Dr. K K Sawlani Department of Medicine KGMU, Lucknow 30.07.14 OSTEOPOROSIS Dr. K K Sawlani Department of Medicine KGMU, Lucknow 30.07.14

OSTEOPOROSIS A disease characterized by low bone mass (reduced bone density) and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. Most common bone disease Affects million of people worldwide

Development of osteoporotic bone This slide shows how the imbalance in turnover leads to a deterioration in bone micro architecture. A comparison of normal (left) and osteoporotic (right) trabecular structures is shown in these two scanning electron micrographs. In osteoporosis the trabecular continuity is disrupted by trabecular perforation, and thin rods replace the normal plate-like trabeculae. Rizzoli R, ed. In: Atlas of Postmenopausal Osteoporosis (First Edition). Science Press, 2004. Rizzoli R ed In Atlas of Postmenopausal Osteoporosis (1st edition) Science Press, 2004

OSTEOPOROSIS Fractures related to osteoporosis affect around 30 % of women and 12 % of men in developed countries. Major public health problem Osteoporotic fractures can affect any bone The most common sites are Spine (vertebral fracture) Forearm (Colles fracture) Hip

Vertebral Fracture

Hip Fracture

Wrist Fracture (Colles fracture)

OSTEOPOROSIS Hip fractures are the most serious Immediate mortality is about 12 % Continued increase in mortality of about 20 % when compared with age matched controls. Account for the majority of health care cost associated with osteoporosis.

OSTEOPOROSIS The prevalence increases with age reflecting that bone density decreases with age especially in women Accompanied by increased risk of fractures Fall in bone density Increased risk of falling

Pathopysiology Occurs because of defect in attaining peak bone mass and/or because of accelerated bone loss. In normal individuals bone mass increases to reach a peak between the age of 20 and 40 years but falls thereafter.

Age-related changes in bone mass Attainment of peak bone mass Consolidation Age-related bone loss Menopause Bone mass Men Fracture threshold This figure illustrates the changes in bone mass throughout life and highlighted the two main causes of low bone mass mentioned in the definition The two main causes of osteoporosis are the menopause and ageing Bone mass in both men and women increases until a peak is attained at around age 30 In women, there is a phase of accelerated bone loss following the menopause. Rates of bone loss in postmenopausal women can be as great as 6% per year In women, oestrogen deficiency is the major determinant of bone loss after the menopause Compston JE. Clin Endocrinol 1990; 33: 653–682. Women 0 10 20 30 40 50 60 Age (years) Compston JE. Clin Endocrinol 1990; 33: 653–682.

Pathopysiology Peak bone mass and bone loss are regulated by both genetic and environmental factors. Polymorphisms have been identified in several genes that contribute to pathogenesis. Many of these are in the RANK and Wnt signaling pathways which play critical role in regulating bone turnover.

Major risk factors Non modifiable Modifiable Age Race Female gender Early menopause Slender build Positive family history Modifiable Low calcium intake Low vitamin D intake Estrogen deficiency Sedentary lifestyle Cigarette smoking Alcohol excess (> 2 drinks/day) Caffeine excess (> 2 servings / day)

Post menopausal osteoporosis Most common cause Accelerated phase of bone loss after menopause due to estrogen deficiency. Causes uncoupling of bone resorption and bone formation Amount of bone reduced by osteoclasts exceeds the rate of new bone formation by osteoblasts Early menopause ( before the age of 45 years ) is important risk factor

Male osteoporosis Less common in men Secondary cause can be identified in 50% of cases The most common causes are Hypogonadism Corticosteroid use Alcoholism Testosterone deficiency results in increase in bone turnover and uncoupling of bone resorption and bone formation. Genetic factors important in the cases with no identifiable cause.

Corticosteroid induced osteoporosis Risk increases with prednisolone use 5-7.5 mg daily for more than 3 months. Reduced bone formation due to Inhibitory effect on osteoblast function Osteoblast and osteocyte apoptosis Also reduce serum calcium Inhibit intestinal calcium absorption Renal leak of calcium Secondary hyperparathyroidism with increased bone resorption Hypogonadism may also occur with high doses.

