Osteoporos Patogenes, diagnostik, behandling Östen Ljunggren Osteoporosenheten Akademiska sjukhuset Uppsala
Osteoporos Patogenes, diagnostik, behandling 1. Lite om sjukdomspanoramat 2. Patogenes 3. Diagnostik 4. Behandling 5. Kommer det nya behandlingar? 6. Vårdprogram
The disease(s)
Osteoporotic fractures 70 000 / year in Sweden (19 000 hip fractures)
Estimated increase in hip fractures (x1000) 37 8 742 19902050 40 0 668 19902050 3250 629 10 0 19902050 60 0 1990 2050 www.iofbonehealth.org/health-professionals/about-osteoporosis/epidemiology.html
Osteoporos är en kronisk sjukdom Folksjukdom, vårdprogram och hälsoekonomi behövs Men, ibland svårt att bara följa vårdprogram
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;94:646-650
Osteoporosis Enhanced resorption -Hypogonadism -Hyperparathyreoidism Impaired formation Severe Osteoporosis - Aging -Glucocorticoids Boyde A, London Male, age 89 years
Osteoporosis WHO - Definition, 1994 Spine (L1-L4) Hip (Tot, Neck) Normal BMD = T-score >-1 Osteopenia = T-score -1 - -2.5 Osteoporosis =T-score < -2.5 Manifest OP = BMD < -2.5 + fracture
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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Vem skall vi utreda? Att identifiera patienten Frakturpatienter Osteoporos enl DXA Patienter med nög risk för fraktur
Osteoporos Patogenes, diagnostik, behandling 1. Lite om sjukdomspanoramat 2. Patogenes 3. Diagnostik 4. Behandling 5. Kommer det nya behandlingar? 6. Vårdprogram
Åtgärd Riskfaktor Fraktur Kost Motion Reducera fallrisk Livsstil, omgivning Osteoporos Fallolycka
Åtgärd Riskfaktor Fraktur Kost Motion Reducera fallrisk Livsstil, omgivning Läkemedel Osteoporos Fallolycka
Drug targets Osteoclasts -Antiresorptive treatment Osteoblasts -Anabolic treatment
Treatment of osteoporosis 1995 Estrogen Bisphopshonates (in trials) Calcitonin, iv Calcium (Vit D)
Treatment of Osteoporosis 2013 Alendronat Risedronate Ibandronate Didronate Zoledronate Calcitonin Denosumab Raloxifene Teriparatide PTH1-84 Sr-ranelate Calcium Vitamin D (HRT)
Treatment of Osteoporosis 2013 Alendronat Risedronate Ibandronate Didronate Zoledronate Calcitonin Denosumab Raloxifene Teriparatide PTH1-84 Sr-ranelate Calcium Vitamin D (HRT)
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
Vitamin D Källor: Solljus Mejeriprodukter Fet fisk
Vitamin D behövs för att osteoblaster skall kunna mineralisera ben Svår vitamin D brist leder till rakit/osteomalaci Osteoid x (CaxPO4) ---------------- Pyrophosphate
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=1285 85 75 65 55 45 35 25 15 5 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 38.8 25(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
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
Cochrane 2005
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
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
Percetnage of patients with new fractures Alendronate in postmenopausal osteoporosis Fractures 6 5 4 3 2 55% reduction p<0.001 51% reduction p<0.01 2027 postmenopausal women 55-80 years old osteoporosis vertebral fracture Treatment for 3 years Fosamax 10 mg daily placebo 500 mg calcium + 250 IU vitamin D 1 0 placebo Fosamax placebo Fosamax Clinical vertebral fractures Hip fractures Black, et al. Lancet 1996; 348:1535-1541
Bisphosphonates
Cumulative Incidence (%) Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) 3 Placebo (n = 3861) ZOL 5 mg (n = 3875) P <.0001 75% (60%, 85%) 2 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 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 1054 31
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;423:337-342. Bone Resorption 2009 Amgen. All rights reserved. Do not copy or distribute.
Incidence at Month 36 (%) The Effect of Denosumab on Fracture Risks at 36 Months 9% 8% 7% 68% P < 0.001 7,2% 8,0% 20% P = 0.01 Placebo Denosumab 6% 6,5% 5% 4% 3% 2% 2,3% 40% P = 0.04 1% 0% 1,2% New Vertebral Nonvertebral Hip 0,7% Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65
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 10.1002/jbmr.536 Boonen S et al. J Clin Endocrin Metab. 2011;96:1727-1736.
Antiresorptive treatment Alendronate (FIT) Once Weekly Injectable Bisposphonates Denosumab
Antiresorptive treatment Alendronate (FIT) Once Weekly Injectable Bisposphonates Denosumab As good as it gets?
