Tag Archives: negative

Caffeine > 2.5 Cups of Coffee Increases Fracture in Framingham Study

Abstract

Caffeine and the risk of hip fracture: the Framingham Study.

Caffeine increases urinary calcium output and has been implicated as a risk factor for osteoporosis. The authors examined the effect of caffeine on hip fracture risk in 3,170 individuals attending the 12th (1971-1973) Framingham Study examination. Coffee and tea consumption, age, Framingham examination number, weight, smoking, alcohol consumption, and estrogen use were used to evaluate hip fracture risk according to caffeine intake. Hip fractures occurred in 135 subjects during 12 years of follow-up. Fracture risk over each 2-year period increased with increasing caffeine intake (one cup of coffee = one unit of caffeine, one cup of tea = 1/2 unit of caffeine). For intake of 1.5-2.0 units per day, the adjusted relative risk (RR) of fracture was not significantly elevated compared with intake of one or less units per day. Consumption of greater than or equal to 2.5 units per day significantly increased the risk of fracture. Overall, intake of greater than two cups of coffee per day (four cups of tea) increased the risk of fracture. In summary, hip fracture risk was modestly increased with heavy caffeine use, but not for intake equivalent to one cup of coffee per day. Since caffeine use may be associated with other behaviors that are, themselves, risk factors for fracture, the association may be indirect. Further studies should be performed to confirm these findings.

Kiel DP, Felson DT, Hannan MT, Anderson JJ…
Am. J. Epidemiol. Oct 1990
PMID: 2403108

AGE Consumption Increases Resorption in Rats

Abstract

Effects of model Maillard compounds on bone characteristics and functionality.

BACKGROUND: Physical and biomechanical properties of bone can be affected by non-enzymatic crosslinks, which are implicated in bone pathologies such as osteoporosis. The purpose of this study was to analyse the effects of the consumption of model Maillard reaction product (MRP) from glucose-lysine heated for 90 min at 150 °C (GL90) on bone composition and features. Rats were fed either a control diet or a diet containing 30 g kg(-1) GL90 for 88 days. Food consumption and the animals’ body weights were monitored. After sacrifice, the femur, pelvic bone and tibia were removed for analysis of their composition and physical and biomechanical properties. RESULTS: The organic matrix of the femur and the density of the pelvic bone decreased after MRP intake, whereas pentosidine content increased greatly with respect to the control group (41.7 ± 9.9 vs 171.4 ± 3.3 mmol mol(-1) collagen). The rising level of C-telopeptide degradation products from type I collagen (β-CTX) suggested a possible situation of increased bone resorption and/or higher turnover. CONCLUSION: In conjunction, the detrimental effect on the organic matrix, the situation of higher resorption and/or bone turnover indicated by the β-CTX values and the high pentosidine content in bone provoked negative consequences on certain mechanical properties such as the ability to withstand force and absorb energy without failure.

Roncero-Ramos I, Delgado-Andrade C, Rufián-Henares JA, Carballo J…
J. Sci. Food Agric. Feb 2013
PMID: 23420603

IL-17 may Contribute to Osteoporosis in Mice

Abstract

Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis.

