Transcript OSTEOPOROSIS

The evidence for medical treatment
in tertiary prophylaxis of
osteoporosis
Kim Brixen
Department of Endocrinology, Odense
University Hospital, and University of Southern
Denmark, DK-5000 Odense C, Denmark
Conflicts of interest
•
•
•
•
Research grants: MSD and Novartis
Consulting fees: MSD and Osteologix
Travel grants: MSD, Amgen, Eli Lily, Servier and Novartis
Past advisory board membership: Osteologix, Servier, Amgen and
Novartis
• Expert testimony: Osteologix
• Speakers bureau: Novartis, Servier, Amgen and GlaxoSmithKline
Take-home messages
 Evidence based treatment of osteoporosis
 Is possible
 Many drugs with anti-fracture efficacy
 Compliance is an issue
 Treatment is used all to little
 Scenario in 2012?
Lifetime risk of osteoporotic fractures
Women
USA
39.7
Australia
42.1
Sweden
46.4
United Kingdom
53.2
Kanis et al. Osteoporos Int (2005) 16: S3–S7
Men
13.1
22.4
20.7
%
%
%
%
Cumulative incidence of second hip fracture
All 169,145 patients with a first HFx in Denmark during 1977–2001
Followed for up to 25 years and compared with the background population
Ryg et al. JBMR 2009,24,1299
Cumulative incidence of non-hip
fractures following first hip fracture
All 169,145 patients with a first HFx in Denmark during 1977–2001
Followed for up to 25 years and compared with the background population
Ryg J Thesis
Follow-up regarding osteoporosis is rare in
patients with low energy fractures
• 20% of patients with fragility fracture tested or
treated for osteoporosis – Joint Commission – US
Improving and Measuring Osteoporosis Management. The Joint Commission; 2007
• 24% of patients with hip fracture evaluated for
osteoporosis at Mayo Clinic, Jacksonville, US
Roy et al. Clin Orthop Relat Res (2011) 469:1925–1930
• 26% of patients with fragility fractures treated
Roux et al. The Journal of Rheumatology 2013; 40:5
Prevention
General measures
e.g. campaigns to quit smoking
Treatment of patients with low
bone mineral density
I
II
Primary prevention
Secondary prevention
Avoid a health problem
before it arises
Detect a health problem at an early stage
reducing long-term effects
Quaternary Prevention
Tertiary prevention
Identify patient at risk of
overmedicalisation
Reduce the chronic effects of
a health problem
IV
III
Treatment in patients with osteoporosis
complicated with fracture
Sickness
(Patients’ perception)
Modified from Jamoulle et al.
Illness
(Doctors’ perception)
Evidence-based prevention in
post-menopausal osteoporosis
Primary
Target
.
Population
Risk assessment
Collectively
Secondary
Tertiary
Osteoporosis
Osteoporosis
(low BMD)
(Fracture)
Individual
Individual
Life-style modification *
+
+
+
Calcium + vitamin-D
+
+
+
HRT
(SERM)
Bisphosphonates
Denosumab
(+)
+
+
+
(+)
+
+
+
(Strontium ranelate)
+
+
PTH
+
* Physical activity, cessation of smoking, reduction of alcohol intake, prevention of falls, hip protectors
Hvem er i risiko?
Pharmacological therapy
in osteoporosis
Vertebral
fractures
Calcium and vitamin-D
Hip
fractures
A
Peripheral
fractures
A
Etidronate
A
Alendronate
A
A
A
Risedronate
A
A
A
Ibandronate
A
Zoledronate
A
A
A
Denosumab
A
A
A
Teriparatide
A
PTH(1-84)
A
Bisphosphonates
A
Primary prevention with calcium and vitamin-D
1000 mg calcium, 400 IE vitamin-D, 36 months, intention to treat
Population of Randers City, Denmark
Age 65+ (both sexes)
Not institutionalized
N=9.605
Neighborhoods (Social service centers)
Cluster randomization
Calcium + Vitamin-D
Falls prevention
Larsen et al. J Bone Miner Res 2004;19:370 –378
Both interventions
Controls
Primary prevention with calcium and vitamin-D
9.605 residents aged 65+ years, cluster randomized
1000 mg calcium, 400 IE vitamin-D, 36 months, intention to treat
Uptake of treatment 50.3%
Hospital contacts
due to fracture
*
*
**
Larsen, Mosekilde et al. J Bone Miner Res 2004;19:370 –378
P<0.05
Vitamin-D supplementation with dosages above 700
IU/day decreases fracture risk (meta-analysis of RCTs)
RRR=26%
Bischoff-Ferrari et al. JAMA. 2005;293:2257-2264
RRR=23 %
Calcium-indtagelse
median
Kost Calcium-indtagelse
HR
< 805 mg/dg
0.98 (0.69-1.38)
>805 mg/dg
1.85 (1.28-2.67)
P=0.01 for interaction
Meta-Analyse Calcium
Ændring i absolut risiko (tilfælde pr 10.000 kvinder behandlet i 1 år)
BMJ juli 2010
Anbefaling
 Resultaterne giver ikke anledning til at
ændre en vel-indiceret behandling med
calciumtilskud
 Kvinder > 60 år som ikke kan/vil opnå tilstrækkelig
calciumtilførsel (800mg) gennem kosten
 Ptt i medicinsk behandling for osteoporose, som ikke
kan/vil indtage 1200 mg calcium via kosten
Women’s Health Initiative
JAMA 2002;288:321
Women’s Health Initiative
JAMA 2002;288:321
Alendronate
994 post-menopausal women with osteoporosis (T-score <-2.5)
5, 10, or 20/5 mg/day in 3 years
Pt med nye VTX (%)
25
20
Placebo
Alendronate
15
10
p=0.03
5
0
All
Liberman et al. N Engl J Med 1995, 333: 1437
+ Fracture
- Fracture
Bisphosphonates is taken up by osteoclasts by endocytosis
Active
Inactive
Bisphosphonate
Fleisch 1997
Alendronate
2.027 post-menopausal women with manifest osteoporosis
5 / 10 mg/day for 3 years
RR
2
1
0
VTX
Black et al. Lancet 1996:348:1535
Clinical
VTX
Peripheral
Hip
Forearm
Compliance with oral bisphosphonates
(daily or intermittent) is very low
N=110 consecutive patients started on alendronate or etidronate
1,0
General Practice
,8
Bone Clinic
• DEXA
• Prescribe therapy
,6
,4
,2
Survival Function
General Practice
• Follow-up
Censored
Total Population
0,0
0
10
20
30
40
time / months of bisphosphonate treatment
Rasmus Wulff et al. Ugeskrift for Læger, 2004, 166, 49-53.
