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Resveratrol Analogues Show No Effect on Bones In Rats

Abstract

Potential of resveratrol analogues as antagonists of osteoclasts and promoters of osteoblasts.

The plant phytoalexin resveratrol was previously demonstrated to inhibit the differentiation and bone resorbing activity of osteoclasts, to promote the formation of osteoblasts from mesenchymal precursors in cultures, and inhibit myeloma cell proliferation, when used at high concentrations. In the current study, we screened five structurally modified resveratrol analogues for their ability to modify the differentiation of osteoclasts and osteoblasts and proliferation of myeloma cells. Compared to resveratrol, analogues showed an up to 5,000-fold increased potency to inhibit osteoclast differentiation. To a lesser extent, resveratrol analogues also promoted osteoblast maturation. However, they did not antagonize the proliferation of myeloma cells. The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but an effect on bone loss could not be detected. Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling. However, further studies are required to establish their efficacy in vivo.

Kupisiewicz K, Boissy P, Abdallah BM, Hansen FD…
Calcif. Tissue Int. Nov 2010
PMID: 20842496 | Free Full Text

8-Prenylnaringenin > Genistein for Preventing Osteoporosis in Ovariectomized Rats; Resveratrol Has no Effect

Abstract

Comparison of the phytohormones genistein, resveratrol and 8-prenylnaringenin as agents for preventing osteoporosis.

As the average age of society increases, identifying and preventing osteoporosis becomes more important. According to the results of the Women’s Health Initiative study, substitution of estradiol is not recommended in hormone replacement therapy (HRT), although phytoestrogens might be a safe alternative. In this study, the osteoprotective effects of genistein (Gen), resveratrol (Res) and 8-prenylnaringenin (8PN) were evaluated by analysing bone biomechanical strength and bone mineral density. After ovariectomy, 88 female rats received soy-free food (C), and according to their grouping, were fed estradiol (E), GEN, RES or 8PN for 12 weeks. The phytohormones were given in two dosages. To analyse the osteoprotective effects of the tested substances, bone biomechanical properties and bone mineral density (BMD) were evaluated on the upper tibial metaphysis. Bone biomechanical properties were significantly improved after treatment with E (F (max): 90.6 N) and 8PN (85.0 N) compared to GEN (76.0 N), RES (72.6 N) and C (76.6 N). Bone biomechanical properties with 8PN (yL: 55.7 N) supplementation reached a level similar to that seen after E (49.3 N) supplementation. Treatment with GEN (38.5 N) was not as effective as E and 8PN, but demonstrated improved biomechanical properties compared to C (40.1 N) and RES (36.3 N). E (Cn.Dn. 217 mg/cm (3)) and 8PN (165 mg/cm3) showed superior results in the analysis of bone mineral density compared to C (112 mg/cm (3)). GEN (164 mg/cm (3)) also demonstrated superior results, though not as good as E and 8PN. RES (124 mg/cm (3)) revealed no effect on bone density. Treatment with 8PN resulted in very good biomechanical properties and showed an increased BMD. GEN had a smaller effect on bone biomechanical strength, while RES did not have an effect on bone biomechanical strength or BMD. Therefore, 8PN might be a safe alternative for HRT, but further studies are needed.

Sehmisch S, Hammer F, Christoffel J, Seidlova-Wuttke D…
Planta Med. Jun 2008
PMID: 18537073

It is surprising and disappointing that resveratrol had no effect on bone density in this study.

Nervous System Does Not Induce Bone Growth – Only Resorption?

Abstract

Sympathetic nervous system does not mediate the load-induced cortical new bone formation.

