Treatment of osteoporosis Flashcards
What is osteoporosis?
- Progressive loss of bone mass and skeletal fragility
- Occurs in older men and women but it is more pronounced in postmenopausal women
- Osteoblasts forms bone while osteoclasts resorbs bone
What are the different hormones that exerts their effects on the bones?
1) Bone formation:
- Calcitonin (CT) from the thyroid
2) Bone resorption:
- Parathyroid hormone (PTH) from the parathyroid
What are the different treatment strategies for osteoporosis?
1) Non-pharmacological
2) Pharmacological
Describe the non-pharmacological strategy in treating osteoporosis
1) Adequate intake of calcium and vitamin D
2) Weight-bearing exercises
3) Smoking cessation
4) Avoid drugs like glucocorticoids (as they increase bone loss)
What are the different bisphosphonates drugs?
1) Alendronate
2) Ibandronate
3) Risedronate
4) Etidronate
5) Pamidronate
6) Tiludronate
7) Zoledronic acid (zoledronate)
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What is the effect of estrogen on bones?
1) Estrogen decreases bone resorption (so after menopause, resorption will increase)
2) Estrogen decreases the frequency of hip fracture
What are the different pharmacologic therapies used to treat osteoporosis?
1) Bisphosphonates (first-line treatment, this drug has a high specificity, attracted to bone only)
2) Selective estrogen modulators (agonist in some parts of the body and an antagonist in other parts of the body)
3) Calcitonin (useful for women suffering from menopause but it must not be used alone)
4) Denosumab
5) Teriparatide
Explain the bone remodeling cycle
1) Bone resorption:
- OC precursor cells differentiate into osteoclasts that will digest the bone (requires energy)
- Alendronate will deactivate both the differentiation of OC cells and their bone resorption activity
- Raloxifene will deactivate the resorption activity of osteoclasts
2) Bone formation (activated by teriparatide):
- OB precursor cell - OsteBlast cells
- OB cells will secrete osteoid “bone matrix”
- The osteoid will then be mineralized (complex calcium phosphate crystals “hydroxyapatite” are deposited)
What are the clinical uses of bisphosphonates?
1) Prevention and treatment of postmenopausal osteoporosis
2) Paget’s disease
3) Treatment of bone metastases in malignancy
4) Hypercalcemia (bisphosphonates, will absorb the excessive calcium in the blood)
What are the signs and symptoms of Paget’s disease?
1) Loss of appetite
2) Constipation
3) Compression of nerves
4) Extreme fatigue
5) Abdominal pain
6) Headache due to the overgrowth of the head
7) Weakness
8) Pain due to the fracture of bones
What is the mechanism of action of bisphosphonates?
1) Some are Simple compounds that are similar to pyrophosphate “used by the cells to synthesize ATP” (like etidronate)
- which are incorporated into ATP analogues that accumulate within the osteoclasts and promote their apoptosis
2) While others are amino-bisphosphonates (pamidronate, alendronate, risedronate, ibandronate, zoledronate)
- These prevent bone resorption via interfering with the anchoring of the cell surface proteins to the osteoclast membrane (by inhibiting some pathways in the cholesterol biosynthesis), preventing the attachment of osteoclast to the bone
What is Paget’s disease?
- A disease that is characterized by extensive bone remodeling in specific sections of the bone
- Excessive bone resorption is followed by excessive bone growth causing skeletal deformities ad fractures
Describe the pharmacokinetics of bisphosphonates
1) Absorption:
- Oral bisphosphonates (alendronate “oral”, risedronate “oral & there is a sustained release for it”, ibandronate “both oral and IV”) are doses on a daily, weekly, or monthly basis depending on the drug
- Absorption after oral administration is poor <1% of the drug is absorbed
- Food and other medications will significantly interfere with the absorption of oral bisphosphonates
- Zoledronic acid is intravenous, used as a support medication to treat symptoms of cancer like hypercalcemia or to decrease the complications (like fractures & pain) produced by cancer metastasis to the bone
- Ibandronate reduces the incidence of skeletal-related events and bone pain in patients with cancer
2) Distribution:
- Bisphosphonates are rapidly cleared from the blood and they bind to the hydroxyapatite in the bone and cleared from there from hours to years waiting for it to be engulfed by osteoclasts to produce ATP
3) Elimination:
- Primarily by the kidneys
- Bisphosphonates should be avoided in severe renal impairment
- Patients who cannot tolerate bisphosphonates, IV ibandronate and zoledronic acid are the alternatives
What are the dosing instructions for all oral bisphosphonates?
