Transcript 21_Hochberg_Osteoporosis_all good can use

Osteoporosis: Update 2011
Mini-Med School
Marc C. Hochberg, MD, MPH
Professor, Departments of Medicine and
Epidemiology & Public Health
Objectives
► Identify
common types of fractures
► Review current recommendations for
diagnosis and treatment of
postmenopausal women with
osteoporosis
►Who should be tested
►Who should be treated
►How should they be treated
► Discuss
the rare adverse events of
bisphosphonate therapy
Definitions of Osteoporosis
►A
skeletal disorder characterized by
compromised bone strength
predisposing to an increased risk of
fracture.
– NIH Consensus Conference (2000)
► Bone
mineral density that is >=2.5
standard deviations below the young
gender-specific mean
– World Health Organization (1994)
Goals for Therapy
•
Fracture prevention
• Stabilize or increase bone mass
• Provide tolerability and long-term
safety
• Optimize adherence
Vertebral Fractures
► Involve
both the thoracic and lumbar
spine
► Only ~1/3 are associated with acute
back pain
► Presence of vertebral deformities is
associated with chronic back pain
and disability, increased risk of
hospitalization and excess mortality
Hip Fracture
•
Most serious clinical fracture
• Mortality is high
• 20% of patients die within 1 year
• Men have higher mortality than women
•
Morbidity is high
• 50% do not regain independence
• 50% do not regain previous level of function
•
Patients who survive
– are often not treated for osteoporosis
– are at increased risk of additional fractures
Rationale for Measuring BMD
► Bone
mineral density (BMD)
– Strongly related to bone strength
– Independent predictor of fracture risk
• For each SD decrease in BMD, fracture risk
increases 1.5 – 2.5 times
– Gold standard for diagnosis of
osteoporosis
– Can be used to monitor efficacy of
therapy
How to Measure BMD
► Dual
Xray Absorptiometry (DXA) is
the gold standard for measuring
BMD
– Hip (femoral neck and total hip)
– Lumbar spine
– Distal 1/3rd radius
• Primary hyperparathyroidism
• When hips and lumbar spine can’t be
measured or are not valid
Who Should be Tested
► Women aged 65 and above
► Younger postmenopausal women
with
clinical risk factors
–
–
–
–
Prior low trauma fracture
Current smokers
Low body weight
Family history of hip fracture
► Women
with medical conditions or taking
medications that are associated with low
bone mass or an increased rate of bone
loss
Diseases That Can Cause
Secondary Osteoporosis
►
Endocrine diseases
►
– Hyperthyroidism
– Hyperparathyroidism
– Hypogonadism
►
►
– Rheumatoid arthritis
– Chronic lung disease
– Malignancy
GI diseases
– Malabsorption
syndromes
– Chronic liver disease
– Gastric operations
Organ transplant
Other chronic
diseases
►
Dietary disorders
– Vitamin D deficiency/
insufficiency
– Excess alcohol
intake
– Anorexia nervosa
Medications That Can Cause
Secondary Osteoporosis
• Oral glucocorticoids
• Excess thyroid hormone
replacement
• Chemotherapy
• Anticonvulsants
• Gonadal hormone suppression
• Immunosuppressive agents
Who Should Be Treated
► Women
with a hip or vertebral
fracture
► Women with BMD T-score < -2.5 at
femoral neck or lumbar spine
► Women with low BMD and a 10-year
probability of hip fracture > 3.0% or
major osteoporotic fracture > 20%
based on US-adapted FRAX model
US Race-Specific FRAX Model
► Calculates
10-year absolute risk of
major osteoporotic and hip fracture
► Includes age, sex, height, weight, h/o
prior fracture, family h/o hip fracture,
current smoking, current alcohol
consumption, current glucocorticoid
use, medical conditions associated
with 2ary osteoporosis, and BMD
Nonpharmacologic Approaches
•
Calcium intake
• Diet and/or supplementation with an RDA of at least 1200 mg
(upper limit [UL] 2000 mg) in conjunction with vitamin D
Potential Harms of Calcium
Supplementation
► Increased
risk of renal stones when
given in conjuction with vitamin D
– RR = 1.17 (95% CI: 1.02, 1.34)
– 5.7 events per 10,000 women-years
► Increased
risk of nonfatal MI
– RR = 1.31 (95% CI: 1.02, 1.67) for IPD
– RR = 1.27 (95% CI: 1.01, 1.59) for studies
• Bolland MJ et al: BMJ 2010;341:c3691
Nonpharmacologic Approaches
•
Calcium intake
• Diet and/or supplementation with an RDA of at least 1200 mg
