bone loss in postmenopausal women. However, it is not known whether supplementation with low dose MK-4 has beneficial effects on bone metabolism in healthy women. The aim of this study is to examine the effects of the supplementation of 1.5 mg/d MK-4 for 4 wk on bone and lipid metabolism in healthy postmenopausal Japanese women. The study was performed as a randomized double blind placebo-controlled trial. The participants aged 53-65 y were randomly assigned to 2 groups and supplemented with 1.5 mg/d of MK-4 or a placebo for 4 wk (n=20 for each group). The most marked effects of MK-4 intake were observed on serum osteocalcin (OC) concentrations. Serum undercarboxylated OC (ucOC) concentration decreased, and the gamma-carboxylated OC (GlaOC) and GlaOC/GlaOC+ucOC ratio that indicates the degree of OC gamma-carboxylation increased significantly at 2 and 4 wk compared with that at baseline in the MK-4 group. The serum ucOC and GlaOC concentrations in the MK-4 group were significantly different from those in the placebo group at 2 wk. These results suggest that supplementation with 1.5 mg/d MK-4 accelerated the degree of OC gamma-carboxylation. The concentrations of serum lipids and other indices were not different between the groups at either intervention period. Thus, the additional intake of MK-4 might be beneficial in the maintenance of bone health in postmenopausal Japanese women.

Koitaya N, Ezaki J, Nishimuta M, Yamauchi J…
J. Nutr. Sci. Vitaminol. Feb 2009
PMID: 19352059 | Free Full Text

In conclusion, our study clearly shows that the vitamin K status of postmenopausal women taking an extra dose of 1.5 mg MK-4 daily substantially improved after 4 wk. This improved satus was evidenced by the more than 1 ng/mL of serum MK-4 concentration. This suggests that increasing MK-4 intake by 1.5 mg/d led to an increase in the degree of γ-carboxylation of OC. Thus, the supplementation of low doses of vitamin K2 may favorably affect bone health in healthy postmenopausal women. It is desirable that the required amount of vitamin K be taken with daily meals.

Review: Vitamin K and Bone Health

Abstract

Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health.

Vitamin K occurs in nature as a series of compounds with a common 2-methyl- 1,4 naphthoquinone nucleus and differing isoprenoid side chains at the 3 position. They comprise a single major plant form, phylloquinone with a phytyl side chain and a family of bacterially synthesized menaquinones (MKs) with multiprenyl side chains. The major dietary source to humans is phylloquinone for which the chief food contributors are green, leafy vegetables followed by certain vegetable oils (soybean, rapeseed and olive oils). Recent analyses by high pressure liquid chromatography are now providing a wide-ranging database of phylloquinone in foods. Menaquinones are found in moderate concentrations in only a few foods such as cheeses (MK-8 and MK-9). A wider spectrum of MKs is synthesized by the gut microflora, and their intestinal absorption probably accounts for most of the hepatic stores, particularly those with very long side chains (MKs-10-13) synthesized by members of the genus Bacteroides. The site of absorption of floral MKs is not known, but reasonable concentrations are found in the terminal ileum where bile salt-mediated absorption is possible. Both phylloquinone and menaquinones are bioactive in hepatic gamma-carboxylation but long-chain MKs are less well absorbed. Liver stores of vitamin K are relatively small and predominantly MKs-7-13. The hepatic reserves of phylloquinone (approximately 10% of the total) are labile and turn over at a faster rate than menaquinones. Trabecular and cortical bone appear to contain substantial concentrations of both phylloquinone and menaquinones. A majority (approximately 60-70%) of the daily dietary intake of phylloquinone is lost to the body by excretion, which emphasizes the need for a continuous dietary supply to maintain tissue reserves.

