New therapies for osteoporosis. Dr.Shobhana Mohandas.MD.DGO.FICOG. Sun Medical centre, Thrissur, Kerala.

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1 New therapies for osteoporosis Dr.Shobhana Mohandas.MD.DGO.FICOG. Sun Medical centre, Thrissur, Kerala.

2 Osteoclastic resorption Sema 4 D Plexin B1 from osteo TGF-β1, and IGF-1 Osteoblast Migration Osteoblast differentiation

3 Osteoporosis Imbalance between bone resorption and bone formation High rate of remodelling in menopause Increased NO and depth of resorption cavities Perforation of trabecular plates Loss of trabecular elements of cancellous bone, Thinning and porosity of cortical bone

4 Inhibitors of bone resorption Bisphosphonates, Estrogens, Calcitonin Selective estrogenreceptor modulator Treatment for osteoporosis Stimulators of bone formation Parathyroid hormone (PTH), Strontium Ralenate

5 Bisphosphonates Decreased resorption. Increased mineralisation Increased amount of formed bone Decreased bone Remodelling space Increased Bone mineral density

6 Selective Estrogen Receptor Modulators (SERMs)

7 The ER can interact directly with specific DNA sequences as well as indirectly through binding to proteins such as activator protein (AP) 1 to activate transcription An updated model of nuclear receptor (NR) pharmacology. Agonists bind to the receptor, alter the receptor's shape, and in general allow for the recruitment of coactivators (CoA) to activate transcription

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9 It can be seen that Bazedoxifene has a very positive effect on the bone with out any negative effects on breast or endometrium. It also does not affect vasomotor activity. Bazedoxifene contains an indole-based core binding domain that binds with high affinity to estrogen receptors and exhibits favourable effects on bone

10 Bazedoxifene Third-generation SERM High affinity for the estrogen receptor alpha. Daily doses of 2.5, 5.0, 10,20, 30, and 40 mg BZA in a phase II study were generally well tolerated Significant decreases in uterine bleeding compared with placebo, suggesting estrogen antagonist activity in the endometrium.

11 In a three-year randomized clinical trial (RCT), the incidence of new vertebral fractures was signif-icantly lower in women treated with bazedoxifene or raloxifene versus placebo (fracture rates of 2.3, 2.5, and 2.3 vs. 4.1%)

12 Estrogen alone Endometrial cancer Estrogen with progesterone Breast cancer Combining Estrogen with an agent other than progesterone will treat hot flashes without stimulating the endometrium would be fruitful. 20 mg Bazedoxafene With 0.625mg of conjugated equine estrogen Decreased hot flashes Improved BMD No endometrial hyperplasia

13 Estrogen alone Endometrial cancer Estrogen with progesterone Breast cancer 20 mg Bazedoxafene With 0.625mg of conjugated equine estrogen Decreased hot flashes Improved BMD No endometrial hyperplasia

14 3397 healthy post menopausal women aged 40 to 75 years Baze doxafene With Conjugated equine estrogen Raloxefene 60 mg Placebo Cumulative amenorrhoea rates are same For bazedoxafene+ cee And placebo. Fertility and Sterility Vol. 92, No. 3, September

15 Ospemifene Ospemifene has an estrogenic effect on bone, as seen by improved bone mineral density, strength, mass, and histomorphometry One tablet daily with food Side effects: Hot flush, vaginal discharge, muscle spasms, genital discharge, increased sweating.

16 Lasofoxifene. In a 2-year phase 2 study of 410 postmenopausal women, lasofoxifene.25 mg and 1.0 mg per day significantly increased lumbar spine BMD versus raloxifene 60 mg daily or placebo, and increases in total hip BMD were similar in all treatment Reductions in LDL cholesterol were significantly greater with lasofoxifene significantly reduced vertebral and nonvertebral fracture risk, increased BMD, and decreased levels of bone marker turnover relative to placebo. Decreased the risk of breast cancer. Improves vaginal atrophy, High adverse effects, high incidence of hot flashes. An increase in endometrial thickness and the incidence of endometrial polyps and vaginal bleeding compared with placebo.

17 Denosumab Denosumab is designed to inhibit RANKL (RANK ligand)

18 Osteoblast Rank;-L Denosumab Prevents Rank-L activity Rank receptor on osteoclast membrane RanK : Receptor activator of nuclear factorkappa B. Rank L : Rank ligand Osteoclast differentiation,activation and survival

19 Denosumab 35% risk reduction 31% fracture recurrence FREEDOM trial Dosage & When it is to be taken : Administer 60 mg every 6 months as a subcutaneous injection in 7808 women aged 60 to 90 the upper arm, upper thigh, or abdomen Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily Side Effects : Placebo 17%Risk reduction 71% Fracture recurrence Most Common - Fatigue/weakness, decreased level of phosphate and calcium in blood, nausea, diarrhea, headache and cough

20 Denosumab Denosumab is contraindicated in patients with hypocalcemia, and Sufficient calcium and vitamin D levels must be reached before starting on Denosumab therapy

21 Denosumab In women with PMOP and multiple RiskFractures, Those with a history of fracture with renal failure, Those who cannot tolerate or have failed other treatments. Although its cost may seem high, the need for only semiannual administration of this compound renders it equivalent in cost to other preparations that are administered daily,weekly, or monthly.

