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Nicotine Not Responsible for Negative Effects of Smoking on Bone Density in Rats


The effect of long-term nicotine exposure on bone mineral density and oxidative stress in female Swiss Albino rats.

To evaluate the effect of long-term low or high-dose nicotine exposure on bone mass via measuring bone mineral density (BMD) and oxidant-antioxidant status markers.
Thirty-five female Swiss Albino rats weighing 70 ± 10 g were divided as the control group (n = 12), low-dose nicotine group (n = 12) and high-dose nicotine group (n = 11). While the control group was given only normal drinking water, the low-dose nicotine group had 0.4 mg/kg per day and the high-dose nicotine group, 6.0 mg/kg per day of nicotine added to their water for the period of 1 year. BMD was determined with X-ray absorptiometry of lumbar vertebra, corpus femoris, proximal and distal femur. To evaluate oxidant-antioxidant status malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities were determined.
When comparing the nicotine groups and controls, neither BMD nor oxidant-antioxidant status markers showed any statistically significant difference. In comparison to the controls, 12 months of high-dose oral nicotine exposure did not have a significant effect on BMD and low-dose nicotine exposure led to a statistically insignificant increase in BMD.
Contrary to common belief, the results of this study show that nicotine is not responsible for the decrease in BMD leading to osteoporosis frequently seen in smokers. However, there is a need to explore the other harmful materials in tobacco which may be responsible for the alterations seen in BMD of smokers.

Turan V, Mizrak S, Yurekli B, Yilmaz C…
Arch. Gynecol. Obstet. Feb 2013
PMID: 22955292

Vitamin E Does Not Prevent Bone Loss in Rats


Vitamin E does not prevent bone loss and induced anxiety in rats with ligature-induced periodontitis.

The purpose of this study was to investigate the effect of vitamin E on alveolar bone loss (ABL) and anxiety in rats with ligature-induced experimental periodontitis (EP).
Wistar rats were subjected to ligature-induced EP and treated with vitamin E (500mg/kg, orally) for 9 days. Then anxiety was tested using the elevated plus-maze (EPM) test. All of the animals were euthanised by cervical dislocation on day 11. ABL was analysed morphometrically and histopathologically. Lipid peroxidation quantification, activity of the enzyme superoxide dismutase and immunohistochemistry to tumour necrosis factor-alpha (TNF-α) and inducible isoform of nitric oxide synthases (iNOS) were also tested.
EP induced a marked inflammatory process and intense ABL. Treatment with vitamin E decreased inflammatory reaction, prevented malondialdehyde formation and reduced the immunoreactivity to iNOS, but did not decrease ABL. Vitamin E had an anxiogenic effect on rats with or without EP.
Vitamin E may have potential to reduce oxidative damage and inflammatory response in EP but does not prevent ABL. Attention should be given to indiscriminate use of vitamin E due to the risk of causing anxiety in patients.

Carvalho Rde S, de Souza CM, Neves JC, Holanda-Pinto SA…
Arch. Oral Biol. Jan 2013
PMID: 22664314

Bread Crust Does Not Negatively Affect Calcium in Rats


Effects of dietary bread crust Maillard reaction products on calcium and bone metabolism in rats.

Maillard reaction products (MRP) consumption has been related with the development of bone degenerative disorders, probably linked to changes in calcium metabolism. We aimed to investigate the effects of MRP intake from bread crust on calcium balance and its distribution, and bone metabolism. During 88 days, rats were fed control diet or diets containing bread crust as source of MRP, or its soluble high molecular weight, soluble low molecular weight or insoluble fractions (bread crust, HMW, LMW and insoluble diets, respectively). In the final week, a calcium balance was performed, then animals were sacrified and some organs removed to analyse calcium levels. A second balance was carried out throughout the experimental period to calculate global calcium retention. Biochemical parameters and bone metabolism markers were measured in serum or urine. Global calcium bioavailability was unmodified by consumption of bread crust or its isolate fractions, corroborating the previously described low affinity of MRP to bind calcium. Despite this, a higher calcium concentration was found in femur due to smaller bones having a lower relative density. The isolate consumption of the fractions altered some bone markers, reflecting a situation of increased bone resorption or higher turnover; this did not take place in the animals fed the bread crust diet. Thus, the bread crust intake does not affect negatively calcium bioavailability and bone metabolism.

