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

2. 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

3. Anti-resorptive therapy
Anabolic therapy
Anti-resorptive therapy

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

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

6. Denosumab

7. Denosumab

8. Denosumab

9. 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.

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 < 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.

11. FREEDOM Study : Result
The FREEDOM Study demonstrated a significant decrease in vertebral fractures compared to placebo (P < ) 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.

12. 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

13. 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.

14. 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.

15. Changes of BMD with 10 years with Alendronate

16. 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.

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

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

19. 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.

20. 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.

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

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

23. 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

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

25. 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

26. 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

27. 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 at all sites). Denosumab significantly decreased sCTX-1 compared with risedronate
at month 1 (median change from baseline of −78% vs −17%; p b ) and month 6 (−61% vs −23%;
p b ). 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

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

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

30. Denosumab vs. Bisphosphonate

31. Denosumab vs Bisphosphonate
Bisphosphonates

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

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

34. Changes of BMD with 10 years with alendronate

35. 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

36. 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 (?)

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

38. Teriparatide

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

40. Parathyroid hormone on bone

41. Anabolic window
stimulating Osteoblast
stimulating Osteoclast

42. 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):

43. 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):

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

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

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

47. 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]

48. 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]

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

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

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

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