Oligogalacturonic Acid Inhibits Resorption In Vitro

Abstract

Oligogalacturonic acid inhibit bone resorption and collagen degradation through its interaction with type I collagen.

In this study, we showed that oligogalacturonic acid (OGA) purified from flax pectin inhibit in vitro osteoclastic bone resorption in a dose-dependent manner. The OGA inhibitory effect was neither linked to an effect on osteoclast apoptosis, nor to an inhibition of cathepsin K activity. By means of an in vitro collagen degradation assay we demonstrated that OGA prevented triple-helical type I collagen cleavage by cathepsin K in a dose and chain length dependent manner. This inhibition was not restricted to cathepsin K, since collagenolytic activity of other lysosomal cysteine proteases, such as cathepsin B and cathepsin L, as well as matrixmetalloproteinases such as MMP-9 were also inhibited. Interestingly, using non-collagen substrates we demonstrated that OGA does not inhibit the proteolytic activity of cathepsin B and L, suggesting that OGA inhibits collagen degradation without affecting the lysosomal cysteine enzyme proteolytic activity. Finally, preliminary study using surface plasmon resonance (SPR) showed that OGA binds to type I collagen but not to albumin, consistent with a specific effect on collagen. These results suggest that the observed inhibition of collagen degradation by OGA may be due to its ability to bind to the collagen molecule. By masking the collagen surface, OGA may render the collagen cleavage site less accessible to enzymes and thus prevent its enzymatic degradation.

Lion JM, Mentaverri R, Rossard S, Jullian N…
Biochem. Pharmacol. Dec 2009
PMID: 19647720

Resistive Vibration Exercise May Reduce Bone Loss During Bed Rest in Men

Abstract

Resistive vibration exercise attenuates bone and muscle atrophy in 56 days of bed rest: biochemical markers of bone metabolism.

During and after prolonged bed rest, changes in bone metabolic markers occur within 3 days. Resistive vibration exercise during bed rest impedes bone loss and restricts increases in bone resorption markers whilst increasing bone formation. To investigate the effectiveness of a resistive vibration exercise (RVE) countermeasure during prolonged bed rest using serum markers of bone metabolism and whole-body dual X-ray absorptiometry (DXA) as endpoints.
Twenty healthy male subjects underwent 8 weeks of bed rest with 12 months follow-up. Ten subjects performed RVE. Blood drawings and DXA measures were conducted regularly during and after bed rest.
Bone resorption increased in the CTRL group with a less severe increase in the RVE group (p = 0.0004). Bone formation markers increased in the RVE group but decreased marginally in the CTRL group (p < 0.0001). At the end of bed rest, the CTRL group showed significant loss in leg bone mass (-1.8(0.9)%, p = 0.042) whereas the RVE group did not (-0.7(0.8)%, p = 0.405) although the difference between the groups was not significant (p = 0.12).
The results suggest the countermeasure restricts increases in bone resorption, increased bone formation, and reduced bone loss during bed rest.

Armbrecht G, Belavý DL, Gast U, Bongrazio M…
Osteoporos Int Apr 2010
PMID: 19536451

Judo Provides Powerful Oseogenic Stimuli Despite Off-Season Weight Loss

Abstract

Bone density in elite judoists and effects of weight cycling on bone metabolic balance.

Weight cycling has been shown to exert negative effects on bone metabolism and bone mass, whereas weight-bearing activity is positively associated with bone mineral density (BMD). Bone health in judoists and effects of weight cycling on bone metabolism have not previously been investigated. To examine potential disrupter and stimulators of bone integrity, this study analyzed bone parameters at baseline and the effects of the first weight cycle of the season on bone metabolic status in 48 male and female elite judoists.
Body composition and lumbar, femoral, and total body BMD were evaluated by dual-energy x-ray absorptiometry. Cortisol, osteocalcin, C-terminal telopeptide of type I collagen (CTx), and bone uncoupling index (UI) were measured in judoists at normal body weight, after weight reduction, and after regaining weight. As a comparison, a control group of moderately active students was included at baseline. Training, menstrual status, and calcium intake were assessed by questionnaires.
Euweighted judoists displayed high BMD and an increased rate of bone formation. Precompetitive weight loss averaged 4 +/- 0.3% of body weight and induced an acute rise in cortisol (81%, P < 0.05) and CTx (33%, P < 0.0001), with a metabolic imbalance in favor of bone resorption. A 4 +/- 0.5% weight regain restored a positive UI in favor of bone formation. Metabolic responses were not dependent on gender. BMD was unaltered by weight cycling.
Increased bone formation rate pertaining to judo athletes lent protection from alterations in bone metabolic balance associated with weight cycling. This observation suggests that powerful osteogenic stimuli provided by judo’s unique biomechanical environment may help prevent bone loss associated with weight loss.