Zolendronate in HFx-patients
2127 patients with recent hip fracture (41% osteoporosis, 35% -penia)
Lyles et al. ; N Engl J Med 2007;357.
Denosumab in post-menopausal osteoporosis
N=7,868 women; T-score < –2.5 at the lumbar spine or total hip
but T-score > –4.0 at both sites
Risk Reduction = 68%
P < 0.001
Risk Reduction = 20%
P = 0.01
Placebo
Denosumab
Risk Reduction = 40%
P = 0.04
Primary Endpoint
Cummings SR, et al. N Engl J Med. 2009;361:756-765.
Risk of atypical femoral fracture
following bisphosphonates
Review of radiographs of of all femoral subtrochanteric and shaft
fractures that occurred in 2008 in the entire population of Sweden
Linked with databases on prescriptions and co-mobidity
N
Bisphosphonat
e use
1,521,131
Women 55+ yrs
5%
12,777
Femur fractures
11%
1,351
Subtrochanteric or shaft fractures
17%
59
Atypical fractures
78%
A total of 83,311 women received bisphosphonates and 59 had
atypical fractures
Absolute risk 5.5:10.000 patient-years
Schilcher et al. N Engl J Med 2011;364:1728-37.
Incidence of osteonecrosis of the jaw
following bisphosphonates
• Osteoporosis
• Oral BP
• Oral BP + tooth extraction
0.01-0.04%
0.09-0.34%
• Cancer
• Breast cancer
• Multiple myeloma
• Prostate cancer
0.6-6.2%
1.7-15%
0-18.6%
Human parathyroid hormone 1-34
H2N-
1
Ser
10
Val
Ser
Glu
Ile
Gln
Leu
Met
His
Asn
Leu
Glu
Val
20
Arg
Arg
Lys
Lys
Gly
Glu
Met
Ser
Asn
Leu
His
Lys
Leu
Gln
Asp
Val
His
Asn
Phe
Trp
Leu
COOH
Effect of biosynthetic PTH(1-34)
Patients with new fractures (%)
Post-menopausal women, n= 1637, 2+ VTX or 1+ VTX and T-score<-1
Continous PTH(1-34) for 21 months
16
Placebo
PTH 20 ug
PTH 40 ug
14
12
10
P<0.001
8
P<0.02
6
4
2
0
VTX
Neer et al. NEJM: 2001;344:1434
Appendicular
Use of anti-osteoporosis drugs
in Denmark (population 5 mio)
Data extracted from MedStat.dk and converted from Recommended Daily Dosages
Anabolic window?
Resorption
Formation
PTH
Treat to target?
BMD
Normal
Osteoporosis
PTH
Bisphos
PTH
Bisphos
Pathophysiology of glucocorticoidinduced osteoporosis
Corticosteroids
 estrogen
 testosterone
 adrenal
androgens
Sarcopenia
(Decreased
muscle mass)
 Bone formation
(osteoblasts)
 GI calcium absorption
 urinary calcium excretion
Bone
resorption
(osteoclasts)
 apoptosis
 life span
 function
Bone loss
Fractures
 serum calcium
 serum PTH
Effect of alendronate in glucocorticoid-induced osteoporosis
n=477 men and women, > 1 year prednisolon >7.5 mg/dg
Alendronat 5 / 10 mg/day in 48 weeks
p=0.05
Pt med
nye
new
with
Patients
VTX
VTX (%)
(%)
14
12
10
8
6
4
n.s.
2
n.s.
0
Men
Saag et al. NEJM;1998:339:292
Post-menop.
Pre-menop.
Prevalence of risk factors for
fractures and use of DXA scans
Prevalance of risk
factor
(n=3,860)
History of DXA in those
with risk factor
Current smoker
20.5%
15.3%
Age 80+
15.9%
22.8%
History of low-energy fracture
11.5%
34.3%
Premature menopause
11.3%
25.7%
Parental hip fracture
10.7%
23.4%
History of falls
6.9%
30.7%
Oral glucocorticoids
4.5%
52.3%
BMI<19 kg/m2
3.7%
30.8%
2.0
25.0%
Alcohol > 3 units/dat
Rubin et al. Osteoporos Int. 2010 Aug 4
Sclerostin blocks bone formation
Conclusions
• Evidencebased treatment of osteoporosis
• Is certainly possible
• Many drugs with proven efficacy on hard endpoints
• Compliance is an issue
• Side effects are not the major cause
• Patient education or once-every-year injection
• Treatment is used all to little
• Scenario in 2013?
• Treat to target
• Glucocorticoid-induced osteoporosis eradicated