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Vitamin D: more than a bone factor
Effects of this vitamin may affect the care of patients with cancer.
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We all know about vitamin D. It is the vitamin that prevents rickets, preserves bone density in postmenopausal women and is not produced in patients with chronic renal failure. In this final situation renal osteodystrophy is the result.
However, there is increasing recognition that the effects of vitamin D are multifaceted and involve many aspects of health that may affect on the care of patients with or at risk for cancer.
Vitamin D is really a hormone. It is synthesized in the body as a class of molecules. Sunlight strikes the skin and causes a reaction that converts 7 dehydrocholesterol to cholecalciferol (vitamin D3). Vitamin D3 is hydroxylated in the liver to form 25-OH D3 and in the kidney to form the most active vitamin D molecule, 1,25 di(OH)D3 or calcitriol.
1,25 di(OH)D3 is further catabolized by CYP24 (24 hydroxylase), which produces 1,24,25 D3 and limits the activity of calcitriol; 1,24,25D3 is a poor VDR ligand. 25(OH)D3 is the chemical that is readily measurable by commercial assays and is the best reflection of adequate vitamin D stores.
The normal serum concentration of 25(OH)D3 is 32 ng/mL to 100 ng/mL, and normal is defined as the concentration that is associated with no further decrement in parathyroid hormone or improvement in BMD. These are the measures that have been taken as indicative of optimal vitamin D nutrition.
There are limited data regarding the relationship of parathyroid hormone with BMD and how it modulates the effect of vitamin D on tissues other than bone. As there is uncertainty regarding the optimal level of 25(OH)D3, there is controversy about the optimal daily requirement of dietary vitamin D. The recommended daily allowance established by the USDA is 400 IU of D3 per day. This is the amount of D3 necessary to avoid rickets in children. Some have argued that this allowance is too low by a factor of between three to six or more.
Populations at risk
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There are many studies that indicate there is an inverse relationship between environmental light exposure, estimated and measured blood vitamin D and cancer frequency and mortality rate. Prostate, breast, lung, colorectal, pancreatic cancer and lymphoma have all been shown to be more frequent among populations estimated to have low vitamin D levels.
There is considerable evidence that cancer cells exposed in vitro or in vivo to calcitriol undergo differentiation, cell cycle arrest and apoptosis, depending on the model and the dose of calcitriol. In addition, increasing evidence indicates that vitamin D is an important factor in angiogenesis, and in certain settings high dose vitamin D may inhibit tumor growth through disruption of angiogenesis. Finally, many investigators have shown that calcitriol potentiates the antitumor activity, in vivo and in vitro, of a number of cytotoxic agents: taxanes, anthracyclines, alkylating agents and antimetabolites.
These data have led several groups to evaluate combinations of high-dose calcitriol and a variety of antitumor agents. No additive toxicity has been seen in a number of studies. The limitation of these trials has been that the commercially available preparations of calcitriol are unsuitable for high-dose therapy. Apparent absorption and exposure are unpredictable and saturable as doses of commercially available calcitriol are escalated. This has led a new company, Novocea, to develop an improved, high-dose calcitriol formulation. Based on encouraging phase-2 data from Thomas Beer and colleagues in androgen independent prostate cancer, this company conducted a phase-3 randomized trial of docetaxel (Taxotere, Sanofi Aventis) at 32 mg/m2 on day two with or without calcitriol at 0.5 mcg/kg at day one along with weekly X4 every six weeks.
The endpoint for this trial was improved prostate specific antigen response. While this endpoint was not achieved, survival appeared to be improved and toxicity reduced in the calcitriol arm. This has led to a 1,000-patient trial to attempt to confirm this intriguing observation.
Our own research group has noted in murine and canine models that calcitriol in high dose potentiates the in vivo antitumor effect of cisplatin, paclitaxel, gemcitabine (Gemzar, Eli Lilly) and mitoxantrone. Accrual of patients is ongoing.
While considerable work remains, these data suggest that calcitriol in high doses may be a useful adjunct to standard cancer chemotherapy. A pressing issue that requires delineation is the appropriate dose of high-dose calcitriol.
