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Calcium Intake of 903mg to 1025mg Associated with Lowest Fracture Risk, More and Less Increases Risk

Abstract

Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study.

To investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis.
A longitudinal and prospective cohort study, based on the Swedish Mammography Cohort, including a subcohort, the Swedish Mammography Cohort Clinical.
A population based cohort in Sweden established in 1987.
61,433 women (born between 1914 and 1948) were followed up for 19 years. 5022 of these women participated in the subcohort.
Primary outcome measures were incident fractures of any type and hip fractures, which were identified from registry data. Secondary outcome was osteoporosis diagnosed by dual energy x ray absorptiometry in the subcohort. Diet was assessed by repeated food frequency questionnaires.
During follow-up, 14,738 women (24%) experienced a first fracture of any type and among them 3871 (6%) a first hip fracture. Of the 5022 women in the subcohort, 1012 (20%) were measured as osteoporotic. The risk patterns with dietary calcium were non-linear. The crude rate of a first fracture of any type was 17.2/1000 person years at risk in the lowest quintile of calcium intake, and 14.0/1000 person years at risk in the third quintile, corresponding to a multivariable adjusted hazard ratio of 1.18 (95% confidence interval 1.12 to 1.25). The hazard ratio for a first hip fracture was 1.29 (1.17 to 1.43) and the odds ratio for osteoporosis was 1.47 (1.09 to 2.00). With a low vitamin D intake, the rate of fracture in the first calcium quintile was more pronounced. The highest quintile of calcium intake did not further reduce the risk of fractures of any type, or of osteoporosis, but was associated with a higher rate of hip fracture, hazard ratio 1.19 (1.06 to 1.32).
Gradual increases in dietary calcium intake above the first quintile in our female population were not associated with further reductions in fracture risk or osteoporosis.

Warensjö E, Byberg L, Melhus H, Gedeborg R…
BMJ 2011
PMID: 21610048 | Free Full Text


From the full text:

• Dietary calcium intakes below approximately 700 mg per day in women were associated with an increased risk of hip fracture, any fracture, and of osteoporosis

• The highest reported calcium intake did not further reduce the risk of fractures of any type, or of osteoporosis, but was associated with a higher rate of hip fracture

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Resveratrol Stimulates Bone Formation or Mineralization in Obese Men

Abstract

Resveratrol Increases Bone Mineral Density and Bone Alkaline Phosphatase in Obese Men: A Randomized Placebo-Controlled Trial.

Context: Metabolic syndrome (MetS) is associated with low-grade inflammation, which may harmfully affect bone. Resveratrol (RSV) possesses anti-inflammatory properties, and rodent studies suggest bone protective effects. Objective: This study sought to evaluate effects of RSV treatment on bone in men with MetS. Setting and Design: The study was conducted at Aarhus University Hospital as a randomized, double-blinded, placebo-controlled trial assessing changes in bone turnover markers, bone mineral density (BMD), and geometry. Participants: The study population comprised 74 middle-aged obese men with MetS recruited from the general community, of which 66 completed all visits. Mean age of participants was 49.3 ± 6.3 years and mean body mass index was 33.7 ± 3.6 kg/m(2). Intervention: Oral treatment with 1.000 mg RSV (RSVhigh), 150mg RSV (RSVlow), or placebo daily for 16 weeks. Main Outcome Measure: Prespecified primary endpoint was change in bone alkaline phosphatase (BAP). Results: BAP increased dose dependently with RSV (R = 0.471, P < .001), resulting in a significantly greater increase in BAP in the RSVhigh group compared with placebo at all time-points (week 4, 16.4 ± 4.2%, P < .001; week 8, 16.5 ± 4.1%, P < .001; week 16, 15.2 ± 3.7%, P < .001). Lumbar spine trabecular volumetric bone mineral density (LS vBMDtrab) also increased dose dependently with RSV (R = 0.268, P = .036), with a significant increase of 2.6 ± 1.3% in the RSVhigh group compared with placebo (P = .043). In addition, changes in BAP and LS vBMDtrab were positively correlated (R = 0.281, P = .027). No consistent changes were detected in bone density at the hip. Conclusions: Our data suggest that high-dose RSV supplementation positively affects bone, primarily by stimulating formation or mineralization. Future studies of longer duration comprising populations at risk of osteoporosis are needed to confirm these results.

