Osteoporosis treatment & Recent updates.pptx

osteoporosis diagnosis, Prevention, management, and Recent advances.

1. Osteoporosis- Investigations & Recent advances Moderator - Dr. Jayant Jain Presenter - Dr. Karthik M V

2. CLINICAL FEATURES M/C presentation – Fragility fractures Most common sites :- HIP (neck of femur, IT fracture) WRIST (Colle’s fracture ) Vertebrae (Compression fracture ) Proximal Humerus fracture

3. CLINICAL FEATURES Chronic low backache Progressive loss of height associated with vertebra deformities Appearance of thoracic kyphosis (DOWAGER’S HUMP )

4. X-Ray loss of trabecular definition thinning of the cortices Compression fractures of the vertebral bodies

5. Radiography doesn’t reveal osteoporotic changes until they affect the cortical bone Cortical bone is not affected by osteoporosis until > 30% bone loss occurred

6. Spinal Deformity Index Percentage height reductions are used to grade fractures as Grade 0 – Normal vertebra Grade 1 - Mild (20–25% reduction in height) Grade 2 - Moderate (25–40% reduction in height) Grade 3 - Severe (>40% height reduction). Moderate and severe vertebral fractures predicts future Hip fracture

7. Spinal Deformity Index The scores are then added up for T4–L4 vertebrae. The spinal deformity index (SDI) value ranges between 0 and 39, higher the SDI greater is chance of incident fracture

8. Normal difference in anterior and posterior heights of vertebral body is taken as 1–3 mm A difference of more than or equal to 4 mm is abnormal The biconcave pattern of vertebrae commonly referred to as fish vertebrae Fish vertebrae are seen in osteoporosis, Paget’s disease, osteomalacia and hyperparathyroidism

9. KLEER KOPER Score  Assessment of vertebral fractures in osteoporosis Vertebra assessed are T4-L5 X-ray beam focused over T8 for thoracic and L3 for lumbar spine Normal - grade 0 Biconcave deformity - grade 1 Wedge deformity – grade 2 Compression deformity – grade 3

10. Minimum score -0 (normal) Maximum score -42 Higher the score, greater the impact of osteoporosis

11. Singh index   The trabecular pattern of the proximal end of the femur is an excellent indicator of the severity of the osteoporosis

12. Singh Index Based on the completeness and presence of tensile and compressive trabeculae in proximal femur the index divides femurs radiologically into six grades PRIMARY COMPRESSIVE GROUP Major weight bearing trabeculae Thickest and most densely packed Appears accentuated in osteoporosis Last to be obliterated

13. Grade 6: All normal trabecular groups are visible • Grade 5: Prominent Ward triangle • Grade 4: Marked reduction, but continuous tensile trabeculae. Secondary compressive trabeculae lost ( Equivocal evidence ) • Grade 3 ( definite osteoporosis ): Definite break in the continuity of tensile trabeculae • Grade 2: Primary tensile trabeculae remnants visible along lateral cortex, rest vanish.( Marked osteoporosis ) • Grade 1: Essentially empty proximal femur ( Severe Osteoporosis )

14. Investigations Primary aim is to confirm the diagnosis of osteoporosis To assess fracture risk and to exclude secondary causes of osteoporosis

15. INVESTIGATIONS 1. Full Blood Count And Erythrocyte Sedimentation Rate (ESR) 2. Serum Calcium, Phosphate 3. Alkaline Phosphatase 4. Renal Function test 5. Plain X-rays: Lateral Thoracolumbar Spine Or Hip (As Indicated) 6. Parathyroid Hormone (PTH) If Serum Calcium Level Is High More Than 10.5% Mg. Other Investigations To Rule Out Secondary Causes Like Free Triiodothyronine (Ft4) Thyroid Stimulating Hormone (TSH)

16. Investigation Single Photon absorptiometry- Involves passing a high energy photon from a radioactive source through a peripheral bone such as radius or calcaneus. Bone density was estimated based on degree of attenuation of the beam