22 Anabolic treatments The only anabolic therapies currently approved to treat osteoporosis to date are 1.Recombinant forms of human PTH. 2.Human Recombina nt PTH 1 34 (teriparatide) and PTH 1 84 have been approved in several countries to treat osteoporosis. Stopping treatment with these agents leads to rapid bone loss, Patients are usually switched to long-acting bisphosphonates or other agents to consolidate BMD gained during treatment

23 Chronic high dose Intermittent low dose

24 Parathhormone(Teriparatide) Stimulates bone formation quickly Within 1 month of treatment initiation.

25 Indicated in women with several fragility fractures or in those who cannot tolerate other treatments. Administered subcutaneously 20umg daily for up to two years; after this time, treatment with another antiresorptive drug should be initiated. Most common side effects are dizziness and cramps. Administration is contraindicated in patients with risk of osteosarcoma,paget s disease, hypercalcemia, prior radiation therapy, or history of previous bone malignancies.

26 Strontium Ranelate Strontium nucleus is very nearly the same size as that of calcium, the body easily takes up strontium and incorporates it into bones and tooth enamel in the place of calcium. Increased risk of myocardial infarction

27 Calcitriol 200Iu daily in alternating nostrils, 100IU SC or IM on alternate days.

28 Sclerostin Antibodies Sclerostin inhibits bone Formation through LRP S/S. Frizzled gene on Osteoblast membrane. Sclerostin inhibitor antibodies Inhibit this action of Sclerostin on the Wnt Gene Pathway.

29 Romosumab Humanized monoclonal antibody that targets sclerostin for the treatment of osteoporosis. Specific to bone It had mild injection side effects. It is expected to be on the market in 2017 and is predicted to be the gold standard in osteoporosis treatment by 2021.

30 419 postmenopausal women 55 to 85 years of age Low bone mineral density Romosuzab or 210mg SC/month Or 140mg,210mg SC /3 months Placebo Increased BMD at 12 months at spine

31 In another study, Romosozumab was better than Alendronate and Teriparatime

32 Anti-dickkopf antibodies Stimulate the Wnt/-catenin pathway in osteoblasts, leading to new bone formation. Only for research use

33 Integrin Antagonists The alphavbeta3 integrin (vitronectin)receptor plays a pivotal role in bone resorption. Integrins medi-ate the adhesion of osteoclasts to the bone surface, inhibiting boneresorption and thus increasing BMD

34 Cathepsin K inhibitors Cathepsin K inhibitors appear to have Antiresorptive and Anabolic actions. They inhibit one of the major osteoclast digestive enzymes without suppressing bone formation, thereby leading to anabolic effects on bone.

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36 Odanacatib Odanacatib (MK-0822) is a new selective cathepsin K inhibitor Causes a moderate sustained decrease in bone resorption, Lesser and more transient decrease in bone formation. Completed phase I and II clinical trials in postmenopausal women

37 Omega 3 fatty acids Omega-3 fatty acids inhibit osteoclast activity and promote osteoblast activity Omega-3 fatty acids potentiate the effects of oestrogen on bone Moderation of peroxisome activated receptor gamma (PPAR-), S.J. Vanlint, K. Ried / Maturitas 71 (2012) 44 48

38 40 women given alagal oil with 400mg docosahexanoic acid or placebo All were given calcium and Vitamin D. BMD at baseline and at 12 months BMD increased with this combination

39 Drug Rout e Dose Alendronate Oral 5mg/d2y 70mg/w5y vert bral Non -vb hip limitations Ann.cost Esophagitis, osteonecrosis of jaw, atypical femoral fractures, myalgia 1300 Risedronate Oral 5mg/d 35mg/w 150mg/m Zolendronic acid IV 5mg infu/year Esophagitis, flu-like symptoms, hypocalcaemia Renal toxicity, flu-like symptoms, severe dizziness, anemia Raloxifene oral 60mg/d 30 NR NR Worsen vasomotor symptoms, venous thrombosis, peripheral edema, vaginal bleeding, breast pain, fatal strokes 19,516 3,650 Strontium Oral 2g/d Risk of myocardial infarct, venous thromboembolism, DRESS syndrome 19,345 ERT Oral/ td 34 NR 34 Risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, deep vein thrombosis 2400 Teriparatide S.C 20mcf/day- 2y Dizziness, muscle cramps, infrequent hypercalcemia, increase risk of osteosarcoma, daily subcutaneous injections 1,44000 Denosumab s.c 60mg/6m- 3y Arthralgia, hypocalcaemia, eczema, cataract 1,20000

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41 Glucocorticoid therapy induced osteoporosis Chronic glucocorticoid therapy > 7.5mg prednisone or equivalent Osteoporosis High potency Prolonged low dose Inhalor therapy Low bone mass Bisphosophonates are the first line option for GIOP(Grade A) Calcitriol is used for preventing GCIOP and post transplant-related bone loss(grade A) Teriparatide counteracts many aspects of GIOP better than bisphosphonates