(upper limit [UL] 2000 mg) in conjunction with vitamin D
•
Vitamin D supplementation
• Diagnose and treat deficiency or insufficiency (< 20 ng/ml)
• Supplement with at least 600-800 IU D3/day (UL 4000 IU/day)
Vitamin D and Fractures:
Bischoff-Ferrari Meta-analysis
►
Systematic review of double-blind RCTs of at
least 1 year duration with more than 1 fracture
► 7 studies with informative data for non-vertebral
fractures: RR = 0.83 (0.70, 0.98)
► 5 studies with informative data for hip fractures:
RR = 0.88 (0.69, 1.13)
► Heterogeneity based on vitamin D dosage
– Vitamin D at a dose of 700-800 IU/d, but not 400 IU/d,
reduced risk of both hip and nonvertebral fractures
Bischoff-Ferrari H et al: JAMA 2005;293:2257-64
Vitamin D and Fractures:
AHRQ-Ottawa Meta-analysis
►
Systematic review of double-blind RCTs of at
least 1 year duration with more than 1 fracture
► 13 studies with informative data for total
fractures: RR = 0.90 (0.81, 1.02)
► 7 studies with data for non-vertebral fractures:
RR = 0.87 (0.75, 1.00)
► 7 studies with informative data for hip fractures:
RR = 0.83 (0.68, 1.00)
► Heterogeneity based on residence of participants
– Significant fracture reduction among institutionalized
subjects but not among community-dwelling elders
Cranney A et al: IOM 2011 report
Vitamin D and the Risk of Falling
Primary Analysis
Odds Ratio
(95% CI)
Pfeifer et al (2000)
0.47 (0.20–1.10)
Bischoff et al (2003) 0.68 (0.30–1.54)
Gallagher et al (2001) 0.53 (0.32–0.88)
Dukas et al (2004)
0.69 (0.41–1.16)
Graafmans et al (1996)0.91 (0.59–1.40)
Pooled (uncorrected) 0.69 (0.53–0.88)
Pooled (corrected)
0.78 (0.64–0.92)0.1
Favors
Vitamin D
0.5
Favors
Control
1.0
Odds Ratio
Bischoff-Ferrari HA. JAMA. 2004;291:1999–2006
5.0 10.0
Potential Harms of Vitamin D
Supplementation
► Increased
risk of renal stones when
given in conjunction with calcium
– RR = 1.17 (95% CI: 1.02, 1.34)
– 5.7 events per 10,000 women-years
► No
clinically important adverse
effects of vitamin D supplementation
• Rosen CJ: NEJM 2011;364:248-54
Nonpharmacologic Approaches
•
Calcium intake
• Diet and/or supplementation with an RDA of at least 1200 mg
(upper limit [UL] 2000 mg) in conjunction with vitamin D
•
Vitamin D supplementation
• Diagnose and treat deficiency or insufficiency (< 20 ng/ml)
• Supplement with at least 600-800 IU D3/day (UL 4000 IU/day)
•
Regular load-bearing and muscle-strengthening
exercise (no weight lifting if BMD in spine is low)
•
Fall prevention advice
•
Smoking cessation
•
Avoid excess alcohol intake
•
Home safety evaluation
Current FDA-Approved Treatments for
Postmenopausal Osteoporosis: 2011
► Bisphosphonates
–
–
–
–
Alendronate
Risedronate
Ibandronate
Zoledronic acid
► Calcitonin
► Denosumab
► Hormone therapy
► Raloxifene
► Teriparatide
Pharmacologic Approaches:
Summary
•
All FDA-approved treatments reduce
the incidence of vertebral fractures
•
Some, but not all, reduce the incidence
of non-vertebral fractures
•
Some, but not all, of the drugs that
reduce the incidence of non-vertebral
fractures also reduce the incidence of
hip fractures
WHI Clinical Trials of HT
– Two large, parallel group, randomized, placebocontrolled trials sponsored by NIH
•
Unopposed CEE vs placebo (E-alone study)
•
CEE plus MPA vs placebo (E+P study)
– Objective: To evaluate the balance of chronic
disease risks and benefits of postmenopausal HT
– Primary outcomes
•
CHD (nonfatal MI, CHD death)
•
Invasive breast cancer
– Approximately 8 years of follow up were planned
for each trial
HT = hormone therapy; CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate.
The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.
What Happened to the WHI
Clinical Trials of HT?
– E+P trial stopped by the Data Safety Monitoring
Board in July 2002 after a mean follow-up of 5.2
years1
•
•
Breast cancer risk crossed pre-specified monitoring
boundary
Global index indicated trend towards greater risk than
benefit
– E-alone trial stopped by NIH in March 2004 after a
mean follow-up of 6.8 years2
•
1Writing
Trend toward increased risk of stroke without overall
benefit
Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; 2Women's Health Initiative
Steering Committee. JAMA. 2004;291:1701-12.