Ornstrup MJ, Harsløf T, Kjær TN, Langdahl BL…
J. Clin. Endocrinol. Metab. Oct 2014
PMID: 25322274

Resveratrol May Increase Bone Length in Pre-pubertal Rabbits

Abstract

Resveratrol treatment delays growth plate fusion and improves bone growth in female rabbits.

Trans-resveratrol (RES), naturally produced by many plants, has a structure similar to synthetic estrogen diethylstilbestrol, but any effect on bone growth has not yet been clarified. Pre-pubertal ovary-intact New Zealand white rabbits received daily oral administration of either vehicle (control) or RES (200 mg/kg) until growth plate fusion occurred. Bone growth and growth plate size were longitudinally monitored by X-ray imaging, while at the endpoint, bone length was assessed by a digital caliper. In addition, pubertal ovariectomized (OVX) rabbits were treated with vehicle, RES or estradiol cypionate (positive control) for 7 or 10 weeks and fetal rat metatarsal bones were cultured in vitro with RES (0.03 µM-50 µM) and followed for up to 19 days. In ovary-intact rabbits, sixteen-week treatment with RES increased tibiae and vertebrae bone growth and subsequently improved final length. In OVX rabbits, RES delayed fusion of the distal tibia, distal femur and proximal tibia epiphyses and femur length and vertebral bone growth increased when compared with controls. Histomorphometrical analysis showed that RES-treated OVX rabbits had a wider distal femur growth plate, enlarged resting zone, increased number/size of hypertrophic chondrocytes, increased height of the hypertrophic zone, and suppressed chondrocyte expression of VEGF and laminin. In cultured fetal rat metatarsal bones, RES stimulated growth at 0.3 µM while at higher concentrations (10 μM and 50 μM) growth was inhibited. We conclude that RES has the potential to improve longitudinal bone growth. The effect was associated with a delay of growth plate fusion resulting in increased final length. These effects were accompanied by a profound suppression of VEGF and laminin expression suggesting that impairment of growth plate vascularization might be an underlying mechanism.

Karimian E, Tamm C, Chagin AS, Samuelsson K…
PLoS ONE 2013
PMID: 23840780 | Free Full Text

Review: Resveratrol Pre-Clinical Evidence

Abstract

Resveratrol Supplementation Affects Bone Acquisition and Osteoporosis: Pre-Clinical Evidence Towards Translational Diet Therapy.

Osteoporosis is a major public health issue that is expected to rise as the global population ages. Resveratrol (RES) is a plant polyphenol with various anti-aging properties. RES treatment of bone cells results in protective effects, but dose translation from in vitro studies to clinically relevant doses is limited since bioavailability is not taken into account. The aims of this review is to evaluate in vivo evidence for a role of RES supplementation in promoting bone health to reduced osteoporosis risk and potential mechanisms of action. Due to multiple actions on both osteoblasts and osteoclasts, RES has potential to attenuate bone loss resulting from different etiologies and pathologies. Several animal models have investigated the bone protective effects of RES supplementation. Ovariectomized rodent models of rapid bone loss due to estrogen-deficiency reported that RES supplementation improved bone mass and trabecular bone without stimulating other estrogen-sensitive tissues. RES supplementation prior to age-related bone loss was beneficial. The hindlimb unloaded rat model used to investigate bone loss due to mechanical unloading showed RES supplementation attenuated bone loss in old rats, but had inconsistent bone effects in mature rats. In growing rodents, RES increased longitudinal bone growth, but had no other effects on bone. In the absence of human clinical trials, evidence for a role of RES on bone heath relies on evidence generated by animal studies. A better understanding of efficacy, safety, and molecular mechanisms of RES on bone will contribute to the determination of dietary recommendations and therapies to reduce osteoporosis. This article is part of a Special Issue entitled: Resveratol: Challenges in translating pre-clincial findigns to iproved patient outcomes.