17. Single Photon absorptiometry-

18. DUAL ENERGY X-RAY ABSORPTIOMETRY (DEXA) Gold standard in measuring BMD BMD – average concentration of mineral per square unit area of bone Two X-ray beams with different levels aimed at pt’s bone, Soft tissue absorption is subtracted out, BMD can be determined from the absorption of each beam by bone It affords fast, reliable and accurate measurement of bone mass so is commonly used in screening population

19. Z-score compares patient’s value to an age-matched and sex-matched reference range young adults and postmenopausal females less than 50 years of age T-score is a comparison to mean bone mass of young adult normal individuals defined as healthy women population 20–40 years of age T-score may be called young adult z-score T-scores are used to both predict fracture risk and classify disease status as in WHO definition

20. The central DEXA sites of the hip and spine are commonly preferred Higher precision The quantity of trabecular bone at central sites is usually indicative of the osteoporosis burden, and hence fracture risk Bone loss begins early in the trabecular bone as it is highly metabolically active is predominant in central skeleton

21. Pitfalls in DEXA Osteophytes may yield a falsely elevated bone mass Lateral spine scan is still limited in accuracy by soft tissue attenuation due to greater thickness and nonuniformity of soft tissues in this projection

22. DEXA T DEXA should be Considered for patients over the age of 50 years who suffer a fragility fracture

23. Quantitative Ultrasound (QUS) Heel is validated skeletal site for Qus Qus of Calcaneus in postmenopausal women to predict hip, vertebral fracture and in men > 65 years to predict hip fractures

24. Quantitative Computed Tomography (QCT) Measures BMD as true volume density (in g/cm3 ) Not influenced by bone size Used in both Childrens and adults Most sensitive –measures trabecular bone within vertebral body Advantage – low cost than Dexa - portability

25. Prevention of osteoporosis Exercises Balanced Nutrition Avoid tobacco and alcohol consumption Yearly BMD assessment especially in females Calcium rich diet

26. MANAGEMENT Four major goals: 1. To prevent fracture 2. To stabilize bone mass or achieve increased bone mass 3. To relieve symptoms of fractures and skeletal deformity 4. To maximize physical function

27. MANAGEMENT Non Pharmacological prevention - Nutrition - Life style modification - Prevention of fall - Hip protectors

28. Non-Pharmacologic Treatment Diet changes- -A well balanced diet with adequate calcium and vitamin D is essential for healthy bone. -Calcium contributor - Dairy products like milk, yogurt, cheese -Most vitamin D comes from sun induced skin conversion Vitamin D contributors - fatty fish, few unfortified foods.

29. LIFESTYLE MODIFICATIONS Physical activity  weight bearing and muscle strengthening exercises Exercise improves bone strength by 30%to 50% Cessation of smoking, alcohol Adequate sun exposure

30. Non-Pharmacologic Treatment Prevention of falls - Exercises like balance training, lower limb strengthening exercises - Correction of sensory impairment like correction of low vision and hearing impairments Hip protectors- Prevent direct impact on hip

31. The recommended daily dosage of elemental calcium is: VIT D – good source is sunlight exposing 20% of body surface for 30min between 10am – 3pm

32. Pharmacological treatment ANTIRESORPTIVE AGENTS Bisphosphonates Calcitonin SERM Denosumab STIMULATING BONE FORMATION Sodium Fluoride PTH (Teriparatide) Vit D analogues Dual action Strontium Ranelate

33. Pharmacological Treatment of osteoporosis 1. Anti- resoptives Bisphosphonates Analogues of pyrophosphate First line of treatment in osteoporosis MOA – Inhibit osteoclast activity and resorption of bone - Disruption of ruffled bodies of osteoclast - this allow osteoblast activity to improve BMD

34. Non Nitrogen containing they inhibit osteoclastic activity by producing toxic analogs of ATP (competes with natural ATP) causes apoptosis Examples – Clodronate, etidronate Nitrogen Containing they inhibit the prenylation and function of GTP binding proteins required for osteoclast formation, function and survival They alter cholesterol metabolism in osteoclast by inhibiting the enzyme farnesyl diphosphate synthase Examples – alendronate , pamidronate, risedronate .

