Biological Agents: RANKL Inhibitors – Bone and Calcium Medications

00:01 I’m going to add another category in here called the biologics.

00:05 Now this is a bit complicated so we’ll go through this slowly.

00:08 First of all, I’m gonna do some definitions.

00:11 We’ll start off with RANKL, R-A-N-K-L.

00:14 RANKL stands for Receptor Activator Of Nuclear Factor Kappa-B Ligand - it’s really a big mouthful.

00:23 There is another name for it called Tumor Necrosis Factor Ligand Superfamily Member number 11, so it’s this long acronym.

00:31 It’s actually the same molecule, we didn’t know that when we were naming them.

00:35 Okay, what do we do with this RANKL? First of all, it’s a type 2 membrane protein.

00:41 It is on the surface of the membrane of certain types of cells in the bone.

00:46 They have multiple effects, first of all, it’s an apoptosis regulator gene - what does that mean? That means that apoptosis which is programmed cell death needs to be regulated.

00:57 If you have dysregulation of apoptosis you have inappropriate cell death and you have osteoporosis.

01:04 If you have inappropriate reduction of apoptosis then the cells last too long, they become these old ineffective cells and they don’t do their jobs properly so apoptosis is important.

01:17 It is a binding partner to osteoprotegerins, we’ll get into that in a minute.

01:23 It affects bone metabolism and growth, so RANKL is responsible as an endogenous molecule to affect bone metabolism and growth.

01:34 It also has effects on other tissues so obviously because theirs two names for it, you know that it’s active in two different areas of medicine one being bone mineral homeostasis and the other being a tumor necrosis or tumor cancer therapy so it is a complicated molecule that has multiple effects.

01:56 Okay, now we know what RANKLs does. Let’s talk about RANKL inhibitors.

02:01 So there’s a drug called denosumab, it is most commonly sold around the word as Prolia but there are other names as well.

02:09 What does this drug do? Now remember that pre-osteoclasts - so those cells that are not yet mature, they express this thing called a rank protein not RANKL but rank.

02:24 The rank is activated by RANKL, okay? So the rank is a ligand, RANKL are cell surface proteins on osteoblasts with a B.

02:36 Rank is on an osteoclast with the C.

02:40 The relinking of the RANKL with the rank causes maturation of that immature osteoclast into a mature osteoclast so now you start to see the mechanisms of how this work.

02:53 Denosumab inhibits this binding so the binding of the osteoblasts to the immature osteoclasts doesn’t occur that osteoclast remains immature.

03:06 Now how do we know that this would have worked and who came up with this idea in the first place? Well, scientists have known for a long time that there is a molecule called osteoprotegerin that is naturally occurring.

03:19 It is an endogenous RANKL inhibitor and we think that it’s associated or maybe reduced in osteoporosis so we know that this mechanism of action had occurred for a long time.

03:31 We just never had the technology before to actually interfere with this process.

03:36 With this very complicated drug, Prolia, we've had incredible success in altering the course of osteoporosis.

03:46 Now we have other agents in bone disease.

03:48 I’m going to mention them mostly because they are available in other countries and they have been used in other countries, a lot of them had been abandoned in the United States.

03:57 Strontium is an example. It’s used extensively in Eastern Europe.

04:01 It is an organic ion that promotes osteoclasts death so there is reduced osteoclasts activity with Strontium.

04:09 It is less used because of the increased risk of deep venous thrombosis.

04:13 I don’t want you to get the impression that it is not an effective treatment of osteoporosis.

04:18 I just want to point out that the increase DVT rates are what led to its decreased use.

04:24 Gallium nitrate is another agent.

04:27 It’s used for the treatment of hypercalcemia in patients with Paget’s disease of the bone and in malignancies.

04:33 We inhibit bone resorption with this product.

04:37 Now, patients need to be very, very well hydrated when they take gallium nitrate because it can lead to significant nephrotoxicity.

04:47 Plicamycin is another agent that’s used in the treatment of hypercalcemia.

04:51 It has serious toxicity associated with it though including thrombocytopenia.

04:56 You can get hemorrhages that are very difficult to treat, you can get hepatic disease and hepatic damage and you can get kidney disease and kidney damage from this medication so it isn’t used as much now because we have other agents like the bisphosphonates and the RANKL inhibitors that are much more effective and much safer.