Primum Non Nocere: Why Calcitriol («Vitamin» D) Hormone Therapy Is Not a Magic Bullet

Vitamins are commonly referred to as essential nutritional additives that cannot be synthesized by the human body because diets low or deficient in these molecules have been implicated in diseases, among them scurvy (vitamin C) and pernicious anemia (vitamin B₁₂). However, the human body produces cholecalciferol (known as «vitamin» D₃) from 7-dehydrocholesterol in the skin on UV exposure.^9,10 The fact that cholecalciferol still became classified as a vitamin rather than as a steroid hormone is because of historical accident⁹—but also to ignorance. In 1922, Adolf Windaus in Göttingen, Germany, generated from plant sterines—named D₁ and D₂—through UV light photolysis an activated D₃ form, 7-dehydrocholesterol (ergocalciferol), which in his publications he referred to as a «vitamin».¹¹ Six years later, Windaus was awarded the Nobel Prize in Chemistry “for the services rendered through his research into the constitution of the sterols and their connection with the vitamins.” Even the Nobel Prize committee had ignored the steroid nature of the molecules. Windaus had quickly capitalized on his discovery the year before, selling his patents to the E. Merck and I.G. Farbenindustrie companies which started producing and selling «Vigantol» in 1927.¹²

Fifty years have passed since Mark Haussler and Anthony Norman first purified a nuclear receptor¹³ which binds steroids today still referred to as vitamins. This steroid receptor, known as the VDR («vitamin» D receptor), belongs to the nuclear receptor superfamily of ligand-activated transcription factors and is present in multiple organs, including those of the cardiovascular system.¹⁰ Binding of calcitriol (1α,25(OH)₂ cholecalciferol) to VDR initiates signaling events that ultimately lead to transcription of select target genes.¹⁰ Calcitriol’s precursor molecule cholecalciferol («vitamin» D₃) is biologically inert and requires activation by hydroxylation to bind to VDR: cholecalciferol serves as substrate for hepatic 25-hydroxylase, producing 25-hydrocholecalciferol which is then converted to 1α,25(OH) ₂ cholecalciferol by 25(OH)D₃-1α-hydroxylase (which is encoded by the Cyp27 gene¹⁴) expressed in vascular smooth muscle cells, proximal tubules of the kidney, pancreatic islets, and white blood cells.^9,10,15–17 Thus, it is conceivable that chronic infections, vascular or renal disease, beta cell injury in diabetes mellitus, or fatty liver disease will affect formation and bioactivity of calcitriol—irrespective of whether cholecalciferol was endogenously produced or administered exogenously.

The complexity of calcitriol biosynthesis is illustrated by its interaction with other steroid hormones: vascular smooth muscle cells 25(OH)D₃-1α-hydroxylase is upregulated by estrogens;¹⁵ thus, in premenopausal women, calcitriol synthesis in the vasculature also depends on intact ovarian function. Moreover, some neuroprotective effects of calcitriol/VDR seem to require cross-talk with GPER (G protein-coupled estrogen receptor) as calcitriol-mediated protection is abrogated in animals lacking GPER.¹⁸ Mice completely lacking 25(OH)D₃-1α-hydroxylase show poorly developed endometrium, do not ovulate, and thus lack an estrous cycle, resulting in infertility,¹⁹ whereas heterozygotes remain fertile.¹⁴ The role of VDR activation in vascular pathology has been previously addressed in experimental studies, yielding conflicting results. Both enhancing as well as inhibitory effects of calcitriol on the growth of vascular smooth muscle cells have been reported.^20,21 Similarly, VDR activation has been shown to either aggravate experimental atherosclerosis and vascular calcification²² or to exert protective effects.^23,24 While VDR activation blocks endothelial cell proliferation and angiogenesis,²⁵ it has also been implicated in protective effects, such as maintaining endothelium-dependent, NO-mediated vasodilation under certain conditions.²⁶

Over the past decade, calcitriol hormone therapy (mostly under the misnomer «vitamin» D “supplementation”) has been increasingly propagated as a magic bullet based on the prevailing misconception that it might protect from diseases, such as osteoporosis, cardiovascular disease, and cancer. However, the evidence suggested by most studies was only in part supporting such notions, and little focus was put on potential risks. Between 2000 and 2010, hormone blood tests for cholecalciferol among US Medicare beneficiaries increased 83-fold,²⁷ whereas the number of persons on calcitriol hormone treatment increased by a factor of 4.²⁸ Scragg et al²⁹ recently reported the results of a randomized, placebo-controlled trial of 3.3 years of calcitriol hormone therapy in 5108 individuals showing that treatment did not reduce cardiovascular events—a finding that mirrors the results of previous trials on dietary supplementation of vitamins E or C showing no benefits on cardiovascular disease risk.^30,31 Manson et al³² have just reported the results of the randomized placebo-controlled VITAL trial (Vitamin D and Omega-3 Trial) studying the effects of calcitriol treatment over 5.3 years in 25 871 individuals and found no effect of calcitriol on cardiovascular events. The US Preventive Services Task Force now advises against calcitriol hormone therapy, referring to the insufficient evidence with regard to potential benefits and harms.³³ What the potential vascular adverse effect of calcitriol hormone therapy might be in the presence of obesity—which is characterized by low-grade systemic inflammation⁶—had not been studied so far.

