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Omega-3 Associated with Peak Bone Density in Men

Abstract

n-3 Fatty acids are positively associated with peak bone mineral density and bone accrual in healthy men: the NO2 Study.

Knowledge of the influence of nutritional intake on bone health is limited. Polyunsaturated fatty acids have been suggested to influence bone growth and modeling in humans, although data are sparse.
The objective was to investigate the role of fatty acids in bone accumulation and the attainment of peak bone mass in young men.
The cohort studied consisted of 78 healthy young men with a mean age of 16.7 y at baseline. Bone mineral density (BMD; in g/cm(2)) of total body, hip, and spine was measured at baseline and at 22 and 24 y of age. Fatty acid concentrations were measured in the phospholipid fraction in serum at 22 y of age.
Concentrations of n-3 fatty acids were positively associated with total BMD (r = 0.27, P = 0.02) and spine BMD (r = 0.25, P = 0.02) at 22 y of age. A positive correlation between n-3 fatty acid concentrations and the changes in BMD at the spine (r = 0.26, P = 0.02) was found between 16 and 22 y of age. Concentrations of docosahexaenoic acid (DHA, 22:6n-3) were positively associated with total BMD (r = 0.32, P = 0.004) and BMD at the spine (r = 0.30, P = 0.008) at 22 y of age. A positive correlation was also found between DHA concentrations and the changes in BMD at the spine (r = 0.26, P = 0.02) between 16 and 22 y of age.
The results showed that n-3 fatty acids, especially DHA, are positively associated with bone mineral accrual and, thus, with peak BMD in young men.

Högström M, Nordström P, Nordström A
Am. J. Clin. Nutr. Mar 2007
PMID: 17344503 | Free Full Text

High Omega-6:Omega-3 Ratios Increase Fracture Risk and Doubles Risk for Ratios > 6

Abstract

The association of red blood cell n-3 and n-6 fatty acids with bone mineral density and hip fracture risk in the women’s health initiative.

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA) in red blood cells (RBCs) are an objective indicator of PUFA status and may be related to hip fracture risk. The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women. A nested case-control study (n = 400 pairs) was completed within the Women’s Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study. Cases were 1:1 matched on age, race, and hormone use with non-hip fracture controls. Stored baseline RBCs were analyzed for fatty acids using gas chromatography. After removing degraded samples, 324 matched pairs were included in statistical analyses. Stratified Cox proportional hazard models were constructed according to case-control pair status; risk of fracture was estimated for tertiles of RBC PUFA. In adjusted hazard models, lower hip fracture risk was associated with higher RBC α-linolenic acid (tertile 3 [T3] hazard ratio [HR]: 0.44; 95% confidence interval [CI], 0.23-0.85; p for linear trend 0.0154), eicosapentaenoic acid (T3 HR: 0.46; 95% CI, 0.24-0.87; p for linear trend 0.0181), and total n-3 PUFAs (T3 HR: 0.55; 95% CI, 0.30-1.01; p for linear trend 0.0492). Conversely, hip fracture nearly doubled with the highest RBC n-6/n-3 ratio (T3 HR: 1.96; 95% CI, 1.03-3.70; p for linear trend 0.0399). RBC PUFAs were not associated with BMD. RBC PUFAs were indicative of dietary intake of marine n-3 PUFAs (Spearman’s rho = 0.45, p < 0.0001), total n-6 PUFAs (rho = 0.17, p < 0.0001) and linoleic acid (rho = 0.09, p < 0.05). These results suggest that higher RBC α-linolenic acid, as well as eicosapentaenoic acid and total n-3 PUFAs, may predict lower hip fracture risk. Contrastingly, a higher RBC n-6/n-3 ratio may predict higher hip fracture risk in postmenopausal women.

Orchard TS, Ing SW, Lu B, Belury MA…
J. Bone Miner. Res. Mar 2013
PMID: 23018646 | Free Full Text

The full text has a nice chart showing the hazard ratios for the various fatty acids they looked at.

