Romosozumab for the treatment of osteoporosis in women: Efficacy, safety, and cardiovascular risk

1. OSTEOPOROSIS:
A HOT TOPIC!
Dr Felicity Kaplan

2. Osteoporosis is a skeletal disorder characterised by
compromised bone strength predisposing a person to
an increased risk of fracture
Osteoporosis is present when the bone mineral density
or bone mineral content is over 2.5 standard deviations
below the young adult mean (–2.5 T-score)
Osteoporosis

3. Bone
Mass
Age (years)
Attainment of Peak
Bone Mass
Consolidation Age-related Bone Loss
Men
Women
Menopause
0 10 20 30 40 50 60
Fracture
Threshold
Compston JE. Clin Endocrinol 1990; 33:653–682.
Age Related Changes in
Bone Mass

5. Clinical Impact of
Osteoporosis Over Time
Signs
 Kyphosis
 Loss of height
 Abdo bulges
 Clinically
diagnosed
fracture
Symptoms
 Neck becomes
weak
 Pain in back
 Breathing
difficulties
 Indigestion &
GOR
 Stress
incontinence
 Difficulty with
mobility
following a
fracture

6. National Osteoporosis Society http://www.nos.org.uk/PDF/AreYouAtRisk.pdf
Risk Factors For Osteoporosis
For women – a lack of oestrogen caused by:
 Early menopause (before the age of 45 years)
 Early surgical menopause (before the age of 45
years), especially if both ovaries are removed
(oophorectomy)
 Missing periods for 6/12 or more (excluding
pregnancy) as a result of over-exercising or over-
dieting
For men
 Low levels of testosterone (hypogonadism)

7. For men and women
• Low body weight
• Maternal history of a hip fracture
• Malabsorption, inflammatory bowel disease and gastric
surgery
• Use of oral glucocorticoids and other Rx’s…
• Long-term immobility
• Heavy drinking
• Smoking
National Osteoporosis Society http://www.nos.org.uk/PDF/AreYouAtRisk.pdf
Risk Factors For Osteoporosis

8. Bone-unfriendly drugs
 TZDs
 PPIs (studies suggest increased fracture risk)
 Aromatase inhibitors eg anastrozole
 Ovarian suppressing agents (depot-
medroxyprogesterone acetate)
– Risk assess after 2 years
 Androgen deprivation therapy (PCa)
 Anticonvulsants esp Phenytoin/CMZ
 Heparin

9. Current treatments in OP
 Antiresorptive
– Estrogens and SERMs
– Bisphosphonates
– Calcitonin
– Denosumab
– Anabolic (stimulate bone formation)
– Parathyroid hormone
 Dual action agents
– Strontium ranelate

12. Vitamin D levels
 25-OHD Vit D status Manifestation Management
 <25 nmol/l Deficient Rickets/ Osteomalacia High-dose
calciferol
 25-50 nmol/l Disease risk Vit D supps
 50-75 nmol/l Adequate Healthy Lifestyle advice
 >75 nmol/l Optimal Healthy None
– Divide by 2.5 for ug/L

13. Treatment of vitamin D deficiency
Deficiency (25-OHD <25 nmol/l)
10 000 IU calciferol daily or 60 000 IU
calciferol weekly for 8-12 weeks*
or
Calciferol 300 000 or 600 000 IU orally or
by intramuscular injection once or twice

14. Treatment of vitamin D insufficiency
Insufficiency (25-OHD 25-50 nmol/l) or maintenance
therapy following deficiency
1000-2000 IU calciferol daily
or
10 000 IU calciferol weekly
*To convert IU to μg of calciferol, divide by 40.
†One off high dose treatments are effective, but should be followed by a
maintenance therapy dose of calciferol.

