Denosumab for the Treatment of Osteoporosis

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New Osteoporosis Therapy

Clinical Benefits of Denosumab for the Treatment of Osteoporosis

한일병원 내분비내과 신 미 선 Previous osteoporosis Tx.

# Strontium: 심혈관 질환 증가로 다른 약제 사용할수 없는 경우 사용, 사용전에 심혈관 질환 위험성 평가하고 투여, 희귀의약품 센터 구입 Case

• 81/F

• 65세 BMD L-spine T score -2.7/ femur -2.9

 10년간 Fosamax® (alendronate) 투여

 임플란트 치료하게 되면서 약제 변경,

3년간 Evista® (raloxifene) 복용

 Vertebral Fx. 발생 !

 Fosamax® (alendronate) 로 변경하여 3년 투여

 BMD L-spine T score -2.1/ femur -3.5, Rib Fx. 발생. Case

• 이 환자에서의 선택은 ?

① Bisphosphonate (Fosamax® ) 를 그대로 유지한다.

② Bisphosphonate 중 효과가 강한 Zoledronic acid로 변경한다.

③ Teriparatide (Forsteo ® or Teribone ®)로 변경한다.

④ Denosumab (Prolia ®)로 변경한다. NEW osteoporosis Tx. Contents

• Mechanism of action and pharmacological profile • Efficacy of denosumab on fracture protection • Long-term efficacy profile of denosumab • Safety profile of denosumab in short and long-term • Right time to switch and long-term management of osteoporosis • Summary & conclusion Bisphosphonate vs. Denosumab

. Preferentially calcium binding . Accumulates at high concentrations only in bone . Inhibit osteoclast activity, induce osteoclast apoptosis

. Repeated doses accumulate in bone, continues to be released for months or years Osteoclast after treatment is stopped. . Terminal half life: similar to bone mineral, approximately 10.5Yrs Bisphosphonate vs. Denosumab

• Fully human IgG2 monoclonal antibody, High-affinity and highly specific targeting RANKL . Inhibition of osteoclast formation, function, and survival  Bone resorption inhibition

. Is not incorporated into bone . Fast action, reversible effect

. RANKL: primary signal for bone removal . No dose adjustment required for patients with renal RANKL, receptor activator of nuclear factor-κB legends RANK, receptor activator of nuclear factor-κB. impairment OPG, osteoprotegerin Pharmacokinetic and Pharmacodynamic Properties of Denosumab

• Due to the large molecular weight, it is not metabolized by the liver or cleared through the kidneys • Reduction in bone turnover markers within 3 days and sustained for up to 6 months • Serum denosumab concentrations declined over 4–5 months

• Dosing schedule: every 6 months McClung MR, et al. N Engl J Med. 2006;23:821-831. Peterson MC, et al. J Bone Miner Res. 2005;20(suppl 1):S293. Contents

Effects of various bisphosphonates on clinical vertebral fractures, Harrison 19th Denosumab: FREEDOM study

68% ↓ 40% ↓

20% ↓

PM women, N=7868, denosumab vs. placebo, 3 yr f/u. NEJM, 2009;361(8):756-65 Incidence of hip fracture increases in old ages The Effect of Denosumab on New Hip Fractures The Pivotal Phase 3 Trial – Higher Risk Sub-analysis

Boonen S, et al. J Clin Endocrin Metab. 2011;96:1727-1736. Contents

FIT1,2 RCT – FLEX3 Alendronate Alendronate (N=3236) Alendronate 5 mg (N=329) or 10 mg (N=333) Placebo (N=3223) Placebo (N=437)

7 VERT-MN/NA4,5 RCT – EXT6 OL-EXT RIS 7 yrs (N=83) Risedronate Risedronate (N=407) Risedronate (N=135) PBO 5 yrs/Ris 2yrs Placebo (N=407) Placebo (N=130) (N=81)

HORIZON-PFT8 RCT – EXT9 RCT – EXT10 Zoledronic acid Zoledronic acid (N=3889) Z6 (N=616) Z9 (N=95) Placebo (N=3876) Z3P3 (N=617) Z6P3 (N=95)

MORE11 CORE12 Raloxifene Raloxifene (N=5129) Raloxifene (N=2725) Placebo (N=2576) Placebo (N=1286)

FREEDOM17 OL-EXT18 Denosumab Denosumab (N=3933) Denosumab 10 yrs+ (N=2343) Placebo (N=3935) Placebo 3 yrs/Denosumab 7 yrs+ (N=2207)

