Nieuwe ontwikkelingen in osteoporose behandelingen

1. Nieuwe ontwikkelingen in
osteoporose behandeling
Prof. Em. Dr Piet Geusens
Reumatoloog
Maastricht UMC+ & Faculteit Geneeskunde
UHasselt, België
copyrigth Prof. Dr. P. Geusens

2. Disclosure Statement
Honoraria, research grants, and/or consultant fees from:
Pfizer, Abbott/Abbvie, Janssen, Celgene, Lilly, Amgen, MSD, UCB,
Will, Roche, BMS, Novartis, Sanofi
PP-TE-NL-0031
copyrigth Prof. Dr. P. Geusens

3. Drug development pathways
Khosla, Lancet Diab Endo, 2017
copyrigth Prof. Dr. P. Geusens

4. C Climbers in fracture prevention …
1950’s
HRT
2002
CV risk
Breast Ca
1960’S
nandrolone
1980’s
Masculinisation
1981
calcitonin
2013
Cancer risk
1982
tibolone
2008
Stroke
1994
Fluoride
Increase in BMD
with increase
of VF risk
1990
etidronate
1995
Mineralisation
defect
2004
strontium
2017
CV risk
2007
PTH
2014
Hypercalcemia
2008
odanacatib
2016
Stroke
2017
abaloparatide
2018
FDA approved
EMA:
Palpitations
GCP
1992
Ca+vitD
1995
oral BPs
1999
raloxifene
2002
teriparatide
2006/7
zoledronate
2010
denosumab
20xx
Romosozumab?
… and fallers
Gallagher, Menopause, 2018
copyrigth Prof. Dr. P. Geusens

5. Old data on treatment needs
• After multiple/severe vertebral fractures
• Alendronate, 3 yrs (>1VF: 32%): clinical VF↓, any clinical fractures↓, wrist and hip fracture↓
• Risedronate, 1 and 3 yrs (mean 3 VFs/patient): VF↓
• Teriparatide, 18 months (mean 2.3 VFs/patient) : VF↓, NVF↓
• After recent fracture
• Zoledronate after recent hip fracture (life expectancy >6 months): clinical VF↓, NVF↓, mortality↓
• Head-to-head studies with fracture prevention as pimary endpoint = ?
• Sequential treatment
• Fracture during adequate anti-resorptive treatment = ?
• Bone forming agents first = ?
• Osteopenia
• Anti-resorptive and teriparatide RCTs included osteopenia if patients had also VFs
• Alendronate not effective in osteopenia without VFs
• Drug holiday: BPs: yes, denosumab: no
copyrigth Prof. Dr. P. Geusens

6. New data on old treatment needs: the appearance
and revival of bone forming agents
• Bone forming agents versus anti-resorptive treatment
• After multiple/severe vertebral fractures with low BMD
• After recent fracture
• Head-to-head comparisons of bone forming agents versus anti-resorptive
treatment with fracture prevention as pimary endpoint
• Sequential treatment
• Bone forming agents first or subsequently?
• Osteopenia
• To treat or not to treat?
• Drug holiday?
copyrigth Prof. Dr. P. Geusens

7. Bone forming agents
copyrigth Prof. Dr. P. Geusens

8. Anabolic windows for Teriparatide and
Romosozumab
Tabacco, Br J Clin Pharmacol. 2018
Appelman, Drug Design, Development and Therapy, 2017
Bone formation
Bone resorption
copyrigth Prof. Dr. P. Geusens

9. Teriparatide
copyrigth Prof. Dr. P. Geusens

10. VERO trial
teriparatide versus risedronate
•Inclusion criteria:
• Prevalent vertebral fractures: 2 moderate or 1 severe
• T-score (spine and/or hip) <-1.5
Kendler, Lancet, 2018
copyrigth Prof. Dr. P. Geusens

11. PP-TE-NL-0031
Teriparatide versus risedronate
Incidence of new vertebral fractures
Kendler, Lancet, 2018
copyrigth Prof. Dr. P. Geusens

12. Teriparatide versus risedronate
Incidence of first clinical vertebral fracture over 24 months
No. atRisk
Time(Months)
Teriparatide 680 631 600 579 493
Risedronate 680 627 606 579 501
Hazard ratio:0.29
(95% CI: 0.14 - 0.58)
p=0.002
Kendler, Lancet, 2018
copyrigth Prof. Dr. P. Geusens

13. *Clinical vertebral and non-vertebral fragility fractures (clavicle, scapula, ribs, sternum, sacrum, coccyx, humerus,
radius, ulna, carpus, pelvis, hip, femur, patella, tibia, fibula, ankle, calcaneus, tarsus, or metatarsus).
Teriparatide versus risedronate
Incidence of first clinical fracture over 24 months
Kendler, Lancet, 2018
copyrigth Prof. Dr. P. Geusens

14. Teriparatide versus risedronate
Incidence of first non-vertebral major fragility fracture over 24 months
*Hip, radius, humerus, ribs, pelvis, tibia, or femur.
Kendler, Lancet, 2018
copyrigth Prof. Dr. P. Geusens

