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Fatigue fractures in military conscripts : A study on risk factors, diagnostics and long-term consequences Ruohola, Juha-Petri University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, Orthopaedics and Traumatology, Helsinki University Central Hospital Centre of Military Medicine, Helsinki 2007-03-09 Doctoral dissertation (article-based) It seems likely that low vitamin D levels are related to fatigue fractures, and that an increasing trend exists between TRACP-5b bone resorption marker elevation and fatigue fracture incidence. Though seldom detected by plain radiography, fatigue fractures often underlie unclear lower leg stress-related pain occurring in the distal parts of the tibia. Femoral neck fatigue fractures, when displaced, lead to long-term morbidity in a high percentage of patients, whereas, when non-displaced, they do not predispose patients to subsequent adverse complications. Importantly, an educational intervention can diminish the incidence of fracture displacement by enhancing awareness and providing instructions for earlier diagnosis of fatigue fractures

Stress fractures in the Israeli defense forces from 1995 to 1996. Givon U, Friedman E, Reiner A, Vered I, Finestone A, Shemer J. Clin Orthop Relat Res. 2000 Apr;(373):227-32. PMID: 10810481 Serum levels of bone specific alkaline phosphatase and osteocalcin were elevated in patients with high grade stress fractures compared with control subjects with no symptoms: 37.6 versus 26.2 units/L, and 10.8 versus 8.8 ng/mL, respectively. Levels of 25-hydroxy vitamin D were lower in patients with high grade stress fractures (25.3 ng/mL) than in control subjects (29.8 ng/mL). This study revealed that several parameters can distinguish soldiers with high grade stress fractures, but their predictive value and precise pathogenetic role remain unclear.

Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men. Ruohola JP, Laaksi I, Ylikomi T, Haataja R, Mattila VM, Sahi T, Tuohimaa P, Pihlajamäki H. J Bone Miner Res. 2006 Sep;21(9):1483-8. doi: 10.1359/jbmr.060607 Conclusions: A lower level of serum 25(OH)D concentration may be a generally predisposing element for bone stress fractures. Considering the obvious need of additional vitamin D in prevention of stress fractures, the effects of vitamin D fortification of foods and supplementation will be subjects of interest for future research PMID: 16939407

Comment: Although lower risk associated with vitamin D exposure was shown most consistently for ER+/PR+ tumors, the result might simply reflect that this tumor subtype was the most common. Nonetheless, these findings support vitamin D's beneficial effects on breast cancer risk, regardless of hormone-receptor status. Sun exposure and dietary intake (Table 1) are key sources of vitamin D.

The role of vitamin D in cancer prevention. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. Am J Public Health. 2006 Feb;96(2):252-61. Epub 2005 Dec 27. Review. PMID: 16380576 DOI: 10.2105/AJPH.2004.045260 Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk. The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.

Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG; Iowa Women's Health Study. Arthritis Rheum. 2004 Jan;50(1):72-7. PMID: 14730601 DOI: 10.1002/art.11434 CONCLUSION: Greater intake of vitamin D may be associated with a lower risk of RA in older women, although this finding is hypothesis generating.

Why would vitamin D be prescribed when vitamin D3 is available over-the-counter? Let's review the known differences between vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol): --D3 is the human form; D2 is the non-human form found in plants. --Dose for dose, D3 is more effective at raising blood levels of 25-hydroxy vitamin D than D2. It requires roughly twice to 250% of the dose of D2 to match that of D3 (Trang H et al 1998). --D2 blood levels don't yield long-term sustained levels of 25-hydroxy vitamin D as does D3. When examined as a 28-day area under the curve (AUC--a superior measure of biologic exposure), D3 yields better than a 300% increased potency compared to D2. This means that it requires around 50,000 units D2 to match the effects of 15,000 units D3 (Armas LA et al 2004). --D2 has lower binding affinity for vitamin D-binding protein, compared to D3 --Mitochondrial vitamin D 25-hydroxylase converts D3 to the 25-hydroxylated form five times more rapidly than D2. --As we age, the ability to metabolize D2 is dramatically reduced, while D3 is not subject to this phenomenon

