I mention this effect in another post, but wanted to post the studies as well. Basically, the studies with vitamin D alone have been disappointing and in some cases quite negative. For instance, taking only calcium and vitamin D has shown negative effects on CVD and cancer. While the authors struggled to explain the reasons, it likely lies in the fact that without vitamin A and K to ensure proper calcium control, vitamin D alone results in hypercalcemia and calcification of soft tissue. So, combining vitamin D with sufficient vitamin A and K is crucial to not ending up with calcified arteries and organs.
The dosage used for vitamin A were various and the highest one was equivalent to about 150,000 IU daily (retinyl acetate). The last reference is to a human study which used 15mg retinyl palmitate, which amounts to "only" about 27,000 IU retinyl palmitate daily and still ameliorated the hypercalcemic effects of vitamin D.
http://jn.nutrition.org/content/135/7/1647.long
http://jn.nutrition.org/content/129/12/2246.full
http://www.ncbi.nlm.nih.gov/pubmed/11585356
The takeaway from the studies is mainly this:
"...In addition to the effect of retinyl acetate on vitamin D2 seen in rats fed a rachitogenic diet, retinyl acetate also inhibited vitamin D2 action in rats fed a normocalcemic diet (Table 4). Serum calcium concentration, without vitamin D2 in the diet, was 1.37 mmol/L. In rats administered 5.2 ng vitamin D2/d without retinyl acetate supplementation, the serum calcium level was raised to 2.34 mmol/L, an approximately normal value. By increasing the retinyl acetate levels to 3448 μg/d, the serum calcium response to 5.2 ng of vitamin D2 was eliminated. Thus, an antagonism of vitamin D2 by high doses of retinyl acetate is clearly evident in the elevation of serum calcium."
"...Serum levels of 1,25(OH)2D3 and retinyl esters increased (1.7-fold and 8.3-fold, respectively; p < 0.01). As expected, serum calcium (S-calcium) increased (2.3%; p < 0.01) and S-parathyroid hormone (PTH) decreased (-32%; p < 0.05) after 1,25(OH)2D3 intake. In contrast, retinyl palmitate intake resulted in a significant decrease in S-calcium when taken alone (-1.0%; p < 0.05) and diminished the calcium response to 1,25(OH)2D3 after the combined intake (1.4%; p < 0.01). S-PTH was unaffected by retinyl palmitate. No significant changes in serum levels of the degradation product of C-telopeptide of type I collagen (CrossLaps), or U-calcium/creatinine levels were found. In conclusion, an intake of vitamin A corresponding to about one serving of liver antagonizes the rapid intestinal calcium response to physiological levels of vitamin D in man."
From the human study - a dose of vitamin A found in one serving of liver blocked the hypercalcemic effect of vitamin D in humans. More importantly, vitamin A did NOT prevent the (presumably) beneficial effect of vitamin D on reducing (by about 32%) levels of parathyroid hormone (PTH). So, it looks like with vitamin D you can have your cake and eat it too (with vitamin A).
In summary, for those people supplementing with vitamin D3 and wanting to avoid the resulting hypercalcemia (prolonged hypercalcemia is harmful) - make sure to take sufficient vitamin A. A good rule of thumb is a ratio of 1:5 for Vitamin D : Vitamin A. Adding vitamin K will ensure the calcium goes to the bone and not the soft tissues. Adding vitamin E to the mix will ensure the vitamin A does not oxidize.
The dosage used for vitamin A were various and the highest one was equivalent to about 150,000 IU daily (retinyl acetate). The last reference is to a human study which used 15mg retinyl palmitate, which amounts to "only" about 27,000 IU retinyl palmitate daily and still ameliorated the hypercalcemic effects of vitamin D.
http://jn.nutrition.org/content/135/7/1647.long
http://jn.nutrition.org/content/129/12/2246.full
http://www.ncbi.nlm.nih.gov/pubmed/11585356
The takeaway from the studies is mainly this:
"...In addition to the effect of retinyl acetate on vitamin D2 seen in rats fed a rachitogenic diet, retinyl acetate also inhibited vitamin D2 action in rats fed a normocalcemic diet (Table 4). Serum calcium concentration, without vitamin D2 in the diet, was 1.37 mmol/L. In rats administered 5.2 ng vitamin D2/d without retinyl acetate supplementation, the serum calcium level was raised to 2.34 mmol/L, an approximately normal value. By increasing the retinyl acetate levels to 3448 μg/d, the serum calcium response to 5.2 ng of vitamin D2 was eliminated. Thus, an antagonism of vitamin D2 by high doses of retinyl acetate is clearly evident in the elevation of serum calcium."
"...Serum levels of 1,25(OH)2D3 and retinyl esters increased (1.7-fold and 8.3-fold, respectively; p < 0.01). As expected, serum calcium (S-calcium) increased (2.3%; p < 0.01) and S-parathyroid hormone (PTH) decreased (-32%; p < 0.05) after 1,25(OH)2D3 intake. In contrast, retinyl palmitate intake resulted in a significant decrease in S-calcium when taken alone (-1.0%; p < 0.05) and diminished the calcium response to 1,25(OH)2D3 after the combined intake (1.4%; p < 0.01). S-PTH was unaffected by retinyl palmitate. No significant changes in serum levels of the degradation product of C-telopeptide of type I collagen (CrossLaps), or U-calcium/creatinine levels were found. In conclusion, an intake of vitamin A corresponding to about one serving of liver antagonizes the rapid intestinal calcium response to physiological levels of vitamin D in man."
From the human study - a dose of vitamin A found in one serving of liver blocked the hypercalcemic effect of vitamin D in humans. More importantly, vitamin A did NOT prevent the (presumably) beneficial effect of vitamin D on reducing (by about 32%) levels of parathyroid hormone (PTH). So, it looks like with vitamin D you can have your cake and eat it too (with vitamin A).
In summary, for those people supplementing with vitamin D3 and wanting to avoid the resulting hypercalcemia (prolonged hypercalcemia is harmful) - make sure to take sufficient vitamin A. A good rule of thumb is a ratio of 1:5 for Vitamin D : Vitamin A. Adding vitamin K will ensure the calcium goes to the bone and not the soft tissues. Adding vitamin E to the mix will ensure the vitamin A does not oxidize.