Osteoporosis

OSTEOPOROSIS

1. OSTEOPOROSIS Presented by Dr Rahul Roy Dr Ram Mohan Maj Guarav Datta Moderator: Col J Muthukrishnan , SM Professor, (Medicine & Endocrinologist)

2. OUTLINE Definition Epidemiology Pathophysiology Causes Clinical features Diagnosis Treatment

3. OSTEOPOROSIS Osteoporosis : S keletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Normal Bone Osteoporotic Bone

4. OSTEOPOROSIS WHO definition: Bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same sex Also referred to as a T-score of –2.5

5. T-score A comparison of a patient's BMD to that of a healthy young adult (20 years) of the same sex and ethnicity. Normal T-score of -1.0 or higher Z-score A comparison of a patient's BMD to that of a healthy adult of the same age, sex and ethnicity. Used in premenopausal women, men under the age of 50 and in children .

6. WHO, Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis . T - Score WHO Osteoporosis Guidelines

7. EPIDEMIOLOGY O steoporosis comes second to cardiovascular disease as a global health problem Worldwide Lifetime risk for osteoporotic fractures Females - 30-50% Males - 15-30%. 1.6 million hip fractures each year worldwide, the incidence to increase to 6.3 million by 2050 Hip fractures 20 % mortality at one year International Osteoporosis Foundation (IOF)

8. EPIDEMIOLOGY India - One of the largest affected countries in the world . 1 out of 3 females 1 out of 8 males High incidence of Hip # among men (men : women =1) lower age of peak incidence (50 – 60 years) compared to Western countries ( 70 – 80 years ). International Osteoporosis Foundation

9. Background The most common fractures in the elderly osteoporotic patient include: Hip Fractures Femoral neck fractures Intertrochanteric fractures Subtrochanteric fractures Ankle fractures Proximal humerus fracture Distal radius fractures Vertebral compression fractures Image courtesy of International Osteoporosis Foundation

10. B one density is only one risk factor for fracture . Instead of treating the T score identified by DXA scans , aim is to reduce an individual’s risk of future fracture. This change in emphasis has been enabled by the development of fracture risk assessment tools (FRAX). The FRAX ® tool has been developed by WHO to evaluate fracture risk of patients. ASSESSMENT OF FRACTURE RISK

11. The FRAX ® tool

12. AGE T-Score = -1.0 T-Score = -2.5 50 6 % 11 % 60 8 % 16 % 70 12 % 23 % 80 13 % 26 % RISK OF FRACTURES OVER 10 YEARS IN WOMEN ABSOLUTE FRACTURE RISK IN 10 YEARS: low: <10% moderate: 10-20% high: >20%

13. Peak bone mass Skeletal mass increases from approximately 70 to 95 g at birth to 2400 to 3300 g in young individual 25% of PBM is acquired during the 2-year period across the adolescent growth spurt Factors affecting PBM Hereditary factors Ethnicity Nutritional Physical activity

14. Pathophysiology There are three major pathogenetic reasons for low bone mass. Failure to achieve optimal peak bone mass. Increased bone resorption in osteoporotic patients. Inadequate bone formation.

15. Bone Mass Age (years) Attainment of Peak Bone Mass Consolidation Age-related Bone Loss Men Women Menopause 0 10 20 30 40 50 60 Fracture Threshold Compston JE. Clin Endocrinol 1990; 33:653–682. Pathophysiology

16. Pathophysiology In childhood bone formation exceeds resorption -continued skeletal growth. Normal bone loss- 0.7 per cent per year. Menopause : 2-5 per cent per year, which may continue for up to 10 years Level of peak bone mass achieved at puberty is a major determinant

17. OSTEOPOROSIS - TYPES Primary (senile ) osteoporosis Post menopausal osteoporosis Secondary osteoporosis

18. SECONDARY CAUSES OF OSTEOPOROSIS Endocrine diseases Hypogonadism Hypothyroidism Hypoparathyroidism Cushing’s syndrome Inflammatory diseases Inflammatory bowel diseases Rheumatoid Arthritis Ankylosing spondylitis

19. SECONDARY CAUSES OF OSTEOPOROSIS – DRUGS Aluminum (in antacids) Anticoagulants (heparin) Anticonvulsants Aromatase inhibitors Barbiturates Chemotherapeutic drugs Cyclosporine A & tacrolimus Depomedroxyprogesterone Glucocorticoids GNRH antagonists and agonists Lithium Methotrexate Proton pump inhibitors SSRI`s Tamoxifen ( premenopausal use ) Thiazolidinediones Thyroid hormones ( in excess ) Parenteral nutrition

