The Calcium Paradox Revisited

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Recent findings may help explain the calcium paradox—the relationship between osteoporosis and atherosclerosis—that plays a large role in aging and is a particular concern in those with chronic kidney disease (CKD).

Patients with CKD have a higher incidence of vascular calcification and a greatly increased risk of cardiovascular death. The mechanisms involved in the accelerated vascular calcification observed in CKD have recently become more clear, leading to the hypothesis that perhaps a lack of natural inhibitors of calcification may trigger calcium deposition.

Aging can be seen as a process of calcification, the literal ossification of the body’s tissues—including the arteries, heart, kidney, and brain—while at the same time calcium is lost from bone, resulting in thinning and fracturing of the bones, or osteoporosis.

Osteoporosis results when the body removes more bone than it replaces. Calcification outside the bone tissue is due to the body’s regulators of calcium metabolism becoming less efficient as aging progresses.

A recent study looked at the progression of aortic calcification in chronic dialysis patients with disorders of mineral metabolism (Nephrol Dial Transplant 2011; 5:1747–8).

“Aortic calcification progressed in almost a third of the patients during dialysis,” said Marlies Noordzil of the department of clinical epidemiology at the University of Amsterdam. “Hypercalcemia and hyperparathyroidism were associated with an increased risk of progression.”

It’s well known that Vitamin D3 and vitamin K-complex, as well as magnesium, help normalize the efficiency of calcium metabolism ensuring proper calcification of bone tissue while preventing pathological calcification of the vascular and organ systems. These vitamins work synergistically to keep calcium where it belongs.

Much has been written about vitamin D recently and the “monitoring and maintenance of vitamin levels throughout the stages of CKD” said Eleanor Lederer, professor of medicine, Robley Rex VA Medical Center and University of Louisville School of Medicine in Louisville, KY. “A fall in 1,25 hydroxyvitamin D is the first measurable change in mineral metabolism noted during the course of CKD, long before the onset of hyperparathyroidism, hyperphosphatemia, or hypocalcemia. The nearly universal prevalence of bone mineral disorders in this population suggests strongly the need for vitamin D replacement.”

In December of 2010, the Institute of Medicine (IOM) raised the Recommended Daily Allowance (RDA) of vitamin D for young adults from 200 IU (International Units) to 600 IU while the RDA for people over 70 was raised to 800 IU.

Vitamin D3 is a vital cofactor in both bone mineralization and calcium absorption in the intestines. When synthesized in the kidneys, the vitamin is released into the circulation and acts as a hormone, regulating (among other things) the concentration of calcium and phosphate in the bloodstream, promoting the healthy mineralization, growth, and remodeling of bone tissue. It does this by binding to vitamin D binding protein (VDR). The binding of vitamin D3 to the VDR acts as a transcription factor that modulates gene expression of transport proteins such as TRPV6 and calcindin, which are involved in calcium absorption in the intestine.

Vitamin D also acts to inhibit vascular calcification by blocking the release of fat-derived inflammatory cytokines that contribute to both inflammation and adhesion in the arteries and elsewhere. These cytokines play a role in atherosclerosis and osteoporosis. Several inflammatory cytokines are induced by oxidative stress, and are a factor in chronic inflammation.

Also taking center stage for its role in mediating calcium regulation is Vitamin K. Research shows that without adequate vitamin K to meditate this process, calcium saturates the arterial walls and other soft tissues. It appears that vitamin K deficiency helps to explain the “calcium paradox”—the apparent relationship between osteoporosis and atheroscelosis.

The discovery that blood vessel cells can transform into bone-forming cells confirmed this link. While low vitamin D is linked with arterial disease and osteoporosis, vitamin K’s role is to stimulate bone formation and modify specific Gla proteins that prevent calcification outside of bone tissue.

How does Vitamin K help prevent calcification outside of bone? It acts as a co-factor required to convert the amino acid glutamate into one of about 15 human proteins with Gla domains, including matrix Gla protein (MGP).

MGP is a vitamin K–dependent protein secreted in cartilage, lung, heart, kidney, and arteries. While the precise mechanism of action is not completely understood, it is generally accepted that MGP is a strong inhibitor of soft tissue calcification.

In the April 2010 issue of the Clinical Journal of the American Society of Nephrology, Leon Schurgers noted that “Vitamin K–dependent MGP acts as a calcification inhibitor,” and that, “levels of the inactive, dephosphorylated, uncarboxylated MGP (dp-uc MGP) increased progressively in a CKD setting, and thus could be a marker for vascular calcification in CKD.”

Noting that “the majority of dialysis patients exhibit pronounced vitamin K deficiency,” the authors of a February 2011 Journal of the American Society of Nephrology article said that more study needs to be done to see whether vitamin K supplementation improves outcomes in hemodialysis patients. The article, “Circulating nonphosphorylated carboxylated gla protein predicts survival in ESRD,” was jointly authored under G.Schlieper of the Department of Nephrology and Clinical Immunology, Rheinishe -Westfalishe Technische, in Aachen, Germany.