Hot Topics in Osteoporosis and Fracture Prevention

Transcription

1 Hot Topics in Osteoporosis and Fracture Prevention Sid Feldman, MD CCFP (COE) FCFP Sandra Kim, MD, FRCPC November 15, 2018 Family Medicine Forum, Toronto

2 Faculty/Presenter Disclosure Faculty: Sid Feldman Relationships with commercial interests: Grants/Research Support: None Speakers Bureau/Honoraria: Osteoporosis Canada, McMaster University (Geras Centre), Centre for Effective Practice, OCFP Consulting Fees: None Other: Employee of Baycrest Health Sciences, College of Family Physicians of Canada (educator). Member Osteoporosis Canada Scientific Advisory Committee (co-chair of guideline development Fracture Risk Assessment working group)

3 Mitigating Potential Bias Will identify Osteoporosis Canada recommendations

4 Faculty/Presenter Disclosure Faculty: Sandra Kim Relationships with commercial interests: Grants/Research Support: None Speakers Bureau/Honoraria: None Consulting Fees: None Other: Physician at Women s College Hospital (WCH), WCH is a stakeholder of the Ontario Osteoporosis Strategy, Chair of Osteoporosis Canada Scientific Advisory Council, Co-Chair of Pharmacotherapy Working Group for Osteoporosis Canada Guidelines Update, Member of the Board of Directors for Osteoporosis Canada

5 Mitigating Potential Bias Will identify Osteoporosis Canada recommendations

6 Disclosure of Commercial Support This program has received no financial support This program has received no in-kind support Potential for conflict(s) of interest: None

7 Learning Objectives Compare fracture risk assessment strategies Explain absolute benefits and harms of treatment Identify when an osteoporosis drug holiday is appropriate or inappropriate Adjust management after fracture while on treatment for osteoporosis

8 What are the consequences of underdiagnosing and undertreating osteoporosis? In women with hip fracture: Fracture begets future fracture Reduced quality of life Long-term care admission Mortality 40% had prior fracture 1 40% need assistance walking 2 18% enter LTC 3 23% die within 1 year 4 Lifetime risk of hip fracture in women >50 years old is 12.1% 5 1. Hajcsar EE, et al. CMAJ 2000, 163: ; 2. Cooper C. Am J Med. 1997:103:12S-19S; 3. Jean et al. JBMR 2012 On-line September Ioannidis G, et al. CMAJ 2009;181: Hopkins et al Osteo Intl 2012; 23:

9 What are the consequences of overdiagnosing and overtreating osteoporosis? Labelling and restricted activities due to fear of falling and fracture Unnecessarily subjected to risks of medication False sense of security from medications that have less benefit than purported Over-testing and over-monitoring (eg. frequency of bone density) 9

10 Comparing fracture risk assessment strategies Strategies for deciding whom to screen with a BMD Choosing Wisely Age criteria Risk factors OST (Others) Strategies for deciding whom to treat Osteoporosis based on WHO bone density criteria (T-score -2.5) CAROC FRAX

11 Don t order DXA screening for osteoporosis on low risk patients. While all patients aged 50 and older should be evaluated for risk factors for OP using tools such as the OST, BMD screening via DXA is not warranted on women under 65 or men under 70 at low risk 11

12 Screening BMD based on age alone Guideline Women Men OC (2010) Choosing Wisely UK NICE (2012) USPSTF (2017) Insufficient evidence Screen younger individuals when risk factors present

13 OC: additional risk factors Fragility fracture after age 40 Prolonged glucocorticoid use Other high-risk medication use* Parental hip fracture Vertebral fracture or osteopenia identified on X-ray Current smoking High alcohol intake Low body weight (< 60 kg) or major weight loss (>10% of weight at age 25) Rheumatoid arthritis Other disorders strongly associated with osteoporosis At least three months cumulative therapy in the previous year at a prednisone-equivalent dose > 7.5 mg daily; * e.g. aromatase inhibitors, androgen deprivation therapy. Papaioannou A, et al. CMAJ 2010;182:

14 Osteoporosis Self-assessment Tool (OST) Weight (kg) Age (years) If 10 or greater, low risk for osteoporosis If < 10, higher risk and should be offered BMD Koh LK et al. Osteoporos Int 2011;12: Korownyk C et al. CFP 2015:61(7) 612

15 Fracture Risk Assessment Risk Factors: Sex Age BMD Fragility fracture after 40 CAROC* FRAX ǂ Systemic glucocorticoid use ( 3 months) Additional Risk Factors: Low BMI Parental history of fracture (especially hip) Current smoking Alcohol intake 3 units/day Rheumatoid arthritis, or other secondary causes of osteoporosis CAROC may add simplicity, requiring only 5 parameters FRAX can be used in the absence of BMD FRAX has country-specific tools; ensure the Canadian version is used Papaioannou A, et al. CMAJ 2010;182: *Canadian Association of Radiologists and Osteoporosis Canada, months in the prior year of a prednisone equivalent dose 7.5mg daily ǂ Fracture Risk Assessment Tool of the World Health Organization 15

16 CAROC or FRAX? OC 2010: CAROC or FRAX Direct comparison using Manitoba data, FRAX outperformed CAROC but requires web access and more time consuming to calculate. (NNS 36) Leslie WD et al. Osteoporos Int DOI /s

17 SCOOP Trial RCT (n=12,000) UK women aged x 5 yrs FRAX vs no screening->bmd if high-risk Use of AOM 78% in high-risk vs 4% in controls Hip fractures reduced from 3.5% to 2.6% (ARR 0.9%, NNT = 111) No difference in all clinical fractures or mortality Shepstone L et al. the Lancet 2018;391:

18 Case: 58yo woman otherwise healthy Recent left wrist fracture from a fall No other risk factors Would you order a screening BMD? Baseline BMD: L1-L4 T-score = -2.8 Femoral neck T-score = -2.5 Total Hip T-score = -2.3 CAROC: high risk FRAX: moderate risk Would you recommend pharmacotherapy?

19 When to treat Moderate risk Further risk stratification (spine xray) Vertebral fracture Wrist fracture > 65yo or with T-score -2.5 Spine T-score much lower vs femoral neck T-score Rapid bone loss High risk for falls ( 2 falls in the past 12 months) Long-term or repeated systemic steroid use that does not meet conventional criteria Other medications or active conditions associated with osteoporosis or bone loss Consider patient preference 19 Papaioannou A, et al CMAJ 2010.

20 RANK Ligand Denosumab RANK Ligand Inhibitor Raloxifene Estrogen Reduce RANK Ligand Bisphosphonates bind to bone inhibit osteoclasts Teriparatide PTH Analog 20

21 Osteoporosis Medication Options Anti-Resorptive (Inhibits Bone Loss) Bisphosphonates Alendronate (Fosamax) Risedronate (Actonel) Zoledronic Acid (Aclasta) Anabolic Agent (Bone Forming) Teriparatide (FORTEO) Denosumab (Prolia) Raloxifene (Evista) Hormone Therapy (Estrogen) Papaioannou A, et al CMAJ 2010.

22 What are the BENEFITS of Medications? Reduce risk of fracture by about 50% Improve or stabilize bone density HIGH risk patients benefit the most

23 Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis Vertebral Fractures *Not available in Canada Odds Lower Upper Ratio Limit Limit P value Odds Ratio and 95% CI Teriparatide Denosumab Zoledronate Risedronate Alendronate Raloxifene *Bazedoxifene *Ibandronate Calcium Vitamin D Vitamin D + Calcium Favours Treatment Favours Control 23 Murad MH, et al. J Clin Endocrinol Metab. 2012;97(6):

24 Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis Hip Fractures *Not available in Canada Odds Lower Upper Ratio Limit Limit P value Teriparatide Alendronate Risedronate *Ibandronate Denosumab Zoledronate Vitamin D + Calcium Raloxifene Vitamin D Calcium Odds Ratio and 95% CI Favours Treatment Favours Control *Not available in Canada 24 Murad MH, et al. J Clin Endocrinol Metab. 2012;97(6):