Th17 cells produce IL-17, and the latter promotes bone loss in collagen-induced arthritis in mice. Blocking IL-17 action in mouse model of rheumatoid arthritis reduces disease symptoms. These observations suggest that Th17 cells may be involved in the pathogenesis of bone loss. However, the role of Th17 cell in estrogen (E2) deficiency-induced bone loss is still not very clear. We investigated the effect of E2 on Th17 differentiation in vivo and IL-17 mediated regulation of osteoclast and osteoblast differentiation. Additionally, effect of IL-17 functional block under E2 deficiency-induced bone loss was studied. In murine bone marrow cells, E2 suppressed IL-17 mediated osteoclast differentiation. IL-17 inhibited formation of mineralized nodules in osteoblasts and this effect was suppressed by E2. E2 treatment to mouse calvarial osteoblasts inhibited the IL-17-induced production of osteoclastogenic cytokines and NF-kB translocation. In ovariectomized mice, there was increase in the number of Th17 cells, transcription factors promoting Th17 cell differentiation and circulating IL-17 levels. These effects were reversed by E2 supplementation. Treatment of neutralizing IL-17 monoclonal antibody to Ovx mice mitigated the E2 deficiency-induced trabecular bone loss and reversed the decreased osteoprotegerin-to-receptor activator of nuclear factor kappa B ligand (RANKL) transcript levels in long bones, increased osteoclast differentiation from the bone marrow precursor cells and decreased osteoblast differentiation from the bone marrow stromal cells. Our findings indicate that E2 deficiency leads to increased differentiation of Th17 cells with attendant up regulation of STAT3, ROR-γt and ROR-α and downregulation of Foxp3 which antagonizes Th17 cell differentiation. Increased IL-17 production in turn induces bone loss by increasing pro-osteoclastogenic cytokines including TNF-α, IL-6 and RANKL from osteoblasts and functional block of IL-17 prevents bone loss. IL-17 thus plays a critical causal role in Ovx-induced bone loss and may be considered a potential therapeutic target in pathogenesis of post menopausal osteoporosis.

Tyagi AM, Srivastava K, Mansoori MN, Trivedi R…
PLoS ONE 2012
PMID: 22970248 | Free Full Text

EPA and DHA may Decrease, but GLA may Increase, Osteoclasts in Mouse Cells

Abstract

Long chain polyunsaturated fatty acids alter membrane-bound RANK-L expression and osteoprotegerin secretion by MC3T3-E1 osteoblast-like cells.

Inflammation triggers an increase in osteoclast (bone resorbing cell) number and activity. Osteoclastogenesis is largely controlled by a triad of proteins consisting of a receptor (RANK), a ligand (RANK-L) and a decoy receptor (osteoprotegerin, OPG). Whilst RANK is expressed by osteoclasts, RANK-L and OPG are expressed by osteoblasts. The long chain polyunsaturated fatty acid (LCPUFA) arachidonic acid (AA, 20:4n-6) and its metabolite prostaglandin E2 (PGE2), are pro-inflammatory and PGE2 is a potent stimulator of RANKL expression. Various LCPUFAs such as eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3) and gamma-linolenic acid (GLA, 18:3n-6) have anti-inflammatory activity. We aimed to determine if AA itself can stimulate RANKL expression and whether EPA, DHA and GLA inhibit RANKL expression in osteoblasts. MC3T3-E1/4 osteoblast-like cells were cultured under standard conditions with each of the LCPUFAs (5microg/ml) for 48h. Membrane-bound RANKL expression was measured by flow cytometry and OPG secretion measured by ELISA. In a second experiment, RANKL expression in MC3T3-E1/4 cells was stimulated by PGE2 treatment and the effect of EPA, DHA and GLA on membrane-bound RANKL expression and OPG secretion determined. The percentage of RANKL-positive cells was higher (p<0.05) than controls following treatment with AA or GLA but not after co-treatment with the cyclooxygenase inhibitor, indomethacin. DHA and EPA had no effect on membrane-bound RANKL expression under standard cell culture conditions. Secretion of OPG was lower (p<0.05) in AA-treated cells but not significantly different from controls in GLA, EPA or DHA treated cells. Treatment with prostaglandin E2 (PGE2) resulted in an increase (p<0.05) in the percentage of RANK-L positive cells and a decrease (p<0.05) in mean OPG secretion. The percentage of RANKL positive cells was significantly lower following co-treatment with PGE2 and either DHA or EPA compared to treatment with PGE2 alone. Mean OPG secretion remained lower than controls in cells treated with PGE2 regardless of co-treatment with EPA or DHA. Results from this study suggest COX products of GLA and AA induce membrane-bound RANKL expression in MC3T3-E1/4 cells. EPA and DHA have no effect on membrane-bound RANKL expression in cells cultured under standard conditions however both EPA and DHA inhibit the PGE2-induced increase in RANKL expression in MC3T3-E1/4 cells.

