Zainab Al-dabi - Shahd Alqudah - Dr. Malik

Transcription

1 - 4 - Zainab Al-dabi - Shahd Alqudah - Dr. Malik 1

2 In the USA there are 10 million cases of osteoporosis, most of which belong to women, this represents 3-4% of the population which is a relatively high percentage that shows the importance of knowing the proper management of the disease and other diseases linked to bone resorption such as cancers(mostly) and cancer metastasis to the bone. Osteoporosis is a silent disease that most patients are unaware of, it causes bone resorption but bone fractures are the main manifestation that can be observed especially in the hips and spine and may occur on both sides. Generally speaking the efficacy of the drugs used in treatment of osteoporosis is determined by how much those fractures are reduced. Management: 1. We must check that the patient does not suffer from vitamin D deficiency. 2. We can then administer low and intermittent doses of parathyroid hormone; teriparatide (in order to produce more osteoblastic activity than osteoclastic activity), BUT it is an expensive drug and not that common. However, there are more common drugs that can be used in the management of osteoporosis, such as: Non-hormonal agent affecting bone mineral homeostasis 1) Bisphosphonates: -This group of drugs has interesting characteristics. - They are analogues of pyrophosphate in which the P-O-P bond is replaced by a nonhydrolyzable P-C-P bond. Note that the oxygen is replaced with a carbon atom. NOTE: There is a large number of drugs available for clinical use we do not need to memorize them but we should know that bisphosphonate group of drugs end with dronate. (Etidronate, Pamidronate, Alendronate, Risedronate, Tiludronate, Ibandronate, Zoledronate.) A) MECHANISM OF ACTION: they decrease bone resorption by reducing the activity of osteocalsts in bones; Bisphosphonate molecules preferentially "stick" to calcium and bind to it, and as we know that the largest store of calcium in the 2

3 body is in bones, so bisphosphonate accumulates to a high concentration there, where it actually needs to work. - Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts. - They induce apoptosis of osteoclasts, decrease their proliferation and inhibit osteoclastogenesis. - They build-up only in osteoclasts; because they chelate calcium and go together towards the bone where they will be ingested by osteoclasts. So, the use of Bisphosphonates is considered a selective therapy towards osteoclasts. ** But HOW do they induce apoptosis? It is a debatable issue so we will not go into details, but there are two classes of bisphosphonates that we need to know; one has a nitrogen atom and the other doesn t. Our body recognizes them as false metabolites that inhibit the cholesterol biosynthetic pathway which is important for osteoclast function, krebs cycle, in addition to other pathways. Each one of these drugs has its own mechanism. However, they all share the same outcome which is the disruption of the normal pathways of osteoclasts, thus causing three things: triggering apoptosis (apoptosis inducing drugs), reducing osteoclast proliferation, and increasing osteoclast death. -They retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system" from slides" B) PHARMACOKINETICS: -Different formulas of these drugs are available: oral, subcutaneous (SC) and IV. - Can be used daily, weekly, monthly, or even yearly. This mainly depends on the bioavailability* of the drug used, and how much it builds-up in the bone. So, generally speaking, orally taken drugs are partially absorbed, thus having a low bioavailability (1%-10%), and low build-up in bones. Therefore they are administered daily although there are some exceptions to this rule. * Extra Note: bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, and it depends on the route of administration. - The more bioavailability the drug has, the more build-up in bone there will be and so the less times the patient requires taking it (weekly, monthly and so on). 3