Roncero-Ramos I, Delgado-Andrade C, Haro A, Ruiz-Roca B…
Amino Acids Jun 2013
PMID: 22109787

Vitamin K1 and K2 (MK-4, MK-7) Don’t Prevent Bone Loss in Rats Fed Adequate Nutrients


Vitamin K supplementation does not prevent bone loss in ovariectomized Norway rats.

Despite plausible biological mechanisms, the differential abilities of phylloquinone (PK) and menaquinones (MKn) to prevent bone loss remain controversial. The objective of the current study was to compare the effects of PK, menaquinone-4 (MK-4) and menaquinone-7 (MK-7) on the rate of bone loss in ovariectomized (OVX) Norway rats. A secondary aim was to compare the effects of vitamin K with those of bisphosphonates (BP) on bone loss.
Rats (n = 96) were randomized to 6 dosing groups [n = 16/group; Sham; OVX; OVX + BP (100 μg/kg/100 μg/mL saline sc); OVX + PK; OVX + MK-4; and OVX + MK-7] for 6 wk. Equimolar daily doses of 107 mg PK/kg, 147 mg MK-4/kg, and 201 mg MK-7/kg diet were provided.
BP significantly increased bone strength and bone mineral density (BMD) vs. OVX (P < 0.05). However, PK, MK-4 or MK-7 did not change bone strength or BMD compared to the OVX group. Whereas supplementation of PK, MK-4 and MK-7 increased serum and tibia concentrations of each respective form, PK concentrations were consistently higher despite equimolar intakes.
PK, MK-4, and MK-7 do not appear to prevent bone loss in OVX rats when administered concurrent with adequate intake of other nutrients.

Fu X, Moreines J, Booth SL
Nutr Metab (Lond) 2012
PMID: 22348311 | Free Full Text

In conclusion, supplementation of PK, MK-4 or MK-7 did not confer a beneficial effect on bone loss in ovariectomized Norway rats fed a diet that meets nutritional requirements for other nutrients, including calcium and vitamin D. This would suggest that equivocal findings in the literature regarding the effect of various forms of vitamin K on bone cannot be attributed to differences among the forms studied. These data are also consistent with a growing number of clinical studies that report no beneficial effect of vitamin K supplementation on bone loss in the elderly who are otherwise calcium and vitamin D-replete [1,18,19].

Vitamin K Intake Not Associated with Fracture in Chinese Men and Women


No association between dietary vitamin K intake and fracture risk in chinese community-dwelling older men and women: a prospective study.

Data on the association between dietary vitamin K intake and fracture risk are limited among Chinese. This study examined such an association in community-dwelling elderly in Hong Kong. We present data from 2,944 subjects (1,605 men, 1,339 women) who participated in a prospective cohort study. Baseline dietary intakes of energy, protein, calcium, vitamin D, and vitamin K were assessed using a food-frequency questionnaire. Data on incident hip fracture and nonvertebral fracture during a median of 6.9 follow-up years were collected from a hospital database. Cox regression analyses were performed with adjustments for age, education attainment, smoking status, alcohol use, body mass index, hip bone mineral density, physical activity, use of calcium supplement, and energy-adjusted nutrient intakes. There were 29 (1.8 %) men and 19 (1.4 %) women with incident hip fractures and 97 (6.0 %) men and 88 (6.6 %) women with nonvertebral fractures. The median (interquartile range) of dietary vitamin K intake was 241.8 (157.5-360.8) and 238.9 (162.4-343.6) μg/day in men and women, respectively. Similar dietary vitamin K intakes were observed between subjects with hip or nonvertebral fractures and subjects without hip or nonvertebral fractures. In both men and women, dietary vitamin K intake was not associated with fracture risks at all measured sites in either crude or adjusted models. In Chinese community-dwelling elderly, hip or nonvertebral fracture risk was not associated with dietary vitamin K intake. The high dietary vitamin K intake of the studied group may have limited the ability to detect the association between vitamin K intake and fracture risk.

Chan R, Leung J, Woo J
Calcif. Tissue Int. May 2012
PMID: 22451220

Glucosamine no Effect on Bone Resorption or Formation Markers


Evaluation of the effect of glucosamine administration on biomarkers of cartilage and bone metabolism in bicycle racers.