It is clear that high-dose intermittent therapy is safe and nontoxic. We have given up to 100 mcg per week by IV without toxicity, and we are conducting a phase-2 trial in prostate cancer with 77 mcg IV weekly, with no appreciable toxicity. Therefore, determination of the optimal or maximally tolerated dose of calcitriol is a critical step in evaluating this agent as a drug for use in cancer therapy.
Beyond calcitriol
In addition to the potential for high-dose calcitriol as a cancer therapy, there are increasing data that vitamin D deficiency or insufficiency is common in the population in general and in cancer patients in particular.
There are broad health consequences of low vitamin D levels. Among the clues to the systemic consequences of vitamin D deficiency are the findings in the vitamin D receptor knockout mouse. There are at least two forms of this mouse, and in this model vitamin D signaling is markedly diminished.
In addition to the expected disorders of bone and mineral metabolism these mice show abnormalities in hair, cardiac muscle, skeletal muscle, blood vessel development and susceptibility to infection and thrombogenesis. These data are intriguing in view of clinical data that suggest that infection, immune function, motor function, thrombogenesis and blood pressure control are dysregulated in individuals with low serum vitamin D levels.
Finally, it is sobering to recognize how common low serum 25(OH)D3 levels are. Beer and colleagues were among the first to point out the frequency of vitamin D deficiency among hospitalized patients. They found that more than 250 patients admitted to the Massachusetts General Hospital, 57% had levels of 25(OH)D3 less than 15 ng/mL.
We have recently examined 25(OH)D3 levels among ambulatory patients with prostate and colorectal cancer. Among more than 400 individuals, 70% of patients had 25(OH)D3 levels less than 32 ng/mL, the currently recognized lower limit of normal. In our studies, and those of many others, risk factors for vitamin D insufficiency are black race, season of the year of assessment and level of activity/sun exposure.
Whether certain kinds of patients with cancer are more likely to have low vitamin D levels is unclear. In our studies, family members and acquaintances who accompanied our patients to their ambulatory visits had a similar frequency of low 25(OH)D3 levels.
There is little information about the effect of cholecalciferol replacement on cancer risk or the risk for other ills associated with low 25(OH)D3 levels. There are randomized trials among nursing home residents showing that D3 replacement reduces the risk for falls. A recent study suggested that D3 of 1,100 IU per day plus calcium replacement reduces cancer risk.
We have begun careful studies of replacement in cancer patients that we hope will clarify how often replacement is needed, factors predictive of the need for larger doses and the optimal replacement dose.
Vitamin D likely has much broader health effects than simply those associated with bone and mineral metabolism.
Vitamin D deficiency, often defined as a serum 25(OH)D3 level of 15 ng/mL or less, is frequent and insufficiency, defined as 25(OH)D3 level of 32 ng/mL, is common. Low 25(OH)D3 levels are common because of low dietary intake, limited sun exposure and infrequent use of sufficient supplements.
I have begun to recommend that all cancer patients ask their doctors to measure their 25(OH)D3 levels and oversee supplementation to assure blood levels are at least in the normal range. I think this is a reasonable for all adults, though the health benefits of this approach or a more aggressive replacement strategy have not been evaluated.
Vitamin D supplementation merits continued study as a potential cancer preventive approach. In addition, we will find that the use of calcitriol in combination with standard chemotherapy will improve therapy and reduce toxicity in some situations. Exactly what situations and what schedule, dose and formulation of calcitriol will be the focus of considerable study during the next few years.
For more information:
- Donald L. Trump, MD, is CEO of Roswell Park Cancer Institute in New York and section editor of Hem/Onc Today’s Genitourinary Cancers section.
- Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007;85:649-650.
- Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006;98:451-459.
- Deeb KK, Trump DL, Johnson CS. Vitamin D signaling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer. 2007;7:684-700.
- Beer TM, Ryan CW, Venner PM, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007;25:669-674.
- Demay MB. Mechanism of vitamin D receptor action. Ann N Y Acad Sci. 2006;1068:204-213.
- Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783.
- Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res. 2003;18:343-351
- Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-1591.