Prouteau S, Pelle A, Collomp K, Benhamou L…
Med Sci Sports Exerc Apr 2006
PMID: 16679985

Comment: Cycling and bone health: a systematic review

Abstract

Bike racing, recreational riding, impact sport and bone health.

Cycling has been shown to confer considerable benefits in terms of health, leading to reductions in death rates principally due to cardiovascular improvements and adaptation. Given the disparity between the benefits of cycling on cardiovascular fitness and previous research finding that cycling may not be beneficial for bone health, Hugo Olmedillas and colleagues performed a systematic review of the literature. They concluded that road cycling does not appear to confer any significant osteogenic benefit. They postulate that the cause of this is that, particularly at a competitive level, riders spend long periods of time in a weight-supported position on the bike. Training programs may be supplemented with impact loading to preserve bone health; however, the small increased risk of soft tissue injury must also be considered. See related study.

Carmont MR
BMC Med 2012
PMID: 23256478 | Free Full Text

Review: Cyclists Have Low Bone Density

Abstract

Cycling and bone health: a systematic review.

Cycling is considered to be a highly beneficial sport for significantly enhancing cardiovascular fitness in individuals, yet studies show little or no corresponding improvements in bone mass.
A scientific literature search on studies discussing bone mass and bone metabolism in cyclists was performed to collect all relevant published material up to April 2012. Descriptive, cross-sectional, longitudinal and interventional studies were all reviewed. Inclusion criteria were met by 31 studies.
Heterogeneous studies in terms of gender, age, data source, group of comparison, cycling level or modality practiced among others factors showed minor but important differences in results. Despite some controversial results, it has been observed that adult road cyclists participating in regular training have low bone mineral density in key regions (for example, lumbar spine). Conversely, other types of cycling (such as mountain biking), or combination with other sports could reduce this unsafe effect. These results cannot yet be explained by differences in dietary patterns or endocrine factors.
From our comprehensive survey of the current available literature it can be concluded that road cycling does not appear to confer any significant osteogenic benefit. The cause of this may be related to spending long hours in a weight-supported position on the bike in combination with the necessary enforced recovery time that involves a large amount of time sitting or lying supine, especially at the competitive level.

Olmedillas H, González-Agüero A, Moreno LA, Casajus JA…
BMC Med 2012
PMID: 23256921 | Free Full Text

Eldecalcitol > Alfacalcidol in Ovariectomized Rats

Abstract

Effects of combined treatment with eldecalcitol and alendronate on bone mass, mechanical properties, and bone histomorphometry in ovariectomized rats: a comparison with alfacalcidol and alendronate.

Eldecalcitol (ELD), a 2β-hydroxypropyloxy derivative of 1α,25 (OH) 2D3, inhibits bone resorption more potently than alfacalcidol (ALF) while maintaining osteoblastic function in an ovariectomized (OVX) osteoporosis rat model. Alendronate (ALN), which is the most common bisphosphonate used for the treatment of osteoporosis, increases the bone mineral density (BMD) by suppressing bone resorption. In this study, we investigated the effects of combination treatments with ELD and ALN or with ALF and ALN on bone mass and strength in OVX rats. Seventy female rats, 32 weeks old, were assigned to seven groups: (1) a sham-operated control group; (2) an OVX-control group; (3) an ELD group; (4) an ALF group; (5) an ALN group; (6) an ELD+ALN group; and (7) an ALF+ALN group. OVX rats were orally treated with ELD (0.015 μg/kg), ALF (0.0375 μg/kg), or ALN (0.2mg/kg) daily for 12 weeks. In both the lumbar spine and the femur, ELD and ALF monotherapy significantly increased the BMD, and ELD+ALN and ALF+ALN significantly increased the BMD, compared with ALN monotherapy, as an additive effect. In particular, ELD+ALN resulted in a significantly higher BMD than ALF+ALN in the femur. On mechanical testing of the lumbar spine, ELD and ALF monotherapy significantly increased the ultimate load, and ELD+ALN and ALF+ALN significantly increased the ultimate load compared with ALN monotherapy. In the femur, ELD, ELD+ALN, and ALF+ALN treatment significantly increased the ultimate load, compared with the OVX-control group, and ELD+ALN resulted in a significantly higher ultimate load than ALN monotherapy. A histomorphometric analysis showed that ELD monotherapy and ELD+ALN combination therapy had a potent inhibitory effect on bone resorption parameters (osteoclast surface and eroded surface), while maintaining bone formation parameters (osteoblast surface and osteoid surface). By contrast, ALF and ALF+ALN significantly lowered the histological parameters of both bone resorption and formation. These results suggested that ELD or ALF used in combination with ALN has therapeutic advantages over ALN monotherapy, with ELD+ALN combination treatment producing an especially beneficial anti-osteoporotic effect by inhibiting osteoclastic bone resorption and maintaining osteoblastic function, compared with ALF+ALN combination treatment.

