Transcript Osteoporosis treatment - International Menopause Society

OSTEOPOROSIS
Florence TREMOLLIERES, MD, PhD
Menopause and Metabolic Bone Diseases Center
Hôpital Paule de Viguier
University Hospital of Toulouse
Toulouse, France
Postmenopausal
osteoporosis
• Physiopathology of osteoporotic fractures
• Epidemiology and consequences of fractures
• Assessment of the risk of fracture
– Risk factors
– Measurement of bone mineral density
– Bone turnover markers
• Current treatment options
• MHT and the prevention of osteoporosis at
menopause
• The future of osteoporosis treatment
Osteoporosis
"A systemic disease characterized by low bone mass and
micro-architectural deterioration of bone tissue, leading to
enhanced bone fragility and a consequent increase in
fracture risk"
Healthy bone
WHO definition,
1994
Osteoporotic bone
Pathophysiology of
osteoporotic fracture
Skeletal
factors
Quantitative
factors
Low BMD
Extra-skeletal
factors
Qualitative
factors
Microarchitectural defects
Bone remodeling
Geometry (hip axis length...)
Bone fragility
Type of trauma
Way of falling
Protection...
Trauma
FRACTURE
Epidemiology of fracture
• 200 million people worldwide suffer from osteoporosis1
• 30% of postmenopausal women have osteoporosis in the US and
Europe2,3
• At the age of 50 yr, the combined lifetime risk of hip, forearm and
vertebral fractures in women is around 40%, which is equivalent to
the risk of cardiovascular diseases4
• In US women 55 yrs and older, the hospitalization burden of
osteoporotic fractures is greater than that of myocardial infarction,
stroke, or breast cancer5
• Ageing of populations worldwide will be responsible for a major
increase in the incidence of osteoporosis in postmenopausal
women. By 2050, the incidence of hip fracture is projected to
increase by 240% in women6
1. Cooper C, et al. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992; 2:285-9 - 2. Melton III LJ, et al. Perspective: How many women have
osteoporosis? J Bone Miner Res 1992; 7:1005-10 - 3. EPOS Group. Incidence of vertebral fracture in Europe: Results from the European Prospective Osteoporosis Study (EPOS).
J Bone Miner Res 2002;17:716-24 - 4. Cummings SR, Melton III JR. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002; 359:1761-7 - 5. Singer A et al. Burden
of illness for osteoporotic fractures compared with other serious diseases among postmenopausal women in the United States. Mayo Clin Proc 2015; 90:53-62 - 6. Sambrook
P, Cooper C. Osteoporosis. Lancet 2006; 367:2010-18
Incidence of osteoporotic
fracture in postmenopausal
women
40
Yearly Incidence
per 1000 women
Vertebrae
30
20
Femur
10
Wrist
50
60
70
80
Age
Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999
Main types of osteoporotic
fracture
Wrist
fracture
Proximal
humerus
fracture
Vertebral
fracture
Hip fracture
Clinical impact of vertebral
fracture
Loss of height
Dorsal kyphosis
Acute & chronic pain
Loss of functional
capabilities
Depression
Anxiety
Loss of self-esteem
Impairment of
autonomy
P.D Delmas, RD Chapurlat L’ostéoporose John Libbey Eurotext 2003, Gold T. Bone 1996
Main consequences of hip
fracture
Increased mortality
Long-term nursing care
Surgical complications
Deterioration of
functional capacity
Depression
Anxiety
Fear of falling
Deterioration of
mental status
Loss of
autonomy
Marks R et al. Hip fractures among the elderly: causes, consequences and control. Ageing Research Reviews 2003; 2:57–93
Survival curves according to
type of fracture
Bliuc D et al, Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 2009; 301:513-21
Fracture risk assessment
• Clinical risk factors and FRAX assessment tool
• Bone Mineral Density measurement
• Bone turnover markers
Clinical risk factors
•
•
•
•
•
•
•
•
•
•
•
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Age
Previous fragility fracture
Family history of hip fracture
Low BMI
Premature menopause
Primary and secondary amenorrhea
Cigarette smoking
Excessive alcohol consumption
Low dietary calcium intake and vitamin D deficiency
Corticosteroid therapy
Secondary osteoporosis
Increased risk of falls (visual impairment, impaired cognition, impaired
mobility and gait, neuromuscular disorders, psychotropic drugs use…)
Fracture probability is ageand BMD-dependent
11.5
1.7
-2.5
Kanis JA et al. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 2001; 12:989-95
Prevalent vertebral fracture increases
the risk of subsequent fractures
Vertebral fracture
Non vertebral
fracture
Hip fracture
12
Relative Risk
10
8
6
4
2
0
0
1
2
>3
0
1
2
>3
0
1
2
>3
Number of vertebral fractures at baseline
Black DM et al. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group.