WHI Fracture Results
– E+P used an average of 5.6 years1
•
•
•
•
↓ hip fractures 33%
↓ clinical vertebral fractures 35%
↓ forearm/wrist fractures 29%
↓ total fractures 24%
– Unopposed E used an average of 6.8 years2
• ↓ hip fractures 39%
• ↓ clinical vertebral fractures 38%
• ↓ total fractures 30%
1Cauley
JA, et al. JAMA. 2003;290:1729-38.
Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
2Women’s
WHI Fracture Results:
Clinical Implications
• Women treated with E alone or E+P for
menopausal symptoms do not need
another anti-resorptive agent to reduce
either the decline in BMD or risk of fracture
• HT is the only therapy that has been
demonstrated to prevent fractures in a
population of postmenopausal women at
relatively low risk of fracture
Selective Estrogen Receptor
Modulators (SERMs)
►
►
►
►
Raloxifene, others in
clinical trials
Binds to ERs
Effects on many
tissues
Bone effects mainly
anti-catabolic 
– increases BMD
– reduces risk of vertebral
fractures
– Does not reduce risk of
nonvertebral fractures
• Approved for
prevention and
treatment of postmenopausal
osteoporosis
• Reduces risk of ER+
breast cancer
• Can be used with
other nonhormonal
therapies
• Adverse effects
include hot flashes,
risk of VTE
Bisphosphonates
► Drug
class of choice for treatment
– Oral: alendronate or risedronate
– IV: zoledronic acid
► Contraindications
– Impaired swallowing (oral only)
– eGFR < 35 ml/min
– Hypocalcemia
– Vitamin D deficiency
Favus MJ: NEJM 2010;363:2027-35.
Evidence-Based Review ALN Trials:
Non-vertebral Fractures
•
Data on incidence of NVFx in 9 trials
• Only 5 trials could be pooled for effects of 10
mg daily dose
•
Pooled estimate for RR = 0.84 (0.74–0.94)
for all non-vertebral fractures at doses of
10 mg or higher
• RR reduction greater in the 4 treatment trials
(RR=0.77 [0.64, 0.92])
No difference using T-score of <-2.5 or
<-2.0 as cut-point
• Pooled estimate for hip fracture derived
from 6 trials
•
• RR = 0.61 (95% CI 0.40, 0.92)
Wells G et al: Cochrane Database Syst Rev 2008;(1):CD001155.
Evidence-Based Review of RIS Trials:
Nonvertebral Fractures
• Pooled estimate from 4 treatment
trials for all nonvertebral fractures of
RR=0.80 (0.72–0.90)
• Results consistent across trials
• Pooled estimate from 3 treatment
trials for hip fractures
• RR = 0.74 (95% CI: 0.59, 0.94)
Wells G et al: Cochrane Database Syst Rev 2008;(1)CD004523.
Effect of Ibandronate on Fracture
Risk in Women with PMO
►
►
►
Post-hoc individual patient data meta-analysis of
data from 4 phase III RCTs of at least 2 years
duration
Subjects categorized by estimated annual
cumulative exposure: low, medium, high
Patients in the high ACE group (either 150 mg
orally once monthly, 2 mg IV bimonthly or 3 mg IV
quarterly) had a lower adjusted incidence of nonvertebral fractures than women in pooled placebo
groups
– RR = 0.70 (0.50. 0.99) for all non-vertebral fractures
– RR = 0.66 (0.45, 0.96) for “Big 6” fracture sites
Harris S, et al: Curr Med Res Opin 2008:24;237-45.
Once- Yearly Zoledronic Acid:
The Horizon Trial
► 7765
postmenopausal women aged 65 to
89 years randomized to IV zoledronic acid
5 mg or PBO annually for 3 years
► Inclusion criteria
– Femoral neck BMD T score < -2.5
– T-score < -1.5 and morphometric VFx (2 mild or
1 mod)
► Stratified
randomization
– 1: No concomitant OP medication at baseline
– 2: OP meds, other than BPs, at baseline
Black DM et al: NEJM 2007;356:1809-22
Once-Yearly Zoledronic Acid:
The Horizon Trial
Relative risk
Percent w/
fractures
12
10
Spine 0.30 (0.24,0.38)
Hip
0.59 (0.42,0.83)
Nonvert 0.75 (0.64,0.87)
Clinical 0.67 (0.58,0.77)
8
6
4
2
0
PBO
ZA
Treatment group
Vertebral
Nonvertebral
Hip
Black DM et al: NEJM 2007;356:1809-22
Comparative Efficacy of Ncontaining Bisphosphontes
Comparison
NVFx
HipFx
ALN v RIS
0.96 (0.78, 1.19)
0.63 (0.34, 1.20)
ALN v ZA
1.04 (0.82, 1.31)
0.80 (0.40, 1.58)
RIS v ZA
1.08 (0.90, 1.30)
1.25 (0.83, 1.89)
ALN v IBAN
1.17 (0.77, 1.77)
N/A
RIS v IBAN
1.21 (0.82, 1.80)
N/A
IBAN v ZA
0.89 (0.59, 1.34)
N/A
Hochberg M: Curr Osteoporos Rep 2008;6:89-94.