Years 1 2 3 4 5 6 7 8 9 10

*FREEDOM extension study is now complete in Australia and due for completion globally in 2015. Note: Treatment with teriparatide has been excluded as is limited to 18 months in Australia. 1. Black DM, et al. Lancet 1996;348:1535–41; 2. Cummings SR, et al. JAMA 1998;280:1077–2082; 3. Black DM et al. JAMA 2006;296:2927–38; 4. Reginster JY, et al. Osteoporos Int 2000;11:83–91; 5. Harris ST, et al. JAMA 1999;282:1344–52; 6. Sorensen OH, et al. Bone 2003;32:120–6; 7. Mellström DD, et al. Calcif Tissue Int 2004;75:462–8; 8. Black DM, et al. N Engl J Med 2007;356:1809–22; 9. Black DM, et al. J Bone Miner Res 2012;27:243–54; 10. Black DM, et al. J Bone Miner Res 2015;30:934–44; 11. Ettinger B, et al. JAMA 1999;282:637–45; 12. Siris ES, et al. J Bone Miner Res 2005;20:1514–24; 13. Meunier PJ, et al. N Engl J Med 2004;350:459–68; 14. Reginster J-Y et al. J Clin Endocrinol Metab 2005; 90:2816–22; 15. Reginster J-Y et al. Bone 2009;45:1059–64; 16. Reginster J-Y et al. Osteoporos Int 2012;23:1115–22; 17. Cummings SR, et al. N Engl J Med 2009;361:756–65; 18. Papapoulos S, et al. Osteoporos Int 2015;26:2773–83. Effect of Long-term Alendronate Treatment

Total Hip BMD Changes from FIT Baseline

1. Adapted from Black DM, et al. JAMA 2006;296:2927–38; 2. Schwartz, AV, et al. J Bone Miner Res 2010;25:976–82. Effect of Long-term Zoledronate Treatment

• 6 Years of ZOL Treatment Maintains Increases in Femoral Neck BMD • Similar Risk of Nonvertebral Fracture in • Significantly Fewer New Morphometric Vertebral Years 3 to 6 (Z6 vs Z3P3) Fractures in Years 3 to 6 (Z6 vs Z3P3) Effects of Denosumab on Lumbar Spine BMD and New Vertebral Fractures Through 10 Years Effects of Denosumab on Total Hip BMD and Nonvertebral Fractures Through 10 Years Differing effects of denosumab and alendronate on cortical and trabecular bone

Adapted from Zebaze RM et al. Bone 2014; 59:173 - 179 BPs & denosumab are distributed differently

Bisphosphonates are rapidly Denosumab circulates in blood absorbed to bone surfaces at sites and extracellular fluid including of bone turnover, thought to act bone tissue, can reach both primarily on trabecular bone1-3 trabecular and cortical bone1,4

ALN on bone surfaces at 24 hrs Control Denosumab

Trabecular bone ALN ALN

Blood Vessel Tibial Cortex

1. Baron R et al, Bone 2011;48: 677-692. 2. Kimmel DB J Dent Res 2007;86:1022-1033 3. Masarachia P, et al. Bone 1996;19:281-290. 4. Kostenuik PJ, et al. J Bone Miner Res 2009;24:182-195 Proposed mechanisms for the long-term increase in cortical bone volume and total hip BMD

• Clinical outcomes with 5 years of denosumab likely reflect closing of the remodeling space and increases in secondary mineralization of bone matrix.

• Additional mechanisms may contribute to long-term clinical outcomes, including reduction in cortical porosity and modeling-based bone formation. Effects of Denosumab: Cortical Porosity

• Maintained trabecular architecture • Increased cortical mass and thickness • Decreased cortical porosity – greater with denosumab vs alendronate

Compact cortex

Control Alendronate

Denosumab 29 year old 93 year old Images courtesy of Dr. Roger Zambaze

Zebaze RM, Bone 2014;59:173–9 Denosumab increases hip cortical thickness at 36 months

• Femoral cortical bone of 80 PMO women aged >74 in FREEDOM were analyzed by Q- CT. Cortical mass and thickness were significantly increased in denosumab group1

Anterior Posterior

Placebo

Denosumab

Poole K et al. JBMR;2015:30:46-54. Contents

ONJ in the US FDA’s adverse event reporting system (FAERS), JBMR 2016: 31(2):336–340 Atypical femoral fractures

• 2 AFFs (8 per 100,000 person-years) were reported with the prolonged use of denosumab (up to 7 or 10 years) in treatment-naïve postmenopausal women with osteoporosis (Bone HG et al., 2017)

• One in the long-term, year 4 of denosumab

• One in the cross-over, year 3 of denosumab

• Incidence rates of AFF range from 1.8 per 100,000 cases per year with a 2-year BP exposure to 113.1 per 100,000 cases per year with BP exposure from 8 to 9.9 years (Shane et al., 2014).

Bone HG et al. Lancet Diabetes Endocrinol. 2017;5(10):768-769. Adverse Events Over 36 Months

• The overall safety profile of denosumab was similar to that in the placebo group

Denosumab Placebo 60 mg Q6M Adverse events, n (%) (n = 3,876) (n = 3,886) P value All adverse events 3,607 (93.1) 3,605 (92.8) 0.91

Serious adverse events 972 (25.1) 1,004 (25.8) 0.61

Deaths 90 (2.3) 70 (1.8) 0.08

AEs leading to study discontinuation 81 (2.1) 93 (2.4) 0.39

AEs leading to discontinuing the study drug 202 (5.2) 192 (4.9) 0.55

Cummings SR, et al. N Engl J Med. 2009;361:756-765. Exposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Subject-years)