Bone Miner Res 1999; 14:821-8
FRAX assessment tool
DXA bone mineral density measurement
Relationship between BMD and the risk of fracture
Incidence of
fracture
Hip
Spine
Wrist
 - 1SD
RR = 1.5 to 2.7
Low BMD
Marshall D et al. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254-9
WHO definition of
osteoporosis
• Normal :
T-score ≥ -1
• Osteopenia : -1 ≥ T-score > -2.5
• Osteoporosis :
T-score ≤ -2.5
WHO, 1994
Bone turnover markers
(BTM)
• Markers reflecting the activity of bone resorption and
bone formation can be measured in serum or urine1
• Combining BMD measurement and BTM could improve
fracture prediction in postmenopausal women2,3
• Measurement of BMT is useful to monitor the bone
efficacy of antiresorptive therapy after 3-6 months of
treatment4. It has been suggested that they can be used
to assess patient’s adherence to treatment5
1. Garnero P, Delmas PD. Biochemical markers of bone turnover. Applications for osteoporosis. Endocrinol Metab Clin North Am 1998; 27:303-23 - 2. Garnero P et al.
Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res 1996; 11:1531-8 - 3. Sornay-Rendu E et al. Identification of
osteopenic women at high risk of fracture: the OFELY study. J Bone Miner Res 2005; 20:1813-9 - 4. Delmas PD et al. The use of biochemical markers of bone turnover in
osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos Int 2000; 11 (S6):S2-17 - 5. Delmas PD et al. Effect of monitoring
bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2007; 92:1296-304
Clinical management of
osteoporosis
General recommendations
• Rule out secondary causes of osteoporosis
• Encourage patients to quit smoking and excessive alcohol intake
• Advise patients regarding sufficient intake of calcium (1000-1200
mg/day, including supplements if necessary) and vitamin D (800
- 1000 IU/day of vit. D3)
• Suggest regular exercise, with both weight-bearing and musclestrengthening activities (prevention of falls)
• Begin treatment in high-risk patients
Osteoporosis Treatment
Options - 2015
• Anti-remodeling agents (inhibit bone turnover)
–
–
–
–
–
Menopause Hormone Therapy
Selective Estrogen Receptor Modulator (raloxifene, bazedoxifene)
Bisphosphonates (oral and IV)
RANK ligand inhibitor (denosumab)
Tissue Selective Estrogen Complex (bazedoxifene/CEE) (not available in
every country)
– Calcitonin (not available in every country)
• Remodeling stimulator (increases formation and resorption)
– Teriparatide and PTH1-84
• Other (no effect on bone turnover)
– Strontium ranelate (not available in the US)
Effect on fracture risk
Effect on vertebral fracture risk
Effect on non-vertebral fracture risk
Osteoporosis (OP)
Established OPa
+
+
Raloxifene
+
+
+
NA
NA
Bazedoxifene
+
+
NA
NA (+)b
Alendronate
+
+
NA
+ (including hip)
Risedronate
+
NA
+
NA
+ (including hip)
+
NA
+b
+
+
NA
+ (including hip)
+
NA
+
TPTD/PTH
+
NA
+
NA
+ (including hip)
Denosumab
+
+
NA
+ (including hip)
MHT
Ibandronate
Zoledronic acid
Strontium ranelate
MHT: Menopause hormone therapy
TPDT: Teriparatide
Osteoporosis (OP)
Established OPa
+
NA: No evidence available
+ : Effective drug
a Women with a prior vertebral fracture
b Post-hoc analysis in subsets of patients only
Osteoporosis treatment
Practical considerations
• Choosing among treatments for osteoporosis
• Long-term treatment strategies :
– Duration of treatment
– Use drugs in sequence (or combination) ?
