Osteoporos Patogenes, diagnostik, behandling

Transkript

1 Osteoporos Patogenes, diagnostik, behandling Östen Ljunggren Osteoporosenheten Akademiska sjukhuset Uppsala

2 Osteoporos Patogenes, diagnostik, behandling 1. Lite om sjukdomspanoramat 2. Patogenes 3. Diagnostik 4. Behandling 5. Kommer det nya behandlingar? 6. Vårdprogram

3 The disease(s)

4 Osteoporotic fractures / year in Sweden ( hip fractures)

5 Estimated increase in hip fractures (x1000)

6 Osteoporos är en kronisk sjukdom Folksjukdom, vårdprogram och hälsoekonomi behövs Men, ibland svårt att bara följa vårdprogram

7 Osteoporosis, definition Systemic skeletal disease Less amount of bone Loss of Trabeculi No osteomalacia *Increased fracture risk Boyde A, London Female, age 30 years Consensus Development Conference: Diagnosis, Prophylaxis and Treatment of Osteoporosis. Am J Med 1993;94:

8 Osteoporosis Enhanced resorption -Hypogonadism -Hyperparathyreoidism Impaired formation Severe Osteoporosis - Aging -Glucocorticoids Boyde A, London Male, age 89 years

9 Osteoporosis WHO - Definition, 1994 Spine (L1-L4) Hip (Tot, Neck) Normal BMD = T-score >-1 Osteopenia = T-score Osteoporosis =T-score < -2.5 Manifest OP = BMD < fracture

10 Osteoporosis is a risk factor for fracture Continous increase in fracture risk 10 % BMD = 1SD = RRx2 BMD as risk factor similar in men and women Other Risk factors Previous fracture Glucocorticoid treatment Famili history

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12 Vem skall vi utreda? Att identifiera patienten Frakturpatienter Osteoporos enl DXA Patienter med nög risk för fraktur

14 Åtgärd Riskfaktor Fraktur Kost Motion Reducera fallrisk Livsstil, omgivning Osteoporos Fallolycka

15 Åtgärd Riskfaktor Fraktur Kost Motion Reducera fallrisk Livsstil, omgivning Läkemedel Osteoporos Fallolycka

16 Drug targets Osteoclasts -Antiresorptive treatment Osteoblasts -Anabolic treatment

17 Treatment of osteoporosis 1995 Estrogen Bisphopshonates (in trials) Calcitonin, iv Calcium (Vit D)

18 Treatment of Osteoporosis 2013 Alendronat Risedronate Ibandronate Didronate Zoledronate Calcitonin Denosumab Raloxifene Teriparatide PTH1-84 Sr-ranelate Calcium Vitamin D (HRT)

19 Treatment of Osteoporosis 2013 Alendronat Risedronate Ibandronate Didronate Zoledronate Calcitonin Denosumab Raloxifene Teriparatide PTH1-84 Sr-ranelate Calcium Vitamin D (HRT)

20 Treatment of osteoporosis 2015 *Anabolic treatment PTH 1-34 *Antiresorptive treatment alendronate zoledronate denosumab (raloxifen) *Calcium och Vitamin D *Life style, Fall prevention, Hip protectors

21 Vitamin D Källor: Solljus Mejeriprodukter Fet fisk

22 Vitamin D behövs för att osteoblaster skall kunna mineralisera ben Svår vitamin D brist leder till rakit/osteomalaci Osteoid x (CaxPO4) Pyrophosphate

23 PTH (pg/ml) Lindrigare vitamin D brist leder till ökad benresorption PTH Levels Rise as 25(OH)D Levels Fall Below 38.8 ng/ml Postmenopausal women with osteoporosis (worldwide) 95 N= (OH)D concentration (ng/ml) PTH=parathyroid hormone Study Design: Observational, cross-sectional study of 1285 community-dwelling women with osteoporosis from 18 countries to evaluate serum 25(OH)D distribution. Lim S-K et al. Poster presented at ISCD, February 16 19, 2005, New Orleans, Louisiana, USA. Severe Osteoporosis Boyde A, London Male, age 89 years

24 Vitamin D Andra sjukdomar Antal träffar i Pubmed Vitamin D & Cancer 5162 Vitamin D & Osteoporosis 5091 Vitamin D & cardiovasuclar disease 1643 Vitamin D & Diabetes 1094 Vitamin D & dementia 148 M.fl

25 Cochrane 2005

26 Svårt att se en roll för enbart Vitamin D och Kalcium 87 år Tidigare frakturer Osteoporos Förr: Nu: Kanske endast kalcium och vitamin D Benspecifik behandling + Kalcium och Vit D Osteoporosläkemedel fungerar oavsett ålder

27 Bisphosphonates Mechanism of action I) Bisphosphonates without nitrogen atom (e.g. etidronate, clodronate) alter cell s production of ATP, impeding normal cellular metabolism II)Bisphosphonates with one or more nitrogen atoms inhibit mevalonate pathway Responsible for production of cholesterol, other sterols, and isoprenoid lipids isoprenoid lipids required for modification (prenylation) of small enzymes (GTPases) Prenylated enzymes regulate important osteoclast functions

