Anti-Osteoporotic drugs Old & New 분당서울대학교병원 내분비내과 김 경 민

Formation by Osteoblast Resorption by Osteoclast Osteoblasts Osteoclasts Balanced Bone Remodeling Resorption Rate = Formation Rate No Net Bone Loss Imbalanced Bone Remodeling Resorption Rate > Formation Rate Net Bone Loss Formation by Osteoblast Resorption by Osteoclast Osteoclast Osteoblast

Anti-resorptive therapy Anabolic therapy Anti-resorptive therapy

Teriparatide (Weekly) OLD NEW Selective Estrogen Receptor Modulator Denosumab Bisphosphonates Teriparatide (daily) Teriparatide (Weekly)

Teriparatide (Weekly) OLD NEW Selective Estrogen Receptor Modulator Denosumab Bisphosphonates Teriparatide (daily) Teriparatide (Weekly)

Denosumab

Denosumab

Denosumab

Denosumab FREEDOM Study (Phase 3) Multinational, randomised, double-blinded trial of 7,868 po stmenopausal women The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every Six Months) Study was a Phase 3 study that evaluated the efficacy and safety of Prolia® in treating women with postmenopausal osteoporosis.1 The study protocol randomly assigned patients to receive:1 Prolia® 60 mg subcutaneous injection administered Q6M Placebo subcutaneous injection administered Q6M Follow-up continued for 3 years. The primary endpoint was the incidence of new vertebral fractures.1 Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:1-10. Cummings SR, et al. N Engl J Med. 2009;361:1-10.

Percent change in bone mineral density over 36 months with denosumab Denosumab 60 mg Q6M Placebo Lumbar spine Study months 2 2 4 6 8 10 12 24 36 * Mean percent change in BMD 9.2% † Total hip Study months 36 2 2 4 6 8 10 12 24 * Mean percent change in BMD 6.0% † Key point After 3 years, denosumab increased BMD by 9.2% (95% CI: 8.2, 10.1) at the lumbar spine and 6.0% (95% CI: 5.2, 6.7) at the total hip compared with placebo. Supplementary information In this substudy of 441 patients, BMD of the lumbar spine and hip were measured at baseline, 1 month, 6 months, 1 year, 2 years, and 3 years. The relative increase was 9.2% in the BMD at the lumbar spine and 6.0% at the hip after 3 years for patients in the denosumab arm compared with placebo arm in this substudy. The BMD analysis included all patients with at least one follow-up measurement at or before the time point under consideration. The last observation was carried forward for all missing values. Cummings SR et al. N Engl J Med 2009;361:756–65. Intent-to-treat, last observation carried forward analysis. *P < 0.001 for denosumab vs placebo. † denosumab group relative increase in BMD vs placebo at month 36 Cummings SR et al. N Engl J Med. 2009;361:756–65.

FREEDOM Study : Result The FREEDOM Study demonstrated a significant decrease in vertebral fractures compared to placebo (P < 0.0001) after 3 years of treatment. Compared to placebo-treated patients, risk reductions in skeletal sites at year 3 for Prolia®-treated patients were:1 68% reduced risk of vertebral fractures 40% reduced risk of hip fractures 20% reduced risk of nonvertebral fractures Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:1-10. Cummings SR, et al. N Engl J Med. 2009;361:1-10.

FREEDOM Extension Study Design International, multicenter, open-label, single-arm study Year 1 2 3 4 5 6 7 8 9 10 R A N D O M I Z T Denosumab 60 mg SC Q6M (N = 3902) Denosumab 60 mg SC Q6M (N = 2343) Long-term Denosumab Treatment Calcium and Vitamin D Placebo SC Q6M (N = 3906) Denosumab 60 mg SC Q6M (N = 2207) Cross-over Denosumab Treatment Year 1 2 3 4 5 6 7 Key Inclusion Criteria for the Extension: Completed the FREEDOM study (completed the 3-year visit, did not discontinue investigational product, and did not miss > 1 dose) Not receiving any other osteoporosis medications Amgen Corporate Template

Pivotal Phase 3 Fracture Trial Pivotal Phase 3 Fracture Trial Serum CTX and P1NP concentrations through 10 years of Denosumab treatment Placebo Continued Denosumab Cross-over Denosumab Serum CTX Serum P1NP 1.0 100 Pivotal Phase 3 Fracture Trial Extension Study Pivotal Phase 3 Fracture Trial Extension Study 0.8 80 0.6 60 Serum P1NP, μg/L Serum CTX, ng/mL In the extension study, serum CTX and P1NP levels continued to remain low in the denosumab treatment group through year 10.1 Bone HG, Brandi ML, Brown JP, et al. Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157. 0.4 40 0.2 20 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 Study Year Study Year Data represent medians and interquartile ranges. Dashed lines represent the premenopausal reference ranges: 0.20 to 0.90 ng/mL for serum CTX and 17.4 to 61.6 µg/L for P1NP. CTX = C-telopeptide of type 1 collagen; P1NP = procollagen type 1 N-terminal propeptide Adapted from: Bone HG, et al. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157.