Tou JC
Biochim. Biophys. Acta Oct 2014
PMID: 25315301

Silicon Associated with Bone Density in Men and Women

Abstract

Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring cohort.

The role of dietary silicon in bone health in humans is not known. In a cross-sectional, population-based study (2847 participants), associations between dietary silicon intake and BMD were investigated. Dietary silicon correlated positively and significantly with BMD at all hip sites in men and premenopausal women, but not in postmenopausal women, suggesting that increased silicon intake is associated with increased cortical BMD in these populations.
Osteoporosis is a burgeoning health and economic issue. Agents that promote bone formation are widely sought. Animal and cellular data suggest that the orthosilicate anion (i.e., dietary silicon) is involved in bone formation. The intake of silicon (Si, approximately 30 mg/day) is among the highest for trace elements in humans, but its contribution to bone health is not known.
In a cross-sectional, population-based study, we examined the association between silicon intake and bone mineral density (BMD) in 1251 men and 1596 pre- and postmenopausal women in the Framingham Offspring cohort (age, 30-87 years) at four hip sites and lumbar spine, adjusting for all potential confounding factors known to influence BMD and nutrient intake.
Silicon intake correlated positively with adjusted BMD at four hip sites in men and premenopausal women, but not in postmenopausal women. No significant association was observed at the lumbar spine in any group. Categorical analysis by Si intake, or energy-adjusted Si intake, supported these findings, and showed large differences in BMD (up to 10%) between the highest (> 40 mg Si/day) and lowest (< 14 mg Si/day) quintiles of silicon intake. A significant association at the lumbar spine in men was also observed. Further analyses indicated that some of the effects seen for moderate consumption of alcoholic beverages on BMD might be attributed to Si intake.
These findings suggest that higher dietary silicon intake in men and younger women may have salutary effects on skeletal health, especially cortical bone health, that has not been previously recognized. Confirmation of these results is being sought in a longitudinal study and by assessment of the influence of silicon intake on bone markers in this cohort.

Jugdaohsingh R, Tucker KL, Qiao N, Cupples LA…
J. Bone Miner. Res. Feb 2004
PMID: 14969400

Silicon Deprivation Decreases Bone Collagen Formation in Rats

Abstract

Silicon deprivation decreases collagen formation in wounds and bone, and ornithine transaminase enzyme activity in liver.

We have shown that silicon (Si) deprivation decreases the collagen concentration in bone of 9-wk-old rats. Finding that Si deprivation also affects collagen at different stages in bone development, collagen-forming enzymes, or collagen deposition in other tissues would have implications that Si is important for both wound healing and bone formation. Therefore, 42 rats in experiment 1 and 24 rats in experiment 2 were fed a basal diet containing 2 or 2.6 microg Si/g, respectively, based on ground corn and casein, and supplemented with either 0 or 10 microg Si/g as sodium metasilicate. At 3 wk, the femur was removed from 18 of the 42 rats in experiment 1 for hydroxyproline analysis. A polyvinyl sponge was implanted beneath the skin of the upper back of each of the 24 remaining rats. Sixteen hours before termination and 2 wk after the sponge had been implanted, each rat was given an oral dose of 14C-proline (1.8 microCi/100 g body wt). The total amount of hydroxyproline was significantly lower in the tibia and sponges taken from Si-deficient animals than Si-supplemented rats. The disintegrations per minute of 14C-proline were significantly higher in sponge extracts from Si- deficient rats than Si-supplemented rats. Additional evidence of aberrations in proline metabolism with Si deprivation was that liver ornithine aminotransferase was significantly decreased in Si-deprived animals in experiment 2. Findings of an increased accumulation of 14C-proline and decreased total hydroxyproline in implanted sponges and decreased activity of a key enzyme in proline synthesis (liver ornithine aminotransferase) in Si-deprived animals indicates an aberration in the formation of collagen from proline in sites other than bone that is corrected by Si. This suggests that Si is a nutrient of concern in wound healing as well as bone formation.