Improved cholecalciferol nutrition in rats is noncalcemic, suppresses parathyroid hormone and increases responsiveness to 1, 25-dihydroxycholecalciferol. Vieth R, Milojevic S, Peltekova V. J Nutr. 2000 Mar;130(3):578-84. PMID: 10702588 We conclude suppression of 1,25(OH)(2)D and PTH, and higher renal VDR mRNA and 24-hydroxylase did not involve higher free 1,25(OH)(2)D concentration or a first pass effect at the gut. Thus, 25(OH)D or a metabolite other than 1,25(OH)(2)D is a physiological, transcriptionally and biochemically active, noncalcemic vitamin D metabolite. When viewed from a perspective that starts with higher vitamin D nutrition, the results indicate that low vitamin D nutrition may bring about a form of resistance to 1,25(OH)2D. This situation would explain why, in humans, nutritional rickets and osteomalacia are commonly associated with normal or increased levels of 1,25(OH)2D (Chesney et al. 1981Citation , Eastwood et al. 1979Citation , Garabedian et al. 1983Citation ,Rasmussen et al. 1980Citation )-these are not like the low hormone levels associated with any other endocrine-deficiency disorder. A connection between lower vitamin D nutrition and vitamin D resistance helps to explain why the supposedly inactive compound 25(OH)D is more relevant in diagnosing nutritional rickets than is the active hormone 1,25(OH)2D. If the features of improved vitamin D nutrition shown here were demonstrated for any newly synthesized compound, the compound would be classified as a noncalcemic 1,25(OH)2D analogue (Brown et al. 1989Citation , Finch et al. 1999Citation , Goff et al. 1993Citation , Koshizuka et al. 1999Citation ). Thus, we contend that 25(OH)D or a metabolite of it other than 1,25(OH)2D exists as a physiological and biologically-active noncalcemic vitamin D metabolite whose effects require further examination, particularly in relationship to studies involving the synthetic analogs of 1,25(OH)2D.

A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Stolzenberg-Solomon RZ, Vieth R, Azad A, Pietinen P, Taylor PR, Virtamo J, Albanes D. Cancer Res. 2006 Oct 15;66(20):10213-9. PMID: 17047087 doi: 10.1158/0008-5472.CAN-06-1876 Contrary to expectations, subjects with higher prediagnostic vitamin D status had an increased pancreatic cancer risk compared with those with lower status. Our findings need to be replicated in other populations and caution is warranted in their interpretation and implication. Our results are intriguing and may provide clues that further the understanding of the etiology of this highly fatal cancer.

Vitamin D status and the risk of lung cancer: a cohort study in Finland. Kilkkinen A, Knekt P, Heliövaara M, Rissanen H, Marniemi J, Hakulinen T, Aromaa A. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):3274-8. PMID: 18990771v In conclusion, although there was no overall association between vitamin D and lung cancer risk, women and young participants with a higher level of vitamin D were observed to have a lower lung cancer risk. Although experimental data support the suppressing effect of vitamin D on the development of lung cancer, large epidemiologic studies from different populations with repeated measurements of vitamin D are warranted to confirm this finding. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3274-8)

Vitamin D's days of obscurity seem pretty much over. Once just an afterthought to most people-relegated to the sides of milk cartons and the pages of medical texts-it's now on the cusp of becoming a full-fledged disease prevention star. Although vitamin D has long been known as an important factor in bone health, a quickly growing body of evidence now shows that it may also help lower the risk of cancer, heart disease, and even premature death.[1], [2] Not surprisingly, scientists and the public have started to take note, particularly of vitamin D's potential to protect against cancer

Vitamin D2 is much less effective than vitamin D3 in humans. Armas LA, Hollis BW, Heaney RP. J Clin Endocrinol Metab. 2004 Nov;89(11):5387-91. PMID: 15531486 Vitamin D2 potency is less than one third that of vitamin D3. Physicians resorting to use of vitamin D2 should be aware of its markedly lower potency and shorter duration of action relative to vitamin D3.

