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Current impediments to acceptance of the ultraviolet-B-vitamin D-cancer hypothesis. Grant WB, Boucher BJ. Anticancer Res. 2009 Sep;29(9):3597-604. PMID: 19667154 The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was proposed in 1980. There have been numerous ecological, observational and other studies of the hypothesis. There are about 14 types of cancer for which it seems to apply: bladder, breast, colon, endometrial, esophageal, gallbladder, gastric, ovarian, pancreatic, rectal, renal and vulvar cancer and both Hodgkin's and non-Hodgkin's lymphoma. Nonetheless, the hypothesis has not yet been accepted by public health agencies. Some of the reasons for this include a distrust of ecological studies, some mistrust of observational studies, and the existence of just one positive randomized controlled trial, an analysis of a vitamin D and calcium supplementation study involving post-menopausal women in Nebraska. Paradigm shifts such as this generally take time, in part due to opposition from those content with the status quo. In this paper, results of ecological studies in the United States using summertime solar UVB as the index of vitamin D production, which is highly asymmetrical with respect to latitude, and indices for other cancer risk-modifying factors (air pollution, alcohol consumption, dietary iron and zinc, ethnic background, socioeconomic status, smoking and urban/rural residence) are discussed in terms of supporting the hypothesis. These studies were not considered while other ecological studies were examined in recent critiques of the hypothesis. While additional randomized controlled trials would, of course, be helpful, the current evidence seems to satisfy the criteria for causality as outlined by A. Bradford Hill.

The acid-base hypothesis: diet and bone in the Framingham Osteoporosis Study. Tucker KL, Hannan MT, Kiel DP. Eur J Nutr. 2001 Oct;40(5):231-7. PMID: 11842948 RESULTS: As hypothesized, magnesium, potassium, fruit and vegetable intakes were significantly associated with bone mineral density at baseline and among men, with lower bone loss over four years. In contrast to the hypothesis, higher rather than lower protein intakes were associated with lower bone loss. CONCLUSION: Together these results support the role of base forming foods and nutrients in bone maintenance. The role of protein appears to be complex and is probably dependent on the presence of other nutrients available in a mixed diet. A balanced diet with ample fruit and vegetables and adequate protein appears to be important to bone mineral density.

"The diet-heart hypothesis is the idea that saturated fat, and in some versions cholesterol, raises blood cholesterol and contributes to the risk of having a heart attack. To test this hypothesis, scientists have been studying the relationship between saturated fat consumption and heart attack risk for more than half a century. To judge by the grave pronouncements of our most visible experts, you would think these studies had found an association between the two. It turns out, they haven't. The fact is, the vast majority of high-quality observational studies have found no connection whatsoever between saturated fat consumption and heart attack risk. The scientific literature contains dozens of these studies, so let's narrow the field to prospective studies only, because they are considered the most reliable. In this study design, investigators find a group of initially healthy people, record information about them (in this case what they eat), and watch who gets sick over the years."

Tofu and cognitive function: food for thought. Grodstein F, Mayeux R, Stampfer MJ. J Am Coll Nutr. 2000 Apr;19(2):207-9. Review. PMID: 10763901 In addition, a plausible biologic hypothesis is generally an important part of judging epidemiologic relations. While high tofu intake may lead to lower plasma estrogen levels [12], we do not know how tofu influences estrogen levels in the brain; we also know very little about estrogen effects in men. Furthermore, data have not even consistently indicated that low endogenous estrogen levels are directly related to cognitive function in non-demented subjects [13]. The authors also posit a non-estrogen mediated hypothesis for the effects of tofu, namely that soy inhibits hippocampal tyrosine kinase and may block long-term potentiation (the likely mechanism by which humans learn and remember). Still, considerably more work must be done to substantiate this hypothesis. Finally, the single measures of outcome used in this study may have limited value, as cognitive function and brain structure change over time. Factors which predict these measures at one point may or may not be the same as those which predict decline over time; fundamentally, the public health interest is in preventing cognitive decline, as the steepness of the decline trajectory likely provides an early marker for risk of the more clinically relevant result-dementia.

