Rachel , John McLaren , and Michael Y: Ectopic calcification and bone: a comparison of the effect of dietary carbohydrates, sugars and protein.

Introduction

Cardiovascular (CV) calcification presence, extent and progression has been shown in several studies to correlate with fracture or low bone mineral density (BMD), particularly in older men and women1-3. CV calcification shares some similar properties with cortical bone4 and, when severe, can manifest as bone formation in both arteries and valves5,6. CV calcification and impaired bone metabolism are particularly prevalent in chronic kidney disease (CKD), where the condition has become known as mineral-bone disorder (MBD)7. The association between bone and ectopic calcification is further strengthened by studies showing that renal calcification can be prevented by ibandronate, which inhibits bone resorption8. Although calcification can be associated with atherosclerosis (i.e. intimal calcification), the deposition of hydroxyapatite is primarily medial; its pathophysiology is complex, involving not only physicochemical factors but also biological actions in smooth muscle9. Although a number of studies have been carried out on the influence of dietary carbohydrates, sugars and protein on bone, those relating diet to ectopic calcification are considerably fewer and the comparison is necessarily restricted.

Carbohydrates and sugars

Ectopic calcification

In a prospective study of premenopausal women, carbohydrate intake was inversely associated with coronary artery calcification (CAC) five years after menopause but was not associated with aortic calcification or carotid artery plaque10 and a large cross-sectional study showed that whole grain intake was not associated with two measures of subclinical atherosclerosis: carotid intima-media thickness (CIMT) and CAC11. Although there are no studies considering dietary intake of sugars, diabetes mellitus, metabolic syndrome, insulin resistance and high blood glucose, HbA1C and triglycerides are known risk factors for the presence of aortic12, breast13, carotid14 and coronary artery calcification15,16 and may also correlate with the aortic calcification score17 or CAC score18. The relationship between CAC presence and blood glucose levels was found particularly among men19 and may be nonlinear20, with low insulin levels, as well as hyperinsulinaemia, independently predicting CAC presence21. Similarly in animals, a high carbohydrate diet appears to facilitate nephrocalcinosis22, while starch or any form of sugar can result in increased incidence of CV or renal calcification, particularly in magnesium deficiency23,24. Galactooligosaccharides or a high phytate diet, however, can reduce CV and renal calcification25,26. Likewise, in vitro studies have shown that a high glucose medium enhances calcification of vascular smooth muscle cells (VSMCs) and increased expression of markers of bone formation, confirming a cell-mediation process characterized by the transdifferentiation of VSMCs to osteoblast-like cells27.

Bone

Studies of carbohydrate intake and bone parameters show mixed results28,29, with several comparison studies of carbohydrates, proteins or fats showing no difference in markers of bone formation or resorption30,31. Nevertheless, a 12 month study found that BMD was significantly lower with a high carbohydrate diet compared to a high protein diet32. Dietary fibre is generally inversely associated with BMD33. Type 2 diabetes and insulin resistance are strongly associated with impaired bone strength and quality34, although there may be less correlation with BMD35 and bone formation36 or resorption37; some have suggested that it may be hyperinsulinaemia, rather than hyperglycaemia, that underlies the relationship34. The effect of sugar intake depends upon the type, with sucrose or fructose intake correlated with increased bone resorption markers38, adversely affecting mineral homeostasis39, while higher glucose intake decreased bone resorption markers37. Low lactose intake reduced calcium absorption and BMD40 and increased fracture risk41. Prebiotics, such as inulin or fructans, increased mineral absorption in humans but results on bone parameters were not always positive42,43.

In animals, both high44 and low45 carbohydrate intake can have a detrimental effect on bone formation, while higher dietary fibre from legumes can increase calcium absorption, bone calcium content and BMD46. High glucose, sucrose and fructose generally result in lower BMD, particularly in magnesium deficiency, probably through reduced calcium absorption47. Lactose again appears to be beneficial for bone48, while xylitol can slow bone resorption, increasing BMD, BMC and biomechanical properties49. Mannitol and prebiotics can improve bone mineral absorption by increasing gut fermentation, resulting in greater mineral uptake in bone and improved BMD and bone strength50.