15. Hormone replacement
therapy

16. HRT: A CONSENSUS
 Prime role of HRT is relief of menopausal
Sx
 Risks/benefits need to be explained to each
woman (breast Ca extra 2-6 cases per 1000
women treated with HRT for 5 years)
 Use lowest effective estrogen dose, assess
CV risk
 Review need annually (esp aged>60)

17. HRT: A CONSENSUS
 Can give up to age 50 if prem
menopause
 Do not use as primary or secondary
prev. of CAD/CVA, or Alzheimers
 Transdermal estrogen has lower DVT
risk

18. RALOXIFENE
 SERM licensed for OP
 Reduces vertebral (not non-vertebral) fracture risk
 Reduces development of new breast Ca.
 No increased risk of CVD (reduces CV events!)
 Increased risk of thromboembolism
 May worsen flushes
 Well tolerated, easy dosing

19. NICE TA 2005: SERMs
(secondary prevention)
 Raloxifene - alternative in women for
whom bisphosphonates are contraindicated
or not tolerated
 Patients not responding to bisphosphonates
 Patients physically unable to comply with
the recommendations for use of
bisphosphonates
National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005

20. BISPHOSPHONATES
 Etidronate, risedronate, alendronate,
ibandronate, zoledronate
 Interfere with action of osteoclasts
 Alendronate and risedronate firstline option
in postmenopausal osteoporosis
 Strict dosing instructions
 Consider renal function!

21. PARATHYROID HORMONE
PEPTIDE (Teriparatide /
Forsteo)

22. NICE 2005:
(secondary prevention)
 Teriparatide – use in women >65 years
unresponsive to / intolerance of
bisphosphonates, and:
– with extremely low BMD (<-4)
– with very low BMD (<-3), multiple
fractures PLUS an additional risk
factor
National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005

23. Strontium ranelate
Protelos

24. Clinical use of strontium
ranelate
 In women with postmenopausal osteoporosis:
– alternative to bisphosphonates, particularly in the
elderly
– if potential for upper gastrointestinal
complications
– failed (intolerance or inadequate response) to
treatment with other osteoporosis therapies
– Beware rash (DRESS) and VTE (RR 1.4)

25. DENOSUMAB:
A NEW TREATMENT

26. Emerging Rx’s in osteoporosis
Prof Compston
2010
 Denosumab
– Monoclonal Ab to RANKL which drives
osteoclasts
– Subcut every 6/12! 60mg
– Dramatic and quick effect
– Fracture reduction similar to Zoledronate
– Cost similar to risedronate (in 2010)!
– NICE appraised

27. Denosumab Binds RANK Ligand and Inhibits
Osteoclast Formation, Function, and Survival
RANKL
RANK
OPG
Denosumab
Bone Formation Bone Resorption
Inhibited
Osteoclast Formation, Function,
and Survival Inhibited
CFU-GM Prefusion
Osteoclast
Osteoblasts
Hormones
Growth Factors
Cytokines
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.

28. The Effect of Denosumab on Fracture Risks at
36 Months
Phase 3: The FREEDOM Trial
ARR = absolute risk reduction; RRR = relative risk reduction
Cummings SR, et al. N Engl J Med. 2009;361:756-765.
7.2%
8.0%
1.2%
6.5%
0.7%
2.3%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
New Vertebral Nonvertebral Hip
Incidence
at
Month
36
(%)
Placebo
Denosumab
ARR = 0.5%
RRR = 40%
P = 0.04
ARR = 1.5%
RRR = 20%
P = 0.01
ARR = 4.8%
RRR = 68%
P < 0.001
Primary Endpoint

29. Proven osteoporotic fracture reduction
throughout the skeleton
 In the pivotal FREEDOM study (published in the New
England Journal of Medicine), Denosumab reduced the risk
of fracture at key osteoporotic fracture sites versus placebo
PROLIA®: PROTECTION AGAINST FRACTURE
The absolute risk reductions demonstrated for Prolia® versus placebo
were 4.8%, 1.5% and 0.5% for vertebral, non-vertebral and hip
fractures respectively. 1
6
P