The Diet-Heart Hypothesis: Subdividing Lipoproteins Two posts ago, we made the rounds of the commonly measured blood lipids (total cholesterol, LDL, HDL, triglycerides) and how they associate with cardiac risk. It's important to keep in mind that many things associate with cardiac risk, not just blood lipids. For example, men with low serum vitamin D are at a 2.4-fold greater risk of heart attack than men with higher D levels. That alone is roughly equivalent to the predictive power of the blood lipids you get measured at the doctor's office. Coronary calcium scans (a measure of blood vessel calcification) also associate with cardiac risk better than the most commonly measured blood lipids. Lipoproteins Can be Subdivided into Several Subcategories In the continual search for better measures of cardiac risk, researchers in the 1980s decided to break down lipoprotein particles into sub-categories. One of these researchers is Dr. Ronald M. Krauss. Krauss published extensively on the association between lipoprotein size and cardiac risk, eventually concluding (source): The plasma lipoprotein profile accompanying a preponderance of small, dense LDL particles (specifically LDL-III) is associated with up to a threefold increase in the susceptibility of developing [coronary artery disease]. This has been demonstrated in case-control studies of myocardial infarction and angiographically documented coronary disease. Krauss found that small, dense LDL (sdLDL) doesn't travel alone: it typically comes along with low HDL and high triglycerides*. He called this combination of factors "lipoprotein pattern B"; its opposite is "lipoprotein pattern A": large, buoyant LDL, high HDL and low triglycerides. Incidentally, low HDL and high triglycerides are hallmarks of the metabolic syndrome, the quintessential modern metabolic disorder. Krauss and his colleagues went on to hypothesize that sdLDL promotes atherosclerosis because of its ability to penetrate the artery wall more easily

Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Kidd P. Altern Med Rev. 2003 Aug;8(3):223-46. Review. PMID: 12946237 Th1 pathways typically produce activation of cytotoxic T lymphocytes (Tc), NK cells, macrophages, and monocytes, all of which can attack cancer cells and generally defend against tumors. 55 IFN-gamma and other Th1 cytokines are typically lower in advanced cancer patients, while the Th2 marker IL-4 can be higher or unchanged.56 Nodules of non-small cell lung cancer freshly removed from patients expressed a marked imbalance toward Th2, as did biopsy samples from basal cell carcinoma.57 In prostate cancer patients IL-2 was low (Th1) and IL-10 high.58 IL-10 is a confirmed Th1-suppressive cytokine, and heightened IL-10 is a common factor in cancer.55 IL-10 has a variety of suppressive effects that include inhibiting Th1 cytokine production, down-regulating APC and NK cell function, and lowering overall T-cell proliferation.57 Especially under the influence of IL-4 (Th2), tumor cells apparently up-regulate IL-10 that suppresses nearby killer cells. Tumor-derived IL-10 has been documented in lymphoma, ovarian carcinoma, melanoma, neuroblastoma, and renal cell and colon carcinoma.57 IL-12 is another cytokine that can be up-regulated by Th1 activity and inhibited by Th2.59 A low IL-12/IL-10 ratio was found in cervical cancer patients.55 Recent clinical studies suggest elevated IL-10 is predictive of a poor prognosis. 57 With both IL-4 and IL-10 being proven inhibitors of Th1 and promoters of Th2 activity, the recognized capability of cancerous tissue to suppress immunity is readily rationalized.

Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Kidd P. Altern Med Rev. 2003 Aug;8(3):223-46. Review. PMID: 12946237

Enzyme kinetics hypothesis to explain the U-shaped risk curve for prostate cancer vs. 25-hydroxyvitamin D in nordic countries. Vieth R. Int J Cancer. 2004 Sep 1;111(3):468; author reply 469. PMID: 15221979 DOI: 10.1002/ijc.20218

Strong correlations have been noted between cardiovascular diseases and low bone density / osteoporosis-connections so strong that the presence of one is considered a likely predictor of the other. This relationship has led to the hypothesis that these conditions share core pathophysiological mechanisms. Recent advances in our understanding of the complimentary roles played by vitamin D3 and vitamin K2 in vascular and bone health provide support for this hypothesis, along with insight into key metabolic dysfunctions underlying cardiovascular disease and osteoporosis. Part II, The Vitamin K Connection to Cardiovascular Health, reviews the ways in which vitamin K regulates calcium utlization, preventing vascular and soft tissue calcification while complimenting the bone-building actions of vitamin D, and also discusses vitamin K safety and dosage issues, and the necessity of providing vitamin K and vitamin A along with vitamin D to preclude adverse effects associated with hypervitaminosis D.

