Better Bones Blog

Mysteries of bone breakdown revealed: the RANK, RANK-L and OPG system

Each minute, within the skeleton, more than a million sites of old worn-out bone are being eaten away by osteoclast cells, while new fresh bone is laid down by other specialized build-up cells known as osteoblasts. Just how this process of bone recycling and rebuilding is controlled has long been a question of scientific speculation.

Here is where RANK, RANK-L, and OPG enter the picture. Scientific breakthroughs have identified these three strange-sounding proteins and how they participate in the bone turnover process — and thereby identified a new place where science and pharmacology can intervene to prevent bone breakdown.

This insight into the nature of bone breakdown has led to the development of a different kind of osteoporosis drug — Prolia, a monoclonal antibody that was approved for postmenopausal osteoporosis by the FDA on June 1st. Prolia works on the RANK, RANK-L, and OPG proteins, but its mechanisms are unfamiliar to most people. So I thought I would familiarize you with what these acronyms mean:

RANK is short for “receptor activator of NF-kB” — a receptor sitting on bone breakdown osteoclast cells waiting to be activated. Once activated, RANK signals osteoclasts to mature, get active, and to begin breaking down bone.

RANK-L is a molecule that binds to RANK, activating it, and initiating the bone-recycling process. In essence, it turns RANK on.

OPG, short for osteoprotegerin, is a competitor of RANK-L. OPG binds to RANK and does not activate the bone breakdown cells. OPG keeps RANK-L from locking on to osteoclasts, and thus limits the bone breakdown activity of the osteoclasts.

So for someone in good health, the RANK/RANK-L/OPG system is a key regulator of bone breakdown, allowing the body to refresh and renew bone without excessive bone breakdown or excessive bone build-up.

Now for the quiz . . . if you want to reduce bone breakdown what would you do? Well, you could either:

  1. Increase OPG so that it would bind to the RANK receptor on the bone breakdown cells and thus deactivate them; or
  2. You could inhibit the ability of RANKL to bind to RANK, thus avoiding the activation of the bone breakdown cells.

The bone drug Prolia takes the second route, inhibiting RANK-L. Sound good? Well it sure can be in some cases, but there is always a price to pay when you interfere with a mechanism of disease instead of addressing the causes of the disease. Two logical questions arise: What other role(s) does activated RANK play in the rest of the body  — roles that taking Prolia might interfere with? And is it good for overall health to inhibit RANK-L? In an upcoming article, I will talk more about this new osteoporosis medication. For now, you can be ahead of the crowd — you know about RANK, RANK-L and OPG.


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