Shearer MJ, Bach A, Kohlmeier M
J. Nutr. Apr 1996
PMID: 8642453 | Free Full Text

At the present time the human requirements for vitamin K are based solely on its classical function in coagulation being listed as a Recommended Dietary Allowance (RDA) in the United States (Suttie 1992) and a Safe and Adequate Intake in the United Kingdom (Department of Health Report 1991). In both cases these requirements were set at a value of 1 mcg/kg/d. If, as argued by Vermeer et al. and Kohlmeier et al. in this volume, vitamin K is important to bone health and its requirements for this bone function are greater than for its hepatic function, a great challenge to researchers and future committees alike is to determine whether these putative extra demands can be quantified more precisely. Finally, it should be noted that the concept of reexamining the optimal intake of a vitamin with respect to the extra health benefits, which may be conferred by giving amounts over and above those required to protect against the originally discovered deficiency disease, is not new. There is already a recognition of the newer and often unexpected roles played by several other vitamins including in some cases the beneficial effects of extra intakes (Sauberlich and Machlin 1992).

Lactosucrose Enhances Calcium Absorption in Young Women

Abstract

Long-term administration of 4G-beta-D-galactosylsucrose (lactosucrose) enhances intestinal calcium absorption in young women: a randomized, placebo-controlled 96-wk study.

This study determined the effect of long-term administration of 4(G)-beta-D-galactosylsucrose (lactosucrose; LS) on intestinal calcium absorption. In a randomized, single-blind, parallel-group study, LS (n=9, 6.0 g twice daily) or a placebo (maltose; n=8, 6.0 g twice daily) was administered to healthy young women for 92 wk: the study also included a 4-wk post-administration period. All participants completed the study. Dietary nutrient intake; fecal weight, pH, and moisture content; fecal concentrations of short-chain fatty acids (SCFA), putrefactive products, ammonia, and minerals (calcium, magnesium, phosphorus, and iron); and serum calcium and osteocalcin concentrations were measured every 24 wk. Urinary pyridinoline (PYR) and deoxypyridinoline (DPD), and urinary calcium excretion were measured every 12 wk. Significant effects of oligosaccharide treatment, time, and the interaction between oligosaccharide treatment and time were observed for fecal pH, SCFA, ammonia, and putrefactive product values (p<0.05). Fecal pH, ammonia, and putrefactive product values decreased in the LS group, and the fecal SCFA concentration significantly increased during the administration period; these changes were not observed 4 wk post-administration. To examine the mineral balance of calcium, magnesium, and phosphorus in detail, all the participants completed a 6-d mineral balance study, sometime between week 56 and 60 of the longer study. During the mineral balance study, the daily calcium intake was set at 400 mg; all feces and urine were collected each day for 6 d after an 8-d acclimation period. In the balance study, fecal calcium excretion was significantly lower in the LS group than in the placebo group (p<0.05), and apparent calcium absorption and retention, apparent magnesium and phosphorus absorption, and magnesium retention were significantly higher in the LS group than in the placebo group (p<0.05). Our results suggest that the administration of LS produces a long-term enhancement of intestinal calcium absorption in healthy young women with lower than recommended calcium intakes.

Teramoto F, Rokutan K, Sugano Y, Oku K…
J. Nutr. Sci. Vitaminol. Oct 2006
PMID: 17190104 | Free Full Text

BMD did not differ between groups.

The lack of change in BMD might have been influenced by enhanced intestinal phosphorus absorption as a consequence of the enhanced intestinal calcium absorption during LS administration.

The insufficient calcium intake, age of the participants, ratio of calcium to phosphorus in the diet, and changes in LS administration may have influenced BMD.

Review: Statins and Bone Formation

Abstract

Statins, bone formation and osteoporosis: hope or hype?

Osteoporosis is a major health problem affecting both men and women. Statins, besides their action as lipid-lowering agents, seem to have additional pleiotropic properties, among them a beneficial effect on bone mineral density. The entirety of experimental and the majority of clinical studies as well as the only relevant meta-analysis suggest that statins have an anabolic effect on bone metabolism. Statins, osteoporosis and adipogenesis share the same pathway, RANKL/OPG. It would appear that an imbalance in this pathway could be responsible for the manifestation of some metabolic disorders such as diabetes mellitus, atherogenesis, multiple myeloma, osteoporosis. Possibly in the future, drugs which can intervene in this biochemical and pathophysiological cascade, like statins, in a variety of doses, could be used for the management of ectopic ossification syndromes and other bone disorders, even as an additive treatment. Until then, further large longitudinal randomized controlled studies for each statin separately are required to confirm this hypothesis.

