Lecture 4 & 5: Pathophysiology and Pharmaceutical care of Osteoporosis Flashcards
What are some risk factors to osteoporosis?
- Non-modifiable: Previous fracture, Family history, early menopause, women, age
- Modifiable: Low BMI, Smoking, Alcohol
- Coexisting Disease: Diabetes, Inflammatory (RA), malabsorption, CKD
- Drug Therapy: Long-term antidepressants, Antiepileptics, PPI, Oral corticosteroids
What is osteopenia?
- Low bone mineral density - weaker than normal
- Not enough for osteoporosis
- 30-40yrs
What is the effect of excerise on bone?
- Athletes have higher BMD
- Hip fractures associated with lower activity levels between 15-45
What are some of the hormones involved with bone growth and maintenance?
- Calcitriol (active form of vitD)
- Growth hormone
- Thyroxine
- Sex hormones (oestrogen/androgen)
- Parathyroid hormone
- Calcitonin
What are the functions of Growth hormone, Thyroxine and sex hormone and where are each produced?
- Stimulates osteoblast activity and more bone synthesis
- GH: Pituitary gland
- Thyroxine: Thyroid Gland
- Sex hormones: ovaries and testes
What are the different parts of the body that deal with Calcium?
- Bones: Calcium is stored
- Digestive tract: Calcium absorbed
- Kidneys: Calcium excreted
What is the function of the Parathyroid hormone and where is it produced?
- Parathyroid gland
- Increases intestinal absorption of calcium
- Reduces excretion
- Stimulates Osteoclast activity: Resorption and
- Increases Ca2+ conc
What is the function of the Calcitonin hormone and where is it produced?
- Thyroid gland
- Inhibits osteoclast activity
- Promotes CA2+ loss in kidneys
- Causes Ca2+ to deposit in the bones
- Increases longevity of osteoblasts
- Decreases Ca2+ conc
How does vitamin D help calcium absorption?
- 7-dehydrocholestrol-UV>Vit D3-liver enzyme> calcidiol - kidney> calcitriol.
- Stimulates enterocytes to increase calbindin -D proteins which increase calcium absorption and facilitate transport to basolateral membrane -> blood
- Stimulates PTH release
- Excessive calcitriol -> to less active
What is osteomalacia and its treatment?
- Softening of bones, insufficient ca2+ and vit D or long-term anticonvulsant (phenytoin/carbamazebine) - induce CYP450) causes Vit D -> Inactive metabolites
- Abnormal bone formation cause of inadequate mineralisation but has normal resorption and formation
- Weak and flexible
- Treatment: high doses of Vit D
What is osteoporosis?
- Severe bone loss which affects normal function
- Bone reabsorption outpaces bone deposit - trabecular bone more susceptible (vertebrae, hip, wrist)
- Compromised bone strength -> risk of fracture
How is osteoporosis developed?
- Osteoclast recruitment is increased
- Osteoclast-osteoblast coupling is interrupted
- Factors recruiting osteoclasts may not adequately recruit osteoblasts
What are the types of osteoporosis?
- Postmenopausal osteoporosis (type 1)
- Type 2: age related
- Secondary osteoporosis
How does postmenopausal osteoporosis work?
- Hormone dysregulation accelerates osteoporosis
- Oestrogens and androgens maintain bone mass
- Oestrogen defieciency causes increased proliferation and activation of osteoclasts and their increased survival
What are the causes of secondary osteoporosis?
- Endocrine disorders: Hyperthyroidism/ parathyroidism
- Medications: Glucocorticoids, Anticoagulants, Gonadotropin-releasing hormone agonists, antiepilptic, diuretics
- Disorders of calcium balance, malabsorption
How do longterm glucocorticoids cause secondary osteoporosis?
- Reduced calcium absorption (by impairing vit D) and more elimination
- Leads to PTH release which causes bone resorption - secondary hyperparathyroidism)
- Inhibitory effect on sex hormones
- Direct inhibition of osteoblast function -> could be reversed when therapy = stopped
How do anticoagulants cause secondary osteoporosis?
