Osteoporosis PHCL 442 Hadeel Al-Kofide MS.c

Topics to be covered Definition & epidemiology Pathophysiology Classification Risk factors Diagnosis Management: Non-Pharmacological & Pharmacological

Definition Osteoporosis is a systemic skeletal disorder characterized by: low BMD & microarchitectural deterioration of bone tissue, leading to enhanced bone fragility & a consequent increase in fracture risk The condition is usually painless until a fracture occurs It affects 1:2 women & 1:8 men

Pathophysiology Normally there is a balance between osteoblast & osteoclast activity In osteoporosis either one of 2 or both will happen: Space where some bone has been resorbed (due to osteoclast) but not yet replaced during the remodeling process (with osteoblas), this happens by advanced age Remodeling space is increased (due to osteoclast) in postmenopausal osteoporosis

Classification Primary: Type I: Postmenopausal osteoporosis, it occurs in women 3-6 years after menopause (due to increase osteoclast resorption activity) Type II: In both men & women after age 75, female to male ratio 2:1 Secondary: Due to drugs, medical problems & other causes it is equal in men & women

Risk Factors for Osteoporosis Age – especially after 60 yr Female gender Small stature Caucasian, Asian, Latin American Slight body build Estrogen depletion (menopause or amenorrhea) Family history of osteoporosis Lack of exercise

Risk Factors for Osteoporosis Cigarette smoking Underweight Excessive use of alcohol Excessive fiber consumption Excessive caffeine consumption Inadequate lifetime calcium intake Poor vitamin D status

Risk Factors for Osteoporosis Use of certain medications Phenytoin, Phenobarbital Thyroid hormone Corticosteroids Methotrexate Aluminum-containing antacids Heparin

Risk Factors for Osteoporosis Certain diseases or conditions Hyperthyroidism Diabetes Chronic renal failure Chronic diarrhea/malabsorption Hyperparathyroidism Chronic obstructive lung disease

Diagnosis Radiographic measurement of bone density Laboratory biochemical markers Bone resorption markers (eg., collagen cross-linked N- telopeptides) Bone formation markers (eg., bone-specific alkaline phosphatase) Bone biopsy with pathologic assessment: only used under research setting or with difficult to diagnosis cases

Bone Mineral Density Indications: In women with strong risk factors In those with osteoporosis-related fractures (wrist, spine, proximal femur, or humerus after mild or moderate trauma) For monitoring treatment

Bone Mineral Density Techniques:

WHO Diagnostic Categories for BMD Bone Mineral Density WHO Diagnostic Categories for BMD Normal BMD not more than 1 SD below the peak bone mass or young adult mean (T-score above -1) Osteopenia BMD between 1 & 2.5 SD below the young adult mean (T-score between -1 and -2.5) Osteoporosis BMD 2.5 SD or more below the young adult mean (T-score at or below -2.5) Severe osteoporosis (established osteoporosis) BMD 2.5 SD or more below the young adult mean (T-score at or below -2.5) & the presence of one or more fragility fractures

Management

Management & Prevention Keep in mind you have two prevent osteoporosis in 2 settings: Premenopausal women Postmenopausal women

Non-Pharmacological Appropriate levels of exercise should be recommended Smoking & alcohol abuse should be discouraged Physiotherapy & pain relief are important in managing fractures

Pharmacological Calcium & vitamin D Hormone replacement therapy Raloxifene Bisphosphonates Calcitonin Parathyroid hormone peptides Strontium ranelate

Calcium & Vitamin D All patients at risk for osteoporosis (for prevention) & patients with osteoporosis (for treatment) should be on adequate Ca & vitamin D supplements Calcium dose: 1200 mg elemental Ca Vitamin D dose: 400 IU/day if age more than 70 years 600 IU/day

Calcium & Vitamin D Calcium carbonate: highest amount of calcium per tablet, but may cause intestinal gas &/or constipation Calcium citrate: less calcium per tablet, but better absorbed than carbonate; no known side effects Calcium phosphate: most diets already high in phosphorous; better to avoid this form Calcium gluconate: requires many tablets to obtain sufficient calcium

Vitamin D inadequacy worldwide 90 N=1285 81% 80 63% 70 59% 59% 60 51% 52% 50 Prevalence (%) 40 30 20 10 All Australia Latin America Asia Middle East Europe Regions Vitamin D inadequacy defined as serum 25(OH)D <30 ng/ml 1285 community-dwelling women with osteoporosis from 18 countries to evaluate serum 25(OH)D distribution. Lim S-K et al, 2005