Poulsen RC, Wolber FM, Moughan PJ, Kruger MC
Prostaglandins Other Lipid Mediat. Feb 2008
PMID: 18077200

Exercise Limits Effects of Excessive Alcohol on Bone in Rats

Abstract

Regular exercise limits alcohol effects on trabecular, cortical thickness and porosity, and osteocyte apoptosis in the rat.

Excessive alcohol consumption is known to be a cause of secondary osteoporosis whereas physical activity is recommended in prevention of osteoporosis. This study was designed to analyze the effects of physical exercise on bone parameters in chronic alcohol-fed rats.
Forty-eight male Wistar rats were divided in four groups: Control (C), Alcohol (A), Exercise (E) and Alcohol+Exercise (AE). A and AE groups drank a solution composed of ethanol and water (35% volume/volume for 17 weeks). E and AE groups were submitted to treadmill training for 14 weeks (60 min/day, 5 times/week). Bone mineral density (BMD) was assessed by DXA, the trabecular and cortical microarchitectural parameters by microCT and serum osteocalcin, NTx and leptin concentrations by ELISA assays. Bone mechanical parameters were evaluated through mechanical testing. Osteocyte apoptosis was analyzed with cleaved caspase-3 immunostaining.
Alcohol-fed rats had significantly lower body weight (-28%), fat (-46%) and lean mass (-25%) compared to controls. BMD (-8%), trabecular (-12%) and cortical thickness (-27%) were significantly lower with alcohol whereas porosity (+38%) and pore number (+42%) were higher. Exercise combined with alcohol prevented lower Tb.Th (+20%), Ct.Th (+30%), stress (+26%) and higher Ct.Po (-24%) and osteocyte apoptosis (-91%) compared to A. However, WB BMD (-4%) and femur BMD were still lower in AE versus C.
Regular physical activity has beneficial effects on some microarchitectural parameters in alcohol-fed rats. However, regular treadmill exercise does not compensate for the effects of heavy chronic alcohol consumption on whole body bone density.

Maurel DB, Boisseau N, Pallu S, Rochefort GY…
Joint Bone Spine Oct 2013
PMID: 23380443

Silicon as Orthosilicic Acid Decreases Osteoblast Survivability In Vitro

Abstract

Divergent effects of orthosilicic acid and dimethylsilanediol on cell survival and adhesion in human osteoblast-like cells.

Although dietary silicon (Si) is recognized to be an important factor for the growth and development of bone and connective tissue, its biochemical role has yet to be identified. The predominant Si-containing species in blood and other biofluids is orthosilicic acid, Si(OH)(4). Dimethylsilanediol, (CH(3))(2)Si(OH)(2), is an environmental contaminant that results from decomposition of silicone compounds used in personal hygiene, health care and industrial products. We examined the in vitro effects of both Si species on the survival (colony forming efficiency), proliferation (DNA content), differentiation (alkaline phosphatase activity) and adhesion (relative protein content) of the human osteoblast-like cell lines Saos-2 and hFOB 1.19. Orthosilicic acid yielded a small, dose-dependent decrease in Saos-2 cell survivability up to its 1,700 micromol/L solubility limit, by which point survival was 20% less than that of untreated cells. This negative association, although small, correlated with a reduction in the proliferation and adhesion of Saos-2 cells as well as of hFOB 1.19 and osteoclast-like GCT cells. By contrast, dimethylsilanediol treatment had no discernable influence on Saos-2 survivability at concentrations up to 50 micromol/L, and yet significantly enhanced cell survival at higher doses. Moreover, dimethylsilanediol did not affect proliferation or adhesion of any cell line. The findings show that orthosilicic acid and dimethylsilanediol affect osteoblast-like cells very differently, providing insight into the mechanism by which silicon influences bone health, although the specific site of Si activity remains unknown. There was no evidence to suggest that dimethylsilanediol is cytotoxic at environmental/physiological concentrations.