25 Bisphosphonates NNT and Fractures prevented Variable Type of fracture Any non-vertebral, including hip Number needed to treat (3yr) Events prevented per 1000 pts treated x 3 years Hip Vertebral Any fracture 100 Of the 29, 11 will be hip # Black DM NEJM 2016;374:

26 Denosumab and Fractures Prevented 1 RCT (n = 7808) of denosumab vs. placebo for 3 years Variable RR (95% CI) Number needed to treat (3yr) Type of fracture Any non-vertebral, including hip 0.80 ( ) 6.1% vs. 7.5% 71 Hip 0.60 ( ) 0.7%% vs. 1.2% Vertebral 0.32 ( ) 2.3% vs. 7.2% Cummings SR et al. NEJM. 2009; 361: 756.

27 What are the RISKS of Medications? No medication is absolutely safe All drugs have side effects Safe means that benefits of drug therapy outweigh the risks for a person Rare concerning risks: Osteonecrosis of the Jaw (ONJ) Atypical Femur Fracture (AFF)

28 Osteonecrosis of the Jaw (ONJ) Exposed bone in jaw area for 8 weeks or longer in absence of radiation therapy >90% cases in cancer patients on high dose iv bisphosphonates or high dose denosumab Very rare : 1-90 per 100,000 patient-years exposure Mechanism unclear Accumulative dose effect Associated with invasive dental surgeries, poor dental hygiene and dental infection Khan A, et al. Osteoporos Int 2016

29 Atypical Femur Fracture (AFF) Unusual fracture of femur shaft below hip joint No trauma or minimal trauma Complete or incomplete Rare: 1 to 78 cases in 100,000 patient-years exposure Long duration bisphosphonate Reports with denosumab Unclear mechanism Prodromal thigh pain Up to 60% occur both femurs Shane E et al, JBMR 2014; 29: 1-23

30 Bisphosphonates: Benefits and Harms Based on different studies Variable Type of fracture Any non-vertebral, including hip Number needed to treat (3yr) Events prevented per 1000 pts treated x 3 years Hip Vertebral Any fracture 100 Hypothetical RR of AFF Number needed to harm (3yr) Atypical Fractures associated with treating 1000 women for 3 years , , Black DM NEJM 2016;374:

31 Back to the Case: Treatment on alendronate for 5 years No further falls or fractures Follow-up BMD: stable Should a drug holiday be considered or continue therapy?

32 Bisphosphonate How long to treat? Proven anti-fracture efficacy Therapy for 3-5 yrs in large trials reduced vertebral, non-vertebral and hip fractures Unknown optimal duration of therapy Safety concerns with long-term use Long retention of drug in bones after stopping (Ris < Aln < Zol) Rare but serious adverse events

33 Drug Holiday Concept Interruption of bisphosphonate therapy (drug hiatus) May minimize prolonged drug exposure and reduce risk of adverse events while still maintaining some degree of antifracture benefit from residual anti-resorptive effect of retained drug Unique to bisphosphonates Data to support concept is from extension trials (FLEX, HORIZON) Does NOT apply to denosumab, SERMS, estrogen

34 FDA Analysis CONTINUED Tx: BMD maintained or small increase Suppression of BTM STOPPED Tx: BMD decline at hip Gradual increase in BTM Many women who stopped Alendronate after 5 years or Zol after 3 years, did NOT have increased overall fracture risk (residual benefit) Small subset of women had increased risk of vertebral fracture with discontinuation of treatment (those with prevalent VCF or FN <-2.5) Whitaker M, et al. NEJM 2012;366:

35 Limitations Post-hoc analysis Small sample size Extension trials not powered for fracture Not generalizable (studied in healthy largely white PM women) Concept of drug holiday is based on limited data 35

36 Approach to Duration of Bisphosphonate Treatment Low risk can stop treatment Moderate risk consider drug holiday after 3-5 years High risk likely to benefit from continued treatment esp if high risk fracture (spine/hip #) or multiple #s» Continue bisphosphonate» Switch to another class of agents Individualize decision based on multiple risk factors, benefit to risk ratio and patient preference Brown JP, et al, Canadian Family Physician Adler RA et al, J Bone Miner Res. 2016;31(1):16-35.