Change in lumbar spine and total hip BMD through 10 years with Denosumab treatment Placebo Continued Denosumab Cross-over Denosumab Lumbar Spine BMD Total Hip BMD 24 Pivotal Phase 3 Fracture Trial Extension Study 10 b Pivotal Phase 3 Fracture Trial Extension Study b 22 b 20 21.7% b 9.2% 8 b 18 b b b 16 b b 16.5%c b 6 a b 14 b b a 7.4%c 12 Percent Change From Baseline a b 4 b In the extension study, BMD continued to significantly increase through 10 years at the lumbar spine and total hip as compared to baseline of the pivotal phase 3 fracture study and extension baseline.1 Bone HG, Brandi ML, Brown JP, et al. Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157. 10 a a b b 8 a a b b 6 2 a a 4 a a 2 a a a a a –2 –2 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 Study Year Study Year Data represents LS means and 95% CI. ap < 0.05 vs Pivotal Phase 3 study baseline; bp < 0.05 vs Pivotal Phase 3 study baseline and extension baseline; cPercentage change while on denosumab treatment. BMD = bone mineral density; LS = least-squares; CI = confidence interval Adapted from: Bone HG, et al. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157.

Changes of BMD with 10 years with Alendronate

Patterns in changes of BMD with long term treatment Denosumab vs Patterns in changes of BMD with long term treatment Denosumab vs. Alendronate Placebo Continued Denosumab Cross-over Denosumab Lumbar Spine BMD Total Hip BMD 24 Pivotal Phase 3 Fracture Trial Extension Study 10 b Pivotal Phase 3 Fracture Trial Extension Study b 22 b 20 21.7% b 9.2% 8 b 18 b b b 16 b b 16.5%c a b b 6 14 b b a 7.4%c 12 Percent Change From Baseline a b 4 b In the extension study, BMD continued to significantly increase through 10 years at the lumbar spine and total hip as compared to baseline of the pivotal phase 3 fracture study and extension baseline.1 Bone HG, Brandi ML, Brown JP, et al. Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157. 10 Alendronate (~ 14%) a a b b Alendronate (~5%) 8 a a b 6 2 b a a 4 a a 2 a a a a a –2 –2 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 Study Year Study Year Data represents LS means and 95% CI. ap < 0.05 vs Pivotal Phase 3 study baseline; bp < 0.05 vs Pivotal Phase 3 study baseline and extension baseline; cPercentage change while on denosumab treatment. BMD = bone mineral density; LS = least-squares; CI = confidence interval Adapted from: Bone HG, et al. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157.

Denosumab vs. Alendronate (DECIDE) Total hip Lumbar spine Femoral neck JBMR. 2009:24(1):153–161.

Changes in bone turnover markers Denosumab vs. Alendronate (DECIDE) Rapid onset / Strong inhibition JBMR. 2009:24(1):153–161.

Yearly incidence of new vertebral fractures through 10 years Placebo Continued Denosumab Pivotal Phase 3 Fracture Trial Extension Study Yearly Incidence of New Vertebral Fractures, % 1.5 In the extension study, the incidence of new vertebral fractures observed at each year was ≤ 1.5% in the continued denosumab group.1 Bone HG, Brandi ML, Brown JP, et al. Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157. 1.4 1.2 1.3 a a a Years of Denosumab Treatment The primary endpoint of the open-label extension study was safety and tolerability of denosumab for up to 10 yrs. Fractures were collected as AEs in this study. aAnnualized incidence: (2-year incidence) / 2. Adapted from: Bone HG, et al. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157.