The contribution of the SNS to bone’s response to mechanical loading is unclear. Using a noninvasive model of axial loading of the murine tibia, we found that sciatic neurectomy enhances load-induced new cortical bone formation and that pharmacological blockade of the SNS does not affect such responses, indicating that the SNS does not mediate the osteogenic effects of loading in cortical bone.
There is increasing evidence that the sympathetic nervous system (SNS) contributes to the regulation of bone mass and may influence remodeling by modulating bones’ response to mechanical load-bearing. The aim of this study was to examine the effect of sciatic neurectomy (SN) on the changes in cortical bone formation induced in response to mechanical loading and to investigate whether the SNS is directly involved in such load-induced responses.
Accordingly, load-induced responses were compared in tibias of growing and adult control C57Bl/J6 mice and in mice submitted to unilateral SN; noninvasive axial loading that induced 2,000 microstrain on the tibia lateral midshaft cortex was applied cyclically, 5 or 100 days after surgery, for 7 minutes, 3 days/week for 2 weeks, and mice received calcein on the third and last days of loading. Tibias were processed for histomorphometry, and transverse confocal images from diaphyseal sites were analyzed to quantify new cortical bone formation. Chemical SNS inactivation was achieved by prolonged daily treatment with guanethidine sulfate (GS) or by the introduction of propranolol in drinking water.
Our results show that new cortical bone formation is enhanced by loading in all tibial sites examined and that load-induced periosteal and endosteal new bone formation was greater in the SN groups compared with sham-operated controls. This SN-related enhancement in load-induced cortical bone formation in tibias was more pronounced 100 days after neurectomy than after 5 days, suggesting that longer periods of immobilization promote a greater sensitivity to loading. In contrast, the increases in new bone formation induced in response to mechanical loading were similar in mice treated with either GS or propranolol compared with controls, indicating that inactivation of the SNS has no effect on load-induced cortical new bone formation.
This study shows that SN, or the absence of loading function it entails, enhances loading-related new cortical bone formation in the tibia independently of the SNS.

de Souza RL, Pitsillides AA, Lanyon LE, Skerry TM…
J. Bone Miner. Res. Dec 2005
PMID: 16294269

Ukrain No Benefit in Rats #3

Abstract

Effect of intermittent three-month treatment with different doses of Ukrain on subregional bone mineral density of the femur of ovariectomized rats.

Ukrain, thiophosphoric acid alkaloid derivative from Chelidonium majus L., was administered i.p. to ovariectomized rats in doses of 7, 14 and 28 mg/kg every other day for 10 days, followed by a 10-day break, and the procedure was performed five times. At the end of long-term treatment with Ukrain (24 h after the last dose of the drug) the rats’ right femora were harvested and the bone densitometric parameters of the whole bone and distal metaphyseal and basicervical subregions were assessed using the dual-energy X-ray absorptiometry (DXA) densitometric method. The present results show a decrease in bone mineral density in groups of ovariectomized rats that received 7 mg/kg and 14 mg/kg of Ukrain versus untreated ovariectomized animals. Administration of Ukrain at a dose of 28 mg/kg did not significantly alter bone parameters of ovariectomized rats.

Jabłoński M, Gorzelak M, Patyra M, Jagiello-Wójtowicz E
Drugs Exp Clin Res 1998
PMID: 10190095

Antioxidants No Benefit in Population Study, Except Vitamin C with HRT

Abstract

Lack of a relation between vitamin and mineral antioxidants and bone mineral density: results from the Women’s Health Initiative.

Antioxidant defenses are one possible mechanism for decreasing oxidative damage and its potentially negative effects on age-related bone mass.
This study cross-sectionally examined whether higher dietary intakes, total intakes, and serum concentrations of antioxidants may be associated with higher bone mineral density (BMD).
Total hip (and subregions), spine, and total-body BMDs were measured in 11,068 women aged 50-79 y enrolled in the Women’s Health Initiative Observational Study and Clinical Trial at 3 clinics. Antioxidant intakes from diet (vitamin A, retinol, beta-carotene, vitamin C, vitamin E, and selenium) were estimated by using a self-reported food-frequency questionnaire. Antioxidants from supplements were estimated with an interviewer-administered questionnaire. A random subset (n = 379) had serum concentrations of retinol, carotenoids, and tocopherols measured.
After adjustment for important BMD-related covariates, increasing intakes of antioxidants were not independently associated with BMD. A significant interaction effect was observed between intake of total vitamin C (lower three-fourths compared with highest one-fourth) and use of hormone therapy (HT) (P < 0.01). The beneficial effect of current HT use on femoral neck BMD appeared to be greater in women with higher concentrations of total vitamin C. This interaction was also significant for total-body (P < 0.045), spine (P = 0.03), and total-hip BMDs (P = 0.029).
Our results do not support independent associations between dietary intake, total intake, or serum concentrations of antioxidants and BMD in women participating in the Women’s Health Initiative. The extent to which HT use may interact with vitamin C intake and BMD warrants further exploration.