4 Oral drugs as we said have low bioavailability and to prevent reducing it any more they should be taken on an empty stomach, as food interrupts and reduces their absorption. We can eat after two hours of administering the drug. Important -Half of the absorbed drug accumulates in the bone, and the rest is excreted unchanged in urine, the dose must be reduced in renal dysfunction. (slides) -The portion retained in bone remains there for months, depending on the turnover of the bone itself. So these drugs persist for a long time in the bone. C) Pharmacodynamics: - They are potent inhibitors of bone resorption. -They increase bone mineral density and reduce the risk of fractures in the hip, spine and other locations. Remember that we always assess the efficacy of the drug by determining how much it reduces spine and hip fractures. D) Adverse Effects: (mostly GIT-related) - Gastric and esophageal irritation. The patient must be informed to take the drug with a full glass of water and remain upright for 30 minutes; this means either to stand up or sit down but maintain a straight back posture to prevent esophageal reflux. - High doses produce mineralization defect. (Rare) - High doses cause renal deterioration and osteonecrosis of the jaw. (Rare) - Over-suppression of bone turnover may cause subtrochanteric femur fractures in patients on long-term treatment. ** More details on point 4: 4

5 First you should know that we treat postmenopausal induced osteoporosis for five years after the onset of menopause. The five-year treatment comes from the idea illustrated in the figure above, that without treatment there will be a progressive decrease in bone mineral density, until it becomes fixed after 5 years. We do not want this to happen so we will treat these women all over this period (five years) whatever the drug we use is before it is too late. According to a clinical trial that involved 2700 patients, around 34 of them developed femoral fractures (which accounted for less than 1% incidence). This was not a persuasive reason however to stop their use, because they are of high advantage in reducing hip fractures up to 34%. So the benefit outweighs the risk in this case. Accordingly, the FDA didn't withdraw bisphosphonates from markets and we still use them for the same period of time (five years). IT IS STILL THE DRUG OF CHOICE for osteoporosis treatment. E) Contraindications: - Decreased renal function because these drugs are excreted by the kidney. - Esophageal motility disorders especially for orally-administered drugs. - Peptic ulcer disease. F) Therapeutic uses: - Hypercalcemia associated with malignancy. - Paget s disease. - Osteoporosis. 5

6 2) Denosumab: - Denosumab is a human monoclonal antibody that binds to and prevents the action of RANKL. - It is a very expensive drug (produced by recombinant DNA technology) so its uses are mostly directed towards cancer patients (because of its high effectiveness). - RANKL is produced by osteoblasts and other cells, including T lymphocytes. It stimulates osteoclastogenesis via RANK, the receptor for RANKL that is present on osteoclasts and osteoclast precursors. - By interfering with RANKL function, Denosumab inhibits osteoclast formation and activity. - It is at least as effective as the potent bisphosphonates in inhibiting bone resorption. It reduces both hip and spine fractures. A) Therapeutic Uses: - Postmeopusal osteoporosis. - Some cancers such as, breast,prostate and lung cancers to limit the development of bone metastases,which is a common and important site for metastases. Or bone loss resulting from the use of drugs that suppress gonadal function. * Let's explain its use in cancer patients: 1) Limitation of bone metastasis: Denosumab reduces bone resorption by reducing the formation and activity of osteoclasts, this leads to an increase in the density of the bone, so it would be harder to metastasize into bones. -The more the bone is weak and spongy-like, the higher the chance of cancer metastasis to it. 2) Both breast and prostate cancer are hormonal dependent and as we've learned, these patients take a hormonal targeted therapy. This includes: a- Tamoxifen that blocks the estrogen receptor in breast cancer cell and inhibits the binding of estrogen to its receptor simply because estrogen induces the development of breast cancer. b- Aromatease inhibitor which inhibits estrogen and androgen synthesis."i am not sure about it, but it was mentioned by the prof" 6