Strong correlations have been noted between cardiovascular diseases and low bone density / osteoporosis-connections so strong that the presence of one type of pathology is considered a likely predictor of the other. This potentially causal relationship has led to the hypothesis that these conditions share core mechanisms. Recent advances in our understanding of the complimentary roles played by vitamin D3 and vitamin K2 in vascular and bone health provide support for this hypothesis, along with insight into key metabolic dysfunctions underlying cardiovascular disease and osteoporosis. Part I of this review summarizes current research linking vitamin D deficiency to cardiovascular disease, the physiological mechanisms underlying vitamin D's cardiovascular effects, and leading vitamin D researchers' recommendations for significantly higher supplemental doses of the pro-hormone. Part II reviews the vitamin K connection to cardiovascular disease; the ways in which vitamin D and vitamin K pair up to prevent inflammation, vascular calcification and osteoporosis; and the necessity of providing vitamin K along with vitamin D to preclude adverse effects associated with hypervitaminosis D, which include vascular and other soft tissue calcification.

Tufts University Confirms That Vitamin A Protects Against Vitamin D Toxicity by Curbing Excess Production of Vitamin K-Dependent Proteins Tufts University confirmed my hypothesis that vitamin A protects against vitamin D's induction of renal calcification (kidney stones) by normalizing the production of vitamin K-dependent proteins in December, 2008, without citing my hypothesis or telling me they had confirmed it. I am, of course, very grateful that they thought it significant enough to investigate.

Vitamin D: the alternative hypothesis. Albert PJ, Proal AD, Marshall TG. Autoimmun Rev. 2009 Jul;8(8):639-44. Epub 2009 Feb 12. Review. PMID: 19393200 Emerging molecular evidence suggests that symptomatic improvements among those administered vitamin D is the result of 25-D's ability to temper bacterial-induced inflammation by slowing VDR activity. While this results in short-term palliation, persistent pathogens that may influence disease progression, proliferate over the long-term.

Albert et al. Vitamin D: The alternative hypothesis. Autoimmunity Reviews, 2009 doi:10.1016/j.autrev.2009.02.011 

Newmark HL, Newmark J. Vitamin D and Parkinson's disease--a hypothesis. Mov Disord. 2007 Mar 15;22(4):461-8. PMID: 17230473 [PubMed - indexed for MEDLINE]

Serum vitamin D concentration and prostate cancer risk: a nested case-control study. Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, Horst RL, Hollis BW, Huang WY, Shikany JM, Hayes RB; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Project Team. J Natl Cancer Inst. 2008 Jun 4;100(11):796-804. Epub 2008 May 27. PMID: 18505967 doi:10.1093/jnci/djn152 CONCLUSION: The findings of this large prospective study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; indeed, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease. In summary, results from this large prospective study of men who underwent standardized prostate cancer screening in the context of a screening trial do not support the hypothesis that higher serum vitamin D status is associated with decreased risk of prostate cancer. The study showed no association of vitamin D level with nonaggressive disease; however, it raises the possibility that higher vitamin D level may be associated with increased risks for aggressive disease, although a clear monotonic dose-response relationship was lacking. Along with recent reports of adverse associations for higher vitamin D status and risk of pancreatic (32) and esophageal (33,34) cancer, caution should be taken in recommending high doses of vitamin D or sunlight exposure to the general public for prostate cancer prevention. Future analyses are warranted to confirm these results and to further clarify the effects of vitamin D on aggressive prostate cancer.

Th1/Th2 balance: the hypothesis, its limitations, and implications for health and diseaseAlternative Medicine Review, August, 2003 by Parris Kidd

The acid-base hypothesis: diet and bone in the Framingham Osteoporosis Study. Tucker KL, Hannan MT, Kiel DP. Eur J Nutr. 2001 Oct;40(5):231-7. PMID: 11842948

Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Garland FC, Garland CF, Gorham ED, Young JF. Prev Med. 1990 Nov;19(6):614-22. PMID: 2263572 doi:10.1016/0091-7435(90)90058-R Vitamin D from sunlight exposure may be associated with low risk for fatal breast cancer, and differences in ultraviolet light reaching the United States population may account for the striking regional differences in breast cancer mortality. The ecological nature of this study is emphasized, and the possibility that an indirect association with dietary and socioeconomic factors could explain these findings is discussed.

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.

Diet and Coronary Thrombosis., Hypothesis and Fact Yudkin J. The Lancet 1957. (Figure 9 only)