Dr/Wael H. Mansy, M.D. Assistant Professor King Saud University Osteoporosis Dr/Wael H. Mansy, M.D. Assistant Professor King Saud University

Osteoporosis Definition: a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. NIH Consensus Development Conference, March 2000 Bone Strength: Bone Density: Grams of mineral per area or volume (70% bone strength) Bone Quality: Architecture Turnover Mineralization

3 cell types work together to remodel bone

Bone remodeling occurs throughout life

Osteoporosis The most common metabolic bone disorder Systemic skeletal disease characterized by: Low bone mass Microarchitectural deterioration of bone tissue Increased bone fragility and susceptibility to fracture

3-D Micro CT: Healthy vs Osteoporotic Bone 84 year old Female (w/ vertebral fracture) 52 year old Female Borah et al Anat. Rec.(2001)

Risk Factors Certain people are more likely to develop this disease than others. Female Thin and/or small frame Advanced age Family history of osteoporosis Post menopause Certain people are more likely to develop this disease than others. Women have less bone tissue and lose bone more rapidly than men. Thin and/or small frame – these are usually women who weigh less than 127#. Advanced age – bones become less dense and weaker as you age. Family history of osteoporosis and post menopause. 6

Risk Factors Anorexia nervosa or bulimia Diet low in calcium Use of certain medications Low testosterone levels in men An inactive lifestyle Cigarette smoking Excessive use of alcohol Being Asian or Caucasian Anorexia nervosa or bulimia. A diet low in calcium. The use of certain medication such as glucocorticoids, which are used to treat rheumatoid arthritis, endocrine disorders, seizures, and GI disorder my cause side effects that damage bone and can lead to osteoporosis. Low testosterone levels in men. An inactive lifestyle, cigarette smoking, excessive use of alcohol, and being Asian or Caucasian. 7

Pathophysiology of Osteoporosis Bone remodeling occurs throughout an individual’s lifetime In normal adults, the activity of osteoclasts (bone resorption) is balanced by that of osteoblasts (bone formation) With the onset of menopause (mid-forties or fifties), diminishing estrogen levels lead to excessive bone resorption that is not fully compensated by an increase in bone formation

Contributors to Bone Strength Bone size, BMD, and mineralization play a role Bone turnover rates affect the quality of bone Preservation of bone architecture plays a major role in determining bone strength

Bone Mass vs. Age

What causes bone loss in aging? Later in life (age 75+), men and women equally affected by physiologic changes: Slower bone formation Decreased intestinal absorption of calcium Decreased renal retention of calcium (Ca lost in urine) Decreased skin production of vitamin D Decreased renal activation of vitamin D Decline in physical activity Changes in diet 12

What causes bone loss in menopause? Decline in estrogen Rate of bone turnover increases Remodeling becomes imbalanced (decoupled) increases number of osteoclasts disrupts bone cell apoptosis

What causes bone loss in menopause? Estrogen’s effect on bone turnover Healthy balance between bone formation and resorption Before menopause Estrogen After Menopause Osteoblast and osteocyte apoptosis Bone loss Estrogen Too many osteoclasts

Osteoporosis This increases our understanding of the time-course for vertebral fractures. While the bone loss that leads to osteoporosis may be gradual, once patients start to experience vertebral fractures the progression of subsequent fractures can be relatively rapid (within 1 year), resulting in a progressive cascade of fractures (as depicted in slide). Thus, while we may have believed patients progressed through stages of osteoporosis over a number of years (decades?), it is now clear successive fractures can occur in shorter periods of time. In fact, 6% of placebo patients in the VERT-MN study had 2 or more new vertebral fractures in first year. This highlights the need to select a therapy with a demonstrated ability to reduce the risk of fracture in the time interval when the increased risk of fracture is apparent (1 year). This is equally true for PMO and for GIO. Background: while consequences of hip fractures are easily recognized, consequences of vertebral fractures are not well understood. Vertebral fractures result in: Kyphosis (as depicted in slide). Loss of mobility and independence. Loss of height leading to compression of thoracic cavity containing internal organs. Compression of organs leading to pain, indigestion, reflux, incontinence, and difficulty breathing. The effect of these consequences has not been studied, and costs of vertebral fractures are difficult to assess since osteoporosis is not usually linked to these conditions.