28 Percetnage of patients with new fractures Alendronate in postmenopausal osteoporosis Fractures % reduction p< % reduction p< postmenopausal women years old osteoporosis vertebral fracture Treatment for 3 years Fosamax 10 mg daily placebo 500 mg calcium IU vitamin D 1 0 placebo Fosamax placebo Fosamax Clinical vertebral fractures Hip fractures Black, et al. Lancet 1996; 348:

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30 Bisphosphonates

31 Cumulative Incidence (%) Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) 3 Placebo (n = 3861) ZOL 5 mg (n = 3875) P < % (60%, 85%) Time to First Clinical Vertebral Fracture (months) March 31, 2006, analysis report Relative risk reduction (95% confidence interval) vs placebo Black DM, et al. Presented at: ASBMR 28th Annual Meeting; September 15-19, 2006; Philadelphia, Pa. Abstract

32 Excess RANK Ligand Can Increase Bone Resorption Leading to Osteoporosis CFU-GM Prefusion Osteoclast Multinucleated Osteoclast RANKL RANK OPG Decreased Estrogen Leads to Increased RANK Ligand Osteoblasts Activated Osteoclast Bone Formation Adapted from: Boyle WJ, et al. Nature. 2003;423: Bone Resorption 2009 Amgen. All rights reserved. Do not copy or distribute.

33 Incidence at Month 36 (%) The Effect of Denosumab on Fracture Risks at 36 Months 9% 8% 7% 68% P < ,2% 8,0% 20% P = 0.01 Placebo Denosumab 6% 6,5% 5% 4% 3% 2% 2,3% 40% P = % 0% 1,2% New Vertebral Nonvertebral Hip 0,7% Cummings SR, et al. N Engl J Med Aug 20;361(8):756-65

34 Insidens vid Månad 36 (%) Insidens vid Månad 36 (%) FREEDOM Studien Högrisk Grupper RRR = 70% P < 0,001 Kotfrakturer P interaktion = 0,4822 RRR = 64% P < 0,001 Höftfrakturer P interaktion = 0,0714 Placebo Denosumab RRR = 6% P = 0,8490 RRR = 62% P = 0,0065 RRR = relativ riskreduktion McClung MR et al. JBMR, 4 oktober 2011, epub as DOI /jbmr.536 Boonen S et al. J Clin Endocrin Metab. 2011;96:

35 Antiresorptive treatment Alendronate (FIT) Once Weekly Injectable Bisposphonates Denosumab

36 Antiresorptive treatment Alendronate (FIT) Once Weekly Injectable Bisposphonates Denosumab As good as it gets?

37 Fracture reduction due to antiresorptive treatment 65-70% 20% 40-60%

38 Treatment of osteoporosis *Anabolic treatment PTH 1-34 *Antiresorptive treatment alendronate zoledronate denosumab (raloxifen) *Calcium och Vitamin D *Life style, Fall prevention, Hip protectors

39 Teripartide Concentration (pg/ml) Serum Calcium Concentration (mmol/l) Temporal Profiles of Serum Teriparatide and Calcium Concentrations after Injection in Postmenopausal Women with Osteoporosis ULN SCa 10.5 mg/dl Time Since Last Dose (Hours) Krege JH et al., Program & Abstracts ENDO 2004, June 16-19, 2004, #P2-260, page Teriparatide (20 ug) Concentrations Serum Calcium Concentrations

40 Modeling Osteon Treatment with PTH 1-34 Eriksen et al., Calcif Tissue Int 2003:72(4):

41 New Vertebral Fractures During Fracture Prevention Trial PTH Placebo TPTD Patients (%) * Mild Moderate Severe *P<0.001 vs Placebo *

42 Percent Change in BMD Mean ± SE Lumbar Spine BMD Endpoint Months Teriparatide Alendronate Alendronate N= Teriparatide N= Saag KG et al. N Eng J Med. (2007); 357: P<0.001 Teriparatide vs. Alendronate

43 Number of Patients with New Vertebral and Nonvertebral Fractures Alendronate Teriparatide P-value Vertebral radiographic 10/165 (6.1%) 1/171 (0.6%) Clinical vertebral 3/165 (1.8%) 0/171 (0%) 0.07 Nonvertebral 8/214 (3.7%) 12/214 (5.6%) Nonvertebral fragility 3/214 (1.4%) 5/214 (2.3%) Saag KG et al. N Eng J Med. (2007); 357:

44 Future therapies? Kathepsin K inhibitors? Anti-Sclerostin?

45 Odanacatib: Cathepsin K inhibitor Cathepsin K is a cysteine protease expressed exclusively by osteoclasts Cathepsin K is responsible for degradation of collagen ODANACATIB is a selective and reversible inhibitor of cathepsin K ODANACATIB has in preclinical studies been demonstrated to rapidly decrease bone resorption

46 Odanacatib in postmenopausal osteoporosis 399 postmenopausal women years old osteoporosis T-score < -2 at spine or hip No fragility fractures Treatment for 2 years Odanacatib 3, 10, 25 or 50 mg weekly placebo 500 mg calcium daily IU vitamin D weekly Bone et al. JBMR epub 2010

47 Sclerosteosis High Bone Mass Human Genetic Disorder Normal Sclerosteosis Increased bone formation Increased bone mass throughout skeleton Good quality, fracture resistant bone Life long bone overgrowth causes clinical problems in the skull (Brunkow et al., 2001; Janssens et al., 2002).