7 c- GnRH analogues in prostate cancer. It is the most effective therapy that inhibits the production of GnRH by giving the patient GnRH analogue in a countinous manner rather than pulsatile to promote the feedback inhibition to the hypothalamus, consequently resulting in the reduction of FSH, LH, estrogen in ladies and androgen in men. All of these therapies that suppress gonadal function lead to bone loss. Remember that estrogen inhibits osteoclast activity and bone resorption, so we use Denosumab to oppose the action of the previously mentioned anti-cancer drugs in bones. B) ADMINSTRATION: Denosumab is administered subcutaneously every 6 months twice yearly. C) ADVERSE EFFECTS: well tolerated - Increased risk of infection because some immune cells express RANKL and cause inhibition to the immune system. - It can lead to transient hypocalcemia, especially in patients with marked bone loss or compromised calcium regulatory mechanisms, including chronic kidney disease and vitamin D deficiency. Remember that one of the most important calcium resources in the body is the bone (when calcium level in the blood is low, bone resorption provides a portion of the needed calcium) and here we are blocking it and if the patient does not have a compensatory mechanism as the kidney and vitamin D, he might develop hypocalcemia. 3) Calcimimetics (cincalcet): A) MECHANISM : - It mimics calcium and activates the calcium sensing receptor (CaSR) in the parathyroid gland, which blocks PTH secretion. B) THERAPEUTIC USE: 7

8 - We use it when the bone resorption is due to hyperparathyroidism (excess PTH). We do not usually use it in osteoporosis because it will decrease the level of PTH [remember the important role of this hormone in osteogenesis] and we do not want this to happen unless there is hyperparathyroidism [as we've taken previously, PTH effect is dose-dependent]. - Indicated for treatment of secondary hyperparathyroidism in chronic kidney disease because calcium in this case is not being well reabsorbed, so very low calcium level induces more PTH secretion and leads to more bone resorption. - For treatment of parathyroid carcinoma (primary hyperparathyroidism). 4) Plicamycin (Mithramycin): - Is a cytotoxic antibiotic. It s an anti-cancer drug that has some selectivity towards inducing osteoclast apoptosis. The mechanism of that is unknown till now. - Binds to DNA and interrupts DNA directed RNA synthesis and thus protein synthesis. THERAUPEUTIC USE: - Indicated for treatment of Paget s disease and hypercalcemia (1/10 cytotoxic dose). - Its use is very limited especially in osteoporosis, because it is a cytotoxic drug and thus has many side effects. - In hypercalcemia we use it if the other agents didn't work. We can use it because it cause reduction in calcium mobilization from bone and therefore reduce the calcium level in the serum reducing the consequences of having a high calcium serum level that we previously explained. 5) Strontium Ranelate: - Strontium ranelate is composed of two atoms of strontium bound to an organic ion, ranelic acid. 8

9 MECHANISM OF ACTION: - Strontium, which has the atomic symbol Sr and the atomic number 38, belongs to the group II in the periodic table of the elements, just beneath calcium. Because its nucleus is nearly the same size as that of calcium, the body easily takes up strontium and incorporates it into bones in the place of calcium. (extra note) - Strontium resembles the calcium ion so when it is taken orally and absorbed into the blood it will accumulate in bones because the body deals with it as calcium. It blocks differentiation of osteoclasts while promoting their apoptosis, thus inhibiting bone resorption just as bisphosphonates. What is special about Strotium ranelate is that it promotes bone formation in an unknown mechanism. So it has two opposite effects on osteoblasts and osteoclasts, this depends on how each type of cells deal with this substance. [Induces apoptosis of osteoclasts while promoting osteoblastic activity] - Unlike bisphosphonates, Denosumab, or Teriparatide, this drug increases bone formation markers while inhibiting bone resorption markers. The aforementioned sentence was literally taken from the slides and that is what "Katzung book" exactly says, but it's not accurate regarding teriparatide as this drug also promotes bone formation. (Refer to the figure on page 4): you will notice that PTH also promotes bone formation, not only Sr2+. You still should think about Sr2+ as a very special drug which dramatically increases bone density. THERAUPEUTIC USE: -Large clinical trials have demonstrated its efficacy in increasing bone mineral density and decreasing fractures in the spine and hip. - It is used in Europe for the treatment of osteoporosis and is approved in 70 other countries because they believe that the benefit outweighs the risk. But it is not used in the USA. ADVERSE EFFECTS: - Strontium ranelate increases the risk of venous thromboembolism, pulmonary embolism, and serious cardiovascular disorders, including myocardial infarction. As in hypercalcemia, calcium induces thrombus formation and also 9

