Hormonal Regulators: Calcitonin, Estrogen and Glucocorticoids – Bone and Calcium Medications

00:01 The next thing that I want to talk about is calcitonin.

00:05 What is calcitonin? Calcitonin is a peptide that is secreted by the thyroid gland.

00:11 It decreases serum calcium and serum phosphate levels.

00:16 It inhibits renal secretion or loss of calcium and phosphate.

00:22 Calcitonin is used for the treatment of hypercalcemia.

00:26 It's also used sometimes in osteoporosis because of its actions on the bone.

00:30 It is used to treat severe bone pain due to acute vertebral fractures.

00:35 Calcitonin has also been shown to reduce spinal fractures and compression wedge fractures in people with osteoporosis who cannot tolerate bisphosphonates.

00:45 You can see here in the image this person's spine has had what we call a wedge compression.

00:52 Now the spinal column is slanting forwards or hunching forwards because the vertebral column has got a wedge in it instead of a nice round cylinder.

01:03 This is a very common thing that we see in elderly patients and that's why elderly patients tend to have a bit of a stooped posture.

01:10 It's because somewhere in their spine they have a wedge compression fracture.

01:14 We can prevent this through proper treatment of osteoporosis and osteopenia.

01:19 Now we reduce spinal compression fractures with calcitonin, but it's not as effective as some other agents that I'm going to talk about later.

01:28 Long term use is also associated with a small increase in various cancers.

01:34 Calcitonin is often administered as salmon calcitonin, so it comes from the fish, the salmon.

01:42 It is a nasal spray, so it's exceedingly easy to take.

01:46 Most patients can tolerate it quite nicely.

01:49 And it's a psychological benefit too, because patients don't feel that it adds to their medication burden if they're giving us a nasal spray.

01:58 They don't think of it as a pill or as a medication, so it's a nice drug that way.

02:04 Now in terms of where and when we would use salmon calcitonin and why we would use it, these are the indications.

02:12 Now I want to caution you that they're not all the same in all countries, but generally speaking I'm going to be using the US experience.

02:21 We use it in Paget's disease of the bone.

02:23 But be careful on your exam because it is not used in Paget's disease of the nipple, which has absolutely no correlation with bone disease at all.

02:31 It's just that the same doctor discovered the two different diseases.

02:35 It's used in bone metastases.

02:37 We use it in postmenopausal osteoporosis in women who cannot tolerate other treatments.

02:42 It is used to treat severe bone pain due to acute vertebral fractures.

02:46 We use it in severe hypercalcemia, which makes sense the way it works.

02:51 The next category is estrogen.

02:54 Now we know that estrogen has important interactions with bone mineral homeostasis.

02:59 We use estrogens and selective estrogen receptor modulators like roloxaphene in the treatment of several diseases.

03:08 We may delay bone loss in patients who are postmenopausal.

03:13 We also inhibit parathyroid stimulated bone resorption.

03:17 So you can see here there's a micrograph of a person's bony structure.

03:21 And the trabeculations in a normal patient are nice and thick, so the bones are very strong.

03:26 You can see on the other image, the trabeculations are narrower.

03:31 The person has some wedge compression fractures of the spine, and they have increased risk of fracture of the large bones.

03:38 Glucocorticoids is another issue.

03:40 So we don't use glucocorticoids to treat bone fractures, but put it in here because it has a very important effect on bone mineral homeostasis.

03:50 Glucocorticoids, of course, are anti-inflammatory agents, and I cover those drugs in another lecture.

03:57 But let's talk about how they affect bone mineral homeostasis.

04:01 It inhibits bone mineral maintenance.

04:05 The patients who are on chronic use end up developing osteoporosis in many, many, many cases.

04:12 And it can be used in short-term treatment of hypercalcemia, because it reduces calcium levels in the serum.

04:20 How do glucocorticoids work? Now, you can also have a look at my glucocorticoid lecture to see how these things interact with the corticosteroid binding units in the host cell DNA.

04:32 But here's a little bit of a recap.

04:34 Now, we're going to do a slightly different diagram and mechanism just because we're focusing on bone minerals.

04:42 So first of all, the CBG, that's the corticosteroid binding globulin, binds to the substrate, or in this case, let's say a drug like prednisone.

04:53 The prednisone substrate enters into the cell.

04:56 It enters as a free molecule and it binds to the receptor inside the cell.

05:02 The receptor is represented by an R.

05:05 Now, there is another protein on there called an HSP98 protein that is bound to the receptor.

05:12 When the drug binds to the receptor, the HSP is discarded.

05:18 And now you have an active receptor represented by the R with a star beside it.

05:24 So we have this steroid receptor that is an activated receptor.

05:28 That receptor steroid complex enters into the nucleus of the cell.

05:33 That's where all the DNA is.

05:35 And the DNA has a GRE or a glucocorticoid response element in it, which binds to the steroid receptor complex.

05:44 When these two get together, gene transcription is activated and you have the machinery responsible for bone resorption.

05:55 Thyroid hormones play a critical role in skeletal development and bone maintenance.

05:59 They are essential for normal growth and development.

06:02 And both excess and deficiency can lead to significant bone pathology.

06:07 Hyperthyroidism is associated with increased bone resorption and risk of osteoporosis, while hypothyroidism can result in delayed skeletal development and impaired bone mineral increase.

06:21 Growth hormone and its mediator, insulin-like growth factor, are crucial for bone formation and remodeling.

06:30 GH directly stimulates osteoblast activity and bone formation, while IGF-I acts in an endocrine and autocrine paracrine manner to regulate bone growth and maintenance.

06:43 GH deficiency is associated with decreased bone mass, and GH replacement therapy has been shown to increase bone turnover and bone mass.

06:54 Insulin also has significant effects on bone metabolism.

06:58 Insulin receptor signaling in osteoblast is essential for postnatal bone acquisition and maintenance.

07:05 Insulin deficiency, as seen in type 1 diabetes or insulin resistance, as seen in type 2 diabetes, can negatively impact bone health, leading to decreased bone formation and increased fracture risk.