Tsartsalis AN, Dokos C, Kaiafa GD, Tsartsalis DN…
Hormones (Athens)
PMID: 22801558 | Free Full Text

All the available data from the literature, including evidence from experimental studies as well as from the vast majority of observational studies and the results of a single meta-analysis, suggested that there is a positive effect of statins on BMD, although another meta-analysis by Bauer et al72 showed evidence that the beneficial effects on BMD and on fracture risk are observational, while many limitations and the placebo-controlled trials did not demonstrate any clear-cut benefit. However, the in vitro and some clinical studies (Chuengsamarn et al71) suggest that statins inhibit bone resorption and stimulate bone formation, having a dual action on bone metabolism. Therefore, in the future statins might gain a position among drugs used for the prevention and management of osteoporosis, taking into account that clinicians already have a good deal of experience in prescribing statins, for other indications, and feel familiar with this drug family. Their anabolic and anti-resorptive effects on bone make them an ideal candidate for osteoporosis treatment.

EPA + DHA: Possible Mechanism

Abstract

PTH1 receptor is involved in mediating cellular response to long-chain polyunsaturated fatty acids.

The molecular pathways by which long chain polyunsaturated fatty acids (LCPUFA) influence skeletal health remain elusive. Both LCPUFA and parathyroid hormone type 1 receptor (PTH1R) are known to be involved in bone metabolism while any direct link between the two is yet to be established. Here we report that LCPUFA are capable of direct, PTH1R dependent activation of extracellular ligand-regulated kinases (ERK). From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, eicosapentaenoic (EPA) and docosahexaenoic fatty acids (DHA) caused the highest ERK phosphorylation. Moreover, EPA potentiated the effect of parathyroid hormone (PTH(1-34)) in a superagonistic manner. EPA or DHA dependent ERK phosphorylation was inhibited by the PTH1R antagonist and by knockdown of PTH1R. Inhibition of PTH1R downstream signaling molecules, protein kinases A (PKA) and C (PKC), reduced EPA and DHA dependent ERK phosphorylation indicating that fatty acids predominantly activate G-protein pathway and not the β-arrestin pathway. Using picosecond time-resolved fluorescence microscopy and a genetically engineered PTH1R sensor (PTH-CC), we detected conformational responses to EPA similar to those caused by PTH(1-34). PTH1R antagonist blocked the EPA induced conformational response of the PTH-CC. Competitive binding studies using fluorescence anisotropy technique showed that EPA and DHA competitively bind to and alter the affinity of PTH1 receptor to PTH(1-34) leading to a superagonistic response. Finally, we showed that EPA stimulates protein kinase B (Akt) phosphorylation in a PTH1R-dependent manner and affects the osteoblast survival pathway, by inhibiting glucocorticoid-induced cell death. Our findings demonstrate for the first time that LCPUFAs, EPA and DHA, can activate PTH1R receptor at nanomolar concentrations and consequently provide a putative molecular mechanism for the action of fatty acids in bone.

Candelario J, Tavakoli H, Chachisvilis M
PLoS ONE 2012
PMID: 23300710 | Free Full Text

In human studies, it has been shown that consuming EPA improved bone quality in elderly female subjects [21]. Consumption of ω-3 fatty acids was also associated with reduced incidence and severity of inflammatory bone/joint diseases in humans [22]. There is evidence of the potential of EPA to counteract bone loss associated with spaceflight; higher consumption of fish (ω-3) was associated with reduced loss of bone mineral density (BMD) after flight [23]. BMD of the total body showed a significant negative correlation with serum concentrations of oleic acids and monounsaturated fatty acids and significant correlations with DHA and ω-3 fatty acids [24]. A higher ratio of ω-6 to ω-3 fatty acids is associated with lower BMD at the hip in both sexes suggesting the relative amounts of dietary PUFA may play a vital role in preserving skeletal integrity in older age [25].