10 disrupts myocyte contractibility, in addition to AV and SA nodes knowing that all of those depend on the presence of calcium. Secondary Hormonal Regulators of Bone Mineral Homeostasis - A number of hormones modulate the actions of PTH, FGF23, and vitamin D in regulating bone mineral homeostasis. - The physiologic impact of such secondary regulation on bone mineral homeostasis is minor. - In pharmacologic amounts, they may have actions that are useful therapeutically. 1) Calcitonin: - important but not predominant in calcium homeostasis and bone formation. - Calcitonin secreted by the parafollicular cells of the thyroid is a singlechain peptide hormone with 32 amino acids and a molecular weight of Human calcitonin monomer has a half-life of ~ 10 minutes. Salmon calcitonin has a longer half-life of minutes, making it more attractive as a therapeutic agent. The uses of calcitonin are very minimal. - Clearance is mainly achieved by kidney metabolism; little intact calcitonin appears in the urine. - The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. - Calcitonin inhibits osteoclastic bone resorption because it is secreted in the body in response to an increase in calcium level. - In the kidney, calcitonin reduces calcium and phosphate reabsorption as well as reabsorption of sodium, potassium, and magnesium. The reabsorption of calcium, phosphate and many other minerals occurs in the 10

11 ascending loop of Henle as Na +, Mg2 + and K +. This means that it interferes with electrolytes homeostasis. This is a reason that limits the use of calcitonin. - Calcitonin in pharmacologic amounts decreases gastrin secretion and reduces gastric acid output while increasing secretion of sodium, potassium, chloride, and water in the gut. [this drug isn't that good] - In the adult human, no problem develops in cases of calcitonin deficiency (sub total thyroidectomy,radioactive iodine I 131,) even in replacement therapy we don t care about it we only replace thyroid hormone T4 or in excess cases (medullary carcinoma of the thyroid). - The ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget s disease, hypercalcemia, and osteoporosis, but is less effictive than other available agents. We may use it but very rarely. - It increases bone mass and reduces spine fractures, but is less effective than bisphosphonates and teriparatide. 2) Estrogen: - Now we will increase bone density using a hormonal agent rather than drugs. - As we know estrogen is important for bone formation. Its effect is noticed when it decreases after menopause leading to osteoporosis. The most important cause of osteoporosis in postmenopausal women is decreased estrogen level which will lead to hot flushes, mood alteration, nervousness and an increase in bone resorption manifested as osteoporosis. - The question here remains: Why don t we simply administer estrogen to those patients? The answer here is that it increases the risk of breast and uterine cancers. - Remember: Tamoxifene is used after the treatment of breast cancer because we need an agent that suppresses the estrogen effect or release. We have many choices: One of them and the most important being the 11

12 ability of tamoxifen to block estrogen receptors in the breast while still acting as an agonist on bones which is a good thing, as well as acting as an agonist on the endometrium which may induce uterine cancer. This was the reason why we use it only for 5 years. - Tamoxifen is a modulator because it produces different effects on different sites. - Another modulator called Raloxifene is an agonist on bone and an antagonist on both breast and uterus so it increases the bone density, but not very efficiently. At the same time, it reduces breast and uterine cancer. - So the question is why don't we use it instead of Tamoxifen? This is because there are many reasons and many questions about its role in breast and so we still cannot determine its effects. - Scientists are working on new modulators nowadays - The reason why modulators produce different actions in different sites is due to the different 2 nd messenger pathways associated with the receptor activation in those tissues. - Can prevent accelerated bone loss during the immediate postmenopausal period, and at least transiently increase bone in the postmenopausal woman. - Reduces the bone-resorption action of PTH. - Increases 1, 25[OH] 2D level in the blood, which may result from decreased serum calcium and phosphate and increased PTH. - Estrogen receptors have been found in bone, and estrogen has direct effects on bone remodelling. - Men lacking estrogen receptors, or those unable to produce estrogen because of aromatase deficiency, develop marked osteopenia NOT osteoporosis. Osteopenia is associated with less severe effects according to Google, and failure of complete closure of the epiphysis (case reports). 12