15. Romosozumab
copyrigth Prof. Dr. P. Geusens

16. BMD T-score increases at the (A) lumbar spine and (B) total hip
in FRAME relative to FREEDOM and FREEDOM Extension
Cosman, JBMR, 2018
copyrigth Prof. Dr. P. Geusens

17. Romososumab vs teriparatide
% change from baseline in estimated hip strength
by finite element analysis using hip CT scans
Langdahl, Lancet, 2017
copyrigth Prof. Dr. P. Geusens

18. Romosozumab versus alendronate
ARCH study
• BMD T-score <–2.5 and either:
• ≧1 moderate or severe vertebral fractures
• ≧2 mild vertebral fractures
• or BMD T-score <–2.0 and either:
• ≧2 moderate or severe vertebral fractures
• or a fracture of the proximal femur 3-24 months before randomization
ALN ALN
ALNROMO
Saag, NEJM, 2017
copyrigth Prof. Dr. P. Geusens

19. Romosozumab versus alendronate
ARCH study
Saag, NEJM, 2017
ALN ALN
ALNROMO
copyrigth Prof. Dr. P. Geusens

20. Romosozumab versus alendronate
ARCH study
Saag, NEJM, 2017
HR: 0.73
(0.61-0.88)
HR: 0.81
(0.66-0.99)
Hip fractures: HR: 0.62 (0.42-0.92)
at primary analysis (after mean follow up of 2.7 yrs)
HR: 0.72
(0.54-0.96)
ALN ALN
ALNROMO
copyrigth Prof. Dr. P. Geusens

21. Imminent vs long-term
fracture risk
copyrigth Prof. Dr. P. Geusens

22. Imminent fracture risk
• Short-term risk is higher than long-term risk in some specific clinical
situations:
• Subsequent fracture:
• After recent fracture: 1-year RR: 2.0 to 9.0 times higher than expected from FRAX
• After recent VF: RR: 4.0-49.0, depending on age, sex, location
• After recent NVF: RR: 4.0-12.0, depending on age, sex, location
• First fracture
• Within 3 months after start of high dose of GC
• Within 2 years in subjects with high fall risk:
• RR: 6.7 after history of falls
• RR: 1.8 in wheelchair users
Kanis, OI, 2018
Johnell, OI, 2001
Lindsay, JAMA, 2001
van Geel, ARD, 2008
Center, JAMA, 2007
van Staa, JBMR, 2000
Bonafede, Arch Osteoporosis, 2016
Johanson, OI, 2016
copyrigth Prof. Dr. P. Geusens

23. Zoledronate
after recent
hip fracture
(vs placebo)
Lyles, NEJM, 2007
copyrigth Prof. Dr. P. Geusens

24. Teriparatide vs. risedronate after recent vertebral fracture
Effect on clinical (vertebral and non-vertebral) fractures
Pre-specified subgroup analysis
BMD = bone mineral density;
CI = confidence interval;
FAS = full analysis set;
N = total number of patients;
n = number of patients in the
specified category;
% = percentages indicate the
cumulative incidence of fractures
based on Kaplan-Meier method;
VFx = vertebral fracture
Geusens P. et al. J Bone Miner Res. (2018);33(5):783-794
copyrigth Prof. Dr. P. Geusens

25. Romosozumab versus alendronate
ARCH study
(including patients wit a recent hip fracture)
Saag, NEJM, 2017
HR: 0.73
(0.61-0.88)
HR: 0.81
(0.66-0.99)
Hip fractures: HR: 0.62 (0.42-0.92)
at primary analysis (after mean follow up of 2.7 yrs)
HR: 0.72
(0.54-0.96)
ALN ALN
ALNROMO
copyrigth Prof. Dr. P. Geusens

26. Fracture during adequate
anti-resorptive treatment
copyrigth Prof. Dr. P. Geusens

27. Teriparatide vs risedronate
First clinical (vertebral and non-vertebral) fracture
27
BL = baseline;
CI = confidence interval;
FAS = full analysis set;
M = month;
RIS = risedronate;
TPTD = teriparatide
Geusens et al. J Bone Miner Res.
2018 Jan 12. doi: 0.1002/jbmr.3384
BL M 6 M 12 M 18 M 24
TPTD 295 264 247 234 211
RIS 293 262 246 238 215
Number of patients at risk:
Risedronate
Teriparatide
Hazard ratio (95% CI):
0.52 (0.27, 0.99)
Osteoporosis
treatment-naïve
copyrigth Prof. Dr. P. Geusens

28. Teriparatide vs risedronate
First clinical (vertebral and non-vertebral) fracture
28
BL = baseline;
CI = confidence interval;
FAS = full analysis set;
M = month;
RIS = risedronate;
TPTD = teriparatide
Number of patients at risk:
BL M 6 M 12 M 18 M 24
TPTD 359 335 318 303 274
RIS 356 325 311 291 265
Risedronate
Teriparatide
Hazard ratio (95% CI):
0.48 (0.26, 0.88)
Prior use of bisphosphonates
Geusens et al. J Bone Miner Res.
2018 Jan 12. doi: 0.1002/jbmr.3384
copyrigth Prof. Dr. P. Geusens