PLYMOUTH medical researchers have discovered a link between lack of the 'sunshine vitamin' and the onset of dementia.\n\nTeams from the city's Peninsula Medical School and the universities of Cambridge and Michigan have for the first time found a relationship between lower Vitamin D levels and cognitive impairment in older people.\n\nThe results of their large-scale study are to be published in the Journal of Geriatric Psychology and Neurology.

Concentrations of vitamin D3 and 25-hydroxyvitamin D3 in raw and cooked New Zealand beef and lamb. Roger Purchas, Maggie Zoua, Philip Pearcea and Felicity Jackson- Journal of Food Composition and Analysis Volume 20, Issue 2, March 2007, Pages 90-98 For lamb, the highest levels of vitamin D3 were in the shoulder chop both before and after cooking, while levels were lowest in the rack muscle. Similar cut differences were shown for 25OHD3 concentrations. For beef there were no significant differences between the cuts for vitamin D3, but concentrations of 25OHD3 were lower in the striploin before and after cooking, Vitamin D3 levels tended to be higher in beef cuts than in lamb cuts, but the opposite held for 25OHD3. Concentrations of vitamin D3 were similar to those in other reports, but the 25OHD3 levels were at the high end of reported ranges. With 25OHD3 being more potent than vitamin D3, it is concluded that meat can make a useful contribution of this vitamin to the human diet.

Are statins analogues of vitamin D? Grimes DS. Lancet. 2006 Jul 1;368(9529):83-6. Review. PMID: 16815382 doi:10.1016/S0140-6736(06)68971-X There are many reasons why the dietary-heart-cholesterol hypothesis should be questioned, and why statins might be acting in some other way to reduce the risk of coronary heart disease. Here, I propose that rather than being cholesterol-lowering drugs per se, statins act as vitamin D analogues, and explain why. This proposition is based on published observations that the unexpected and unexplained clinical benefits produced by statins have also been shown to be properties of vitamin D. It seems likely that statins activate vitamin D receptors.

Relationships between 25-Hydroxyvitamin D Levels and Plasma Glucose and Lipid Levels in Pediatric Outpatients. Johnson MD, Nader NS, Weaver AL, Singh R, Kumar S. J Pediatr. 2009 Nov 17. [Epub ahead of print] PMID: 19926097 Conclusions Low 25(OH) D levels in children and adolescents are associated with higher plasma glucose and lower HDL concentrations.

"So why is Dr Vieth so frustrated? You might think he'd have cause for celebration. But for him and other vitamin D researchers around the world, the good news comes with a bitter aftertaste. They believe they can prove vitamin D could help millions live longer and be healthier and yet they have not been able to convince their own governments. In the US and Canada, official vitamin D policy is set by the Institute of Medicine. And in the opinion of Vieth, the current recommendations - 200 International Units per day for people under 50, 400 for people aged 51-70, and 600 for those 71 and older - are outrageously low. Bruce Hollis, professor of paediatrics at the Medical University of South Carolina, calls 400 IU a day "a joke". That's because the best research suggests that to achieve the higher vitamin D blood levels associated with disease prevention, most adults in the US would need to take 1,000-2,000 IU a day: five to 10 times more than the current official recommendation for adult In 1999, Reinhold Vieth (pictured right) published a review of vitamin D research in response to the IOM conclusions. In it, he argued that there was no evidence that amounts lower than 20,000 IU a day could be toxic. "Throughout my preparation of this review, I was amazed at the lack of evidence supporting statements about the toxicity of moderate doses of vitamin D," Vieth wrote. Studies have since shown 10,000 IU a day of vitamin D to be safe. While any substance will become toxic in excess, vitamin D researchers today accept that the current vitamin D recommendations could be more than quadrupled with no fear of toxicity.!