The Omega-6:Omega-3 ratios and their respective hazard ratios were:

Omega-6:Omega-3 Ratio 1.48–5.00 5.01–6.07 6.08–10.59
Hazard Ratio 1.00 1.28 (0.71–2.30) 1.96 (1.03–3.70)

[Hazard Ratios] for hip fracture by tertiles of RBC FAs with multivariate adjustment for risk factors per Robbins and colleagues37 are reported in Table 3. No significant associations were found between RBC total SFA, MUFA, or PUFA and risk of hip fracture. However, there was a significant inverse linear association between hip fracture risk and total n-3 FAs in RBCs (p for linear trend 0.0492). When examining individual n-3 FAs, there was a 56% lower relative risk of hip fracture with highest RBC ALA (tertile 3 [T3] hazard ratio [HR]: 0.44; 95% CI, 0.23–0.85; p for linear trend 0.0154), and a 54% lower hip fracture risk with highest EPA levels (T3 HR: 0.46; 95% CI, 0.24–0.87; p for linear trend 0.0181) compared to T1. Neither DHA nor the n-3 index was significantly associated with risk of fracture. In contrast, hip fracture risk nearly doubled in women in the highest tertile of the n-6/n-3 FA ratio (HR T3: 1.96; 95% CI, 1.03–3.70; p for linear trend 0.0399). Because the n-6/n-3 FA ratio in RBCs primarily reflects the ratio of AA to EPA and DHA, we further examined the relation of the AA/EPA + DHA ratio to hip fracture risk. Similar to the n-6/n-3 FA ratio, a higher AA/EPA + DHA ratio produced higher HR for hip fracture, but the association was not significant (T3 HR: 1.69; 95% CI, 0.86–3.31; p for linear trend 0.1242). Although the direction of association between total n-6 FAs, AA, and hip fracture was toward harm, there was no significant relation of either total n-6 FAs or AA with hip fracture. There was an inverse direction of association between LA and hip fracture risk, but again, this was not statistically significant (T3 HR: 0.77; 95% CI, 0.40–1.49; p for linear trend 0.5140). Inclusion of additional potential confounders (alcohol consumption, total energy intake, total calcium intake, total vitamin D intake, and multivitamin use) in the model produced similar results….

Phloretin Reduces Osteoclast Size by Inhibiting Aquaporin 9 In Vitro

Abstract

Involvement of aquaporin 9 in osteoclast differentiation.

Aquaporins (water channels) selectively enhance water permeability of membranes. Since osteoclast differentiation includes a dramatic increase in cell volume, we hypothesize that aquaporin(s) is/are critical for the formation of the multinucleated osteoclast from its mononuclear precursor. Our studies employ two cell models, bone marrow macrophages (BMMs) and the murine macrophage-like cell line, RAW264.7, as osteoclast precursors. Receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) and macrophage-colony-stimulating factor or RANKL alone were used to induce osteoclast differentiation in BMMs or RAW264.7 cells, respectively. We first used qualitative reverse transcription (RT)-PCR to examine which of the aquaporins are expressed in osteoclasts and in their precursor cells. Out of the 10 aquaporins examined, only aquaporin 9 (AQP9) was expressed in osteoclast-lineage cells. AQP9 has unique aqueous pore properties mediating the passage of a wide variety of non-charged solutes in addition to water. Western analyses using specific antibodies revealed a higher AQP9 level in RANKL-treated than in untreated cells. Quantitative real-time RT-PCR analyses also demonstrated higher AQP9 mRNA levels in RANKL-treated cells. Finally, we examined the effect of phloretin, an AQP9 inhibitor, on RANKL-induced osteoclast differentiation. Cells were incubated with RANKL for 5 days, and phloretin was added for the last 2 days, when most fusion occurs. A dramatic reduction in osteoclast size and in the number of nuclei per osteoclast was observed in cultures containing phloretin. The inhibitor did not have a significant effect on the number and size of mononuclear phagocytes in cultures not treated with RANKL. Our results suggest a role for AQP9 in osteoclast differentiation, specifically in the fusion process.

Aharon R, Bar-Shavit Z
J. Biol. Chem. Jul 2006
PMID: 16698796 | Free Full Text

Naringenin Derivative has Bone Anabolic Effects

Abstract

A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts.