Seaborn CD, Nielsen FH
Biol Trace Elem Res Dec 2002
PMID: 12462748

Silicon Increases Osteoblasts and Decreases Osteoclasts in Ovariectomized Rats

Abstract

Short-term effects of organic silicon on trabecular bone in mature ovariectomized rats.

Silicon is known to ensure an essential role in the formation of cross-links between collagen and proteoglycans during bone growth. In this study, we have evaluated the short-term effects of a preventive treatment with silanol, a soluble organic silicon (Si), on trabecular bone in mature ovariectomized rats. Three-month-old rats were sham-operated (sham) or were ovariectomized (OVX) and treated with 10 micrograms/kg/day of 17 beta estradiol (E2), or with 0.1 mg Si/kg/day or 1.0 mg Si/kg/day of silanol for 1 month. Plasma alkaline phosphatase and osteocalcin levels were increased by 50% in OVX rats compared with sham rats and were corrected by E2 but not by silanol treatment. The trabecular bone volume measured at the tibial metaphysis was decreased by 48%, and histomorphometric indices of bone resorption and formation were increased in OVX rats compared with sham, and these parameters were corrected by E2 treatment. Treatment of OVX rats with silanol decreased the osteoclast surface by 31% and the number of osteoclasts by 20%. The mineral apposition rate, the bone formation rate, and the osteoblast surface at the tibia metaphyseal area were increased by 30% at the higher dose of silanol compared with OVX rats. In contrast, silanol treatment had no effect on the periosteal apposition rate. The reduction of the metaphyseal bone resorption and the increased bone formation induced by silanol resulted in a slight improvement of the trabecular bone volume (+14%) compared with controls.

Hott M, de Pollak C, Modrowski D, Marie PJ
Calcif. Tissue Int. Sep 1993
PMID: 8242469

Silicon is Required for Bone Formation in Chicks

Abstract

Silicon: a requirement in bone formation independent of vitamin D1.

Silicon has been reported to be involved in an early stage of bone formation as a result of earlier in vitro and in vivo studies in this laboratory. It is now possible to demonstrate that silicon exerts an effect on bone formation independent of the action of vitamin D. Day-old cockerels were fed Si-deficient and Si-supplemented diets with adequate and no dietary vitamin D under trace element controlled conditions. At the end of 4 weeks chicks receiving dietary vitamin D3 (600 IU) exhibited optimal rates of growth whereas the growth rates of chicks receiving D2 (6000 IU) and no vitamin D were markedly depressed. There were no significant differences between growth of Si-deficient and Si-supplemented chicks on the same level of vitamin D. Skull and bone size was proportional to overall chick growth. However, all chicks on Si-deficient diets irrespective of the level of dietary vitamin D had gross abnormalities of skull architecture, the overall skull appearance being narrower and shorter. The frontal area was narrower and the dorsal median line at the front parietal junction was depressed with a narrowing both posterior and laterally, stunting parietal and occipital areas. These abnormal areas showed fewer trabeculae and less calcification. Analyses of skull frontal bones for hexosamine, collagen, noncollagenous protein, and bone mineral demonstrated that the major difference was in collagen content, the Si-deficient skulls showing considerably less collagen at each level of vitamin D. These findings demonstrate that silicon has a significant effect on the bone matrix independent of vitamin D, and support the earlier postulate that silicon is involved in an early stage of bone formation.

Carlisle EM
Calcif. Tissue Int. 1981
PMID: 6257332

Orthosilicic Acid Stimulates Bone Formation in Osteopenic Women

Abstract

Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial.