Yearly incidence of nonvertebral fractures through 10 years For error bar QC Placebo Continued Denosumab Pivotal Phase 3 Fracture Trial Extension Study Yearly Incidence of Nonvertebral Fractures, % 1.9 1.8 1.6 1.5 The incidence of nonvertebral fracture with up to 10 years of denosumab exposure was low:1 In the continued denosumab treatment group, the incidence was ≤ 1.9% during the extension period. Bone HG, Brandi ML, Brown JP, et al. Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157. 1.2 1.1 0.8 Years of Denosumab Treatment The primary endpoint of the open-label extension study was safety and tolerability of denosumab for up to 10 yrs. Fractures were collected as AEs in this study. Adapted from: Bone HG, et al. Presented at: American Society of Bone and Mineral Research; October 12, 2015; Seattle, WA. Oral presentation LB-1157.

Alendronate, FIT Risedronate, VERT Ibandronate, BONE Zoledronate, 47%↓ 51%↓ 41%↓ 39%↓ Ibandronate, BONE 70%↓ Zoledronate, HORIZON 52%↓ 41%↓

Adverse effect FREEDOM trial Cummings et al., NEJM 2009 Steven R. Cummings, et al. NEJM, 2009

Adverse effects - effects on immune system Inhibition of RANKL has potential infectious and neoplastic complications Denosumab could globally disrupt the signaling pathway that involves RANKL, osteoprotegerin, RANK, and nuclear factor-κB RANK is expressed on cells other than osteoclast precursors, including dendritic cells and T and B cells. RANKL not only regulates osteoclastogenesis but also functions within the immune system. In addition to suppressing osteoclastogenesis, RANKL functions within the immune system. Therefore, an important issue with denosumab is whether its inhibition of RANKL has potential infectious and neoplastic complications [26]. In the trials described above, the proportion of patients experiencing adverse events was similar among the placebo, denosumab, and alendronate groups. However, in some [5,8,15] but not all [11,14] of the trials, there were a greater number of infections requiring hospitalization (eg, diverticulitis, pneumonia, atypical pneumonia, appendicitis, cellulitis, and labyrinthitis) in the denosumab group. In the FREEDOM trial, eczema (3.0 versus 1.7 percent) and severe cellulitis requiring hospitalization (0.3 versus <0.1 percent) were significantly more common in women assigned to denosumab versus placebo [5]. Pancreatitis has also been reported. Although in some early trials there was a nonsignificant increased number of cases of breast, pancreatic, gastrointestinal, ovarian, and uterine tumors [11,27], overall rates of adverse events of neoplasm were similar between treatment groups in subsequent trials, including the larger FREEDOM trial [5,8,11,14,15]. RANKL, a member of the tumor necrosis factor superfamily of ligands and receptors, promotes the differentiation, activation, and survival of bone-resorbing osteoclasts. Osteoprotegerin (OPG) that is produced by osteoblasts, the key modulator of RANKL, acts as a natural soluble decoy receptor for RANKL and blocks its effects. Denosumab functions like OPG and has the effect of decreasing osteoclastogenesis, as revealed by diminished biochemical markers of bone resorption. Henry G. Bone, et al. JCEM, 2008

Adverse events Osteoporos Int. 2015;26:2773–2783.

Adverse events Hypocalcemia Denosumab should not be given to patients with preexisting hypocalcemia until it is corrected. Predisposing to hypocalcemia (CKD, CCr <30 mL/min) should be monitored for hypocalcemia All women were supplemented with daily calcium (1000mg) and vitamin D (400 to 800 units) Steven R. Cummings, et al. NEJM, 2009

Adverse events Osteonecrosis of the jaw Atypical femur fractures FREEDOM extension trial 5 cases of ONJ, 1 case of AFF (after 8 years) 3 cases of ONJ, 1 case of AFF (after 5 year cross over) Henry G. Bone, et al. JCEM, 2008