In the present issue of the Journal, Carmo et al³⁴ now present the first evidence showing how calcitriol can adversely affect vascular health and that it promotes expansive vascular remodeling and arterial calcification in the absence of atherosclerosis in a model of monogenic obesity characterized by insulin resistance and inflammation. In untreated animals, vascular fibrosis was absent in lean controls but substantially increased in the presence of obesity. Carmo et al³⁴ further found that after only 2 weeks of 8000 IU/day calcitriol hormone therapy, obese, but not lean, animals developed substantial expansive (outward) remodeling throughout the entire aorta. Calcitriol treatment doubled vascular calcium levels in both groups and increased vascular calcification in obese but also—albeit to a lesser extent—in lean mice. Yet, only in obese animals apoptosis and induction of osteochondrogenic proteins, such as BMP-2 (bone morphogenetic protein 2) and Runx2 (Runt-related transcription factor 2), were observed after calcitriol treatment. Vascular expression of VDR was downregulated after calcitriol treatment in lean controls, whereas it had no effect in obese mice.³⁴ These findings are novel and important as they provide the first clues to potential mechanisms by which calcitriol can precipitate vascular injury in the setting of low-grade inflammation environment but not under healthy conditions. Should these findings be applicable to vascular disease in humans, they may have substantial clinical implications. Similar to obesity, vascular aging in humans is associated with systemic low-grade inflammation and vascular calcification, and the prevalence of atherosclerotic changes in humans as well as coronary calcium reflects a function of time or age.⁴ Interestingly, coronary calcification remains lower in women than in men throughout life,³⁵ pointing at a protective effect of premenopausal estrogen levels that extends into the postmenopausal years. Whether calcitriol hormone therapy adversely affects vascular structure in obese humans or whether and how it promotes calcification and can make arteries prone to expansive remodeling favoring aneurysmal dilation, as demonstrated in the experimental study by Carmo et al,³⁴ remains to be shown. Potential harmful aspects of calcitriol hormone therapy, such as vascular calcification, have been little studied in the context of disease conditions—thus the recent study by Carmo et al³⁴ in obesity represents a first important step in this direction.

Caution is advised. Still dubbed as «vitamin» D, the steroid hormone calcitriol is not a “magic bullet” for primary cardiovascular disease prevention in otherwise healthy individuals. We are reminded of previous studies conducted more than 2 decades ago using another group of steroid hormones with the goal of primary and secondary prevention of cardiovascular disease: estrogens. These randomized clinical trials, including WHI (Women’s Health Initiative), HERS I and II (Heart and Estrogen-Progestin Replacement Study), and WISDOM (Women’s International Study of Long Duration Oestrogen After Menopause), determined the effects of therapy with (notably horse urine-derived) hormone mixtures on cardiovascular risk in elderly postmenopausal women.³⁶ Study participants often were up to 20 years after menopause, overweight, or obese, and many had already developed significant atherosclerotic vascular disease; not surprisingly, hormone therapy increased adverse events and resulted in early discontinuation of studies.^36,37 Meanwhile, clinical trials using bioidentical human estrogens have been conducted in women of normal weight early after menopause, with some, such as the ELITE trial, reporting positive effects on cardiovascular risk or atherosclerosis disease progression.^37,38

Whatever the effects of calcitriol might be on cardiovascular pathologies in humans, it is likely that such effects may be confined to selected patient populations, possibly present only in certain age groups and that effects may not be seen if comorbidities, such as obesity, exist. For example, low circulating levels of cholecalciferol are linked to poor left ventricular function and increased mortality in patients with heart failure.³⁹ However, to determine whether calcitriol hormone therapy has beneficial—or adverse—effects in heart failure or other disease conditions will require rigorous and well-designed long-term clinical studies. Time has come to realize that calcitriol treatment represents yet another form of hormone therapy. We must not put our patients at risk and need to remind ourselves of Roman physician Scribonius Largus (1 AD–50 AD) who taught what is still relevant for practicing medicine today: “Primum non nocere, secundum cavere, tertium sanare” (Above all, do not do harm, then prevent, lastly heal).⁴⁰