Secondary causes of osteoporosis Endocrine disease Hypogonadism Hyperthyroidism Hyperparathyroidism Cushing,s disease Inflammatory disease Inflammotory bowel disease Ankylosing spondylitis RA Gastrointestinal Malabsorption Chronic liver disease Lung disease COPD Cystic fibrosis Drugs Miscellaneous

Secondary causes of osteoporosis Drugs Corticosteroids Thyroxine over-replacement Anticonvulsants GnRH agonists Thiazolidinediones- pioglitazone Alcohol intake Heparin

Secondary causes of osteoporosis Miscellaneous Myeloma HIV infection Systemic masotcytosis Renal failure BMI < 18 Anorexia nervosa Heavy smokers

Clinical Features Asymptomatic until a fracture occurs Incidental osteopenia on X-ray performed for other reasons. Spine fracture Acute back pain ( 1/3 cases) gradual loss of height , kyphosis and chronic pain Peripheral fracture Local pain, tenderness and deformity Often with an episode of minimal trauma

Investigations Measurement of bone mineral density (BMD) by dual energy X-ray absorptiometry (DEXA). BMD can also be measured by computed tomography (CT) and ultrasound. Central (spine and hip) are best predictors of fracture risk. Peripheral( radius, heel and hands) are less expensive and widely available.

Investigations T-Score: The number of SDs the patient value is below or above the mean value for young normal subjects. Good predictor of fracture risk Z-score: The number of SDs the patient value is below or above the mean value for age matched normal controls. Whether or not the BMD is appropriate for age. Absolute BMD: expressed in g/cm2 Used to calculate changes in BMD during follow up.

Diagnosis Any patient who sustains a fragility fracture. On the basis of BMD T-score ≥ -1 = normal Between -1 and -2.5 = Osteopenia ≤ -2.5 = Osteoporisis

Changes in BMD with age (T-score values) Souce- Davidsons textbook of Medicine 22nd edition

Diagnosis History: early menopause, smoking, excessive alcohol intake, corticosteroid therapy Examination: Signs of endocrine disease, neoplasia, and inflammatory diseases A history of fall should be taken Unstable gait and unsteadiness

Diagnosis - Investigations Renal function Alkaline phosphatase Serum calcium, Vit D 25 (OH) Parathyroid (PTH) Thyroid function tests Immunoglobulins and ESR Celiac disease antibody testing Testosterone (men) 24 hour urine calcium, sodium and creatinine.

Management The aim of treatment is to reduce the risk of fractures Non-pharmacological Pharmacological

Non Pharmacological Treatment Smoking cessation Moderation of alcohol intake Adequate dietary calcium intake Exercise Vitamin D Fall prevention Good nutrition

Pharmacological Treatment Several drugs have been shown to reduce the risk of osteoporotic fractures. Effect on vertebral and non-vertebral fracture is variable. Considered with BMD T-score < 2.5 BMD T-score < 1.5 in corticosteroid induced Vertebral Fractures ,unless resulted from significant trauma

DXA Results T Score Classification Action > minus 1.0 Normal Lifestyle measures. < minus 1.0 > minus 2.5 Osteopenia Consider specific treatment where there is ongoing risk, e.g. steroids, and in those who have had a minimal trauma fracture. < minus 2.5 Osteoporosis Prevent falls. Treatment may be indicated. Look mainly at T-score of total hip and mean of lumber spine. Other area of the hip and individual vertebrae may help especially where results are borderline. Low BMD is an important predictor for fracture. A borderline result may be significant for someone with other risk factors or who is likely to fall, but is of less significance in an otherwise fit person in their fifties. All males with osteoporosis, except the very elderly or frail, should be investigated as 50% will have an underlying cause which may need treatment.

