Endocrine diseases: anatomy, physiology & pharmacology lecture Flashcards
Osteoporosis
- Systemic skeletal disorder of compromised bone strength increased risk of fracture – 34 million Americans: low bone mass – 10 million Americans: osteoporosis
- 1 in 2 women and 1 in 4 men >age 50 will have an osteoporosisrelated fracture in their lifetime
- By 2020, 1 in 2 Americans >age 50 will be at risk for fractures from osteoporosis or low bone mass
Fracture Facts
• 2 million bone breaks a year (“2 million 2 many”)
• Only 2 in 10 patients with osteoporosis get a follow-up test or treatment for osteoporosis
• Fractures may have serious consequences
– Hip fracture
• 10%-20% additional mortality per year
• 20% of hip fracture patients require long-term nursing home care
• Only 40% fully regain their pre-fracture level of independence
Underdiagnosed and Undertreated
• Underdiagnosed: National Osteoporosis Risk Assessment (NORA) study (200,160 postmenopausal women)
– 40% osteopenic
– 7% osteoporotic
– 11% ≥1 fracture after age 45 years
• Undertreated: women meeting criteria for treatment – 15.7% not taking calcium – 18.6% not taking vitamin D – 52.7% not exercising >2 hrs per week – 35.3% not receiving therapy
The Clinical Challenge
• Often asymptomatic
– Until fracture occurs
– Even after some fractures (eg, 2/3 of vertebral fractures are asymptomatic)
• The challenge to clinicians:
– Identify patients at high risk for fracture
– Prevent first fracture
What is Osteoporosis
• Loss in total mineralized bone
• Disruption of normal balance of bone breakdown and build up
• Osteoclasts: bone resorption, stimulated by PTH
• Calcitonin: inhibits osteoclastic bone resorption
• Major mechanisms:
– Slow down of bone build up: osteoporosis seen in
older women and men (men after age 70)
– Accelerated bone breakdown: postmenopausal
• Normal loss .5% per year after peak in 20s
• Up to 5% loss/year during first 5 years after menopause
prevention
estrogen
treatment
calcitonin
pth
denosumab
Osteoporosis Treatment: Calcium and Vitamin D
• Fewer than half adults take recommended amounts
• Higher risk: malabsorption, renal disease, liver disease
• Calcium and vit D supplementation shown to decrease risk of hip fracture in older adults
• 1000 mg/day standard; 1500 mg/day in postmenopausal
women/osteoporosis
• Vitamin D (25 and 1,25): 400 IU day at least;
– Frail older patients with limited sun exposure may need up to 800 IU/day
Osteoporosis Treatment: Bisphosphonates
• Decrease bone resorption
• Stable pyrophosphate analogues
• Amino bisphosphonates (e.g. alendronate, risedronate,
ibandronate, zoledronate)
– Prevent bone resorption by interfering with anchoring of cell-surface proteins
• Multiple studies demonstrate decrease in hip and vertebral fractures
– Those at highest risk of fracture (pre-existing vertebral fractures) had greatest benefit with treatment
• Risedronate – 5 mg po daily
• Alendronate – 10 mg daily
• Alendronate with colecalciferol – 1tablet once weekly, swallow whole with water
• Ibandronate (boniva): 150 mg po once a month or 3mg every 3 months iv
• Zoledronate – 5mg iv once yearly over at least 15 mins
– In patients with low-trauma hip fracture
Important Bisphosphonate Associated Side Effects (MHRA/CHM notices)
• Osteonecrosis of the jaw
– Underlying significant dental disease
– Usually associated with IV formulations
– Case reports associated with oral formulations
• Osteonecrosis of the external auditory canal
– Rare compared to osteonecrosis of the jaw
– Risk factors include steroid use, chemotherapy, ear operation & cottonbud use
– Consider in patients presenting with ear symptoms, including chronic ear
infections, or in patients with suspected cholesteatoma
• Atypical Hip Fractures
– Reported in patients on long term bisphosphonate treatment
– Re-evaluate requirement for bisphosphonates periodically
– Advise patients to report any thigh, hip or groin pain during bisphosphonate treatment
Osteoporosis Treatment: Estrogen Replacement
- Reduction in bone resorption
- Proven benefits in treatment
- Approval now limited because of recent concerns from HERS trial and other data suggesting possible increased total risks with HRT (?increased cardiac risk, increased risk VTE, increased risk cancer)
Osteoporosis Treatment: Selective Estrogen Receptor Modulators
• Raloxifene
– Decrease bone resorption like estrogen
– No increased risk cancer (decrease risk breast cancer)
– Increase in vasomotor symptoms associated with menopause
• PK: Poor bioavailability, but undergoes enterohepatic recycling & tissue accumulation
• ADR: Hot flushes, leg cramps, flu-like symptoms; peripheral oedema; thrombophlebitis, thromboembolism
• Cautions: Avoid in acute porphyrias; manufacturer advises against use during treatment for breast cancer; oestrogen induced tryglyceridemia;
• Contraindications: cholestasis, endometrial cancer, history of venous thromboembolisms, undiagnosed uterine bleeding
Osteoporosis Treatment: PTH
• Teriparatide
• Why PTH when well known association with hyperparathyroidism and osteoporosis???
• INTERMITTENT PTH: overall improvement in bone density
– By enhancing turnover, stimulates osteoblasts & inceases bone formation
– Optimal bone strength relies upon balance between bone breakdown and bone build up;
– studies with increased density but increased fracture risk/fragility with fluoride show that just building up bone is not enough!
Intermittent PTH: Teriparatide
• Studies suggest improved BMD and decreased fractures
• ?risk osteosarcoma with prolonged use (over 2 years): studies with rats
• Subcutaneous injection once daily
– Specialist use in severe osteoporosis
– Option for severe osteoporosis, those on bisphophonates for 7-10 years, those who can not tolerate oral bisphosphonate
• Well tolerated
• Contraindications: Bone metastases; hyperparathyroidism; several other bone diseases
Osteoporosis: Denosumab
- Osteoblasts secrete RANKL • Binds to RANK on preoseteoclasts
- Activation of osteoclasts
- Increased bone resorption
- Overactivity of RANK/RANKL system normally balanced by secretion of OPG from stromal cells/osteocytes