- Long term heparin: causes reversible osteoporosis
- Incraesed osteoclast and decreased osteoblast activity
- Increases collagenase activity: breaks down collagen (connective tissue in bone)
- Decrease in active Vit D by reduced activity of kidney enzyme
- Warfarin: antagonistic effect on Vit K - key in syntheiss of bone matrix proteins (inadequate mineralisation)
What are some important points Gonadotropin-releasing hormone agonists on osteoporosis?
- e.g. leuprolide, goserlin
- Use limited to 6 months
- If more longer: a bone protective agent as low-dose oestrogen, progesterone or bisphosphonates
How do antiepleptic drugs and diuretics cause secondary osteoporosis?
- Induces CYP450 which converts vit D-> inactive metabolites
- Decrease serum calcium. Block Na+/K+ transporter in ascending limb - loss of electrochemical gradient
How is osteoporosis diagnosed?
- Bone mineral density - measured at lumbar spine and hip - xray - repeated evry 2-5yrs
- DXA scan
- T score: number of SDs from peak bone mass of 30yr old of same sex and Z score: number of SDs from average bone mass of same age and sex
- T score between -1 & -2.5 = osteopenia, -2.5 less = osteoporosis, -2.5 + fracture = established osteoporosis
What is the main complication of osteoporosis?
- Fragility fracture
- Usually remains undiagnosed until a fracture
How do you calculate fracture risk in patient?
- Consider assessment in Women 65 older and men 75 older or younger w/ risk factors
- Q fracture (faces) and FRAX score: assesses 10 yr probability of fracture (red, yellow, green graph)
What are the non-pharmacological strategies for treating osteoporosis?
- Lifestyle modification: stop alcohol, smoking, increase Ca in diet
- Regular excerise
- Avoid drugs that cause osteoporosis
What are the pharmacological treatment strategies of osteoporosis?
- Bisphosphonates
- Calcium
- Vit D
- Oestrogen
- Oestrogen receptor modulators (SERM)
How do Bisphosphonates work and some examples?
- First line prevention of osteoporotic fractures
- Reduce bone resorption by inhibiting osteoclast removing calcium from bone
- Bind to hydroxypatite on bone mineral surface
- Taken up by osteoclast and induces apoptosis
- Alendronic acid, risedronate
What is the absorption and elimination like for bisphosphonates and what are their adverse side effects?
- Poorly absorbed from intestine and low bioavailability
- Excreted primarily by kidneys - not recommended in impaired renal function
- Oesophagitis, gastritis, petic ulcer, fever aches, osteonecrosis of jaw (teeth death) and external auditory canal (ear pain, discharge)
What are some counselling tips for bisphosphonates?
- Dont crush
- Once weekly
- Sit upright and take with lots of water
- On empty stomach
- Not at night and keep upright for 30mins
What are some drug interactions with calcium administration and some adverse effects?
- Iron therapy impairs absorption
- Tetracyclines causes intestinal chelation of Ca
- Nausea, Constipation, Abdominal distension, Kidney stones
What is Denosumab and how does it work?
- 2nd line and fully human monoclonal antibody to RANK Ligand (which activates osteoclasts)
- Reduces osteoclast development and increases BMD.
- RANK L is secreted by osteobalasts and bind to RANK on pre-osteoclast. This activation converts pre-osteoclast to osteoclast - Denosumab inhibits
What are some counsellling and side effects of Denosumab?
- SC injection given every 6 months
- Ensure Ca2+ and Vit D are adequate before starting
- Rebound effect
- Similar side effects to bisphosphonates
How do selective oestrogen receptor modulators (SERM) work and name an example?
- Partial agonists of oestrogen receptors
- Induce osteoblast activity
- Used for postmenopausal osteoporosis
- PE/DVT risk
How do Parathyroid Hormone analogues (Teriparatide) work and what are some adverse effects?
- Mimics endogenous PTH hormone
- Ensure Ca2+ and Vit D are adequate before starting
- For serious osteoporosis in men and postmenopausal women
- Injected daily SC
- Adverse Effects: Postural hypertension, hypercalcaemia