48 Potential MOA for Sclerostin: Inhibiting Wnt Signaling and Bone Formation Sclerostin is thought to bind to the Wnt coreceptor, LRP5, and block Wnt signaling thus inhibiting bone formation. OA MacDougald et al., JCI, 116(5) 1202 (2006)

49 In the future? New bone specific drugs? Drugs against sarcopenia? Learn to use the drugs that we have!

50 Future possible strategies in the clinic -Prolonged antiresorptive treatment? -Wash out period, re-treat with antiresorptives? -Anabolic treatment followed with prolonged antiresorptive treatment? -Sequential treatment antiresorptive anabolic - antiresorptive? -Combined treatment, eg teriparatide and denosumab

51 Burden of Disease Osteoporosis 2013 Bone Cell Biology -RANK/RANKL -Sclerostin (LRP5-Wnt) Treatment options Antiresorptive Anabolic Fracture Prediction Health Economy

53 Behandlingsrekommendationer SBU -97, -03 (evidensgranskning) LV -98, -01, -04, -07 SvOS riktlinjer (ingen myndighet) LFN riktlinjer för subvention (Forsteo) Lokala vårdprogram Socialstyrelsen 2012

54 Socialstyrelsens rekommendationer gällande osteoporos Rekommendationer mer rangordning beräkna frakturrisk -mäta bentäthet -behandla med farmaka -fysisk träning Icke göra -kyfo och vertebroplastik -behandling med kalcium och vitamin D som monoterapi.

55 Socialstyrelsens rekommendationer om behandling vid hög frakturrisk, 2012 Hälso och sjukvården bör; -Behandla personer med hög frakturrisk med aledronsyra (prioritet 2) -Ge behandling med zoledronsyra till personer som har hög frakturrisk och som har svårt att fullfölja en behandling med aledronsyra (prioritet 2) -Ge behandling med denosumab till personer med hög frakturrisk och som Har svårt att fullfölja behandling med bisfosfonater (prioritet 3)

56 Osteoporos Läkemedel idag, Uppsalas prioritering Indikation: LV konsensus :a hand: Generiskt alendronat 70 mg/ vecka 2:a hand: Aclasta, vid GI besvär 3:e hand: Prolia, vid njursvikt Forsteo: Evista: Vid uttalad OP Undantagsfall Kalcium och Vitamin D: Forteberedningar

57 Vem skall vi utreda? Att identifiera patienten Frakturpatienter Osteoporos enl DXA Patienter med nög risk för fraktur

58 Frakturkedjor

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61 FractUp Fractures in Uppsala County Pop:

62 FractUp Started 2003 Postmenopausal women, and men above 65, with osteoporotic fractures should be referred to the Osteoporosis unit for DXA and treatment recommendations The result should be sent to the primary care physician, who should initiate treatment. 2003; orthopedic surgeon at the emergency ward 2007; nurse at the orthopedic clinic

63 Sweden, comparison between counties 2010

64 Bisphosphonate prescription in Sweden

65 Problems with FractUp 1. The GPs must accept the patients 2. Continuity regarding orthopedic surgeons and FLN 3. No real control of how many patients that are referred 4. Is the treatment effective?

66 FractUp 2.0 Negotiations started 2011 New program started GPs should be able to treat with Aclasta and Prolia 2. Fracture patients should be identified through Uppsala County computerized charts. 3. DXA with treatment recommendations to GP 4. Severe osteoporosis treated at the osteoporosis unit

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71 Aclasta infusions Uppsala Enköping Tierp Östhammar

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73 FractUp 2.0 All clinics in Uppsala county are using the same electronic chart All diagnoses are entered There is an out data facility Each month the osteoporosis unit obtain data on fractures in Uppsala (femur, vertebra, radius, humerus, pelvis) years of age Patients that are not referred to us via FractUp 1.0 are offered a DXA with answer to their GP

74 FractUp 2.0 Jan 2014 Total 93 Dead 2 Patients at the osteoporosis unit 4 Referred by Fractup Invited for DXA 71 Jan Jul 23% of fracture patients are captured by Fractup % of the patients are not interested in further investigation

75 FractUp 2.0 Data collection # fractures # patients being identified by FLN # patients contacted # patients undergoing DXA # patients with osteoporosis # patients treated Fracture incidence in Uppsala county versus rest of Sweden

77 Osteoporos Patogenes, diagnostik, behandling Östen Ljunggren Tack! Frågor?