Dietary protein

Ectopic calcification

There have been no human studies investigating protein intake and CV calcification and in animals they focus almost exclusively on nephrocalcinosis, with the majority showing that increased dietary protein reduced renal calcification in rats with or without CKD with frequent reduction in urinary calcium excretion51,52. Likewise, a low protein intake induced more severe renal calcification, with decreased glomerular filtration rate and enhanced urinary albumin loss, suggesting kidney damage53. In a study which considered both nephrocalcinosis and bone health, krill protein produced lower renal tubular calcium deposition than casein, but had no effect on BMC or bone strength54; although this shows a positive benefit of krill protein, this may in part be due to the omega-3 fatty acid content. A high calcium, high phosphorus or low magnesium intake can enhance the detrimental effect of low protein intake on renal calcification51,53, while a calcium deficiency combined with high protein intake also enhanced the rate of ectopic calcification54.

Bone

Bone is 50% protein and 50% mineral56 and consequently dietary protein is essential for bone formation57 but it has nevertheless been considered detrimental to bone since protein induces urinary calcium excretion thought to derive from bone resorption58,59. Some recent studies, however, suggest that increased calcium excretion may derive from increased absorption, possibly through elevated gastric acid production58,60, higher glomerular filtration rate or decreased renal calcium reabsorption61. This is born out in a 2009 systematic review and meta-analysis of protein intake studies and protein supplementation trials, which found a small positive association with BMD and no detrimental association with fracture risk62. Recent studies have generally shown that, although there may be little short term effect63, long term high protein intake is positively associated with BMD, BMC and decreased fracture risk64 and slowed bone turnover65. Similarly, animal studies have generally shown that while high protein diets certainly increase urinary calcium excretion, they either have no effect on bone66 or bone calcium content and bone mass is improved67. In fact, it is generally low protein diets that are harmful to bone, particularly after ovariectomy68,69. There has been concern that a high animal/vegetable protein ratio may be detrimental to bone70. Despite this, a 2009 meta-analysis showed that BMD was around 4% lower in vegetarians than in omnivores71, although it was noted that key confounding variables had not been taken into account72. Since then a large study found no association between hip fracture and the animal/plant protein ratio73, while animal protein was found to increase calcium absorption to a greater extent than soy protein74.

Figure 3:

Action of protein and sugars on bone and arteries

Key

IGF-1 Insulin-like growth factor 1

AGEs Advanced glycation end products

RAGEs Receptor for AGEs

NF-KB Nuclear factor kappa B

RANKL Receptor for NF-KB

ROS Reactive oxygen species

icfj.2014.1.4.175-g003.jpg

There may be an interaction with calcium status in humans. Sahni et al found that when calcium intake was <800 mg/d, there was a three-fold increase in fracture risk with a high animal protein intake, while in those consuming ≥800 mg/d calcium those with a high animal protein intake had an 85% reduced risk of hip fracture73. Nevertheless, the body is clearly attempting to compensate since among postmenopausal women, a high protein intake increased calcium retention only in those with a low calcium intake75. Supplementing both protein and calcium significantly reduced bone loss in elderly hip fracture patients76, while protein intake was associated with BMD increase over three years in subjects aged ≥65 receiving calcium and vitamin D76,77. A high protein diet in calcium repletion can also protect against the bone loss of weight reduction78. Age may also play a role; a large study showed that increased protein intake was associated with a decreased risk of osteoporotic hip fracture in subjects aged 50-69 years but not in those aged 70-89, regardless of calcium intake79. Nevertheless, other prospective studies of the elderly have shown a clear relationship between low protein intake and decreased BMD [80].

Potential mechanisms

There may be several shared mechanisms of action between the effect of protein and sugars on ectopic calcification and bone but one of the best studied is insulin-like growth factor (IGF) 1, which is known to stimulate bone formation and, together with its receptor, has a protective effect against arterial calcification81,82. Protein is known to increase production of IGF-183, while blood glucose and insulin levels are important regulators84. In vitro studies show that human VSMCs cultured in advanced glycation end products (AGEs), which are significantly increased in diabetes mellitus, induce enhanced calcification due to both decreased expression of IGF-1 and upregulation of NF-κB, which blocks the IGF-1 receptor. Overexpression of IGF-1 inhibited calcification in VSMCs, while absence of the IGF-1 receptor negated the effect of AGEs on calcification.85 Interestingly, the addition of moderate calcium to the medium induced the IGF-1 receptor and inhibited calcification in VSMCs, although high calcium led to inhibition of the IGF-1 receptor, which increased calcification86. This may help to explain why an imbalance between protein and calcium is detrimental.

