Osteoporosis

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.