Dr. Chih Hao Chen Ku, FACE Endocrinology Unit, San Juan de Dios Hospital Clinical Pharmacology and Toxicology Department, University of Costa Rica

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1 Op*mizing biphosphonate therapy in osteoporosis Dr. Chih Hao Chen Ku, FACE Endocrinology Unit, San Juan de Dios Hospital Clinical Pharmacology and Toxicology Department, University of Costa Rica Conflicts of interest Speaker: Astra Zeneca, AbboR Nutrición, Novar*s Oncology, Novo Nordisk, Merck Sharp & Dohme, Roche, Glaxo SmithKline, Sanofi Aven*s Advisory Board: Novar*s Oncology, Sanofi Aven*s, Astra Zeneca, Novo Nordisk, Stendhal Clinical research: Astra Zeneca, Novar*s Pharma Logis*cs Inc., Merck Sharp & Dohme, Glaxo SmithKline, Organon, Boehringer Ingelheim, Roche, Novo Nordisk Agenda How can we ID the pa*ent that will benefit most with treatment? Treatment for how long? When should we restart treatment? How can we improve adherence? 1

2 Case discussion 55 years old female pa*ent, spontaneous menopause at 49 years A rou*ne bone scan was performed Asymptoma*c No comorbidi*es Non smoker, does a lirle bit of exercise BMI 25 kg/m2 Femoral neck BMD Caso clínico What is this pa*ent s fracture risk? High Low How should we treat her? Non pharmacologic measures Oral biphosphonates Intravenous biphosphonates Denosumab teripara*de Different hypothe*cal scenarios Pa#ent 1 Pa#ent 2 Pa#ent 3 Age Previous fracture No No No Femoral neck BMD BMI FRAX total 6.7% 10% 15% FRAX hip 2.7% 4.1% 6.4% Low RAR, highnnt. For how long should we treat? 2

3 Introduc*on Presence or not of osteoporosis defined by BMD does not mandate pharmacologic treatment, it should be based on fracture risk rather than BMD Fragility fractures: when it is associated with a low BMD and its incidence increases ajer age 50 Most ojen: hip, spine, forearm Hurlund E. Arch Osteoporos. 2013;8:136 BMD and fracture risk Hurlund E. Arch Osteoporos. 2013;8:136 Inclusion criteria Drug Study Inclusion criteria Alendronate FIT Women years with T <- 1.6 in femoral neck, 50% with fractures Risedronate VERT <85 years with more than 5 years of menopause and at least one vertebral fracture and T <- 2 Ibandronate BONE Women years with >5 years of menopause and 1-4 vertebral fractures and T between and in more that 1 vertebrae Zoledronate HORIZON Postmenopausal women years with T <- 2.5 with or without vertebral fractures or <- 1.5 with at least 2 vertebral fractures 3

4 Criterios de inclusión Drug Study Inclusion criteria Ranelato stroncio TROPOS >74 years with femoral neck <- 2.5 or years with an addi*onal risk factor (previous fracture, ins*tu*onalized, frequent falls or family history of fractures) Raloxifeno MORE At least 2 years post menopause, femoral neck or lumbar <- 2.5, and another group with at least 1 vertebral fracture Efficacy: vertebral fracture reduc*on Drug Study ARR NNT Alendronate FIT 7.0% 15 Ibandronate BONE 4.9% 21 Risedronate VERT- NA 5.0% 20 Zoledronate HORIZON 7.6% 14 Raloxifeno MORE 6.5% 16 Ranelato stroncio SOTI 11.9% 9 Teripara*de Neer et al 9.0% 12 Denosumab FREEDOM 4.9% 20 Modificado de Ringe JD. Rheumatol Int. 2010;30:863 Cummings SR. N Engl J Med. 2009;361:756 Hip fracture reduc*on Drug Study ARR NNT Alendronate FIT 1.1% 91 Risedronate HIP 1.1% 91 Zoledronate HORIZON 1.1% 91 Ranelato stroncio TROPOS 2.1% 48 Ringe JD. Rheumatol Int. 2010;30:863 4

5 Hypothe*cal scenarios Pa#ent 1 Pa#ent 2 Pa#ent 3 Age Previous fracture No No No Femoral neck BMD BMI FRAX total 6.7% 10% 15% FRAX hip 2.7% 4.1% 6.4% NNT Low ARR, high NNT. For how long should we treat? Analysis How can we apply these results to the real world? NNT depends on pa*ent s risk Choose the right pa*ent so we can op*mize risk/benefit Effects in mortality? That s the hardest endpoint Mortality metanalisis Bolland MJ. J Clin Endocrinol Metab. 2010;95:1174 5

6 WHO SHOULD WE SCREEN? When should BMD be measured? NOF Measure height annually DEXA: Women >65 years and men >70 years Men and postmenopausal women between 50 and 69 years based on risk profile Men and women over 50 years with a fragility fracture Cosman F. Osteoporosis Int. 2014; online aug 15 When to perform images? NOF Cosman F. Osteoporosis Int. 2014; online aug 15 6