Long-term treatment with anti-resorptive agents Bisphosphonates  Denosumab Bisphosphonate  Denosumab or Bisphosphonates 870 postmenopausal women aged ≥55 years Who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy Denosumab has been shownto reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naïve or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers when compared with alendronate-treated subjects. This trial was designed to compare the efficacy and safety of denosumab with risedronate over 12 months in postmenopausal women who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy. In this randomized, open-label study, postmenopausal women aged ≥55 years received denosumab 60 mg subcutaneously every 6 months or risedronate 150 mg orally every month for 12 months. Endpoints included percentage change from baseline in total hip BMD (primary endpoint), femoral neck, and lumbar spine BMD at month 12, and percentage change from baseline in sCTX-1 at months 1 and 6. Safety was also assessed. A total of 870 subjects were randomized (435, risedronate; 435, denosumab) who had a mean (SD) age of 67.7 (6.9) years, mean (SD)BMD T-scores of−1.6 (0.9),−1.9 (0.7), and−2.2 (1.2) at the total hip, femoral neck, and lumbar spine, respectively, and median sCTX-1 of 0.3 ng/mL at baseline. At month 12, denosumab significantly increased BMD compared with risedronate at the total hip (2.0% vs 0.5%), femoral neck (1.4% vs 0%), and lumbar spine (3.4% vs 1.1%; p b 0.0001 at all sites). Denosumab significantly decreased sCTX-1 compared with risedronate at month 1 (median change from baseline of −78% vs −17%; p b 0.0001) and month 6 (−61% vs −23%; p b 0.0001). Overall and serious adverse events were similar between groups. In postmenopausal women who were suboptimally adherent to alendronate therapy, transitioning to denosumab was well tolerated and more effective than risedronate in increasing BMD and reducing bone turnover. Bone 58 (2014) 48–54

Long-term treatment with anti-resorptive agents Bisphosphonates  Denosumab Bisphosphonate  Denosumab or Bisphosphonates Bone 58 (2014) 48–54

Long-term treatment with anti-resorptive agents Bisphosphonates  Denosumab Bisphosphonate  Denosumab or Bisphosphonates Bone 58 (2014) 48–54

Denosumab vs. Bisphosphonate

Denosumab vs Bisphosphonate Bisphosphonates

Denosumab : Durability of effect Miller et al., JCEM 2008

Denosumab : Durability of effect Miller et al., JCEM 2008

Changes of BMD with 10 years with alendronate

Re-treatment with denosumab 12 months after discontinuing therapy resulted in an increase in LS and TH BMD over 12-month retreatment phase. Paul D. Miller, et al. Bone, 2008

Denosumab vs. Bisphosphonates Action mechanisms Inhibit osteoclastogenesis Promote osteoclasts apoptosis Anti-fractures efficacy Vertebral fractures + Non-vertebral fractures + Non-vertebral fractures (A, R, Z) Over suppression issue + Durability - CKD With caution Rapid onset Strong potency Rebound fractures (?)

Teriparatide (Weekly) OLD NEW Selective Estrogen Receptor Modulator Denosumab Bisphosphonates Teriparatide (daily) Teriparatide (Weekly)

Teriparatide

Teriparatide Teriparatide Recombinant human PTH(1-34) Available from 2002’ in USA, 2003’ in Europe

Parathyroid hormone on bone

Anabolic window stimulating Osteoblast stimulating Osteoclast

Fracture prevention trial (FPT) Changes in BMD LS BMD 1.1% vs 9.7% FN BMD -0.7% vs 2.8% TH BMD -1.0% vs 2.6% Neer et al. N Engl J Med 2001;344(19):1434-41

Fracture prevention trial (FPT) Vertebral fractures New Vertebral Fractures RRR 65% Multiple Fractures RRR 77% Moderate/severe Fractures RRR 90% Neer et al. N Engl J Med 2001;344(19):1434-41

Fracture prevention trial (FPT) Non-Vertebral fractures 47% reduction Neer et al. N Engl J Med 2001;344(19):1434-41

Teriparatide Teriparatide Daily : 20 mcg per day (Self –injection) Weekly : 56 mcg per week (Hospital-based)

Teriparatide Teriparatide Daily : 20 mcg per day (Self –injection) FPT study Weekly : 56.5 mcg per week (Hospital-based) TOWER study

Once-weekly Teriparatide Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial Lumbar Spine BMD Total Hip BMD 6.4% 3.0% [Nakamura T et al., J Clin Endocrinol Metab 97: 3097, 2012]

Once-weekly Teriparatide Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial [Nakamura T et al., J Clin Endocrinol Metab 97: 3097, 2012]

Once-weekly Teripatatide Bone turnover markers P1NP CTX [Nakamura T et al., J Clin Endocrinol Metab 97: 3097, 2012]

BTM changes with once-daily teriparatide [M. Tsujimoto et al. Bone 48 (2011) 798]

FPT Trial (once daily 20mcg Teriparatide) Nausea 8% Withdrawn the study 6%

Individualized treatment Goal-directed therapy Conclusion OLD NEW Selective Estrogen Receptor Modulator Individualized treatment Goal-directed therapy Denosumab Bisphosphonates Teriparatide (daily) Teriparatide (Weekly)