20. Secondary causes of osteoporosis GI diseases Malabsorption Chronic liver disease Nutritional Calcium Vit D Magnesium Miscellaneous causes Myeloma Immobilisation Homocysteinuria ESRD Gaucher’s disease Poor diet / low body weight

21. Risk factors Osteoporotic fractures Non modifiable h/o fracture as an adult h/o fracture in 1 o relative Females Age Caucasians Dementia Potentially modifiable Smoking Low body weight(<58 kg) Estrogen deficiency Low Ca intake Alcoholism Impaired eye sight Falls Physical inactivity Poor health

22. Clinical features & Complications Pain in back Difficulty in bearing weight Kyphosis Loss of height Clinically diagnosed fracture Protuberant abdomen Depression Loss of productivity Loss of independence Death

23. CLINICAL DIAGNOSIS AND TREATMENT

24. Diagnosis Radiographic measurement of bone density Lab biomarkers Bone biopsy with pathological assessment

25. Bone density Single photon absorptiometry Dual photon absorptiometry Dual X ray absorptiometry Qauntitative CT Quantitative USG

26. Indications for Bone Density test 1.All postmenopausal women <65 yr who have one or more additional risk factors for osteoporosis, besides menopause. 2.All women >65 yr regardless of additional risk factors. 3.Documenting reduced bone density in a patient with a vertebral abnormality or osteopenia on a radiograph. 4.Estrogen-deficient women at risk for low bone density 5. Estrogen replacement therapy for prolonged periods to monitor efficacy of a therapeutic intervention. 6.Diagnosing low bone mass in glucocorticoid-treated individuals(Prednisolone at 7.5mg daily for 6m.)

27. 7. patients with asymptomatic primary or secondary hyperparathyroidism 8.Previous low trauma fragility # 9.Premature menopause <45y. 10.Prolonged secondary amenorrhoea (>1.y.) 11.Primary or secondary hypogonadism 13.A meternal h/o hip #

28. Markers of bone formation Osteocalcin (OC) Bone specific alkaline phosphatase (bone ALP) Procollagen type 1 N-terminal propeptide (P1NP) Procollagen type 1 C-terminal propeptide (P1CP)

29. Bone resorption markers Pyridinoline (PYR) Deoxy pyridinoline (DPD) N- telopeptides of type 1 collagen (NTX) C- telopeptides of type 1 collagen (CTX) Pyridinolines are measured in urine Telopeptides can be measured in both serum and urine

30. WHOM TO TREAT Women with a previous hip or vertebral fracture, fragility fracture T score of −2.5 or less at the hip, lumbar spine, or femoral neck, T score between −1.0 and −2.5 and a 10-yr probability of hip fracture >3% or of major osteoporotic fracture >20% In presence of risk factors, If FRAX score exceeds age-specific criteria National Osteoporosis Guideline Group

31. Black DM, Rosen CJ. N Eng l J Med 2016 ;374:254-262 . Guidelines – Professional Organizations for Treatment of Osteoporosis.

32. Non Pharmacological measures Regular weight-bearing & muscle strengthening exercise, F all-prevention strategies, A void smoking and excess alcohol intake Diet rich in calcium & Vit D supplementation

33. Pharmacological measures Ca-rich diet,↑ Ca Supplements Vit -D (monitor serum+urine Ca). Estrogens/Androgens Biphosphonates ( inhibit osteoclast mediated bone resorption ) Calcitonin PTH- Teriparatide /( Forteo )=intermittent low doses

34. Drugs Approved by the FDA for Treatment and Prevention of Osteoporosis . Black DM, Rosen CJ. N Engl J Med 2016;374:254-262

35. Osteoporosis Prevention and Treatment Age Hormonal Replacement Bisphosphonates Strontium SERM 20 40 60 80 Vitamin D PTH Life Style Treatment choice

36. Ca supplements Calcium preparation Ca Citrate Ca Lactate Ca Gluconoate Ca Carbonate Ca Carbonate + 5 ug Vit D2 (Oscal 250) Ca Carbonate (Turns 500) Elemental Calcium 60 mg/300 mg 80 mg/600 mg 40 mg/500 mg 400 mg/g 250 mg/tablet 500 mg/tablet