In the present study, the effect of glucosamine administration (1.5 or 3 g/day) on cartilage and bone metabolism was investigated in bicycle racers, using cartilage‑ and bone‑specific biomarkers, including C‑terminal cross‑linked telopeptides of type II collagen (CTX‑II), C‑terminal propeptides of type II procollagen (CPII), N‑terminal telopeptides of bone‑specific type I collagen (NTx) and bone alkaline phosphatase (BAP). The results indicate that CPII (a marker of type II collagen synthesis) was not substantially changed, however, CTX‑II (a marker of type II degradation) was reduced by glucosamine administration, particularly at a dose of 3 g/day. Consistent with these observations, the ratio of CTX‑II/CPII was reduced by glucosamine administration and the effect of glucosamine was dose‑dependent. By contrast, the levels of NTx (a bone resorption marker) and BAP (a bone formation marker) were not altered by glucosamine administration. A previous study by this group reported that glucosamine exerts a chondroprotective action in soccer players by preventing type II collagen degradation but maintaining type II collagen synthesis. Together these observations indicate that glucosamine may exert a chondroprotective action by preventing type II collagen degradation in athletes of various sports, including soccer players and bicycle racers.

Momomura R, Naito K, Igarashi M, Watari T…
Mol Med Rep Mar 2013
PMID: 23358550

Glucosamine No Effect on Three Bone Markers in Horses


Serum concentrations of keratan sulfate, osteocalcin, and pyridinoline crosslinks after oral administration of glucosamine to standardbred horses during race training.

To determine the effects of orally administered glucosamine on concentrations of markers of bone and cartilage metabolism in Standardbred horses during race training.
Twenty 16- to 20-month-old Standardbreds beginning race training.
Horses were randomly assigned to 2 groups. One group received glucosamine hydrochloride (4 g, PO, q 12 h), and the second (control) group received glucose (4 g, PO, q 12 h). Serum samples were obtained prior to onset of the study (baseline) and at regular intervals for 48 weeks for determination of concentrations of keratan sulfate (KS), osteocalcin (OC), and pyridinoline crosslinks (PYD).
Osteocalcin concentrations changed significantly with time; mean serum concentrations were significantly higher than baseline values for samples obtained at 24 to 48 weeks after onset of the study. Although a significant effect of time was observed for mean concentration of KS, concentrations did not differ significantly from baseline values at any time during the study when groups were analyzed separately. However, pooled analysis revealed significant increases of mean serum KS concentration at weeks 24 and 30. Significant changes in serum PYD concentrations were not detected. Oral administration of glucosamine did not significantly affect serum concentrations of any of the markers.
Increased serum OC in clinically normal Standardbreds during race training may reflect bone formation that accompanies adaptive remodeling of the appendicular skeleton. For these experimental conditions, glucosamine did not appear to exert a detectable influence on serum concentrations of these 3 markers of connective tissue metabolism.

Caron JP, Peters TL, Hauptman JG, Eberhart SW…
Am. J. Vet. Res. Aug 2002
PMID: 12171162

Vitamin K1 or K2 (MK-4) Does Not Increase Bone Density in Healthy Postmenopausal Women


Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women.

Low vitamin K status is associated with low BMD and increased fracture risk. Additionally, a specific menaquinone, menatetrenone (MK4), may reduce fracture risk. However, whether vitamin K plays a role in the skeletal health of North American women remains unclear. Moreover, various K vitamers (e.g., phylloquinone and MK4) may have differing skeletal effects. The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic, postmenopausal, North American women. In this double-blind, placebo-controlled study, 381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily), or placebo for 12 mo. All participants received daily calcium and vitamin D(3) supplementation. Serum bone-specific alkaline phosphatase (BSALP) and n-telopeptide of type 1 collagen (NTX) were measured at baseline and 1, 3, 6, and 12 mo. Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo. At baseline, the three treatment groups did not differ in demographics or study endpoints. Compliance with calcium, phylloquinone, and MK4 treatment was 93%, 93%, and 87%, respectively. Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX. No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed. This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal, North American women receiving calcium and vitamin D supplementation.

Binkley N, Harke J, Krueger D, Engelke J…
J. Bone Miner. Res. Jun 2009
PMID: 19113922 | Free Full Text

Vitamin K1 500mcg No Benefit for Bone Density Over 3 Years


Effect of vitamin K supplementation on bone loss in elderly men and women.