Fracture reduction due to antiresorptive treatment 65-70% 20% 40-60%
Treatment of osteoporosis *Anabolic treatment PTH 1-34 *Antiresorptive treatment alendronate zoledronate denosumab (raloxifen) *Calcium och Vitamin D *Life style, Fall prevention, Hip protectors
Teripartide Concentration (pg/ml) Serum Calcium Concentration (mmol/l) Temporal Profiles of Serum Teriparatide and Calcium Concentrations after Injection in Postmenopausal Women with Osteoporosis 250 200 150 100 50 ULN SCa 10.5 mg/dl 2.8 2.6 2.4 2.2 0 0 4 8 12 16 20 24 Time Since Last Dose (Hours) Krege JH et al., Program & Abstracts ENDO 2004, June 16-19, 2004, #P2-260, page 369 2.0 Teriparatide (20 ug) Concentrations Serum Calcium Concentrations
Modeling Osteon Treatment with PTH 1-34 Eriksen et al., Calcif Tissue Int 2003:72(4):329 2004
New Vertebral Fractures During Fracture Prevention Trial PTH 1-34 7 6 Placebo TPTD20 5 4 3 Patients (%) 2 1 0 22 448 18 444 28 448 * 4 444 14 448 0 444 Mild Moderate Severe *P<0.001 vs Placebo *
Percent Change in BMD Mean ± SE 10 8 6 4 2 0 Lumbar Spine BMD 0 3 6 12 18 Endpoint Months Teriparatide Alendronate Alendronate N= 195 184 173 159 148 195 Teriparatide N= 198 183 178 170 156 198 Saag KG et al. N Eng J Med. (2007); 357:2028-39 P<0.001 Teriparatide vs. Alendronate
Number of Patients with New Vertebral and Nonvertebral Fractures Alendronate Teriparatide P-value Vertebral radiographic 10/165 (6.1%) 1/171 (0.6%) 0.004 Clinical vertebral 3/165 (1.8%) 0/171 (0%) 0.07 Nonvertebral 8/214 (3.7%) 12/214 (5.6%) 0.362 Nonvertebral fragility 3/214 (1.4%) 5/214 (2.3%) 0.455 Saag KG et al. N Eng J Med. (2007); 357:2028-39
Future therapies? Kathepsin K inhibitors? Anti-Sclerostin?
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
Odanacatib in postmenopausal osteoporosis 399 postmenopausal women 55-85 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 + 5600 IU vitamin D weekly Bone et al. JBMR epub 2010
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).
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)
In the future? New bone specific drugs? Drugs against sarcopenia? Learn to use the drugs that we have!
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
Burden of Disease Osteoporosis 2013 Bone Cell Biology -RANK/RANKL -Sclerostin (LRP5-Wnt) Treatment options Antiresorptive Anabolic Fracture Prediction Health Economy
Osteoporos Patogenes, diagnostik, behandling 1. Lite om sjukdomspanoramat 2. Patogenes 3. Diagnostik 4. Behandling 5. Kommer det nya behandlingar? 6. Vårdprogram
Behandlingsrekommendationer SBU -97, -03 (evidensgranskning) LV -98, -01, -04, -07 SvOS riktlinjer (ingen myndighet) LFN riktlinjer för subvention (Forsteo) Lokala vårdprogram Socialstyrelsen 2012
Socialstyrelsens rekommendationer gällande osteoporos Rekommendationer mer rangordning 1-10 -beräkna frakturrisk -mäta bentäthet -behandla med farmaka -fysisk träning Icke göra -kyfo och vertebroplastik -behandling med kalcium och vitamin D som monoterapi.
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)
Osteoporos Läkemedel idag, Uppsalas prioritering Indikation: LV konsensus 2007 1: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
Vem skall vi utreda? Att identifiera patienten Frakturpatienter Osteoporos enl DXA Patienter med nög risk för fraktur
Frakturkedjor
FractUp Fractures in Uppsala County Pop: 350.000
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
Sweden, comparison between counties 2010
Bisphosphonate prescription in Sweden
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?
FractUp 2.0 Negotiations started 2011 New program started 2014 1. 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
Aclasta infusions Uppsala Enköping Tierp Östhammar
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) 65-85 years of age Patients that are not referred to us via FractUp 1.0 are offered a DXA with answer to their GP
FractUp 2.0 Jan 2014 Total 93 Dead 2 Patients at the osteoporosis unit 4 Referred by Fractup1.0 16 Invited for DXA 71 Jan Jul 23% of fracture patients are captured by Fractup 1.0 35% of the patients are not interested in further investigation
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
Osteoporos Patogenes, diagnostik, behandling 1. Lite om sjukdomspanoramat 2. Patogenes 3. Diagnostik 4. Behandling 5. Kommer det nya behandlingar? 6. Vårdprogram
Osteoporos Patogenes, diagnostik, behandling Östen Ljunggren Tack! Frågor?