37 Factors to Consider for BP Drug Holiday Current fracture risk Age, past fracture at treatment initiation or while on treatment, new drugs or co-morbidities affecting bone health Current BMD Trend (especially at hip sites) Patient characteristics Risks factors for AFF and ONJ Patient preference Which bisphosphonate used and duration Risedronate < Alendronate < Zoledronic Acid How to monitor during the drug holiday? - BMD and bone markers do not appear to be helpful - Clinical fractures, falls, other risk factors - Reassess every 1-3 years Adler RA et al, J Bone Miner Res. 2016;31(1):16-35.

38 How about with Denosumab? FREEDOM extension trial data for 10 years showing continued anti-fracture efficacy and safety Cannot apply drug holiday No skeletal retention once stop therapy: Rapid bone loss (rebound increase bone resorption) Rebound vertebral fractures Denosumab should NOT be stopped without considering alternative treatment to prevent rapid bone loss and potential rebound vertebral fractures 38 Tsourdi E et al, Bone 2017 Cummings S et al, JBMR 2017

39 Denosumab ECTS systemic review and position statement 2017: based on available data, a re-evaluation should be performed after 5 years of denosumab treatment high risk patients should either continue denosumab for up to 10 years or be switched to alternative therapy for low risk patients...decision could be made at 5 years when discontinuing denosumab, bisphosphonate therapy should be considered to reduce or prevent rebound bone turnover however the optimal bisphosphonate regimen postdenosumab is unknown 39 Tsourdi E et al, Bone 2017 Cummings S et al, JBMR 2017

40 Back to the Case: 63F now been on alendronate for 5 years Left wrist fracture from a fall (at age 58) But new right wrist fracture BMD: L1-L4 T-score = -2.5 Femoral neck T-score = -1.9 Total Hip T-score = -2.1 Is this a treatment failure? Should pharmacotherapy be changed? What should be the next steps?

41 New fracture while on therapy Adherence: Adherence is a major issue with bisphosphonates, and fracture rates increase with reduced adherence Fracture risk and risk factors: reassess Secondary cause? Repeat investigations Patient preference Evidence to guide practice? Consider options: continue BP, denosumab, others

42 What predicts fracture while on treatment if adherent? Completed 6 months of therapy (35% of total) Older age Previous fracture Underweight Inflammatory arthritis Use of PPI Vitamin D deficiency Prieto-Alhambra D et al. JBMR 2014;29(1):

43 Adherence Drugs don t work in patients who don t take them. WHO (2003) On average, ½ patients prescribed medications for chronic conditions (e.g. DM, HTN) are not taking them at 1 year. No change in medication adherence rates in over 40 years of studies across many chronic conditions Peyrot P & Rubin RR. Patient Prefer Adherence 2011;5:

44 Effect of compliance on fracture rate <50% marginal benefit >75% Siris ES et al. Mayo Clini Proc 2006;81(8):

45 Adherence Physician communication style critical to improving adherence (OR adherence 1.64) Self-perceived risk: % of women using anti-osteoporosis medication 50% at 5 years if SPR is high, versus 15% if low Family Cohesion: OR 1.74 times higher in cohesive families and OR 1.53 time lower in families with conflict Molfenter TD & Brown RL. Gen Med (Los Angel) 2014;2 DiMAtteo MR. Health Psychol 2004;23: Litwic AE et al. Osteop Int 2017;28:

46 Summary Osteoporosis is a potentially game-changing illness with potential for significant morbidity and mortality Identify fracture risk and treat high risk patients Consider drug hiatus in appropriate patients if on bisphosphonate Beware: drug holiday cannot be applied to denosumab Adherence critical to successful treatment

47 Questions?

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49 Extra Slides

50 FLEX trial: Extension Trials Compared 5 yrs vs. 10yrs of Alendronate Women on Aln for 5 yrs HORIZON extension: Compared 3 yrs vs. 6 yrs of Zoledronic acid Women on Zol for 3 yrs Aln for another 5 yrs Placebo for 5 yrs Zol for another 3 yrs Placebo for 3 yrs Primary outcome: change in BMD Exploratory outcome: fracture incidence

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