Non-hormonal Regulators: Bisphosphonates, Fluoride and Calcimimetics – Bone and Calcium Medications

00:01 There are non-hormonal means of regulating bone mineral homeostasis.

00:06 One of the most commonly utilized in pharmacology is the bisphosphonates.

00:11 Now, bisphosphonates follow a general structure which I've shown here with variations in the R1 and R2 moieties that make up the different drugs.

00:20 The most commonly used bisphosphonates include alendronate, risdrinate, ibendronate, zoldronic acid, and pamidronate.

00:27 I won't go into the differences between all of them, I'll just talk about them as a group.

00:32 We have several indications for bisphosphonate therapy.

00:35 The most common, of course, is osteoporosis, and in particular postmenopausal osteoporosis.

00:41 That makes up the bulk of patients who receive bisphosphonates.

00:45 But it can also be used in Paget's disease of the bone.

00:48 We can also use it in bone metastases and neoplastic fractures.

00:53 We use it in the treatment of hypercalcemia.

00:55 It is used in patients who have multiple myeloma, who of course have hypercalcemia as well.

01:01 And finally, we use it in a disease called osteogenesis imperfecta, where patients have very weak and brittle bones.

01:08 Now, this is actually one of my patients.

01:10 She has blue sclera, which is one of the clinical hallmarks of osteogenesis imperfecta.

01:16 This woman is on a tidronate, and she's doing quite well.

01:19 She had possibly 30 to 40 different fractures in her lifetime prior to seeing me.

01:25 Once we started her on bisphosphonate therapy and some other therapies as well, she's actually done wonderfully well.

01:32 And in the 10 years that I've started seeing her, she's only had one further fracture.

01:36 So I think it's been a real improvement for her.

01:40 Bisphosphonates are structurally similar to a molecule called pyrophosphate, but their activity inhibits the enzymes that use this pyrophosphate.

01:51 Bisphosphonates bind very tightly to calcium, and they bind tightly in the bone itself, and they interfere with the osteoclast, which is an important cell that breaks down bone.

02:02 Bisphosphonates in general have 50% renal excretion, and they're very tightly bound to bone tissue, which gives them a very high volume of distribution.

02:13 So take another look at our original pharmacology lectures in pharmacokinetics and review volume of distribution, and you'll see why this is the case.

02:23 Now the elimination is very, very long.

02:26 It's up to decades to get rid of this product out of your body.

02:30 That makes sense because it's bound to bone.

02:33 There are a number of adverse side effects associated with bisphosphonates.

02:37 They can include stomach and esophageal erosions and ulcers.

02:41 You can get a flu-like illness from this medication, and you can get something called osteonecrosis of the jaw.

02:48 Now let's suppose your patient is going for dental surgery, and you want to start them on a bisphosphonate.

02:54 It would be wise to delay using this medication until after the dental surgery is done.

03:01 If the patient is going to have dental surgery and they've already been on a bisphosphonate, because there's such a long half-life in this drug category, it's kind of hard to justify stopping the medication.

03:13 But if you're going to start it and you have an inkling that they're going to go for dental surgery, just hold off.

03:20 Two of these drugs are associated with atrial fibrillation risk.

03:24 So this is something that we also have to consider when we're starting the medications.

03:28 In terms of long-term risk, there's something unique called bisphosphonate fractures.

03:33 So you can see here a fracture in one of my patients.

03:36 This person had a fracture of their diaphysis, and it was a particularly concerning side effect of bisphosphonate therapy.

03:46 So it seems counterintuitive that this can happen, but it is something that can occur.

03:52 Here is a list of some commonly prescribed bisphosphonates for osteoporosis.

03:57 A lendronate, known as Phosomax, is available in tablet and oral solution forms.

04:03 Next on the list is Rhizodrenate, marketed as Actinol.

04:07 This medication comes in tablets and delayed release tablets.

04:10 There are several others, including the last two listed on the slide.

04:14 When administering these medications, it's crucial to take them with water on an empty stomach and remain upright for at least 30 minutes post-dose.

04:24 Additionally, avoid eating, drinking anything other than plain water, or taking other medications for at least 30 minutes after ingestion.

04:38 I'm going to put another, I won't say drug, but let's say element in here called fluoride.

04:45 Fluoride is extensively used in dental health.

04:48 Medical doctors don't use it so much, but you see dentists using it all the time.

04:53 It does not appear to be effective in postmenopausal osteoporosis, but it is highly effective in dental health.

05:01 It may increase bone density though, we're not really sure, but we do know that there's no reduction in bone, large bone fractures with fluoride treatment.

05:10 There is no question though that fluoridation of community water sources is an effective means of reducing dental infections, including dental caries.

05:20 And we know that fluoridation of water does not cause harm despite, let's say the political craziness of today's society in believing that fluoride is somehow poisoning patients.

05:35 Fluoride does not cause significant harm in the population according to the science, and it's definitely helpful for dental health.

05:47 We have calcium mimetics.

05:49 These calcium mimetics mimic the action of calcium inside the human body, and they can be used for calcium homeostasis.

05:56 So calcium mimetics mimic the action of calcium on tissues.

06:00 They are allosteric activators of calcium, sensing receptors in the parathyroid gland.

06:07 What that gives you is a reduced output of parathyroid hormone.

06:12 So if you have high parathyroid levels, you can give a calcium mimetic to stimulate the receptor to tell the parathyroid hormone to turn off.

06:23 We use this obviously in secondary parathyroidism, especially in patients who have chronic kidney disease.

06:30 Hypercalcemia is also a disease that we treat, but only in patients who have parathyroid carcinoma.

06:39 The adverse effects, obviously a drug that's designed to reduce calcium levels can cause severe hypocalcemia, so you have to be careful to monitor the levels.

06:48 You may also get some adynamic bone disease because you're closing down the rebuilding of the bone and you can get a fracture.

06:56 You can also have nausea and vomiting from these agents because they are GI toxic for sure.

07:02 In terms of the uses of calcium mimetics, there's one drug called synacalset, which is effective to maintain levels by mimicking calcium right at the parathyroid gland.

07:15 Edicalcitide is another calcium mimetic that treats secondary hyperparathyroidism in patients with chronic kidney disease, and in fact, it's often given at the end of a dialysis session because this particular drug is fully dializable.

07:34 It may be given concomitantly with vitamin D to maintain calcium levels.