![ Abaloparatide is a synthetic analog of PTH-related protein (PTHrP) .
Abaloparatide is currently under development, most of its clinical data
come from a phase 3 clinical study (Abaloparatide Comparator Trial in
Vertebral Endpoints [ACTIVE]).
IT increased BMD and reduced vertebral and non-vertebral fractures in
postmenopausal women with osteoporosis over 18 months . The
reduction of non-vertebral fractures by abaloparatide was significant
when compared with placebo.
The superior anti-fracture effects, especially on non-vertebral fractures
may render abaloparatide a safe and effective anabolic agent when
approved for the treatment of osteoporosis.
ABALOPARATIDE](https://image.slidesharecdn.com/recentadvancesinosteoporosisnewcopy-180507092659/85/Recent-advances-in-osteoporosis-new-copy-31-320.jpg)
Recent advances in osteoporosis new copy
- 1. RECENTADVANCESINT/TOF OSTEOPOROSIS DR SOURYA MOHAPATRA 1ST YR PGT DEPT OF PHARMACOLOGY
- 2. INTRODUCTION Osteoporosis is a condition characterized by deterioration of bone mass and microarchitecture of bone resulting in increased bone fragility and propensity to fracture . A/T TO WHO: T SCORE : < -2.5,DEFINES OSTEOPOROSIS. SEX INCIDENCE:Women-30-5O%, Men -15-30%. AGE INCIDENCE: women >=45yrs, Men >60-70 yrs. SITES INVOLVED: Vertebral bodies ,distal radius ,proximal femur .But generalized fragility occurs and fractures at Ribs and long bones are common. # incidence increases with age and spine and hip # a/w bad prognosis.
- 7. TYPES OF OP 1) PRIMARY : A)Type 1: loss of trabecular bone owing to estrogen lack. B)Type 2: loss of cortical and trabecular bone in men and women due to long term remodelling insuff,dietary in adequacy . 2)SECONDARY
- 13. CALCIUM The crystalline bone is made of 99% Calcium (of total body calcium) along with p04.(hydroxyapatite) Ca.Is essential for normal bone development and its maintainance through all stages of life. Normally Ca.rich milue is essential to impregnate the osteoid (organic matrix) laid down by osteoblasts. In osteoporosis suppresses bone turnover and incr.Bmd. PREP. AVAILABLE: CA.CARBONATE: M/C USED-1000mg/d. IF >50 YRS- 1200mg /d
- 14. Given along with Calcium. Increases Ca. absorption from intestine ,suppresses bone remodelling and increases BMD in individuals with marginal or deficient vit D status. Also decreases the fracture incidence in individuals. PREPARATIONS AVAILABLE: Calciferol(D2)- oily solution in gelatin capsules -25000/50000 IU caps wkly once. Cholecalciferol(D3)- ORAL AND IM INJ given 3-4 wk interval. Calcitriol : 0.25 -1mcg orally on alt.days. Alfacalcidol :prodrug –rapidly hyrolysed to calcitriol in liver . Dose:1-2 mcg/day. VIT -D
- 17. CONT: At tissue level: bone turnover due to decr.in bone resorption. net positive whole body bone balance,Thus reduces risk of vert.# by , 70% ,non vert # by 25% and hip # by 40%. At cellular level: osteoclast recruitment ,adhesion,depth of resorption site,release of cytokines in macrophages. osteoblast no.and differentiation.
- 18. CONT Alendronate,Risedronate ,Ibandronate ,Zolendrenic acid-approved for post menopausal OP. Alendronate ,Risedronate ,Zolendronic acid –for T/T OF steroid induced OP. Risedronate and Zolendrenic acid for prevention of steroid induced OP. Alendronate ,Risedronate,Zolendronic acid for t/t of OP in men.
- 19. CONT: PREP AVAILABLE: Alendronate: oral Dose: 10mg OD or 70 mg once wkly. Prevention: 5mg OD or 35mg once wkly for 2yrs. Decreases vert# risk by 50%,and multiple # by 90% and hip # upto 50%. . Given in the morning with full glass of water and pt.is advised not to lay down for 30mins. Ibandronate: oral ,i.v Oral: 2.5mg OD or 150mg once a mn. Iv: 3mg every 3mn. Vert# decreased by 40%. Resedronate: oral IR: 5mg OD or 35mg once wkly or 150mg once a mn. DR: 35mg once wkly. Vert #risk decreased by 40-50% over 3yrs. Zolendronic acid: iv INJ 5mg once a yr. reduces vert #risk by 70% ,hip # by 40% and non vert # by 25%.
- 20. SERM:SELECTIVE ESTROGEN REUPTAKE INHIBITORS Osteoblasts express ER alpha and beta receptors . Estrogen inhibits osteoclast action directly. All SERMS bind to ER and decrease bone resorption and osteoclastic activity. PREP AVAILABLE: RALOXIFENE:FDA APPROVED IN POST MENO.OP. DOSE:60MG/D ,DECRE.VERT#BY 30-50% IN POST MENOPAUSAL WOMEN. LASOFOXIFENE:3RD GEN SERM ,increases bmd and decrea. in bone turnover in post meno.op. BAZEDOXIFENE:FDA APPROVED IN 2013 FOR POST MENO.OP. DOSE :20MG WITH 0.45MG CONJUGATED ESTROGEN.