1) Take 150-250 ml of water
2) 30 minutes before a meal and 60 in case of ibandronate
3) Risedrinate delayed released tablets must be taken after breakfast immediately
4) You must stay upright for 30 minutes and 60 in-case of ibandronate
What are the adverse effects of bisphosphonates?
1) Diarrhea
2) Abdominal pain
3) Musculoskeletal pain
4) Osteonecrosis of the jaw (BRONJ), a chronic condition of the oral cavity resulting in mucosal ulceration (rare)
5) Esophagitis and esophageal ulcers
6) Osteomalacia “bone softening” (with chronic etidronate administration)
7) Atypical fractures (uncommon)
What is the importance of estrogen and estrogen receptor modulators?
- Low estrogen levels after menopause promote the proliferation and activation of osteoclasts, and the bone mass can decline rapidly
- Estrogen replacement therapy is effective for the prevention of postmenopausal bone loss, but on the other hand, it increases the risk of endometrial cancer, breast cancer, venous thromboembolism, and coronary events, so to avoid these dangerous effects we use estrogen modulators to get the good action of estrogen-only
What is an example of a drug that is considered as selective estrogen receptor modulator?
Raloxifene
What is the use of raloxifene?
1) Selective estrogen receptor modulator approved for the prevention and treatment of osteoporosis
2) It has an agonist effect on estrogen in the bone and an antagonist effect on the breast and endometrial tissue, (thus sometimes it is used as a drug that treats cancer where iacts as an antagonist)
3) An alternative for postmenopausal osteoporosis in women who are intolerant to bisphosphonates
4) It increases bone density
5) It does not increase the risk of endometrial cancer
6) It decreases the risk of breast cancer
7) Reduces the level of total low-density lipoprotein cholesterol (LDL) (it makes you lose fat)
What are the adverse effects of raloxifene?
1) Hot flashes
2) Leg cramps
3) Risk of venous thromboembolism similar to estrogen
Describe the use of calcitonin
1) Indicated for the treatment of osteoporosis in women who are at least 5 years postmenopausal
2) Reduces bone resorption, though less effective than bisphosphonates
3) Relieves the pain associated with osteoporotic fracture
4) Available as intranasal and parenteral formulations, but the parenteral formulation is rarely used to treat osteoporosis
5) May be beneficial for patients with recent vertebral fracture
6) We do not administer it alone, but along with bisphosphonates
What are the adverse effects of calcitonin?
1) Rhinitis and other nasal symptoms
2) Resistance to calcitonin has been observed with long-term use in Paget’s disease
3) It might increase the risk of malignancy, it should only be given to patient that cannot tolerate other drugs for osteoporosis
What are the features of denosumab?
- Approved for the treatment of postmenopausal osteoporosis woman at high risk of fracture
- It is administered subcutaneously every 6 months
- It has been associated with an increased risk of infections (as it inhibits a lot of immune modulators), dermatological reactions, hypocalcemia, osteonecrosis of the jaw, and atypical fractures
- This drug is reserved for woman at high risk of fracture and those who are intolerant or unresponsive to other osteoporosis therapies
What is the use of denosumab?
- It is a human monoclonal antibody (hence the suffix -mab)
It targets the receptor activator of nuclear factor kappa-B ligand (RANKL) and inhibits the osteoclast formation & function
1) RANKL (generated by osteoblasts) binds to RANK receptor on the osteoclasts increasing its activity (stimulating resorption)
2) RANK-RANK-L signaling is elevated in osteoporosis due to a decrease in the sex hormones specifically estrogen
3) Monoclonal antibodies (denosumab) bind to RANKL stopping them from attaching to the RANK receptor inhibiting osteoclast activity
What are the features of Teriparatide?
- A recombinant form of the PTH, consists of 34 biologically active amino acids of the hormone (it has an opposite effect to PTH)
- Administered subcutaneously daily for the treatment of osteoporosis
- First medication to be approved for the treatment of osteoporosis that stimulates bone formation, via stimulating osteoblastic activity
- It should be reserved for patients with high risk of fractures or the ones that cannot tolerate other osteoporosis therapies