Naringenin and its derivatives have been assessed in bone health for their oestrogen-‘like’ effects but low bioavailability impedes clinical potential. This study was aimed at finding a potent form of naringenin with osteogenic action.
Osteoblast cultures were harvested from mouse calvaria to study differentiation by naringenin, isosakuranetin, poncirin, phloretin and naringenin-6-C-glucoside (NCG). Balb/cByJ ovariectomized (OVx) mice without or with osteopenia were given naringenin, NCG, 17β-oestradiol (E2) or parathyroid hormone (PTH). Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labelling of bone. Plasma levels of NCG and naringenin were determined by HPLC.
NCG stimulated osteoblast differentiation more potently than naringenin, while isosakuranetin, poncirin or phloretin had no effect. NCG had better oral bioavailability than naringenin. NCG increased the mRNA levels of oestrogen receptors (ERs) and bone morphogenetic protein (an ER responsive gene) in vivo, more than naringenin. In OVx mice, NCG treatment in a preventive protocol increased bone formation rate (BFR) and improved trabecular microarchitecture more than naringenin or E2. In osteopenic mice, NCG but not naringenin, in a therapeutic protocol, increased BFR and improved trabecular microarchitecture, comparable with effects of PTH treatment. Stimulatory effects of NCG on osteoblasts were abolished by an ER antagonist. NCG transactivated ERβ but not ERα. NCG exhibited no uterine oestrogenicity unlike naringenin.
NCG is a potent derivative of naringenin that has bone anabolic action through the activation of osteoblast ERs and exhibited substantial oral bioavailability.

Swarnkar G, Sharan K, Siddiqui JA, Mishra JS…
Br. J. Pharmacol. Mar 2012
PMID: 21864313 | Free Full Text

Calcium Threonate may Influence Bone Mineralization Through its Action on Vitamin C

Abstract

Pharmacokinetics and safety of calcium L-threonate in healthy volunteers after single and multiple oral administrations.

To evaluate the pharmacokinetics of L-threonate after single or multiple oral administrations and its safety profile in healthy Chinese volunteers. This was an open-label, single- and multiple-dose study. The subjects were assigned to receive a single dose, 675, 2025, or 4050 mg, of calcium L-threonate (n=12) or repeated doses of 2025 mg twice daily for 4 d (n=12). Serial plasma and urine samples were analyzed with HPLC-MS/MS. Pharmacokinetic parameters of L-threonate were calculated using non-compartmental analysis with WinNonlin software.
In the single dose group, C(max) reached at 2.0 h and the mean t(1/2) was approximately 2.5 h. Area under curve (AUC) and C(max) increased with dose escalation, but dose proportionality was not observed over the range of 675 to 4050 mg. AUC and C(max) in the fasted subjects were lower compared with those in the non-fasted subjects. Cumulative urinary excretion of L-threonate over 24 h represented 5.9% of the administered dose with a mean Cl/r of 0.8 L/h. In the multiple-dose study, no accumulation appeared upon repeated doses of 2025 mg twice daily for 4 d. There were no serious adverse events that occurred during this study.
Calcium L-threonate was well tolerated in healthy Chinese subjects, with no pattern of dose-related adverse events. Plasma exposure increased with dose escalation, but linear pharmacokinetics were not observed over the studied doses. L-threonate was absorbed rapidly, and its absorption was enhanced by food intake. No systemic accumulation appeared after repeated administrations.

Wang HY, Hu P, Jiang J
Acta Pharmacol. Sin. Dec 2011
PMID: 21986570 | Free Full Text

The introduction is the most interesting part of the article.

L-Threonic acid is an active metabolite of vitamin C5, 6, 7, 8. It has been reported that L-threonic acid exhibits significant stimulatory action on vitamin C uptake and prolongs the retention of vitamin C in human T-lymphoma cells9, 10. It is also well known that vitamin C is a marker for osteoblast formation and has been shown to stimulate procollagen and enhance collagen synthesis11, 12, 13, 14. Therefore, L-threonic acid may play a role in the mineralization process through its positive action on vitamin C. This hypothesis was confirmed in 1999 by Rowe DJ15. It was reported that in vitro treatment with ascorbate-containing vitamin C metabolites enhanced the formation of the mineralized nodules and collagenous proteins and that L-threonate was one of the metabolites that was found to influence the mineralization process15. Recently, a preclinical study was performed to investigate the effect of L-threonate on bone resorption of rabbit osteoclasts16. This study contained a total of six culture groups, including one control group and five groups treated with drugs (calcium L-threonate, sodium L-threonate, alendronate, 17β-estradiol and calcium gluconate). The levels of type I collagen C-telopeptide (CTx) and bone slice resorptive area were measured. This study found that L-threonate, especially calcium L-threonate, inhibited the bone resorption of osteoclasts in vitro; however, the reductive effects on the CTx level and resorptive area were not as significant as alendronate and 17β-estradiol at the same concentration.