29. Sequential and combination
therapy
copyrigth Prof. Dr. P. Geusens

30. Teriparatide: Cumulative proportion of women enrolled in the
followup study who had one or more nonvertebral fragility
fractures after baseline
Lindsay, JBMR, 2005
60% on subsequent
osteoporosis treatment
at 50 months
copyrigth Prof. Dr. P. Geusens

31. DATA-Switch study design
Leder, Lancet, 2015
copyrigth Prof. Dr. P. Geusens

32. Mean % change in BMD
Leder, Lancet, 2015
copyrigth Prof. Dr. P. Geusens

33. Median percent change in bone markers
Leder, Lancet, 2015
copyrigth Prof. Dr. P. Geusens

34. Teriparatide (low vs high dose) + denosumab
Leder, ASBMR, 2018
copyrigth Prof. Dr. P. Geusens

35. “Anabolic
window”
An Expanded Anabolic Window: the Model
Months
IndexofBoneTurnover
Peak
Bone Formation
Bone Resorption
copyrigth Prof. Dr. P. Geusens

36. Zoledronate 5 mg/18-month vs placebo
+ calcium 1 g/d advised
+ vitamin D before start: 120,000 IU, followed by 60,000 IU/month
copyrigth Prof. Dr. P. Geusens

37. (>65 yrs)
163 had osteoporosis (T<-2.5 at spine or hip)
copyrigth Prof. Dr. P. Geusens

38. Zoledronate (5mg/18 months) vs placebo
FRAX MOF
FRAX MOF
FRAX MOF
Similar results after exclusion of:
- patients with osteoporosis
- patients with high FRAX
No effect on hip fracture risk
copyrigth Prof. Dr. P. Geusens

39. Drug holiday?
copyrigth Prof. Dr. P. Geusens

40. Lumbar spine BMD during one year after
cessation of treatments for osteoporosis
Appelman, Nat Rev Endo, 2018
copyrigth Prof. Dr. P. Geusens

41. DATA study: Long-term follow up
Leder, Bone, 2017
copyrigth Prof. Dr. P. Geusens

42. Why a drug holiday?
• Atypical femur fractures (AFF)
• Rare:
• 2/100,00 after 2 yr, 11/100,000 after 8-10 years
• 1 for every 1200 prevented fractures, including 135 hip fractures
• Risks: GC users, Asian ancestry, duration of AR therapy (?) PPI (?)
• Incidence quickly reversible after stopping BPs
• Query about thigh pain during long-term BPs treatment
• Osteonecrosis of jaw (ONJ)
• Rare:
• in oncology patients (high doses of BPs or Dmab): estimated at 1%–15%
• In fracture prevention (much lower doses): estimated at 0.001%–0.01%.
• Risks: invasive dental procedures, bad tooth hygiene, GC, DM, periodontal disease,
denture use, smoking, anti-angiogenic agents
• Need for tooth hygiene
Adams, ASBMR, 2018
Black, ASBMR, 2018
McClung, AJM, 2013
Abrahamson, BMJ, 2016
Dell, JBMR, 2011
Kahn, J clin Dns, 2017
Black, Endocrine Rev, 2018
copyrigth Prof. Dr. P. Geusens

43. Drug holiday
Therapy duration holiday fracture risk
BPs >3 yr ≥ 12 mo (M:3 yr) NS (opo-related fragility fractures)
BPs 3-5 yr 32 mo clinical fractures +40%
BPs >3 yr >2 yr hip fracture +22%
Denosumab ≥ 2 doses mean: 1.6 yr increased risk of multiple vertebral
fractures when prevalent VF
0.5 (range: 0.3-1.4) yr OR: 3.9
Adams, JBMR, 2018
Mignot, OI, 2017
Curtis, ASBMR, 2018
Cummings, JBMR, 2018
copyrigth Prof. Dr. P. Geusens

44. Denosumab should not be stopped without considering alternative
treatment in order to prevent rapid BMD loss and a potential rebound
in vertebral fracture risk
copyrigth Prof. Dr. P. Geusens

45. New data on old needs
• After recent fracture
• Teriparatide superior to risedronate after recent VF (VF and all clinical fractures)
• Romosozumab after recent hip fracture
• Very low BMD
• Romosozumab (T-score: + 0.8 in spine and +0.3 in hip within one year)
• Prevalent multiple/severe vertebral fractures
• Teriparatide superior to risedronate (VF and all clinical fractures)
• Romosozumab superior to alendronate (VF, clinical, NVF and hip fractures)
• Fracture during adequate anti-resorptive treatment
• Teriparatide superior to risedronate (VF and all clinical fractures)
• Sequential therapy
• In “severe osteoporosis” (e.g. VF + low BMD, very low BMD): start with bone forming agents
• Teriparatide
• Romosozumab
• Osteopenia + high risk
• Zoledronate/18 months
copyrigth Prof. Dr. P. Geusens

46. T2T
• In high risk patients:
• Increase BMD
• Increase bone strength
• Decrease fracture risk
• Integrate fall prevention
• Safety
• Cost/benefit
Roux, Nat Rev Rheumato, 2018
copyrigth Prof. Dr. P. Geusens