Wolf RL, Cauley JA, Pettinger M, Jackson R…
Am. J. Clin. Nutr. Sep 2005
PMID: 16155271 | Free Full Text

TMG No Benefit for Bones in Homocystinuria

Abstract

The effect of oral betaine on vertebral body bone density in pyridoxine-non-responsive homocystinuria.

Five pyridoxine-non-responsive homocystinuric patients aged 5 to 32 years were treated with oral betaine, 3 g b.i.d, in a double-blind, placebo-controlled, two-year crossover study of its effect on bone mineralization. Betaine therapy significantly reduced mean plasma homocystine (36 +/- 9 (SEM) mumol L-1 to 9 +/- 4 mumol L-1), with variable increases in plasma methionine and no adverse effects. Bone density, measured by computerized tomographic scanning of vertebral bodies, was below normal in all patients at the start of the study, and was not significantly altered by betaine therapy administered according to this protocol.

Gahl WA, Bernardini I, Chen S, Kurtz D…
J. Inherit. Metab. Dis. 1988
PMID: 3148071

Why is this interesting? It’s interesting because several studies show an association between homocysteine and osteoporosis. TMG is known to lower homocysteine. Yet, in this study, there was no increase in bone density despite homocysteine being cut 75%.

Creatine Has No Effect on Bone Mass in Hypertensive Rats

Abstract

Influence of creatine supplementation on bone mass of spontaneously hypertensive rats.

Recent evidence has suggested that creatine supplementation (Cr) can increase the bone mineral density (BMD) of the femur in healthy growing rats. Nevertheless, studies assessing the efficacy of the Cr supplementation in conditions characterized by bone mass loss are scarce.
To investigate the effect of Cr supplementation on BMD and bone mineral content (BMC) in spontaneously hypertensive rats (SHRs), an experimental model of osteoporosis.
Sixteen 8-month-old male SHRs were randomly allocated into two groups matched by body weight: 1) Pl group: SHRs treated with placebo (distilled water; n = 8); and 2) Cr group: SHRs treated with Cr (n = 8). After nine weeks of supplementation, the animals were euthanized and their femur and spine (L1-L4) were analyzed by use of densitometry (Dual Energy X-Ray Absorptiometry).
No significant difference was observed between the groups regarding either the spine or the total femur measures as follows: spine – BMD (Pl = 0.249 ± 0.003 g/cm² vs. Cr = 0.249 ± 0.004 g/cm²; P = 0.95) and BMC (Pl = 0.509 ± 0.150 g vs. Cr = 0.509 ± 0.017 g; P > 0.99); and total femur – BMD (Pl = 0.210 ± 0.004 g/cm² vs. Cr = 0.206 ± 0.004 g/cm²; P > 0.49) and BMC (Pl = 0.407 ± 0.021 g vs. Cr = 0.385 ± 0.021 g; P > 0.46).
In this study, using the experimental model of osteoporosis, Cr supplementation had no effect on bone mass.

Alves CR, Murai IH, Ramona P, Nicastro H…
Rev Bras Reumatol
PMID: 22641599 | Free Full Text

Creatine: No Bone Benefit in Swimmers

Abstract

Effects of creatine supplementation on the performance and body composition of competitive swimmers.

The objective of this study was to determine the effect of creatine supplementation on performance and body composition of swimmers. Eighteen swimmers were evaluated in terms of post-performance lactate accumulation, body composition, creatine and creatinine excretion, and serum creatinine concentrations before and after creatine or placebo supplementation. No significant differences were observed in the marks obtained in swimming tests after supplementation, although lactate concentrations were higher in placebo group during this period. In the creatine-supplemented group, urinary creatine, creatinine, and body mass, lean mass and body water were significantly increased, but no significant difference in muscle or bone mass was observed. These results suggest that creatine supplementation cannot be considered to be an ergogenic supplement ensuring improved performance and muscle mass gain in swimmers.