35. 1 st Generation – Etidronate & Tiludronate 2 nd Generation - Alendronate, Pamidronate, Ibandronate 3 rd Generation – Risedronate, Zoledronate

36. Adverse effects Oesophageal irritation ( taken with glass of water & upright 30min) Upper GI syndrome Rash and Iritis Renal impairment Insufficiency fractures (Bisphosphonate-induced subtrochanteric fractures Jaw Osteonecrosis Oesophageal Ca

37. Atypical fractures Bone “ freezing/ Arrest ” effect Microcrack keep accumulating in the bone and do not get repaired for absence of remodeling These are transverse fractures without thickening of the cortices The risk to fracture reduces rapidly as the treatment with drug is discontinued

38. Atypical fractures

39. 2. SERMS (Selective Estrogen Receptor Modulators) Provides beneficial effects of estrogen Two SERMs are used currently in postmenopausal women: Raloxifene (60 mg/d) and Tamoxifen MOA – decreases resorption through action on estrogen receptors Adverse effects DVT Stroke Hot flashes

40. Hormonal Replacement therapy MOA – Estrogen effective in inhibiting bone resorption, increases BMD by binding to estrogen receptors and blocking the production of specific cytokine that increase osteoclast Adverse Effects Combined estrogen and progesterone – risk of breast cancer, MI, stroke and venous thromboembolism Estrogen alone – risk for stroke and Venous thromboembolic events

41. Calcitonin Available as Daily nasal spray or Subcutaneous injection MOA – decreases osteoclastic activity Reserved in pt who refuse or in whom estrogen is contraindicated Intranasal spray available as 200IU of drug Side effects – Nasal discomfort, nasal mucosal congestion, epistaxis

42. DENOSUMAB Humanised Monoclonal antibody directed against the Nuclear factor – Kappa B ligand ( RANK L) which is key mediator of resorptive phase in bone remodelling It decreases the resorption by inhibiting the osteoclast activity Approved dosage is 60mg given subcutaneously every 6 months

43. O steoblast secrete RANK Ligand to regulate the activation and differentiation of Osteoclasts that then affect remodelling Denosumab is a drug which inhibits RANK ligand and prevent bone resorption Used in Osteoporosis

44. Adverse reactions Dysregulation of immune system Hypocalcemia Cellulitis Skin Rash

45. TERIPARATIDE Recombinant human PTH When given continuously associated with increased osteoblastic activity and osteoblastic turnover -> net bone loss Intermittent administration of low-dose PTH enhances osteoblast activity and bone formation Used for treatment of patients with osteoporosis (both men & women) at high risk of fracture (BMD<-3.5) and those with pre-existing fragility fractures.

46. Dosage - 20 mcg/day Subcutaneous, should not bet taken > 2 years Serum calcium are monitored at 1, 6, and 12 months Contraindications - Hypercalcemia, h/o radiation, bone tumors or mets

47. Sodium Fluoride Potent mitogenic agent for osteoblast Dose – 20-30mg daily Low therapeutic window The routine use of fluoride is not recommended. Adverse effects- Gastric irritation

48. Strontium ranelate Strontium is a divalent alkaline element that is combined with ranelic acid Strontium usually acts as calcium agonist Within bone and calcified tissues it is adsorbed on surface of hydroxyapatite crystals and may participate in bone mineralization. Dual action, increasing bone formation and decreasing resorption Recommended daily dose is one 2 g sachet once daily Contraindicated in pt with Renal disease, DVT

49. Surgical treatment of osteoporosis FRAGILITY FRACTURES – as per WHO fractures caused by injury that would be insufficient to fracture a normal bone with the result of reduced compression and/or torsional strength on bone Fractures due to minimal trauma such as fall from height Typical osteoporosis fracture include vertebral fractures, Hip fracture (neck of femur, inter trochanteric fractures), Distal radius fractures, Proximal humerus fractures

50. Due to cortical thinning – only two screw threads are engaged in cortex (normally 4-5 screw threads are to be engaged) Principles of internal Fixation in Osteoporosis is Use of Load sharing implants Wide buttress Locking compression plates Bone Augmentation Impaction and compression

