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

by Pravin Shukle, MD

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

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

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

    00:20 The ones that I think are worth remembering are drugs like etidronate, but there are many that you can see here in my list.

    00:27 Now etidronate, alendronate and residronate are the most commonly used medications in North America but here are others that are available as well.

    00:36 I won’t go into the differences between all of them I’ll just talk about them as a group.

    00:40 We have several indications for bisphosphonates therapy.

    00:43 The most common of course is osteoporosis and in particular post-menopausal osteoporosis.

    00:50 That makes up the bulk of patients who receive bisphosphonates but it can also be used in Paget’s disease of the bone.

    00:57 We can also use it in bone metastasis and neoplastic fractures because it may also not just fix the fracture or help the fracture heal but it may reduce cancer spread in bone.

    01:08 We use it in the treatment of hypercalcemia.

    01:11 We’ve used it in patients who have multiple myeloma who of course have hypercalcemia as well.

    01:16 We also use it in complex regional pain syndromes through an unknown mechanism.

    01:22 And, finally, we use it in a disease called osteogenesis imperfecta where patients have very weak and brittle bones.

    01:29 Now, this is actually one of my patients.

    01:31 She has blue sclera which is one of the clinical hallmarks of osteogenesis imperfecta.

    01:37 This woman is on etidronate and she’s doing quite well.

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

    01:47 Once we started her on bisphosphonates therapy and some other therapies as well.

    01:51 She’s actually done wonderfully well and in the ten years that I’ve started seeing her she’s only had one further fracture, so I think it’s been a real improvement for her.

    02:00 Bisphosphonates are structurally similar to a molecule called pyrophosphate but their activity inhibits the enzymes that use this pyrophosphate.

    02:12 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.

    02:24 Bisphosphonates in general have 50% renal excretion and they are very tightly bound to bone tissue which gives them a very high volume of distribution, so take another look at our original pharmacology lectures and pharmacokinetics and review about volume of distribution and you’ll see why this is the case.

    02:45 Now, the elimination is very, very long - it’s up to decades to get rid of this product out of your body.

    02:51 That makes sense because it’s bound to bone.

    02:54 There are a number of adverse side effects associated with bisphosphonates.

    02:58 They can include stomach and esophageal erosions and ulcers.

    03:02 You can get a flu-like illness from this medication and you can get something called osteonecrosis of the jaw.

    03:10 Now, let’s suppose your patient is going through dental surgery and you wanna start them on a bisphosphonate.

    03:15 It would be wise to delay using this medication until after the dental surgery is done.

    03:23 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, but if you're going to start it and you have an inkling that they're gonna go for dental surgery, just hold off.

    03:41 Two of these drugs are associated with atrial fibrillation risk, so this is something that we also have to consider when we’re starting the medications.

    03:50 In terms of long term risk there’s something unique called bisphosphonates fractures.

    03:55 So you can see here a fracture in one of my patients.

    03:57 This person had a fracture of their diaphysis and it was a particularly concerning side effects of bisphosphonate therapy so it seems counterintuitive that this can happen but it is something that can occur.

    04:13 I’m going to put another - I won’t say drug, but let’s say element in here called fluoride.

    04:20 Fluoride is extensively used in dental health.

    04:23 Medical doctors don’t use it so much but you see dentists using it all the time.

    04:28 It does not appear to be effective in postmenopausal osteoporosis but is highly effective in dental health.

    04:36 It may increase bone density though, we’re not really sure, but we do know that there’s no reduction in large bone fractures with fluoride treatment.

    04:46 There is no question though that fluoridation of community water sources is an affective means of reducing dental infections including dental carries 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.

    05:10 Fluoride does not cause significant harm in the population according to the science and it’s definitely helpful for dental health.

    05:22 We have calcimimetics.

    05:24 These calcimimetics mimic the action of calcium inside the human body and they can be used for calcium homeostasis. So calcimimetics mimic the action of calcium on tissues.

    05:36 They are allosteric activators of calcium - sensing receptors in the parathyroid gland.

    05:43 What that gives you is a reduced output of parathyroid hormone.

    05:48 So if you have high parathyroid levels, you can give a calcimimetic to stimulate the receptor to tell the parathyroid hormone to turn off.

    05:59 We use this obviously in secondary parathyroidism especially in patients who have chronic kidney disease.

    06:05 Hypercalcemia is also a disease that we treat but only in patients who have parathyroid carcinoma.

    06:15 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.

    06:24 You may also get some adynamic bone disease because you’re closing down the rebuilding of the bone and you can get a fracture.

    06:31 You can also have nausea and vomiting from these agents cuz they are GI toxic, for sure.

    06:37 In terms of the uses of calcimimetics there’s one drug called cinacalcet, which is affective to maintain levels by mimicking calcium right at the parathyroid gland.

    06:51 Etelcalcetide is another calcimimetic 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 dialyzable.

    07:10 It may be given concomitantly with vitamin D to maintain calcium levels.

    About the Lecture

    The lecture Non-hormonal Regulators: Bisphosphonates, Fluoride and Calcimimetics – Bone and Calcium Medications by Pravin Shukle, MD is from the course Endocrine Pharmacology.

    Included Quiz Questions

    1. Osteogenesis imperfecta
    2. Osteonecrosis of the jaw
    3. Osteochondroma
    4. Plantar fasciitis
    5. Frozen shoulder
    1. Osteoclast inhibition
    2. Osteoblast inhibition
    3. Osteoblast and osteoclast activation
    4. Osteoclast activation
    5. Osteoblast activation
    1. Fractures
    2. Flu-like illness
    3. Atrial fibrillation
    4. Diarrhea
    5. Esophageal erosions

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

     Pravin Shukle, MD

    Pravin Shukle, MD

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