Mendes RR, Pires I, Oliveira A, Tirapegui J
J. Nutr. Biochem. Aug 2004
PMID: 15302082

FOS Has No Bone Benefits in Chicks

Abstract

Effects of age, vitamin D3, and fructooligosaccharides on bone growth and skeletal integrity of broiler chicks.

A study was conducted to evaluate the effects of age, vitamin D(3), and fructooligosaccharides (FOS) on bone mineral density (BMD), bone mineral content (BMC), cortical thickness, cortical and trabecular area, and mechanical properties in broiler chicks using peripheral quantitative computed tomography and mechanical testing. A total of 54 male broiler chicks (1 d old) were placed in battery brooders and fed a corn-soybean starter diet for 7 d. After 7 d, the chicks were randomly assigned to pens of 3 birds each. Each treatment was replicated 3 times. There were 6 treatments: 1) early age control (control 1); 2) control 2; 3) 125 µg/kg of vitamin D(3); 4) 250 µg/kg of vitamin D(3); 5) 2% FOS); and 6) 4% FOS. The control 1 chicks were fed a control broiler diet and killed on d 14 to collect femurs for bone analyses. The remaining groups were killed on d 21. Femurs from 3-wk-old chicks showed greater midshaft cortical BMD, BMC, bone area, thickness, and marrow area than those from 2-wk-old chicks (P = 0.016, 0.0003, 0.0002, 0.01, and 0.0001, respectively). Total, cortical, and trabecular BMD of chick proximal femurs were not influenced by age. However, BMC and bone area were significantly affected by age. The femurs of 2-wk-old chicks exhibited significantly lower stiffness and ultimate load than those of 3-wk-old chicks (P = 0.0001), whereas ultimate stress and elastic modulus of the femurs of 2-wk-old chicks were significantly higher than that of femurs of 3-wk-old chicks (P = 0.0001). Chicks fed 250 µg/kg of vitamin D(3) exhibited significantly greater midshaft cortical BMC (P = 0.04), bone area (P = 0.04), and thickness (P = 0.03) than control 2, 2% FOS, or 4% FOS chicks. In summary, our study suggests that high levels of vitamin D(3) can increase bone growth and mineral deposition in broiler chicks. However, FOS did not have any beneficial effects on bone growth and skeletal integrity. Age is an important factor influencing skeletal integrity and mechanical properties in broiler chicks.

Kim WK, Bloomfield SA, Ricke SC
Poult. Sci. Nov 2011
PMID: 22010225 | Free Full Text

Inulin Has No Effect On Bone Mineralization in Pigs

Abstract

Effect of dietary mineral level and inulin inclusion on phosphorus, calcium and nitrogen utilisation, intestinal microflora and bone development.

An experiment was conducted to investigate the interaction between dietary phosphorus (P) level (4 vs 6 g total P kg(-1)) and inulin inclusion (0 vs 20 g kg(-1)) on coefficients of total tract apparent digestibility, nitrogen (N), P and calcium (Ca) utilisation, bone mineralisation, selected gastrointestinal microflora, intestinal volatile fatty acid concentrations and digesta pH in the ileum, caecum and proximal colon. Owing to the design of the experiment, as dietary P level increased, there was also an increase in dietary Ca level in order to maintain a sustainable dietary Ca/P ratio. Entire male finisher pigs (n = 10 per treatment) with a similar initial body weight (51 kg, standard deviation 2.4 kg) were used.
Inulin inclusion lowered (P < 0.01) Enterobacteriaceae populations in the proximal colon compared with pigs offered diets without added inulin. However, intestinal bacterial populations of Lactobacillus and Bifidobacterium spp. were unaffected. Inulin inclusion had no effect on mineral digestibility or bone mineralisation. Pigs offered low P and Ca diets had lower (P < 0.01) bone mineralisation than pigs offered high P and Ca diets.
Intestinal bacterial populations of Enterobacteriaceae in the proximal colon were lowered by inulin inclusion. Inulin inclusion did not affect P, Ca or N utilisation or bone mineralisation in the finisher pig when offered either a low or a high P diet. Increasing the P and Ca content of the diet led to an increase in bone mineralisation.

Varley PF, McCarney C, Callan JJ, O’Doherty JV
J. Sci. Food Agric. Nov 2010
PMID: 20661921