Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Tuesday, October 28, 2008


Bone density is based on the balance between bone production and demineralization. Inflammatory cell signaling is required for release of calcium. Muscle building exercise favors increased bone density.

Newborns do not have fully formed bones in their limbs. The reason that milk has so much calcium, is that babies mineralize their cartilage bone scaffolds after they are born. Cartilage is made by chondrocytes (sisters of blood vessel endothelial cells and fat adipocytes, with the same stem cell parents) and the chondrocytes will continue to burrow through existing cartilage and make new cartilage, if mineralization does not take place. The cells that synthesize bone are called osteoblasts. They adhere to a framework of cartilage and begin to secrete collagen I, the major protein of bone and osteocalcin, the calcium binding protein that initiates the deposition of hydroxyapatite [Ca5(PO4)3(OH)]. As the bone forms, the osteoblasts become trapped in lacunae within the bone and stop secreting osteocalcin and begin to secrete hormones in response to the mechanical stress on the bone.

Bone is degraded by osteoclasts that colonize the completed bone after migrating from bone marrow. The total bone mass and density is determined by the dynamic balance between the deposition of bone by osteoblasts and disassembly of bone by osteoclasts. Approximately 10% of bone is being remodeled at any time and the porus trabecular bone in the pelvis, hips, wrist and spine is most actively remodeled. If there is an imbalance that leads to a bone deficit, it usually shows in weak trabecular bone.

Problems with low bone density, i.e. osteoporosis, can result from decreased estrogen (menopause), inadequate vitamin D/sunlight/dietary calcium, or medication, e.g. heparin or warfarin.

The ability of heparin to cause osteoporosis with prolonged use caught my attention. Heparin is anti-inflammatory and inflammation reduces heparin production. Thus, the inflammation caused by high blood glucose levels in diabetics results in loss of heparin production in kidneys and loss of protein from the urine. If heparin causes loss of bone mass, then it might be decreasing inflammation that is needed for bone accumulation.

Osteoclasts are activated by the RANK (receptor activator of nuclear factor κB) system. As the name states, RANK is a receptor that activates the inflammatory transcription factor NFkB. The cytokine that binds to RANK is the corresponding ligand, RANK-L, which is related in structure (and function) to TNF. RANK-L is secreted by osteoblasts, binds to RANK on osteoclasts, activates NFkB and stimulates bone demineralization. A protein called osteoprotegerin, is a soluble receptor of RANK-L that binds the bone and immobilizes the RANK-L and keeps it from activating osteoclasts.

Heparin could interact with many of these components. For example, the binding of RANK and RANK-L is mediated by heparan sulfate proteoglycans. The heparin deficiency that usually accompanies inflammation, and in this case excitation of osteoclasts, could be decreased by administration of heparin. Thus, demineralization would result in osteoporosis.

Warfarin-based osteoporosis could be based on upsetting vitamin K metabolism in osteoblasts. Vitamin K recycling is inhibited by warfarin and vitamin K is needed for a special modification of glutamic acids in particular proteins, such as osteocalcin. The action of osteocalcin in binding calcium is based on three glutamic acids that have been carboxylated using vitamin K. This is shown in the figure as three green calcium atoms bound to red dicarboxylic glutamic acids. You can also notice that the osteocalcin also has a substantial heparin binding domain (blue) at the top. Thus warfarin could cause osteoporosis by disrupting mineralization.

When I was trying to figure out the warfarin/osteoporosis relationship, I tried to find protein structures in the NCBI data base, which had warfarin bound. All I found was warfarin bound to human serum albumin, the protein that carries warfarin and many alkaloids through the blood. I was always suspicious of the use of heparin and warfarin somewhat interchangeably in many different settings in which the mode of action was assumed to be anticoaggulation of blood. I was not surprised when I found that the aromatic rings of warfarin (oxygens in red) were bound to arginines (blue) in a ligand-binding pit on the serum albumin.