30. Effects of Treatment on Femoral Neck BMD Over 12
Months
Phase 3: The STAND Trial
n = number of patients who have a baseline and ≥ 1 postbaseline evaluation.
*P < 0.01.
Adapted from: Kendler DL, et al. J Bone Miner Res. 2010;25:72-81
Percent
Change
From
Baseline
(Least
Squares
Mean
±
95%
CI) Alendronate 70 mg QW (n = 241)
Denosumab 60 mg Q6M (n = 246)
Study Month
0 6 12
0.0
0.4
0.8
1.2
1.6
2.0
*
*

31. Adverse Events Over 36/12
Adverse events, n (%)
Placebo
(n = 3,876)
Denosumab
60 mg Q6M
(n = 3,886)
P
value
Serious adverse events
Malignancy 125 (3.2) 144 (3.7) 0.28
Infection 133 (3.4) 159 (4.1) 0.14
Cardiovascular events 178 (4.6) 186 (4.8) 0.74
Stroke 54 (1.4) 56 (1.4) 0.89
Coronary heart disease 39 (1.0) 47 (1.2) 0.41
Peripheral vascular disease 30 (0.8) 31 (0.8) 0.93
Atrial fibrillation 29 (0.7) 29 (0.7) 0.98
Serious adverse events occurring with  0.1% incidence and P  0.01
Cellulitis (includes erysipelas) 1 (< 0.1) 12 (0.3) 0.002
Concussion 11 (0.3) 1 (< 0.1) 0.004

32. Factors influencing treatment
PROLIA®: REAL WORLD
Efficacy
Adherence Cost
Safety/
tolerability
Convenience/
patient choice

33. Approximate annual costs
2012 (£)
 Denosumab 366
 Alendronate 12
 Risedronate 22
 Zoledronate IV 267
 Raloxifene 259
 Strontium 353
 Teriparatide sc 3308

34. –In a head-to-head, double-dummy study, 77%* of
patients preferred a 6-monthly injection
to a weekly oral tablet
* Among patients who reported a preference (n = 1322, p < 0.0001)

35. NICE: Denosumab recommended by NICE for the
primary and secondary prevention of osteoporotic
fractures in postmenopausal women 18
 Denosumab is a cost effective use of NHS resources in the
primary and secondary prevention of fractures in
postmenopausal women for whom oral bisphosphonates*
are unsuitable
 There is good quality evidence to support the clinical
effectiveness of denosumab compared with placebo.
 Denosumab may improve adherence to therapy, particularly
for women who have problems swallowing or standing to
take oral bisphosphonates.
 Secondary and primary care have a role to play in the
delivery of denosumab.
*

36. NICE: Denosumab for the secondary prevention
of fractures
 a treatment option for secondary prevention of
osteoporotic fragility fractures only in
postmenopausal women at increased risk of
fractures:
 who are unable to comply with the special instructions for
administering
alendronate and either risedronate or etidronate, or have an
intolerance of,
or a contraindication to, those treatments.

37. NICE: Denosumab for the primary
prevention of fractures
– a treatment option for the primary prevention of
osteoporotic fragility fractures only in
postmenopausal women at
–increased risk of fractures:
 who are unable to comply with the special instructions for
administering alendronate and either risedronate or
etidronate, or have an intolerance of, or a contraindication
to, those treatments and
 who also have a combination of T-score, age and number of
independent clinical risk factors for fracture as indicated in
the following table:

38. Number of independent clinical risk factors for fracture
Age (years) 0 1 2
65–69 –a -4.5 -4.0
70–74 -4.5 -4.0 -3.5
75 or older -4.0 -4.0 -3.0

39. QOF
 Osteoporosis indicators approved for
inclusion on QOF menu from 4/2012
 Payment for
– prospective register of patients with fragility
fractures
– Treating those with fragility fracture with
appropriate Rx

40. 40
The Domino Fracture Effect