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.

00:36 The cytokine protein RankL impacts various tissues with its two different names reflecting its wide range of activity.

00:43 It plays a crucial role in bone mineral homeostasis and it also shares properties with other members of the tumor necrosis factor, TNF superfamily.

00:53 This superfamily comprises at least 19 ligands and 29 receptors characterized by their ability to bind to specific receptors with homologous extracellular domains.

01:05 Members of the TNF superfamily, including RankL, are involved in a wide range of biological processes including immune responses, inflammation, apoptosis, and cell proliferation.

01:16 Rank is a crucial ligand produced by osteoblasts and activated T lymphocytes.

01:21 It binds to the rank receptor on osteoclast precursors and mature osteoclasts, initiating key signaling pathways.

01:29 These pathways activate transcription factors like NF-kappa-B and others, which are essential for osteoclast differentiation and function.

01:37 The process involves a signal propagation complex of rank and others that induces calcium signaling necessary for osteoclast survival.

01:47 Osteoprotejaren, OPG, produced by osteoblasts and other bone marrow cells is a natural inhibitor of the rank-rankle interaction.

01:57 It is part of a negative feedback mechanism to ensure that only the needed number of new osteoclasts are formed during bone remodeling.

02:05 OPG may be reduced in osteoporosis.

02:09 Okay, now we know what RANKL does. Let’s talk about RANKL inhibitors.

02:14 So there’s a drug called denosumab, it is most commonly sold around the word as Prolia but there are other names as well.

02:22 What does this drug do? Denosumab is a monoclonal antibody that binds to rankle, preventing rankle from interacting with its receptor, rank, which is found on the surface of osteoclast precursors and mature osteoclasts.

02:37 It is the first and only FDA-approved monoclonal antibody that targets and neutralizes rankle.

02:43 Denosumab is used to 1. Increase bone mass and reduce fracture risk in osteoporosis.

02:53 2.

02:54 Decrease the risk of pathological fractures in patients with bone metastases from solid tumors.

02:59 3.

03:00 Treat and manage giant cell tumor of bone.

03:05 4.

03:06 Address hypercalcemia of malignancy in patients unresponsive to bisphosphonate therapy.

03:13 Its mechanism of action involves denosumab binding to rankle, preventing it from interacting with the receptor on osteoclasts and their precursors.

03:23 This disruption reduces the differentiation of osteoclasts, decreases their activity, and promotes their apoptosis, leading to reduced bone resorption and increased bone mass and strength.

03:36 The advantages of denosumab include significantly increasing bone mineral density and reducing the risk of various fractures.

03:43 It is also conveniently administered as a 60 mg subcutaneous injection every six months.

03:50 Unlike bisphosphonates, it does not require renal monitoring, making it suitable for patients with renal impairment.

03:57 The disadvantages are that it increases the risk of serious infections, similar to other anti-TNF drugs.

04:05 Discontinuation can cause a rapid increase in bone turnover and a high risk of vertebral fractures, often requiring a transition to bisphosphonates.

04:16 It is also much more expensive than generic bisphosphonates.

04:20 In summary, while denosumab is effective for osteoporosis, bisphosphonates are often preferred initially due to their cost effectiveness and long-term data.

04:35 Calcium and phosphate are essential minerals for maintaining bone mineral homeostasis, primarily through their role in forming hydroxyapatite, the mineral component of bone.

04:45 Bone contains about 99% of the body's calcium and 80% of its phosphate, stored as hydroxyapatite crystals within the bone matrix.

04:56 These crystals provide bones with their rigidity and strength.

05:00 The regulation of calcium and phosphate homeostasis involves several key hormones, including parathyroid hormone, PTH, vitamin D, and fibroblast growth factor, 23, FGF23.

05:16 Parathyroid hormone, PTH, stimulates the resorption of bone tissue, releasing calcium into the bloodstream.

05:23 Additionally, PTH increases the reabsorption of calcium in the kidneys.

