Vitamin D and Phosphate: Relevance to Muscle Weakness in Vitamin D Depletion & Significance of Lipoprotein Binding of Orally-Administered Vitamin D

Chudley et al. (1981) [Chudley et al., 1981: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1862641&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/6793223)] noted that muscle weakness and low-level indications of peripheral neuropathy (and overt neuropathy, but the authors don't really discuss that) can occur in people who are hypophosphatemic, and it's interesting that researchers have commonly found muscle weakness and balance problems (predisposing to falls in elderly people) and muscle pain to be associated with vitamin D deficiency (given that vitamin D supplementation is used to treat hypophosphatemia due to a number of different causes). There's actually evidence that the phosphate depletion that results (in part) from the secondary hyperparathyroidism that, in turn, results from vitamin D deficiency does contribute to muscle weakness and the associated problems (muscle pain, balance problems) (http://scholar.google.com/scholar?q=phosphate+%22vitamin+D%22+muscle+weakness&hl=en). It actually seems likely that the muscle weakness could partly be due to neuropathy induced, in part, to the phosphate depletion that accompanies vitamin D deficiency. I should mention that I don't think vitamin D (or rather the elevations in 25-hydroxyvitamin D) produced in response to UVB is as calcemic as oral vitamin D is, and I base that statement on various lines of evidence. I think it might be that oral vitamin D is converted into 25-hydroxyvitamin D and then into 1alpha,25-dihydroxyvitamin D locally, in enterocytes in the GI tract (the cytochrome P450 enzyme(s) that display(s) vitamin D 25-hydroxylase activity is/are expressed in a wide variety of tissues), or it may be a result of the fact that the oral vitamin D becomes more highly bound to lipoproteins [Haddad et al., 1993: (http://www.pubmedcentral.nih.gov/picrender.fcgi?pmid=8390483&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/8390483)]. That could cause its transport into cells to be regulated in different ways, etc. That article by Haddad et al. (1993) is great, and they say that vitamin D3 produced in the skin (and not just 25-hydroxyvitamin D produced in the liver) is primarily bound to vitamin D binding protein (Gc globulin), but orally-administered vitamin D becomes bound to chylomicrons and lipoproteins and enters the liver much more rapidly than skin-derived vitamin D. The issue wouldn't just be the rate of transport into the liver, though, because the lipoprotein-bound vitamin D and 25-hydroxyvitamin D would enter cells in ways that would not be subject to the same endosomal regulatory mechanisms, etc., as the transport of vitamin-D-binding-protein-bound vitamin D or 25-hydroxyvitamin D would be subject to.

Regardless of the mechanisms, there does seems to be some difference that, in my opinion, makes oral vitamin D more calcemic, and that could be important in the context of some of these issues related to the effects of vitamin D repletion on phosphate homeostasis. I remember reading an old article in which someone suggested that some of the neuroprotective effects of vitamin D, in the context of in vitro or animal experiments, might be mediated by its effects on phosphate homeostasis (on the preservation of ATP, as a result of its phosphate-"sparing" effects and effects on phosphate transport, etc.), but I forget what the article was specifically testing (and I can't find it right now). There would be a limit to the supposed beneficial effects of vitamin D repletion on phosphate homeostasis, and the concomitant elevations in serum calcium could, to some extent, negate the benefits associated with the vitamin D-mediated reductions in urinary phosphate loss (an effect that is, in part, secondary to the localized conversion of 25-hydroxyvitamin D into hormonal vitamin D, in the parathyroid tissue, and autocrine/paracrine suppression of parathyroid hormone release, etc.).