Duivenvoorden WC, Middleton A, Kinrade SD
J Trace Elem Med Biol 2008
PMID: 18755397

Silicon Antagonizes Calcium and Magnesium in Animals

Abstract

Effects of high levels of dietary silicon on bone development of growing rats and turkeys fed semi-purified diets.

Two experiments were conducted using a completely randomized design to study the effects of high levels of silicon (Si) supplementation on bone development, structure, and strength in growing rats and turkeys. Rats were supplemented at two dietary Si levels: 0 and 500 ppm; and the turkeys were supplemented at four dietary Si levels: 0, 135, 270, and 540 ppm in semi-purified diets of dextrose-albumin for rats and dextrose-casein for turkeys. The experiments lasted 8 and 4 weeks for the rats and turkeys, respectively. Physical, mechanical, and chemical parameters of bones were measured. All the physical and mechanical measures of bone size and strength were not different (P > 0.05) between treatments in rats and turkeys except the moment of inertia, which was lower (P < 0.01) in rats on the 500 ppm Si level of supplementation. There were small but consistent reductions in structural and strength parameters with Si supplementation which were not wholly due to differences in bodyweights of the rats and turkeys. Although bone mineral composition was not affected (P > 0.05) by Si supplementation, plasma magnesium (P = 0.08) in rats and plasma calcium (P < 0.05) in turkeys were reduced by high levels of Si supplementation. The antagonistic relations of high Si levels with calcium and magnesium were deemed to be the mechanisms through which high Si imposes its deleterious effects on bone size and strength.

Kayongo-Male H, Julson JL
Biol Trace Elem Res 2008
PMID: 18418557

Phenytoin Inhibits Osteoblasts In Vitro and In Vivo; Low Doses Increase Osteoblasts In Vitro

Abstract

Long-term anticonvulsant therapy leads to low bone mineral density–evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells.

Anticonvulsant therapy causes changes in calcium and bone metabolism and may lead to decreased bone mass with the risk of osteoporotic fractures. The two widely used antiepileptic drugs phenytoin and carbamazepine are recognized to have direct effects on bone cells. The aim of our study was to measure the influence of long-term treatment with antiepileptic drugs on bone mineral density (BMD) and to look on direct effects of carbamazepine and phenytoin on human osteoblast-like cells. BMD was measured by dual-energy X-ray absorptiometry. Markers of bone formation and bone resorption were determined in serum and urine. Data of 59 patients were compared to 55 age and sex matched controls. Direct effects of phenytoin and carbamazepine on human osteoblast-like cells were investigated in experimental studies. BMD in the lumbar spine region (L2 through L4) was significantly lower in the patient group as compared to controls (p < 0.0004). At femoral sites BMD was lower in patients, but this difference did not reach statistical significance. The decrease in BMD at both sites was dependent on the duration of therapy. Excretion of pyridinoline crosslinks was markedly increased in the patients. 25-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 were significantly decreased in patients. Proliferation rate of human osteoblast-like cells was increased by phenytoin in low doses. Both, phenytoin and carbamazepine inhibited cell growth at concentrations equivalent to therapeutic doses for the treatment of epileptic diseases. Our clinical and experimental data indicate that long-term treatment with anticonvulsant drugs leads to a lower BMD. The experimentally observed decrease in bone cell proliferation might be clinically associated with impaired new bone formation. Beside alterations in calcium and vitamin D homeostasis leading to osteomalazia, direct effects of anticonvulsant drugs on bone cells may contribute to the damaging effects on the skeletal system.