"We are fond of grumbling about Britain's grey skies, but there may be a good medical reason for doing so. It seems the dreary weather is bad for our hearts - worse, even, than raised cholesterol and an unhealthy diet. That's the controversial claim being made by Dr David Grimes, a gastroenterologist from Blackburn. He's been gazing at the sky for 20 years for clues about why his patients get more sick than those in the south of the country. And what he's found turns key assumptions about heart disease on their head. 'It's not diet or cholesterol levels that raise your risk of heart disease,' he claims. 'It's where you live. People in the north are more likely to be ill because they get less sunshine Basically they are suffering from 'latitude' sickness. The link is vitamin D. While we get some from our diet, the main source is the sun - sunlight converts a compound in the skin into vitamin D, so the amount you make is directly related to the amount of sunshine you get. In a new book Dr Grimes argues the higher the level of vitamin D in your blood, the lower your risk of heart disease and a range of other illnesses. If he's right, what we need is not diet and lifestyle advice, but food fortified with vitamin D. For years the vitamin was thought to be useful only for preventing rickets. So how does he treat them? 'You can do it with diet,' he says 'One Bangladeshi woman eats oily fish every day and now has a vitamin D blood level of 40. 'We give supplements of 1,000 international units (IU) a day or we can give an injection of 300,000 IU that lasts for a year. 'The patients respond well,' says Grimes 'but what's needed is a proper controlled, long-term trial and who is going to fund that? Not a drug company.'"

"I discussed in my last post how Dr Vieth has a model of tissue 1,25(OH)2D synthesis and degradation in which the level of active substance is pretty well independent of blood vitamin D level, provided the level is either rising or stable. I think it is also worth pointing out that he is talking, hypothetically, about tissue 1,25(OH)2D, not plasma level... As we know, almost nothing is known about tissue 1,25(OH)2D control. By Vieth's hypothesis tissue 1,25(OH)2D is OK so long as there is at least SOME vitamin D present in plasma and the level dose not vary too much. Obviously there is a level below which you can have as much of the enzyme for converting vitamin D to the active form as you like, if there is no vitamin D in your blood you can't make any 1,25(OH)2D in your tissues, or in your kidneys for export to your blood to control calcium levels. At the lower extremes we have rickets and osteomalacia. These are clear cut, unarguable markers of vitamin D deficiency, in the absence of confounding factors (there are a few)."

Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers. Chen W, Dawsey SM, Qiao YL, Mark SD, Dong ZW, Taylor PR, Zhao P, Abnet CC. Br J Cancer. 2007 Jul 2;97(1):123-8. Epub 2007 Jun 5. PMID: 17551495 We prospectively examined the relation between pretrial serum vitamin D status and risk of oesophageal and gastric cancers among subjects who developed cancer over 5.25 years of follow-up, including 545 oesophageal squamous cell carcinomas (ESCC), 353 gastric cardia adenocarcinomas, 81 gastric noncardia adenocarcinomas, and an age- and sex-stratified random sample of 1105 subjects. We found no associations for gastric cardia or noncardia adenocarcinoma. Among subjects with low vitamin D status, higher serum 25(OH)D concentrations were associated with significantly increased risk of ESCC in men, but not in women. Further refinements of the analysis did not suggest any factors, which could explain this unexpected result. In conclusion, we found a direct association between higher serum 25(OH)D concentration and increased risk of ESCC in men but not women in a large population-based prospective cohort study from rural China. We found no association with risk of gastric cardia or noncardia adenocarcinoma in either sex. Greater than 50% of our cohort had an inadequate serum 25(OH)D concentration, yet higher concentrations were associated with increased risk of ESCC compared to lower concentrations.