Hormone Replacement Therapy In the past was considered as 1st line treatment It is an appropriate option in younger postmenopausal women at high risk of fracture, particularly those with vasomotor symptoms Generally a second line treatment option because risk-benefit balance is unfavorable in older women

Raloxifene Mechanism of action: Selective estrogen receptor modulator (SERM) Mixed estrogen receptor agonist/antagonist Acts as an agonist in the bone, reducing turnover by inhibiting osteoclast recruitment & activity Acts as an antagonist in the breast & uterus

Raloxifene Role in Therapy: Second line agent for the treatment of postmenopausal osteoporosis Advantage: Favorable changes in lipid profile Decreases the risk for CV events and breast cancer

Raloxifene Dose: 60 mg/day Adverse effects: Hot flushes, & leg cramps Increase in the relative risk of venous thromboembolism

Bisphosphonates Mechanism of action: Deposited in bone at the site of mineralization; apparently causing the death of osteoclasts which results in decreased bone resorption They have very long half life 1-2 years Less than 10% absorbed

Bisphosphonates Alendronate & risedronate have been shown to reduce vertebral & non-vertebral fractures, including hip fractures They are considered first line options for treating postmenopausal osteoporosis

Bisphosphonates Dose: Alendronate Oral 70 mg 1/w, or 5 mg or 10 mg OD Most common regimen used Alendronate Oral 70 mg 1/w, or 5 mg or 10 mg OD Etidronate Oral 400 mg OD for 2 w every 3 mo Ibandronate Oral IV 150 mg 1/mo 3 mg 1/3 mo Risedronate Oral 35 mg 1/w, or 5 mg OD The only one with IV form

Bisphosphonates Adverse effects: Acid regurgitation, dyspepsia, abdominal distention, gastritis, nausea & dysphagia Esophageal ulceration & strictures Musculoskeletal pain, headache & rash

Bisphosphonates Contraindications: Not given if CrCl less than 35 ml/min If hypocalcaemia exists it should be corrected before starting therapy Caution in patients with upper GI problem (esophagus)

Bisphosphonates Precautions: Oral bisphosphonates must be taken fasting, with a full glass of water The individual must be upright & stay sitting or standing without taking food or drink for the next 30-60 minutes This is done to prevent esophageal ulceration

Calcitonin Mechanism of action: Inhibits osteoclast formation & attachment Analgesic effect? Dose: 200 IU/day by nasal spray 100 IU/day IM

Calcitonin Adverse effects: Rhinitis & epistaxis (from nasal form) Arthralgia, headache & back pain Flushing, nausea, vomiting & local irritation (IM)

Calcitonin Precautions: Nasal form should be refrigerated until it is open for use After opening it is only stable for 30 days at room temperature Role in Therapy: Not used as first line treatment Mainly used in patients with back pain & acute vertebral fracture

Parathyroid Hormone Mechanism of action: Produced normally by PT gland, helps control calcium exchange between the bones & the blood stream Low dose synthetic human PTH causes anabolic response, increasing the number and action of osteoblasts

Parathyroid Hormone Side effects: Asymptomatic mild hypercalcemia Increase risk of osteosarcoma Dose: Teriparatide (rPTH): 20 mcg/d SC for upto 24 months

Parathyroid Hormone Contraindications: Children, adolescents & patients with paget’s disease because of increased risk of osteosarcoma Hypercalcemia Role in Therapy: Postmenopausal women & men with osteoporosis who are at high risk for fracture, such as individuals with prior osteoporotic fractures (mainly as second line agent)

Strontium Ranelate Mechanism of action: It has a dual mode of action, both increasing bone formation & decreasing bone resorption It has been shown to enhance osteoblastic cell replication & increase collagen synthesis while it decreases bone-resorbing activity of mature osteoclasts

Strontium Ranelate Adverse effects: Diarrhoea, nausea, headache, dermatitis & eczema Rare: DVT Contraindications: Not recommended in patients with a CrCl below 30 ml/min Dose: 2 g sachet once daily 2 hours after food, must taken as suspension in water & drink immediately

Strontium Ranelate Role in Therapy: Postmenopausal women & men with osteoporosis who are at high risk for fracture, such as individuals with prior osteoporotic fractures (mainly as second line agent)

Which Dug for Which Patient??

Which drug for which patient? LOOK AT THE ATTACHED GUIDELINE Agent Rx PM OP to reduce risk of Steroid induced OP OP in men Vertebral fractures Hip fractures Alendronate a Risedronate r Etidronate Raloxifene Strontium ranelate Teriparatide LOOK AT THE ATTACHED GUIDELINE

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