Mounting evidence supports a physiological role for silicon (Si) as orthosilicic acid (OSA, Si(OH)4) in bone formation. The effect of oral choline-stabilized orthosilicic acid (ch-OSA) on markers of bone turnover and bone mineral density (BMD) was investigated in a double-blind placebo-controlled trial.
Over 12-months, 136 women out of 184 randomized (T-score spine < -1.5) completed the study and received, daily, 1000 mg Ca and 20 microg cholecalciferol (Vit D3) and three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. Bone formation markers in serum and urinary resorption markers were measured at baseline, and after 6 and 12 months. Femoral and lumbar BMD were measured at baseline and after 12 months by DEXA.
Overall, there was a trend for ch-OSA to confer some additional benefit to Ca and Vit D3 treatment, especially for markers of bone formation, but only the marker for type I collagen formation (PINP) was significant at 12 months for the 6 and 12 mg Si dose (vs. placebo) without a clear dose response effect. A trend for a dose-corresponding increase was observed in the bone resorption marker, collagen type I C-terminal telopeptide (CTX-I). Lumbar spine BMD did not change significantly. Post-hoc subgroup analysis (baseline T-score femur < -1) however was significant for the 6 mg dose at the femoral neck (T-test). There were no ch-OSA related adverse events observed and biochemical safety parameters remained within the normal range.
Combined therapy of ch-OSA and Ca/Vit D3 had a potential beneficial effect on bone collagen compared to Ca/Vit D3 alone which suggests that this treatment is of potential use in osteoporosis.

Spector TD, Calomme MR, Anderson SH, Clement G…
BMC Musculoskelet Disord 2008
PMID: 18547426 | Free Full Text


From the full text:

Collagen provides elasticity and structure in all connective tissues and several studies have indicated that collagen is important for bone toughness [43-45] whereas the mineral component is mainly involved in providing stiffness. Wang et al. [46] demonstrated that the mechanical integrity of collagen fibres deteriorates with ageing in human cortical bones and is associated with a higher fracture risk. When the collagen network becomes weaker with age, it will result in decreased toughness, possibly due to a reduction in natural cross-links or silicon content. It has previously been suggested that Si may be an integral (structural) component of connective tissues as high levels of non-dialysable Si has been reported in connective tissues and their components suggesting strong (covalent) associations [47].

Orthosilicic Acid Increases Bone Density in Ovariectomized Rats

Abstract

Partial prevention of long-term femoral bone loss in aged ovariectomized rats supplemented with choline-stabilized orthosilicic acid.

Silicon (Si) deficiency in animals results in bone defects. Choline-stabilized orthosilicic acid (ch-OSA) was found to have a high bioavailability compared to other Si supplements. The effect of ch-OSA supplementation was investigated on bone loss in aged ovariectomized (OVX) rats. Female Wistar rats (n = 58, age 9 months) were randomized in three groups. One group was sham-operated (sham, n = 21), and bilateral OVX was performed in the other two groups. OVX rats were supplemented orally with ch-OSA over 30 weeks (OVX1, n = 20; 1 mg Si/kg body weight daily) or used as controls (OVX0, n = 17). The serum Si concentration and the 24-hour urinary Si excretion of supplemented OVX rats was significantly higher compared to sham and OVX controls. Supplementation with ch-OSA significantly but partially reversed the decrease in Ca excretion, which was observed after OVX. The increase in bone turnover in OVX rats tended to be reduced by ch-OSA supplementation. ch-OSA supplementation increased significantly the femoral bone mineral content (BMC) in the distal region and total femoral BMC in OVX rats, whereas lumbar BMC was marginally increased. Femoral BMD was significantly increased at two sites in the distal region in OVX rats supplemented with ch-OSA compared to OVX controls. Total lumbar bone mineral density was marginally increased by ch-OSA supplementation. In conclusion, ch-OSA supplementation partially prevents femoral bone loss in the aged OVX rat model.

Calomme M, Geusens P, Demeester N, Behets GJ…
Calcif. Tissue Int. Apr 2006
PMID: 16604283