Feldkamp J, Becker A, Witte OW, Scharff D…
Exp. Clin. Endocrinol. Diabetes 2000
PMID: 10768830

IP-6 Inhibits Osteoclastogenesis and Increases Resorption of Mature Osteoclasts In Vitro

Abstract

Inositol hexakisphosphate inhibits osteoclastogenesis on RAW 264.7 cells and human primary osteoclasts.

Inoxitol hexakisphosphate (IP6) has been found to have an important role in biomineralization and a direct effect inhibiting mineralization of osteoblasts in vitro without impairing extracellular matrix production and expression of alkaline phosphatase. IP6 has been proposed to exhibit similar effects to those of bisphosphonates on bone resorption, however, its direct effect on osteoclasts (OCL) is presently unknown. The aim of the present study was to investigate the effect of IP6 on the RAW 264.7 monocyte/macrophage mouse cell line and on human primary osteoclasts. On one hand, we show that IP6 decreases the osteoclastogenesis in RAW 264.7 cells induced by RANKL, without affecting cell proliferation or cell viability. The number of TRAP positive cells and mRNA levels of osteoclast markers such as TRAP, calcitonin receptor, cathepsin K and MMP-9 was decreased by IP6 on RANKL-treated cells. On the contrary, when giving IP6 to mature osteoclasts after RANKL treatment, a significant increase of bone resorption activity and TRAP mRNA levels was found. On the other hand, we show that 1 µM of IP6 inhibits osteoclastogenesis of human peripheral blood mononuclear cells (PBMNC) and their resorption activity both, when given to undifferentiated and to mature osteoclasts.
Our results demonstrate that IP6 inhibits osteoclastogenesis on human PBMNC and on the RAW264.7 cell line. Thus, IP6 may represent a novel type of selective inhibitor of osteoclasts and prove useful for the treatment of osteoporosis.

Arriero Mdel M, Ramis JM, Perelló J, Monjo M
PLoS ONE 2012
PMID: 22905230 | Free Full Text

IP-6 May Impair Bioavailability of Iron, Calcium, and Zinc in Chinese

Abstract

Phytate intake and molar ratios of phytate to zinc, iron and calcium in the diets of people in China.

To assess the phytate intake and molar ratios of phytate to calcium, iron and zinc in the diets of people in China.
2002 China Nationwide Nutrition and Health Survey is a cross-sectional nationwide representative survey on nutrition and health. The information on dietary intakes was collected using consecutive 3 days 24 h recall by trained interviewers.
The data of 68 962 residents aged 2-101 years old from 132 counties were analyzed.
The median daily dietary intake of phytate, calcium, iron and zinc were 1186, 338.1, 21.2 and 10.6 mg, respectively. Urban residents consumed less phytate (781 vs 1342 mg/day), more calcium (374.5 vs 324.1 mg/day) and comparable amounts of iron (21.1 vs 21.2 mg/day) and zinc (10.6 vs 10.6 mg/day) than their rural counterparts. A wide variation in phytate intake among residents from six areas was found, ranging from 648 to 1433 mg/day. The median molar ratios of phytate to calcium, iron, zinc and phytate x calcium/zinc were 0.22, 4.88, 11.1 and 89.0, respectively, with a large variation between urban and rural areas. The phytate:zinc molar ratios ranged from 6.2 to 14.2, whereas the phytate x calcium/zinc molar ratios were from 63.7 to 107.2. The proportion of subjects with ratios above the critical values of phytate to iron, phytate to calcium, phytate to zinc and phytate x calcium/zinc were 95.4, 43.7, 23.1 and 8.7%, respectively. All the phytate/mineral ratios of rural residents were higher than that of their urban counterparts.
The dietary phytate intake of people in China was higher than those in Western developed countries and lower than those in developing countries. Phytate may impair the bioavailability of iron, calcium and zinc in the diets of people in China.

Ma G, Li Y, Jin Y, Zhai F…
Eur J Clin Nutr Mar 2007
PMID: 16929240