37. Calcium and Vitamin D Inadequate calcium intake in adults older than 70 years of age is associated with increased bone loss and increased risk of fracture Observational studies suggest that bone loss and fracture risk increase when calcium intake is below 700 to 800 mg per day. Combining Vitamin D and calcium supplementation has been shown to increase bone mineral density and reduce the risk of fracture. Age Calcium/day (mg) 0-6 months 210 6 months-1 yr 270 1-3 500 4-8 800 9-18 1300 19-50 1000 51-70 1200 Vitamin-D requirement

38. Selective Estrogen Receptor Modulator (SERM) ( Evista ®) Raloxifene , RALOXIFENE Reduces vertebral ( not non-vertebral ) fracture risk Reduces development of new breast Ca. No increased risk of CVD (reduces CV events!) Increased risk of thromboembolism May worsen flushes Well tolerated, easy dosing

39. BISPHOSPHONATES Etidronate , risedronate ( Actonel ® ), alendronate ( Fosamax ® ), ibandronate ( Boniva ®), zoledronate Interfere with action of osteoclasts &decrease bone resorption , Alendronate and risedronate firstline option in postmenopausal osteoporosis IV Biphosphonates – Zolendrenate , Ibandronate Strict dosing instructions Contraindicated in patients with GFR<35 ml/min, , vitamin D depletion, osteomalacia or H ypocalcemia

40. Clinical use of strontium ranelate ( Protelos ) In women with postmenopausal osteoporosis: A lternative to bisphosphonates, particularly in the elderly if potential for upper gastrointestinal complications Intolerance or inadequate response with other osteoporosis therapies Beware of rash (DRESS) and VTE (RR 1.4)

41. ( Miacalcin ®) Calcitonin For paget’s disease, hypercalcemia, osteoporosis in women > 5 years post menopause Nasal Spray-200 IU/L Mechanism-small increments in bone mass and small reduction in new vertebral fractures Not useful in non vertebral fractures May have an analgesic effect on bone pain

42. PTH- 1-34h Teriparatide PTH- although causes bone loss in chronic elevated condition , has an anabolic effect on bone. Maintainence of trabecular bone mass 20 ug PTH sc daily- 65% ↓ in vertebral fractures and 45%↓ in nonvertebral fractures Single daily dose for maximum of 2 years For treatment naïve patients- montherapy f/b bisphosphonate S/E- muscle pain, headache, dizziness and nausea

43. DENOSUMAB Monoclonal Ab to RANKL which drives osteoclasts Subcut every 6/12! 60mg Dramatic and quick effect Fracture reduction similar to Zoledronate Cost similar to risedronate (in 2010) NICE appraised

44. Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and Survival RANKL RANK OPG Denosumab Bone Formation Bone Resorption Inhibited Osteoclast Formation, Function, and Survival Inhibited CFU-GM Prefusion Osteoclast Osteoblasts Hormones Growth Factors Cytokines Adapted from: Boyle WJ, et al. Nature . 2003;423:337-342.

45. RECENT ADVANCES - DRUGS

46. Odanacatib — cathepsin K inhibitors . In phase 1 studies, odanacatib at an oral dose of 50 - 100 mg once a week reduced serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) by 62%. Daily administration of odanacatib (10 mg) reduced serum CTX by 81%. 64 After 24 months, odanacatib (50 g)increased BMD of the lumbar spine and total hip by 5.7% and 4.1% compared to placebo, Adverse reactions :scleroderma-like cutaneous lesions were not observed . Currently, a phase 3 study is being conducted with over 16,000 postmenopausal women to assess the antifracture efficacy of odanacatib . Odanacatib

47. Saracatinib : Src kinase inhibitor Dose-dependent decrease in serum C-terminal telopeptide of type I collagen levels and urinary N-terminal telopeptide of type I collagen. Bone formation markers were similar to placebo . Adverse reactions: papular rash and loose stools SARACATINIB (AZD0530)

48. Calcilytic agents (MK-5442)— Calcilytics represent a new class of bone-forming agents . Act as antagonists of the CaSR and mimic hypocalcaemia, thus evoking a short pulse of PTH secretion . Calcilytics are administered orally and obviate the need for injections as opposed to PTH therapy. Narrow therapeutic index. These compounds led to sustained PTH secretion and findings that were reminiscent of primary hyperparathyroidism, a catabolic bone disease. Anabolic therapies

49. Wnt-dependent nuclear accumulation of β-catenin is a major trigger of osteoblastic differentiation and bone formation. The endogenous inhibitors of Wnt signalling, sclerostin and Dkk-1 present potential therapeutic targets to enhance osteoblastic bone formation and are under clinical investigation. Sclerostin antibody Dickkopf-1 antibody (BHQ-880) Inhibitors of Wnt antagonists