Extension Years 1–7 Cross-over Denosumab (N = 2206) Long-term Denosumab (N = 2343) Year 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Serious 1.6 1.5 1.1 1.6 1.3 2.2 2.1 1.3 1.2 1.7 2.4 1.2 1.5 2.6 infections Malignancies 1.9 1.7 2.1 2.8 2.2 2.6 2.7 1.9 2.5 1.9 2.8 1.7 2.6 1.6

FREEDOM Years 1–3 Extension Years 1–7 Placebo Cross-over Denosumab Long-term Denosumab (N = 3883) (N = 2206) (N = 2343) All AEs 156.1 96.8 97.0 Infections 30.7 20.7 19.9 Malignancies 1.6 2.0 2.0 Eczema 0.6 0.9 0.9 Hypocalcemia < 0.1 < 0.1 < 0.1 Pancreatitis < 0.1 < 0.1 < 0.1 Serious AEs 10.4 10.1 10.3 Infections 1.3 1.4 1.5 Cellulitis or erysipelas < 0.1 < 0.1 < 0.1 Fatal AEs 0.8 0.8 0.8 Osteonecrosis of the jaw 0 < 0.1 < 0.1 Atypical femoral fracture 0 < 0.1 < 0.1 Contents

Adler RA et al. J Bone Miner Res 2016;31(1):16–35. Previous BP  BPs or Denosumab

Recknor C et al. Obstet Gynecol. 2013; 121:1291-9; Data are least-squares means and 95% confidence intervals. ap < 0.0001; bp < 0.001. ALN, alendronate; BMD, bone mineral density; DMAb, denosumab; IBN, ibandronate; Kendler DL et al. J Bone Miner Res. 2010; 25(1):72-81. RIS, risedronate; ZOL, zoledronic acid. Roux C et al. Bone. 2014; 58:48-54 Daily PTH  oral BPs or Denosumab

TPTD, teriparatide; BP, bisphosphonate; DMAb, denosumab; LS, lumbar spine; TH, total hip; FN, femoral neck; TRACP-5b, isoform 5b of tartrate-resistant acid phosphatase; PINP, N- terminal type I procollagen propeptide; ucOC, undercarboxylated osteocalcin; PTH, parathyroid hormone; ALN, alendronate; RIS, risedronate; MIN, minodronate; SC, subcutaneous Injection. Ebina K, et al. J Bone Miner Metab. 2017;35:91-98. Daily PTH  oral BPs or Denosumab

Figure Mean ± standard error (SE) change from baseline bone mineral density (BMD) in the lumbar spine, total hip and femoral neck. * p<0.05, ** p<0.01, *** p<0.001 change from baseline within each treatment group. # p<0.05, ## p<0.01 switch-to-BP group versus switch-to-DMAb group BP, bisphosphonate; DMAb, denosumab; BMD, bone mineral density.. Ebina K, et al. J Bone Miner Metab. 2017;35:91-98. Long-term strategy of osteoporosis management

• Denosumab (Prolia®) has a unique mechanism of action, providing strong antiresorptive activity and reversibility • Denosumab provides sustained fracture protection throughout the skeleton: vertebral, non-vertebral and hip over 10 years • Denosumab treatment beyond 3 years was associated with a further reduction in non-vertebral fracture rate • Denosumab provides greater BMD gains compared to bisphosphonate continuation • Denosumab is a well tolerated treatment with up to 10 years clinical trial experience Conclusion

• Denosumab is an attractive first line agent for treating postmenopausal osteoporosis and the best current choice for long-term management of osteoporosis Denosumb (Prolia®)

1. 폐경 후 여성 골다공증 환자의 치료 2. 남성 골다공증 환자의 골밀도 증가를 위한 치료 3. 글루코코르티코이드 유발성 골다공증의 치료 및 예방 4. 안드로겐 차단 요법을 받고 있는 비전이성 전립선암 환자의 골 소실 치료 5. 아로마타제 저해제 보조요법을 받고 있는 여성 유방암 환자의 골 소실 치료

• 1 syringe (Denosumab 60mg)를 매 6개월마다 피하 주사. • 모든 환자는 칼슘 1000mg과 비타민D 400IU 이상을 매일 복용해야 한다. • 정기 투여일에 투여하지 못했을 경우, 가능한 빨리 투여한다. 골다공증 치료 – 보험 기준

약제 투여대상 투여기간 칼슘, estrogen 제제 DXA BMD T-score ≤ -1.0 (검사지 첨부 않음)

가): 1년 (2회) Elcatonin 제제, 가) 중심골 [요추, 대퇴(Ward's SERM 제제, triangle 제외)〕: 나): 3년 (6회) 활성형 Vit D3 제제 DXA BMD T-score ≤ -2.5 Bisphosphonate 제제, 추적 검사상 Denosumab 나) 방사선 촬영 등에서 골다공증성 T-score ≤ -2.5 로 약제투여가 계속 (검사지 등 첨부) 골절이 확인된 경우 필요한 경우는 급여

* 단순 X-ray는 골다공증성 골절 확인 진단법으로만 사용 가능 2019.4.1. 시행, 고시 제 2019-57호 Thank you for your attention !