Calcium L-threonate ((2R,3S)-2,3,4-trihydroxy butyric acid calcium) (Figure 1) is a novel drug developed for the treatment of osteoporosis and as a calcium supplement. Phase I clinical trials of calcium L-threonate, including tolerance, pharmacokinetics and calcium absorption evaluation, were performed in Peking Union Medical College Hospital. In this paper, the pharmacokinetics of L-threonate after single or multiple oral administrations and its safety profile in healthy Chinese volunteers are presented.

Strontium Safe and Reduces Fracture Risk Over 10 Years in Postmenopausal Women

Abstract

Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis.

In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (P < 0.01). Vertebral and nonvertebral fracture incidence was lower between 5 and 10 years than in a matched placebo group over 5 years (P < 0.05). Strontium ranelate’s antifracture efficacy appears to be maintained long term.
Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years.
Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (n = 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm.
The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years.
Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.

Reginster JY, Kaufman JM, Goemaere S, Devogelaer JP…
Osteoporos Int Mar 2012
PMID: 22124575 | Free Full Text

Cordyceps Increases Bone Mass in Rats

Abstract

The Protective Effect of Cordymin, a Peptide Purified from the Medicinal Mushroom Cordyceps sinensis, on Diabetic Osteopenia in Alloxan-Induced Diabetic Rats.

The aim of this study was to investigate the protective effect of cordymin on diabetic osteopenia in alloxan-induced diabetic rats and the possible mechanisms involved. The diabetic rats received daily intraperitoneal injection with cordymin (20, 50, and 100 mg/kg/day) for 5 weeks. Cordymin could restore the circulating blood glucose, glycosylated hemoglobin (HbA1c), serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), and insulin levels in a dose-dependent manner. Also, the treatment of diabetic rats with cordymin could partially reverse the β cells death and decrease the total antioxidant status (TAOS) in the diabetic rats. The results may directly and indirectly account for the possible mechanism of the beneficial effect of cordymin on diabetic osteopenia, which was confirmed with the increased bone mineral content (BMC) and bone mineral density (BMD) in diabetic rats (P < 0.05). All those findings indicate that cordymin may play a protective role in diabetic osteoporosis.

Qi W, Zhang Y, Yan YB, Lei W…
Evid Based Complement Alternat Med 2013
PMID: 24174985 | Free Full Text

Cataracts are Associated with Osteoporosis

Abstract

Are cataracts associated with osteoporosis?

Calcium is considered an important factor in the development of both osteoporosis and cataract. This study evaluated the association between osteoporosis and cataracts.
To evaluate the prevalence of osteoporosis among patients undergoing cataract surgery, and the association between the two.
This was a retrospective observational case-control study, conducted in the Central District of Clalit Health Services (a district of the largest health maintenance organization in Israel). All Clalit members in the district older than 50 years who underwent cataract surgery from 2000 to 2007 (n=12,984) and 25,968 age- and sex-matched controls comprised the sample. Electronic medical records of all patients in the study were reviewed. The main outcome measure was the prevalence of osteoporosis and the odds ratio of having osteoporosis among cataract patients compared with controls.
Demographically, 41.8% were men with a mean age of 68.7 ± 8.2 years. A logistic regression model for osteoporosis showed that age, female sex, higher socioeconomic class, smoking, chronic renal failure, hyperthyroidism, rheumatoid arthritis, inflammatory bowel diseases, and cataract are all associated with increased prevalence of osteoporosis. Obesity is a protective factor for osteoporosis. In all age-groups, osteoporosis was more prevalent in cataract patients than in the control group.
Among other well-known risk factors, osteoporosis is associated with the presence of cataracts. Common pathophysiological associations with both conditions, such as calcium imbalance, hormonal abnormalities, and shared genetic predisposition, are discussed.

Nemet AY, Hanhart J, Kaiserman I, Vinker S
Clin Ophthalmol 2013
PMID: 24204110 | Free Full Text

We found a significant association between cataract and osteoporosis among women of all age-groups and in men older than 75 years. Smoking,8 obesity,9 chronic renal failure,10 hyperthyroidism,11 rheumatoid arthritis,12 inflammatory bowel diseases13 are well known to be associated with osteoporosis and have been reported on extensively. Obesity as a protective factor has already been reported.14 To the best of our knowledge, this is the first study to show this association. This section focuses on calcium imbalance as a common key event, hormonal abnormalities associated with both conditions, and shared ultrastructural abnormalities found in cataract and osteoporosis.