7 Screengin USPSTF It is not indicated unless it changes clinical decisions Screening recommended in: All women over 65 years All postmenopausal women with medical condi*ons that will lead to bone loss (HPT, chronic GC therapy) >50 years with risk factors Low trauma fractures NAMS. Menopause. 2010;17:23 Screening USPSTF In women with less than 65 years: 50 years old women, BMI <21 kg/m2, daily alcohol intake, family history of hip fracture 55 years old women with family history of hip fracture 60 years old women with BMI <21 kg/m2 and daily alcohol intake 60 years old women, smoker and daily alcohol intake USPSTF. Ann Int Med. 2011;154:356 Therefore Screening usually is recommended for women over 65 years Younger women only with risk factors In every person with a low trauma fracture 7

8 Why screen ajer 65 years? In younger women, there is no experience with treatment The main issue is to treat fracture risk rather than a BMD threshold Therefore it is not recommended to perform universal screening in younger low risk women RISK STRATIFICATION FIT no baseline vertebral fracture Cummings SR. JAMA. 1998;280:2077 8

9 FIT Cummings SR. JAMA. 1998;280:2077 HIP Women over 80 years A risk factor for hip fracture: Femoral neck <- 4 Femoral neck <- 3 plus hip axis length over 11.1 cm Clinical risk factor: Trouble standing ajer being seated Gait problems Injury due to falls in the last year Ac*ve smoker in the last 5 years Maternal hip fracture McClung MR. N Engl J Med. 2001;344:333 McClung MR. N Engl J Med. 2001;344:333 9

10 Why risk stra*fica*on? It is a fundamental exercise in every primary preven*on interven*on To op*mize risk/benefit rela*onship The higher the risk, higher the benefit Adverse effects risk does not depend on fracture risk, it depends on other risk factor such as polipharmacy Black DM. N Engl J Med. 2016;274:254 10

11 Medica*ons ajer hip fracture Solomon DH. J Bon Min Res. 2014;29:1929 HOW LONG SHOULD WE TREAT? LONG TERM ANTIFRACTURE EFFICACY? 11

12 Black DM. JAMA. 2006;296:2927 Black DM. JAMA. 2006;296:

13 Black DM. JAMA. 2006;296:2927 FLEX: BMD at 5 th year and fracture predic*on Schwartz AV. J Bone Min Res. 2010;25:976 Black DM. J Bone Miner Res. 2012;27:243 13

14 Black DM. J Bone Miner Res. 2016;30:934 HORIZON 9 years Black DM. J Bone Min Res. 2014;30:934 Black DM. J Bone Miner Res. 2016;30:934 14

15 HOW CAN WE PREDICT THERAPEUTIC FAILURE? BMD loss under treatment Chapurlat RD. Osteoporosis Int. 2005;16:842 LONG TERM SAFETY 15

16 Wysowski DK. Bone. 2013;57:423 PROBE 8572 pa*ents Prevalence of 0.10% (IC ) Older NNH age pa*ents of 1100 during 3 years Fracture reduc*on 79 cases Longer exposure *me to biphosphonates 28 cases per pa*ents year with biphosphonate treatment Very important to diagnose correctly Lo JC. J Oral Maxillofc Surg. 2010;68:243 Subtrochanteric fractures (atypical) 16

17 Dell R. J Bone Miner Res. 2012;27:2544 Black DM. N Engl J Med. 2016;274:254 Atypical subtrochanteric femoral fractures It is not clearly related to biphosphonates It may present in pa*ents not exposed to biphosphonates The same pa*ents that are candidates to treatment with biphosphonates have a higher risk of ASFF Mechanism not clearly established 17

18 WHEN SHOULD WE HAVE A DRUG HOLIDAY? Adler RA. J Bone Min Res. 2016;31:16 Villa JC. HSS Journal. Online 9 dec

19 Long term treatment High risk pa*ents: Low BMD T <- 2.5 Previous history of vertebral fractures Con*nuous high dose GC use High bone turnover markers Consider it in: Pa*ents that keep increasing BMD Bone turnover markers not severely suppressed Villa JC. HSS Journal. Online 9 dec MONITORING DURING DRUG HOLIDAY Monitoring No evidence based medicine Consider restart therapy if: High bone turnover markers BMD decrease of >4% A new fracture Villa JC. HSS Journal. Online 9 dec

20 Villa JC. HSS Journal. Online 9 dec HOWEVER, ALL THIS DISCUSSION IS RELEVANT ONLY IF PATIENT IS ADHERENT TO TREATMENT Canadá Discon*nua*on RR 2x Kanis JA. Osteoporosis Int. 2012;23:213 20

21 Persistence ajer 1 year Ringe JD. Rheumatol Int. 2009;30:213 Changes in DEXA Ringe JD. Rheumatol Int. 2009;30:213 Other resources use 6962 pa*ents 10 mg original alendronate 70 mg original alendronate 10 mg generic alendronate (Teva) 10 mg generic alendronate (Unipharm) Adherence RR 1.3 with original Use of gastric medica*ons RR 0.71 with original Halkin H. Ann Pharmacoth. 2007;41:29 21

22 Non adherents vs adherents No vertebral Vertebral clínico Colles Cadera 0 0,5 1 1,5 2 2,5 > Cur*s JR. J Bone Min Res. 2008;23:1435 Conclusions It is fundamental to stra*fy fracture risk in each pa*ent Start biphosphonate therapy in pa*ents at high risk so we can op*mize risk/benefit rela*onship Consider it always ajer a fragility fracture Consider drug holiday depending on risk profile Adherence is essen*al for an*fracture efficacy Ques#ons chenku2409@gmail.com EndoDrChen.Com 22