Vitamin K has been implicated in bone health, primarily in observational studies. However, little is known about the role of phylloquinone supplementation on prevention of bone loss in men and women.
The objective of this study was to determine the effect of 3-yr phylloquinone supplementation on change in bone mineral density (BMD) of the femoral neck bone in older men and women who were calcium and vitamin D replete.
In this 3-yr, double-blind, controlled trial, 452 men and women (60-80 yr) were randomized equally to receive a multivitamin that contained either 500 mug/d or no phylloquinone plus a daily calcium (600 mg elemental calcium) and vitamin D (400 IU) supplement.
Measurements of the femoral neck, spine (L2-L4), and total-body BMD, bone turnover, and vitamins K and D status were measured every 6-12 months. Intent-to-treat analysis was used to compare change in measures in 401 participants who completed the trial.
There were no differences in changes in BMD measurements at any of the anatomical sites measured between the two groups. The group that received the phylloquinone supplement had significantly higher phylloquinone and significantly lower percent undercarboxylated osteocalcin concentrations compared with the group that did not receive phylloquinone. No other biochemical measures differed between the two groups.
Phylloquinone supplementation in a dose attainable in the diet does not confer any additional benefit for bone health at the spine or hip when taken with recommended amounts of calcium and vitamin D.

Booth SL, Dallal G, Shea MK, Gundberg C…
J. Clin. Endocrinol. Metab. Apr 2008
PMID: 18252784 | Free Full Text

Review: Vitamin K1 Cost Effectiveness for Osteoporosis


Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

To determine the clinical and cost-effectiveness of vitamin K in preventing osteoporotic fractures in postmenopausal women.
Searches were conducted in May 2007 in MEDLINE, MEDLINE In-Process, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, BIOSIS, CINAHL, DARE, NHS EED and HTA databases, AMED, NRR, Science Citation Index and Current Controlled Trials. The MEDLINE search was updated in March 2009.
Selected studies were assessed and subjected to data extraction and quality assessment using standard methods. Where appropriate, meta-analysis was carried out. A mathematical model was constructed to estimate the cost-effectiveness of vitamin K1.
The electronic literature searches identified 1078 potentially relevant articles. Of these, 14 articles relating to five trials that compared vitamin K with a relevant comparator in postmenopausal women with osteoporosis or osteopenia met the review inclusion criteria. The double-blind ECKO trial compared 5 mg of phylloquinone (vitamin K1) with placebo in Canadian women with osteopenia but without osteoporosis. Four open-label trials used 45 mg of menatetrenone (vitamin K2) in Japanese women with osteoporosis; the comparators were no treatment, etidronate or calcium. The methodological quality of the ECKO trial was good; however, all four menatetrenone trials were poorly reported and three were very small (n < 100 in each group). Phylloquinone was associated with a statistically significant reduction in the risk of clinical fractures relative to placebo [relative risk 0.46, 95% confidence interval (CI) 0.22 to 0.99]; morphometric vertebral fractures were not reported. The smaller menatetrenone trials found that menatetrenone was associated with a reduced risk of morphometric vertebral fractures relative to no treatment or calcium; however, the larger Osteoporosis Fracture (OF) study found no evidence of a reduction in vertebral fracture risk. The three smaller trials found no significant difference between treatment groups in non-vertebral fracture incidence. In the ECKO trial, phylloquinone was not associated with an increase in adverse events. In the menatetrenone trials, adverse event reporting was generally poor; however, in the OF study, menatetrenone was associated with a significantly higher incidence of skin and skin appendage lesions. No published economic evaluations of vitamin K were found and a mathematical model was thus constructed to estimate the cost-effectiveness of vitamin K1. Comparators were alendronate, risedronate and strontium ranelate. Vitamin K1 and alendronate were markedly more cost-effective than either risedronate or strontium ranelate. The base-case results favoured vitamin K1, but this relied on many assumptions, particularly on the efficacy of preventing hip and vertebral fractures. Calculation of the expected value of sampled information was conducted assuming a randomised controlled trial of 5 years’ duration comparing alendronate with vitamin K1. The costs incurred in obtaining updated efficacy data from a trial with 2000 women per arm were estimated to be a cost-effective use of resources.
There is currently large uncertainty over whether vitamin K1 is more cost-effective than alendronate; further research is required. It is unlikely that the present prescribing policy (i.e. alendronate as first-line treatment) would be altered.

Stevenson M, Lloyd-Jones M, Papaioannou D
Health Technol Assess Sep 2009
PMID: 19818211 | Free Full Text

This is a huge 158 page report. The reason they used K1 instead of K2 was:Vitamin K to prevent fractures in older women: systematic review and economic evaluation

No formal evaluation of vitamin K2 has been undertaken for a number of reasons. This intervention is currently not permitted as a food supplement in the EU because there is no evidence for its independent role in health26 and the price of the intervention is unknown. Additionally, the fracture efficacy data have wide confidence intervals, all of which spanned unity, and the only large (n > 1500 patients per arm) RCT reported a RR of 1.01 for vitamin K2 compared with calcium or no active intervention.