13 - Main role is in prevention and treatment of postmenopausal osteoporosis. - Estrogen therapy has been shown to be associated with endometrial and breast cancer in postmenopausal women and without decreased incidence of cardiovascular disease. - Selective estrogen receptor modulators (SERMs), such as Raloxifene, maintain the benefit to bone without increased risk of breast and uterine cancer, and cardiovascular risk. It may even decrease the risk of breast cancer. - It is not as effective as estrogen in increasing bone density. - Raloxifene may protect against spine fractures but not those of the hip (bisphosphonates and teriparatide protect against both). - It does not prevent hot flushes and imposes the same increased risk of thrombophlebitis as estrogen. Now we will take about the management of hypo and hypercalcemia. Management of hypercalcemia crisis: - It Causes CNS depression, coma, cardiac arrhythmia and death. - Note: hypercalcemia decreases Na permeability and thus muscle excitability which leads to muscles' hypotonicity. The exception is the cardiac muscle, where hypercalcemia increases the heart rate and has a positive inotropic effect (increase in contractility). - Major causes are: a) Thiazide therapy. (diuretic drug) b) Hyperparathyroidism (which increases bone resorption, absorption of Ca from the gut, and reabsorption of Ca from the kidney, therefore increases calcium serum level). 13

14 c) Cancer with or without metastasis, such as, parathyroid cancers and other types of cancers that metastasize into bones and cause their resorption. Management of Hypercalcemic Crisis (( increased Ca level)) you should understand it well because we will not learn about its management again. 1. Saline diuresis: Rehydration with normal saline and diuresis with furosemide (lasix). - Furosemide works on the ascending loop of henle where calcium reabsorption normally occurs, so this drug will inhibit the reabsorption process of Ca there - The normal saline will increase GFR (glomerular filtration rate) so eliminating calcium from the body by increasing diuresis. - Their actions are integrated together to normalize the level of calcium in the body. If we only give normal saline the excretion of Ca will be minimal. This method is considered the first line therapy of hypercalcemia, but some patients may have renal failure or other disorders and this treatment fails with them. So we will give them other agents: 2. bisphosphonate : for fastest action we give it Intravenously. Pamidronate is infused over 2-4 hours with high dose, or zoledronate infused over at least 15 minutes. The effects generally persist for weeks, but treatment can be repeated after 7 days if necessary and if renal function is not impaired. Repeated doses may lead to renal deterioration and osteonecrosis of the jaw rare. 3. Calcitonin: it has the same action as the endogenous calcitonin; it reduces both calcium and phosphate. Proved useful as ancillary treatment. By itself, it seldom restores serum calcium to normal, and refractoriness frequently develops. - Calcimar (salmon calcitonin is available for parenteral and nasal administration). We do not give it alone. Instead, it is given to support other agents like bisphosphonates (if they failed to work alone) 14

15 4.. Plicamycin (Mithramycin): - Because of its toxicity, it is not the drug of first choice for hypercalcemia. It is used when other forms of therapy fail. - The most dangerous toxicity is sudden thrombocytopenia followed by bleeding. - Hepatic and renal toxicity can occur - Hypocalcemia, nausea and vomiting may limit therapy. 5. Phosphate: - IV phosphate is the fastest way to reduce serum calcium but is hazardous. - It binds to calcium and both of them will be eliminated from the body. - Only used when other forms of therapy fail to reduce serum calcium. -Should be given slowly over 6-8 hours (1.5g), and the patient should be switched to oral therapy as symptoms of hypercalcemia are cleared. -Adverse effects (IV): sudden hypocalcemia ( the most important side effect), ectopic calcifications, acute renal failure because calcium and phosphate excretion will be increased, hypotension. -Oral phosphate can also cause ectopic calcification and renal failure but less often with a longer time of onset than IV. DO NOT use it unless all other choices aren't working. It is a bad treatment (dangerous). 6. Glucocorticoids will be taken next lecture.. ** Hypocalcemia is not included** 15