CURRENT THERAPIES Anti-resorptive Anabolic Calcium, Vitamin D, lifestyle modification Adjunct to other treatments 1000-1200 mg/day of calcium 800-1200 U/day of vitamin D

Treatment Options in Osteoporosis Antiresorptive drugs Bisphosphonates Etidronate Alendronate Risedronate Ibandronate Zoledronate Denosumab (monoclonal antibody against RANK-L) SERMs Raloxifene Calcitonin HRT (estrogen) Anabolic drugs Teriparatide(PTH 1-34) Dual Action Bone Agents (DABAs) Strontium ranelate

Bisphosphonates Inhibit bone resorption by binding to hydroxyapatite crystals on bone surface Osteoclasts reabsorb bone-drug released within cell-inhibt key signaling pathways. Increase in Spine BMD of 5-8% and Hip BMD 2-4%. Should be taken on an empty stomach with plain water. No food should be eaten 30-45 minutes after administration

Adverse effects of biphosphonates Common Upper GI intolerance (oral) Acute phase response(intravenous) Less Common Atrial fibrillation (IV zoledronic acid) Renal impairment (IV zoledronic acid) Atypical subtrochanteric fractures Rare Uveitis Osteonecrosis of the jaw

INDICATIONS FOR ANABOLISM Pre-existing osteoporotic fractures Very low BMD Very high fracture risk Unsatisfactory response to antiresorptive therapy Intolerant to anti-resorptive therapy

TERIPARATIDE Daily SC injection 20 mcg Maximum 18-24 months May be followed by anti-resorptive therapy PTH is expensive and is reserved for severe osteoporosis, who fail to response to other therapies. No advantage of combined anabolic and anti-resorptive therapy

Selective estrogen receptor modulator (SERM) Raloxifene 60 mg daily orally Partial agonist of estrogen receptor in bone & liver Antagonist in breast & endometrium SE: muscle cramps, hot flushes, increased risk of VTE. Bazedoxifene is a related SREM

HRT Cyclical HRT wirh estrogen and progestogen Prevents post menopausal bone loss and reduces risk of fractures in post menopausal women Primarily indicated for prevention of osteoporosis in women with early menopause Women in early fifties with troublesome menopausal symptoms. Increased risk of breast cancer and cardiovascular disease

Duration of therapy Oral biphosphonates long term (5 YRS) HRT, raloxifene continuously Denosumab continuously Strontium ranelate not established Teriparatide 2 yrs fb antiresorptive Tt

Response to drug treatment Repeat BMD measurements after 2-3 yrs. Spine BMD best for monitoring Biochemical markers ( N-telopeptide) respond more quickly; can be used to assess adherence.

Surgery Reduce and stabilize osteoporotic fractures Painful vertebral compression fractures Vertebroplasty ( Injection of MMA) Kyphoplasty ( balloon inflation – MMA)

Response to Drugs Fracture risk reduction 30-40% # risk reduction with antiresorptives 60% # risk reduction with teriparatide BMD 2-3% BMD increase with anti-resorptives 4-6% BMD increase with teriparatide

Osteoporosis MCQ 1. Most common cause of osteoporosis Hypogonadism Malabsorption Post menopausal Hyperparathyroidism

Osteoporosis MCQ 2. Most common bone disease is a. Osteomalacia b. Osteoporosis c. Secondaries bone d. Osteopetrosis

Osteoporosis MCQ 3. Which of the following drug is most common cause of drug induced osteoporosis a. Thyroxine over-relacement b. Corticosteroids c. Pioglitazone d. Anticonvulsants

Osteoporosis MCQ 4. Osteopenia is defined as T- Score of a. < -1 b. < -1 to < -2.5 c. < -2.5 d. None of the above

Osteoporosis MCQ 5. Risk of fracture in osteoporosis is best predicted by a. T-score b. Z-score c. Absolute BMD d. Serum calcium levels

Osteoporosis MCQ 6. Risk factors for osteoporosis are all except a. BMI > 30 b. Smoking c. Low calcium intake d. Immobilization

Osteoporosis MCQ 7. Following are all anti-resroptive drugs except a. Biphophonates b. Raloxifene c. Estrogen d. Teriparatide (PTH analogue)

Osteoporosis MCQ 8. Which of the following is drug of choice for severe osteoporosis (T-score 0f < -3.5 ) Teriparatide Biphosphonates Calcitonin Strontium

Osteoporosis MCQ 9. Osteonecrosis of the jaw is seen with the use of Calcitonin PTH analogues Biphosphonates Raloxifene

Osteoporosis MCQ 10. The response to drug therapy is assessed by repeating BMD measurements after 3 months 6months 1 year 2 year