Sugimoto M, Futaki N, Harada M, Kaku S
Bone Jan 2013
PMID: 23041510

Low Dose MK-4 for a Year Maintains Bone Density and Improves Bone Quality in Postmenopausal Japanese Women

Abstract

Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women.

Menaquinone-4 (MK-4) administered at a pharmacological dosage of 45 mg/day has been used for the treatment of osteoporosis in Japan. However, it is not known whether a lower dose of MK-4 supplementation is beneficial for bone health in healthy postmenopausal women. The aim of this study was to examine the long-term effects of 1.5-mg daily supplementation of MK-4 on the various markers of bone turnover and bone mineral density (BMD). The study was performed as a randomized, double-blind, placebo-controlled trial. The participants (aged 50-65 years) were randomly assigned to one of two groups according to the MK-4 dose received: the placebo-control group (n = 24) and the 1.5-mg MK-4 group (n = 24). The baseline concentrations of undercarboxylated osteocalcin (ucOC) were high in both groups (>5.1 ng/ml). After 6 and 12 months, the serum ucOC concentrations were significantly lower in the MK-4 group than in the control group. In the control group, there was no significant change in serum pentosidine concentrations. However, in the MK-4 group, the concentration of pentosidine at 6 and 12 months was significantly lower than that at baseline. The forearm BMD was significantly lower after 12 months than at 6 months in the control group. However, there was no significant decrease in BMD in the MK-4 group during the study period. These results suggest that low-dose MK-4 supplementation for 6-12 months improved bone quality in the postmenopausal Japanese women by decreasing the serum ucOC and pentosidine concentrations, without any substantial adverse effects.

Koitaya N, Sekiguchi M, Tousen Y, Nishide Y…
J. Bone Miner. Metab. Mar 2014
PMID: 23702931

This study appears to be a continuation of this 4 week study: Low Dose MK-4 May Benefit Bones in Postmenopausal Japanese Women

Vitamin K1 Associated With Bone Health in Women

Abstract

Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women: no evidence of gene-nutrient interaction with apolipoprotein E polymorphisms.

Polymorphisms in the apolipoprotein E (APOE) gene are associated with fracture risk, and a potential mechanism is through vitamin K transport.
We investigated the relation between dietary vitamin K(1) intake, APOE polymorphisms, and markers of bone health. We measured bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) in a cohort of Scottish women aged 49-54 y in 1990-1994 (baseline) and in 1997-2000 (visit 2). At visit 2, bone markers (urinary pyridinoline crosslinks and serum N-terminal propeptide of type 1 collagen) were measured, 3199 women completed a food-frequency questionnaire, and 2721 women were genotyped for APOE.
Compared with quartile 3 (Q3) of energy-adjusted vitamin K(1) intake (mean: 116 microg/d), women in the lowest quartile (mean: 59 microg/d) had lower BMD (analysis of variance; FN, Q1: 0.831 +/- 0.122 g/cm(2); Q3: 0.850 +/- 0.126 g/cm(2); P < 0.001; LS, Q1: 1.000 +/- 0.170 g/cm(2); Q3: 1.020 +/- 0.172 g/cm(2); P = 0.009), remaining significant at the FN after adjustment for age, weight, height, menopausal status or use of hormone replacement therapy, socioeconomic status, and physical activity (P = 0.04). Vitamin K(1) intake was associated with reduced concentrations of pyridinoline crosslinks (Q1: 5.4 +/- 2.0 nmol/mmol; Q4: 5.1 +/- 1.9 nmol/mmol; P = 0.003). Carriers of the E2 allele had greater LS BMD at visit 2 and lost less BMD than did carriers of the E4 allele (E2: -0.50 +/- 1.22%/y; E4: -0.71 +/- 1.17%/y; P = 0.05). After adjustment for confounders, the P value for BMD loss (0.03 for LS and 0.04 for FN) did not reach the level of significance required for multiple testing (P = 0.012). No interaction was observed between dietary vitamin K and APOE on BMD.
Vitamin K(1) intake was associated with markers of bone health, but no interaction was observed with APOE alleles on BMD or markers of bone turnover.

Macdonald HM, McGuigan FE, Lanham-New SA, Fraser WD…
Am. J. Clin. Nutr. May 2008
PMID: 18469278 | Free Full Text

Vitamin K1 May Help Prevent Fractures, But Does Not Improve Bone Density in Women with Osteopenia

Abstract

Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial.

Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by -1.28% and -1.22% (p = 0.84) (difference of -0.06%; 95% confidence interval [CI] -0.67% to 0.54%) at the lumbar spine and -0.69% and -0.88% (p = 0.51) (difference of 0.19%; 95% CI -0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.

Cheung AM, Tile L, Lee Y, Tomlinson G…
PLoS Med. Oct 2008
PMID: 18922041 | Free Full Text

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.