- 22. CALCITONIN Inhibits osteoclastic bone resorption and inc. bone mass in pts .with OP ,most prominently in pts.with high intrinsic rates of bone turnover. In OP,reduces the incidence of vertebral compression # by about 40% in postmenopausal women. Prep available: Calcitonin nasal spray :200U /d. in alt.nostril every day.
- 23. PTH AND RELATED COMPOUNDS:
- 24. TERIPARATIDE Recombinant Form of PTH .FDA approved in OP. It is an OSTEO ANABOLIC HORMONE,the only drug causing bone formation. INDICATIONS: Postmenopausal women with OP at high risk of # or previous h/o OP #. Men with primary or hypogonadal OP at high risk of #. Steroid induced OP. Pts.With high risk of # or who have failed or intolerant to other osteoporotic T/T.
- 25. CONT MOA: OSTEOBLAST FUNC. INCREASES GI CA ABSORPTION, INCR. RENAL TUBULAR REABSORPTION OF CA., BMD (by9-13%) ,BONE MASS AND STRENGHT. Decreased vertebral fracture by 65-69%. PREP AVAILABLE: Inj FORTEO : 20mcg s/c daily for 2 yrs. Given along with anti resorptive therapy. The use of teriparatide is limited to 2 years in any life span, and this is because of the development of OSTEOSARCOMA in pre-clinical animal studies and the decrease of effects to increase BMD. Recently Denosumab and Teriparatide Administration (DATA) study indicated that the combination of denosumab and teriparatide produced a more prominent effect on BMD than each drug did alone .
- 26. OTHERS Strontium ranelate :previously used but now withdrawn due to cardiac events and thromboembolism. Thiazides: decreases urinary Ca excretion .
- 28. DENOSUMAB Fully human monoclonal IGG2 ab that inhibits RANKL. MOA: RANK-L is member of TNF and expressed on osteoclasts. RANK-L binds to RANK and promotes osteoclast proliferation and differentiation of OC. Denosumab inhibits the RANK AND RANK-L interaction and thus inhibits bone resorption in osteoporosis. In June 2010 FDA approved its use for postmenopausal op.
- 29. CONT PREP AVAILABLE: Inj 60 mg S/C once every 6MN. Supplement with Ca 1000mg/d and Vit D 400IU/D. S/E: BACK PAIN,HEADACHE, OSTEONECROSIS OF JAW
- 30. Humanized monoclonal ab against Sclerostin and is under clinical development.(PHASE 3) Sclerostin, a glycoprotein selectively secreted from osteocytes is an inhibitor of Wnt signaling and potently inhibits bone formation. A phase 3 study demonstrated that Romosozumab was shown to markedly increase the BMD of lumbar spine by 13.3% and proximal femur by 6.8% in just 12 months and prevent vertebral and clinical fractures in postmenopausal women with osteoporosis . Mouse and human genetic data indicate that canonical Wnt–β-catenin signaling enhances osteoblastic bone formation and inhibits bone resorption via direct and indirect mechanisms. ROMOSOZUMAB
- 31. Abaloparatide is a synthetic analog of PTH-related protein (PTHrP) . Abaloparatide is currently under development, most of its clinical data come from a phase 3 clinical study (Abaloparatide Comparator Trial in Vertebral Endpoints [ACTIVE]). IT increased BMD and reduced vertebral and non-vertebral fractures in postmenopausal women with osteoporosis over 18 months . The reduction of non-vertebral fractures by abaloparatide was significant when compared with placebo. The superior anti-fracture effects, especially on non-vertebral fractures may render abaloparatide a safe and effective anabolic agent when approved for the treatment of osteoporosis. ABALOPARATIDE
- 32. ODANACATIB Cathepsin –K inhibitor. Cathepsin –K is a protease expressed in osteoclasts which degrades the collagen type 1 in the bone matrix. Odanacatib inhibits cathepsin –k and thus dissolution of matrix ,bone resorption and thus improves BMD in postmenopausal op. But development of drug was withdrawn recently due to its serious side effects(e.g stroke and atrial fibrillation)
- 33. IGF-1 AND BONE GH and IGF-1 are fundamental in achieving a normal longitudinal bone growth and mass during the postnatal period and, in association with sex steroids, play a major role in bone growth and development . IGF-1 is considered essential for longitudinal bone growth, skeletal maturation, and bone mass acquisition not only during growth but also in the maintenance of bone in adult life . Lower serum IGF-1 levels in women are strongly associated with low BMD and an increased risk of osteoporotic fractures. In bone IGF-1 Is PTH dependent .Circulating IGF-1 Contributes to cortical bone integrity. In future can serve to maintain the bone integrity in anorexia nervosa pts.
- 34. INTEGRIN ANTAGONISTS Integrin mediates cell and cell matrix interactions. Osteoclast adhesion to the bone surface imp.for bone resorption. Integrin inhibitors inhibit this interaction and thus inhibit bone resorption and incr. BMD. STILL UNDER STUDY.
- 38. OTHERS Biomaterials: Chitosan biopolymers Strontium –modified calcium phosphate cement. Titanium-coated with ca.phos. Coated with collgen type 1 Gut serotonin inhibitors: Studies on rat models indicated that SSRIs like fluoxetine and venlafexine positively or negatively affected the bone loss in rats with periodontitis.
- 41. REFERENCES 1)13th edition GG. 2)KATZUNG BOOK. 3)19th edition Harrison. 4)APLEY”S ORTHOPAEDICS BOOK. 5)Pub med articles and journals.