05:28 It also promotes the activation of vitamin D into its active form.

05:32 Conversely, PTH decreases renal phosphate reabsorption.

05:37 Vitamin D, particularly in its active form, 1.25 dihydroxy vitamin D, plays a significant role in enhancing the intestinal absorption of calcium and phosphate.

05:50 It also facilitates the reabsorption of these minerals in the kidneys.

05:56 Fibroblast growth factor, 23, FGF23, is produced by osteocytes and reduces both intestinal and renal phosphate reabsorption.

06:06 It also suppresses the synthesis of 125 dihydroxy vitamin D, thereby decreasing intestinal phosphate absorption.

06:13 This hormone is part of a feedback loop that includes PTH and vitamin D, ensuring balanced phosphate levels in the body.

06:24 The process of bone mineralization begins with the nucleation of calcium phosphate crystals within matrix vesicles secreted by osteoblasts.

06:35 These vesicles accumulate phosphate and calcium ions, leading to the formation of hydroxyapatite crystals.

06:43 These crystals then integrate with the collagen matrix of bone.

06:48 Here is a list of specific medical conditions that involve calcium and phosphate dysregulation and the therapeutic approaches used to manage them.

06:57 It's important to note that calcium and phosphate supplements are generally not recommended for healthy individuals without specific deficiencies or medical conditions.

07:09 Osteoporosis is a condition characterized by decreased bone mineral density, leading to fragile bones and an increased risk of fractures.

07:18 To prevent and treat osteoporosis, calcium and vitamin D are commonly used.

07:26 The recommended dosage for adults is typically 1,000 to 1,200 milligrams of calcium and 800 to 1,000 international units of vitamin D daily.

07:40 These supplements work together to improve bone health and strength.

07:43 In some cases, calcium phosphate supplements might be preferable to calcium carbonate or citrate salts.

07:50 Hypophosphatemic disorders, such as X-linked hypophosphatemia and tumor-induced osteomalacia, are characterized by low phosphate levels and impaired bone mineralization.

08:02 These conditions are treated with burosumab, an anti-FGF23 antibody.

08:08 Phosphatia works by improving phosphate homeostasis and enhancing bone mineralization, thereby addressing the underlying issue of phosphate dysregulation.

08:17 In patients with chronic kidney disease, CKD, hypophosphatemia is a common and serious problem.

08:23 Elevated phosphate levels can lead to secondary hyperparathyroidism and vascular calcification, both of which have significant health implications.

08:31 To manage hyperphosphatemia, controlling phosphate intake and absorption is crucial.

08:36 The primary therapy for hyperphosphatemia in CKD involves the use of oral phosphate binders.

08:46 Calcium acetate is one option, but for many patients, non-absorbable phosphate binders like Cevilamer are preferred.

08:54 Cevilamer is effective in binding dietary phosphate in the gastrointestinal tract, reducing its absorption and helping to maintain balanced phosphate levels in the body.

09:04 Now we have other agents in bone disease.

09:06 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.

09:15 Strontium is an example. It’s used extensively in Eastern Europe.

09:19 It is an organic ion that promotes osteoclasts death so there is reduced osteoclasts activity with Strontium.

09:27 It is less used because of the increased risk of deep venous thrombosis.

09:32 I don’t want you to get the impression that it is not an effective treatment of osteoporosis.

09:37 I just want to point out that the increase DVT rates are what led to its decreased use.

09:42 Gallium nitrate is another agent.

09:45 It’s used for the treatment of hypercalcemia in patients with Paget’s disease of the bone and in malignancies.

09:51 We inhibit bone resorption with this product.

09:55 Now, patients need to be very, very well hydrated when they take gallium nitrate because it can lead to significant nephrotoxicity.

10:05 Plicamycin is another agent that’s used in the treatment of hypercalcemia.

10:09 It has serious toxicity associated with it though including thrombocytopenia.

10:14 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.