A number of studies have been carried out on AGEs independently of their effect on IGF-1. When AGEs come into contact with their receptor (RAGE), intracellular reactive oxygen species (ROS) are generated and mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-kB) signalling is initiated [87]. VSMCs cultured with AGEs showed enhanced production of ROS, upregulated expression of RAGEs and increased phosphorylation of p38 MAPK, as well as increased activity of markers of bone formation: alkaline phosphatase, osteopontin and osteocalcin88,89. When an antioxidant or anti- RAGE antibody was added to the medium, ROS expression, p38 MAPK phosphorylation and calcification were reduced and endogenous antioxidant expression increased, suggesting that calcification of VSMCs occurs through a RAGE/oxidative stress pathway via osteoblast-like differentiation of smooth muscle cells88,89. A high glucose medium has a similar effect on VSMCs90.

The AGE-RAGE interaction is additionally seen in bone cells, resulting in increased expression of cytokines, growth factors and adhesion molecules, which influence osteoclasts and osteoblasts91 and affect the structural and mechanical properties of bone92. In mouse bone cells, AGEs resulted in an increased number of resorption pits formed by osteoclasts, while rat bone particles incubated with glucose were resorbed to a much greater extent than control bone particles, suggesting that AGEs enhance osteoclast-induced bone resorption93. Similarly, the fructose-induced stimulation of receptor activator of NF-kB ligand (RANKL) significantly increased the number of osteoclasts and pit formation in rat bone, accompanied by an increase in ROS, an effect which could be completely abolished by the antioxidant N-acetylcysteine94. Among the elderly, AGE-modified proteins stimulated monocytes/macrophages to secrete bone-resorbing cytokines such as interleukin-1 beta, interleukin-6 and tumour necrosis factor- alpha, with enhanced net calcium efflux from bone95.

Conclusion

A diet high in carbohydrates appears to increase ectopic calcification, particularly in magnesium deficiency, although the effect of carbohydrate and fibre on bone in humans is unclear but appears to be consistently more detrimental than a high protein diet. Although there are no human studies of the effect of intake of sugars on ectopic calcification, diabetes mellitus, insulin resistance and high blood glucose are risk factors for both ectopic calcification and bone loss. Dietary sugars generally increase ectopic calcification in animals, while in vitro studies show that a high glucose medium significantly enhances calcification of VSMCs, with increased local markers of bone formation through action of AGEs which generate ROS. Sugars generally reduce BMD in humans, although lactose appears beneficial for bone in calcium deficiency but may increase renal and CV calcification in animals. Prebiotics can increase mineral absorption and improve BMD in animals, while also inhibiting ectopic calcification, but the results on bone in humans are inconsistent.

Whereas a high carbohydrate diet can increase ectopic calcification, a diet high in protein may inhibit it, possibly through induction of IGF-1. Dietary protein intake was generally inversely correlated with renal calcification in animals with and without CKD, although there were no human studies of protein intake and ectopic calcification. In both animals and humans, there is a modest positive association between protein intake and BMD and an inverse association with fracture risk; there appears to be little difference between animal and plant proteins. There may be a strong synergistic interaction with calcium, with low calcium and high protein intake significantly increasing fracture risk and enhancing renal calcification, while a high protein and calcium intake significantly reduced fracture risk and inhibited ectopic calcification. Increased protein is known to increase urinary calcium excretion but rather than being taken from bone, this seems more likely to be due to increased intestinal absorption and/or decreased renal reabsorption, although this may only occur in calcium deficiency. In general, therefore, a diet high in carbohydrate and sugars and low in protein is detrimental to both arteries and bone. This finding accords with our previous review, which concluded that the dietary fats which are beneficial or harmful for arteries are also beneficial or harmful for bone.96

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