• The future of osteoporosis treatment
Choosing among treatments
for osteoporosis
• No head-to-head fracture
postmenopausal osteoporosis
studies
in
• Patient populations studied in clinical trials
differ among studies
• Very difficult to compare efficacy among drugs
Choosing among treatments
for osteoporosis
• Treatment in younger women with low to moderate risk of
fracture : Prevention of post-menopausal bone loss
– MHT/TSEC in symptomatic women
– SERMs in asymptomatic women at risk for spine, especially if there are
concerns about breast cancer risk
• Treatment in women with 10 yrs+ of menopause : Prevention of
the risk of fracture (including hip fracture)
– Bisphosphonates : first-line option in absence of contra-indications
(impaired renal function)
– Denosumab : first-line option (not contraindicated with impaired renal
function – concerns in immuno-compromised patients)
– Teriparatide : patients at very high risk of spine fracture (patients on
glucocorticoid therapy)
MHT in the prevention of
osteoporosis
• Prevents postmenopausal bone loss at all bone sites
• Prevents the microarchitectural defects caused by estrogen
deficiency (trabecular bone)
• Decreases the risk of fracture :
–
–
–
Whatever the bone site
Independently of age
Independently of the risk of fracture (even in low risk women)
Every time possible, MHT is the most appropriate treatment
for the prevention of osteoporosis in postmenopausal
women before 60 years or within 10 years after menopause
MHT in the prevention of fracture
WHI (CEE/MPA)
Type of
fracture
Wrist
WHI (CEE only)
Rate/
10 000/yr
HR
[CI 95%]
Rate/
10 000/yr
HR
[CI 95%]
- 18
0,67
ND
ND
-6
0,62
[0,54 - 0,87]
Spine*
-6
0,66
[0,45 - 0,98]
Hip
-5
0,67
[0,42 - 0,93]
-6
[0,47 - 0,96]
Any fracture
- 47
0,76
[0,69 - 0,83]
0,61
[0,41 - 0,91]
- 56
0,70
[0,63 - 0,79]
* Clinical vertebral fracture
Osteoporosis treatment
limitations
• Real or perceived intolerance
• Concerns about safety, especially the long-term safety of
bisphosphonates
• Inconvenient or awkward dosing regimens
• Poor adherence to therapy
• No agent restores skeletal structure or strength to normal
levels i.e., no “cure” for osteoporosis
• Cost
Long-term treatment strategies
Duration of treatment
• A re-evaluation of the risk of fracture is recommended
after 5 years of treatment :
– Re-evaluation does not mean to stop treatment
– Decision based on :
• Age/risk of fracture
• Occurrence of new fractures/new risk factors
• Treat to target (hip T-score > -2.5) /changes in BMD values
• If discontinuation of treatment (drug holiday):
– Re-evaluation of the risk of fracture after 1-2 years
• Resuming treatment is recommended when bone density declines
(bone turnover increases)
The future of osteoporosis
treatment
• Anti-resorptive agents
– Cathepsin K Inhibitors (Odanacatib)
–
–
–
–
Integrin Antagonists
c-Src kinase Inhibitor
Glucagon-like peptide 2
Inhibitors of the acidification process within the resorption lacuna
• Anabolic agents
– Sclerostin antibodies
(Romosozumab, Blosozumab)
– Dkk1 antagonists
– GSK3 inhibitors
– Calcilytics
Modulation of the canonical
Wnt-signaling pathway
Osteoporosis treatment
Summary
• There are several therapies that effectively prevent bone loss
and significantly reduce the risk of fracture in patients with
osteoporosis
– Every drug has its place and its limitations
– In choosing a drug, it must be considered :
•
•
•
•
Strength of evidence of fracture protection
Tolerability and convenience of dosing
Serious safety concerns
Long-term treatment strategies : currently there is no
« cure » for osteoporosis
• Recent insights into regulation of bone remodeling are leading
to exciting new treatment strategies