51. Locking Plates/Screws In normal bone, bicortical fixation is not necessary with locking screws In osteoporotic bone, bicortical fixation of locking screws can enhance the torsional stability of the construct ~3x More stable with bicortical fixation

52. Recent advances In Osteoporosis NEW RISK ASSESSMENT TOOLS Pharmacological treatments Surgical Advances

53. New Risk assessment tools American SOF-study of osteoporosis fracture group -> predicts 10 years risk of Hip fractures FRAX tool used in postmenopausal females, age > 65 years Both FRAX and SOF models demonstrated that older people with Low BMD and h/o fragility fracture at high risk of sustaining further fragility fracture

54. FRAX tool

55. Q Fracture It has some similarities to FRAX, estimates 10 year risk of fracture Advantage – no requirement of Densiometry

56. Recent advances in pharmacological treatment Anti Resorptive agents Cathepsin k inhibitor – Odanacatib Glucagon like peptide 2 Newer SERM – Lasofoxifene Osteoprotegerin C – src kinase inhibitors

57. Cathepsin k inhibitor Cathepsin K is a lysosomal enzyme produce by osteoclast help in bone resorption Drug - Odanacatib Long half life, weekly administration Dose – 50mg/week Side effects – scleroderma like skin changes

58. Glucagon - like peptide 2 Intestinal polypeptide hormone released in response to food intake Bone remodelling occurs in response to circadian rhythm and increases with nocturnal fasting Bone resorption peaks at night GLP-2 at night reduces bone resorption

59. Newer SERM – Lasofoxifene Dose – 0.5mg/day Improves BMD over 5 years Lumbar spine by 3.1 %, femoral neck by 2.7% OSTEOPROTEGERIN Decoy receptor for RANKL

60. C – SRC Kinase Inhibitors The non-receptor tyrosine kinase c – src is required for development of ruffled body in osteoclast (last step) Inhibit bone resorption Saracatinib –orally available

61. Recent advances in pharmacological treatment Anabolic Agents Calcium sensing receptors and Calcilytics Exogenous PTH – Abaloparatide Statins

62. Calcium sensing receptors and Calcilytics These receptors are located on parathyroid gland and kidney, calcium homeostasis Calcium sensing receptor antagonist – Calcilytics – Ronacaleret , inhibit receptor, releasing PTH pulse following each dose

63. Exogenous PTH Abaloparatide is synthetic analogue of PTH – related protein PTH and PTHr bind to PTH 1 receptor (PTH1R) PTH1R has two conformations – R(0) and RG R(0) – prolonged stimulation RG - Transient responses - Abaloparatide Statins Widely used to lower serum cholesterol It also enhances BMP-2 gene expression and bone formation Ex – Simvastatin, lovastatin, mevastatin

64. Surgical Recent Advances Kyphoplasty All vertebral compression # without neurological deficits are treated conservatively for 3 weeks Percutaneous Vertebroplasty and kyphoplasty play a role in fracture which doesn’t respond to Non operative treatment Kyphoplasty is different than vertebroplasty in that a cavity is created by expansion ballon and bone cement injected with less pressure

65. Vertebroplasty Impregnation of polymethyl methacrylate into the vertebral body is called Vertebroplasty Pain relief and rehabilitation Extradural extravasation of bone cement that would cause neurological compromise Formation of cement emboli that may migrate in the spinal canal

66. Kyphoplasty More effective Inflating a balloon inside the vertebra restoring vertebral height and then bone cement is injected into the balloon concerns of compression fractures of adjacent vertebrae Indications - Painful fractures with a back pain - Compression fracture due to osteoporosis - Adjacent vertebra of a fractured and treated one (D12-L1) as preventive

67. References Turek’s orthopaedics – 7 th edition Rockwood and Green’s – 8 th edition Manish Kumar Varshney textbook of orthopaedics Apley & Solomon’s system of orthopaedics GS Kulkarni textbook of orthopaedics

68. THANK YOU