Review: PGE2 is Complicated

The prostaglandin E(2) system: a toolbox for skeletal repair?

Gelse K, Beyer C
Arthritis Rheum. Apr 2011
PMID: 21190302 | Free Full Text

Prostaglandin E2 (PGE2), the most widely produced member of the prostaglandin group, originates from arachidonic acid that is released from the cell membrane by phospholipase A2, followed by enzymatic conversion by cyclooxygenase (COX) and PGE synthase 1 (PGES-1). PGE2 not only triggers pain and inflammation but also promotes matrix degradation and tissue damage by stimulating the expression of matrix-degrading enzymes (2). Inflammatory cytokines such as interleukin-1 or tumor necrosis factor ’ strongly increase PGE2 levels, but PGE2 secretion may also increase in response to other stimuli including growth factors, hypoxia, and a number of hormones.

Apart from the well-defined role of PGE2 in tissue inflammation, there is increasing evidence that it is involved in the maintenance and repair of the skeletal system. At first glance, the effects of PGE2 on tissue homeostasis of bone and cartilage seem confusing, because they conflict with the long-known destructive potential of the prostaglandins. Nevertheless, both catabolic and anabolic effects have already been described for PGE2 in these tissues. In terms of catabolism, PGE2 can promote osteoclastic bone resorption (3,4) and enhance breakdown of the extracellular matrix by increasing the expression of matrix metalloproteinase 3 (MMP-3) or MMP-13 (2,5). Regarding its anabolic aspects, PGE2 may stimulate chondrogenesis, chondrocyte proliferation (6), cartilage matrix synthesis (7), as well as osteoblast activity (8). To shed light on the apparent ambivalent role of PGE2, a multidimensional view is necessary that addresses the developmental stage, type of tissue, disease status, concentration of PGE2, and specific receptor status of the different cell types.

 

PGE2 Increases Bone Formation and Mass in Aging Rats

Abstract

Systemic prostaglandin E2 increases cancellous bone formation and mass in aging rats and stimulates their bone marrow osteogenic capacity in vivo and in vitro.

Prostaglandin E(2) (PGE(2)) has been shown to exert a bone anabolic effect in young and adult rats. In this study we tested whether it possesses a similar effect on bone formation and bone mass in aging rats. Fifteen-month-old rats were injected daily with either PGE(2) at 5 mg/kg or vehicle for 14 days. PGE(2) treatment stimulated the rate of cancellous bone formation (a approximately 5.5-fold increase in bone formation rate), measured by the incorporation of calcein into bone-forming surfaces at the tibial proximal metaphysis. This effect resulted in increased cancellous bone area (+54%) at the same site. Since PGE(2) treatment resulted in a much higher proportion of bone surface undergoing bone formation and thus lined with osteoblasts, we tested the hypothesis that PGE(2) stimulates osteoblast differentiation from bone marrow precursor cells both in vivo and in vitro. We found that ex vivo cultures of bone marrow stromal cells from rats injected for 2 weeks with PGE(2) at 5 mg/kg per day yielded more ( approximately 4-fold) mineralized nodules and exhibited a greater (by 30-40%) alkaline phosphatase activity compared with cultures from vehicle-injected rats, attesting to a stimulation of osteoblastic differentiation by PGE(2). We also compared the osteogenic capacity of bone marrow from aging (15-month-old) versus young (5-week-old) rats and its regulation by PGE(2) in vitro. Bone marrow stromal cell cultures from aging rats exhibited a greatly diminished osteogenic capacity, reflected in reduced nodule formation ( approximately 6% of young animals) and lower alkaline phosphatase activity ( approximately 60% of young animals). However, these parameters could be stimulated in both groups of animals by incubation with 10-100 nM PGE(2). The magnitude of this stimulation was greater in cultures from aging rats (+550% vs +70% in nodule formation of aging compared with young rats). In conclusion, we demonstrate here that PGE(2) exerts a bone anabolic effect in aging rats, similar to the effect we and others have reported in young, growing rats. The PGE(2)-stimulated bone formation, which augments bone mass, most likely results from recruitment of osteoblasts from their bone marrow stromal precursors.

Keila S, Kelner A, Weinreb M
J. Endocrinol. Jan 2001
PMID: 11139777 | Free Full Text