Detection Bone Density Tests: Can detect osteoporosis before a fracture occurs. Predicts your chances of fracturing in the future. Determines your rate of bone loss and monitors the effects of treatment. Think of your bones as a savings account. There is only as much bone mass in your account as you deposit. The critical years for building bone mass are from prior to adolescence to about age 30. To detect osteoporosis a bone density test is effective. They can detect osteoporosis before a fracture occurs, predicts your chances of fracturing in the future. Determines your rate of bone loss and monitors the effects of treatment. The test measures bone density in your spine, hip and wrist. 10

Bone Mass Density The National Osteoporosis Foundation Recommends you have a BDT if: You use medications that cause osteoporosis You have type I diabetes, liver disease, kidney disease or a family history You experience early menopause You’re postmenopausal over 50 and have at least one risk factor. You’re postmenopausal over 65 and never had a test. 11

National Osteoporosis Foundation Guidelines for Bone Density Testing All women aged 65 or older All postmenopausal women under age 65 who have one or more additional risk factors Postmenopausal women who present with fractures

T Score The t score osteoporosis number is a number that indicates whether or not bone loss has occurred. The STANDARD MEASUREMENT is the bone density measurement of a 30-year old premenopausal woman, for that is the age when our bones are the strongest. The t score osteoporosis STANDARD DEVIATION is the number ABOVE or BELOW when peak bone mass occurs (compared to age 30). In other words, a NEGATIVE t score osteoporosis number means there is BONE LOSS.

T Score *In general, for each standard deviation of a "-1" score, that indicates a bone loss of about 10-15%. This further means that with each 10-15% of bone loss, the risk of fracture increases 150-300%! Your doctor will obtain your t score by performing a bone mineral density test (BMD).

WHO Criteria for Diagnosis Classification Normal Osteopenia (low bone mass) Osteoporosis Severe or established osteoporosis T score* < –1 –1 to –2.5 –2.5 or greater –2.5 or greater + fractures

One-Minute Treatment Decision Therapy Decision Treat all patients with an existing fracture High Risk-Treat Moderate Risk - Treat if other risk factors Low Risk- Check again in 1-2 years T-Score * Below -2.0 -1.5 to -2.0 Above -1.5 One can rapidly assess within one minute a patient’s risk and need for treatment by reviewing T-scores. A T-score above -1.5 indicates the patient is at low risk and should be checked again in 1-2 years. A T-score between -1.5 to -2.0 indicates the patient is at moderate risk and should be treated if he/she has other risk factors. A T-score below -2.0 is an indication of high risk and the patient should be treated. JP’s diagnosis of osteoporosis based on the WHO criteria along with his other risk factors are an indication for pharmacologic treatment. 11

Diseases Associated with Decreased Bone Mass Hypogonadism Hypercortisolemia Hyperthyroidism Hyperparathyroidism Anorexia Renal Failure Chronic Liver Disease Malabsorption Inflam. Bowel Dz Pregnancy Type 1 Diabetes HIV

Medications associated with Decreased Bone Mass Corticosteroids Heparin (high dose) Aluminum Anticonvulsants phenobarbital, phenytoin Medroxyprogesterone acetate Cyclosporine Aromatase inhibitors Antiretroviral therapy Retinoids

Glucocorticoid-Induced Bone Loss Glucocorticoid tx at 7.5 mg/day for  3 months often results in rapid loss of trabecular bone Up to 50% of patients taking >7.5 mg/d of prednisone or equivalent will fracture

Management of Osteoporosis: Goals of Therapy Prevent first fragility fracture or future fractures if one has already occurred Stabilize/increase bone mass Relieve symptoms of fractures and/or skeletal deformities Improve mobility and functional status Initiate lifestyle changes to enhance prevention of fractures

Public Health Recommendations 1-1.5 g of daily calcium 400-800 of vitamin D daily Weight-bearing exercise Discourage smoking

Drug therapy for osteoporosis Prevention Treatment HRT Yes No Raloxifene Yes Yes Calcitonin No Yes*? Alendronate Yes Yes Risedronate Yes Yes PTH No Yes

Bisphosphonates for Osteoporosis Benefit: reduction of fracture risk (alendronate, risedronate, ibandronate) Problem: poor adherence to therapy Cause: multifactorial, including issues of convenience (complexity of dosing) and tolerability (GI irritation in clinical experience) Possible solutions: larger doses given less frequently, parenteral administration

HRT When prescribing solely for the prevention of postmenopausal osteoporosis HRT should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered Patients should be treated with the lowest effective dose. Dosage may be adjusted depending on individual clinical and bone mineral density responses

Combination Therapy Bisphosphonate + HRT Bisphosphonate + Raloxifene Combination increases BMD > either agent alone Bisphosphonate + Raloxifene

Recently Approved Boniva – 150 mg monthly 2.5 mg daily approved May, 2003 Vertebral fracture efficacy shown with daily Based on 1 year BMD data, 150 mg monthly is superior to the 2.5 mg daily Fosamax PLUS D – 70 mg/2800 IU weekly

Summary All postmenopausal women should be evaluated for osteoporosis risk factors Bone density testing is the best predictor of fracture risk Treatment should be initiated to prevent osteoporotic fractures and their subsequent morbidity