Osteoprosis updated 2014

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Pharmacology of osteoporosis for education purpose of undergraduate students , to be updated to add new drugs

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Osteoporosis by Dr. Ahmed Shaker ahmedshaker21@yahoo.com:

Osteoporosis by Dr. Ahmed Shaker ahmedshaker21@yahoo.com بسم الله الرحمن ا الرحيم ﴿ قَالَ رَبِّ إِنِّي وَهَنَ الْعَظْمُ مِنِّي وَاشْتَعَلَ الرَّأْسُ شَيْبًا وَلَمْ أَكُن بِدُعَائِكَ رَبِّ شَقِيًّا ﴾ for physiotherapy students

What is osteoporosis:

Osteoporosis literally means “ porous bones ” Defined as : A condition of skeletal fragility due to progressive loss of bone mass What is osteoporosis

What are the most common causes ?:

Postmenopausal deficiency of oestrogen Age related deficiency in bone homeostasis Drugs : glucocorticoids ; thyroxin & some anti convulsants Disease : Rheumatoid arthritis, hyperthyroidism Presence of Risk factors : slim body frame (Low body mass < 19 kg/m2 ) Chronic alcoholism Excessive smoking Never been pregnant absence of menstrual cycle or periods of amenorrhea premature ovarian failure Low dietary calcium and vitamin D intake a family history of osteoporosis, , a sedentary lifestyle, and Caucasian or Asian race. What are the most common causes ?

Overview of bone metabolism:

Bone is continuously subjected to a process of remodeling: the events include the action of Osteoclasts : responsible fore bone resorption Osteoblasts : responsible for bone formation Overview of bone metabolism

Overview of Pharmacotherapy :

Overview of Pharmacotherapy SERM : Selective estrogen receptor modulators Postmenopausal Osteoporosis The following drugs are considered : Raloxifen Selective estrogen receptor modulators (SERM) ( prophylaxis & treatment ) Bisphosphonate ( prophylaxis & treatment calcitriol , calcitonin ( prophylaxis & treatment Terperatide ( treatment ) Corticosteroid –induced Bisphosphonate Calcitriol Hormone replacement ( HRT in women ; testesterone in men )

Bisphosphosphonate:

Bisphosphosphonate Chemistry : Enzyme resistant analogue ( P-C- P) of pyrophosphate ( P-O-P ) w are normally inhibit mineralization of bone Mechanism of action : Reduce OSTEOCLASTIC BONE RESORPTION by inhibit OSTEOCLAST PROTON PUMB promotion of apoptosis of osteoclasts decrease in osteocastic formation/ activation * Relative potency

Clinical use of Bisphosphonate e.g Risedronate:

Clinical use of Bisphosphonate e.g Risedronate prevention and treatment of osteoporosis in postmenopausal women corticosteroid-induced osteoporosis in men and women. treatment of Paget’s disease of bone Other indications Hypocalcaemia caused by cancer treatment of cancer metastasis in bone Administration of risedronate: Once weakly (35 mg) or once daily ( 5 mg ) ??

PK of Bisphosphonates:

15/02/1435 dept of pharmacology 8 PK of Bisphosphonates Absorption: Poor oral bioavability ( < 10 %) √Food specially milk reduce their absorption Pamidornate is given IV only Distribution: About 50 % of absorbed dose accumulate at sites of bone mineralization , remains for long periods ( up to several months ) √Elimination: the free drug is excreted unchanged by renal route

ADE of bisphosphonates:

15/02/1435 dept of pharmacology 9 ADE of bisphosphonates Adverse upper GI effects (e.g., dysphagia, esophagitis, esophageal or gastric ulcer )* Osteonecrosis and osteomyelitis of the jaw , principally in those with cancer incapacitating bone, joint, and/or muscle pain Other ADE ( incidence > 5 % ) include : back, chest or abdominal pain, pain (unspecified), hypertension, flu-like syndrome, peripheral edema, nausea, diarrhea, constipation, arthralgia, joint disorder, depression, headache, dizziness, myalgia, rash, cataract, pharyngitis, rhinitis, urinary tract infection, and infection (unspecified).

Caution & contra-indication:

15/02/1435 dept of pharmacology 10 Caution & contra-indication Caution renal impairment , cardiac disease ; esophageal abnormalities, hypocalcaemia ; other disorders of bone and mineral metabolism contra indications : pregnancy . Lactation

Recombinant PTH {Teriparatide}:

15/02/1435 dept of pharmacology 11 Recombinant PTH {Teriparatide} Mechanism : Stimulate bone formation Clinical finding : Increase spinal bone density Indication: Postmenopausal osteoporosis treatment of glucocorticoid induced osteoporosis Administration : S.C once daily Caution ; renal impairment ADE : GIT , postural hypotension, muscle cramps , urinary disorders, depression

Selective estrogen receptor modulators (SERM) Raloxifen:

Action: Agonist activity on estrogen receptors in bone ( also has agonist action in CVS& antagonist action Oestrogen receptors in mammary glands & uterus ) It produces dose-dependent increase in osteoblast activity and reduction in oesteoclast action Indication : Effective for treatment and prevention of postmenopausal osteoporosis Advantages : increase bone density without increase risk of endometrial cancer & favorable lipid profile Selective estrogen receptor modulators (SERM) Raloxifen

ADE of Raloxifin:

15/02/1435 dept of pharmacology 13 ADE of Raloxifin Hot flushes , leg cramps Venous thromoembolism Drug interaction: Warfaraine ( 10 % increase in proterombin time ) Cholesreamine ( reduce enter hepatic circulation of raloxifin by about 50 %

Pharmacokinetics of Raloxifen:

Pharmacokinetics of Raloxifen Well absorbed orally , but bioav. < 2 % due to extensive first pass metabolism ( converted to glucronides ) Converted to active metabolites : Liver, Kidney, bone & spleen Half- life about 32 h, Excreted mainly in the feaces

Calcitonin:

Calcitonin Synthetic salamon calcitonin [ Salcatonin] Action : decrease bone resorption increase bone architecture Indication : prophylactic of osteoporosis in postmenopausal women ( well tolerated compared to other drugs ) Administered S.C , I M or Nasal spray PK : very short half-life 4-12 min but action takes several hours

Calcitonin cont:

15/02/1435 dept of pharmacology 16 Calcitonin cont ADE & Disadvantages : Unpleasant taste , inflammation at the site of injection GIT disturbances Facial flushing, tingling sensation in the hands Tolerance may occurs with prolonged use

Other drugs:

15/02/1435 dept of pharmacology 17 Other drugs Hormone replacement therapy has been used many ADE, most women don ’ t like. Calcium salts & Vit D : may be of value for prophylaxis in certain situations Sodium fluoride ( under investigation , promising results ) What is new ??

Assignment :

15/02/1435 dept of pharmacology 18 Assignment Summarize drug name ; route, characteristic ADE, or contraindication Non pharmacological strategy for prevention of osteoporosis [Diet, exercise, periodic investigations, drugs to be avoided etc ] Treatment of osteoporosis in elderly men New drugs under investigation

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