A practical note on osteoporosis is that this disease is an exception to many of the degenerative and autoimmune diseases that are based on an inflammatory diet. Osteoporosis is more similar to the problem of gut injury by aspirin. Aspirin blocks COX-2 the enzyme that produces inflammatory and anti-inflammatory prostaglandins from omega-6 and omega-3 fatty acids, resp. Taking aspirin can block inflammation, but the integrity of the lining of the stomach and intestines requires inflammatory prostaglandins, so aspirin can also lead to a bleeding gut. Osteoclasts require NFkB signaling and other aspects of bone production may also require an inflammatory environment. This may explain why corticosteroids also lead to osteoporosis.

Deposition of bone is stimulated by weight bearing exercise that is consistent with the anti-inflammatory lifestyle.


Nigel Kinbrum said...

I only just found this, as Vitamin K isn't in your labels list.

Going off at a tangent, have you seen The Rotterdam Study?

The relative risk (RR) of CHD mortality was reduced in the upper tertile of dietary menaquinone (K2) compared to the lower tertile (RR 0.43, 95% CI: 0.24, 0.77). Phylloquinone (K1) intake was not related to any of the outcomes.

Bad news for Warfarin-takers?

Dr. Art Ayers said...

Thanks for the info on the Rotterdam Study.
The involvement of vitamin K in protein modification to support calcium ion binding is a complex story. It shows up in clotting and calcification of arteries (bad) and bone (good). The roles in different phenomena require a lot of thought. Why?
Thanks for your comments.

JohnN said...

"Phylloquinone (K1) intake was not related to any of the outcomes."

Curious about this seemingly unexpected outcome (the ineffectiveness of MK-1 in preventing calcification of the soft tissues), I did a quick read on the study and found the following statements:

1 On method: "Assessment of diet and vitamin K intake. The participants indicated on a checklist all foods and beverages that they consumed more than once a month during the preceding year. The completed checklist formed the basis for an interview at the study center by a trained dietician. A validated, semiquantitative food-frequency questionnaire was used (12). Intake of total energy, alcohol, macronutrients, and a large number of micronutrients was computed using Dutch food composition tables."

2 On discussion: "In contrast to phylloquinone, intake of menaquinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) (19) is not related to a healthy lifestyle or diet, which makes it unlikely that the observed reduction in coronary risk is due to confounding."

The authors may have inadvertently confounded the results between "plant-eaters" (MK-1) and "meat&egg-eaters" (MK-4) and displayed their confirmed bias.

Anonymous said...

This may go off tangent a bit but I think I may have a case of super warfarin toxicity due to the cumulative use of a particular brand of rodenticide over the course of 15 years in one house. I was diagnosed with Osteopenia in the year 2000 after a stress fracture. The Dr was surprised due to my healthy diet and regular aerobic and strength exercises. Do you think there could be some connection? I just moved out of the house and the change in my energy levels is incredible. My belongings made me sick(after the move) until I washed them twice. Any suggestion on who I might contact? I have an appointment with a toxicologist at the end of May but I was also trying to locate testing labs for my belongings but the toxicity may now be gone, but only after 2 months have passed.

Dr. Art Ayers said...

You have a complex case there. Your observations don't show a clear link to warfarin or other environmental toxins. You may have made numerous other changes during your move.

I would suggest just trying to distance yourself from the problems with as many healthy changes to diet and lifestyle as possible. You probably won't figure out the toxic input, because it would probably have to have been the result of direct contamination of food or a very high aerosol dose. I would be skeptical that it is contamination of household items.

You didn't say what the results of your vit.D blood tests were at the time of your fracture. I would suspect that you were very low. Have you had them checked recently?

I would guess that changes to your diet would be more likely than environmental toxins. That is just my experience.

Thanks for the comment.

Nicholas C. Scott said...

Great Post, I just am a little lost. Oh and I also read that study done with Corticosteroids On PMR , It was awesome and again showed how stopping inflammation resulted in a loss in bone density, and after tooken away bone density improved.

Oh and quick question lol, Living an anti inflammitory diet and lifestyle, does not disrupt inflammation which is required for osteoclast ?