Comparative Efficacy of Ncontaining Bisphophonates
► Mixed
treatment comparison (MTC)
of reduction in vertebral fractures
– 7 placebo-controlled trials
– ZA more likely to be associated with
greater risk reduction than oral BPs
• ZA vs ALN
• ZA vs RIS
• ZA vs IBAN
OR = 0.54 (0.39, 0.75)
OR = 0.49 (0.34, 0.69)
OR = 0.57 (0.36, 0.92)
Jansen JP et al: CMRO 2009;25:1861-8 and Semin Arthritis Rheum 2011;40:275-84.
Comparative Efficacy of Ncontaining Bisphosphontes
Comparison
NVFx
HipFx
ALN v RIS
0.90 (0.66, 1.24)
0.77 (0.37, 1.59)
ZA v ALN
0.55 (0.41, 0.76)* 0.95 (0.54, 1.68)
ZA v RIS
0.50 (0.36, 0.70)* 0.73 (0.37, 1.44)
ALN v IBAN
1.05 (0.68, 1.63)
0.40 (0.09, 1.55)
RIS v IBAN
1.16 (0.74, 1.84)
0.52 (0.12, 2.15)
ZA v IBAN
0.58 (0.37, 0.92)* 0.38 (0.09, 1.43)
Jansen JP et al: Semin Arthritis Rheum 2011;40:275-84.
Bisphosphonates
► Adverse
Events
– Upper GI complaints
– Acute phase reaction (IV >>> oral)
– Erosive esophagitis
– Esophageal cancer
– Osteonecrosis of the jaw
– Atypical femoral fractures
Favus MJ: NEJM 2010;363:2027-35.
Potential Harms of BPs:
Esophageal Cancer
►
►
Two studies that analyzed data from the GPRD
Study 1 (cohort study) found no increase in risk
(HR = 1.07 [95% CI: 0.77, 1.49]) with mean followup of 4.5 years
► Cardwell CR et al: JAMA 2010;304:657-63.
►
Study 2 (case-control) found an increase in risk
(OR = 1.30 [95% CI: 1.02, 1.66]) with mean followup of 7.5 years. Significant dose and duration
response relationships with excess risk for >10
Rxs and duration of use >3 years
► Green J et al: BMJ 2010;341:c4444.
Potential Harms of BPs:
Subtrochanteric Fractures
►
►
Several studies have examined this relationship
Most recent, a nested case-control study of older
women who received Rx for oral bisphosphonate:
716 subtrochanteric and 9723 hip fractures
► Park-Wyllie LY et al: JAMA 2011;305:783-9.
►
aOR = 2.74 (95% CI: 1.25, 6.02) for long-term use
(>5 years) based on 121 cases
► Significant reduction in risk of hip fractures for
both intermediate (3-5 years) and long-term use
► Intermediate
► Long-term
aOR = 0.86 (0.73, 1.00)
aOR = 0.76 (0.63, 0.93)
Anabolic Therapy: Teriparatide
► Recombinant
human PTH 1-34
– PTH 1-84 and other analogs currently under
investigation
► Indicated
for treatment
– of women with PMO at high risk for fracture
– to increase bone mass in men with primary or
hypogonadal osteoporosis who are at high risk
for fracture
► Not
for use in patients with Paget’s
disease, hypercalcemia, renal disease or
skeletal cancer
Effect of Teriparatide on Risk
of New Vertebral Fractures
0%
25%
50%
75%
100%
*P<0.001 vs placebo.
22
19
Placebo
rhPTH 20
rhPTH 40
(n=448)
(n=444)
(n=434)
64
Number of women who had ≥1 fracture
14
12
10
8
6
4
2
0
% of Women
Risk Reduction (RR)
RR 0.31 (95% CI, 0.19 to 0.50)*
RR 0.35 (95% CI,
0.22 to 0.55)*
Effect of Teriparatide on Risk
of Non-vertebral Fractures
7
RR 0.46 (95% CI, 0.25 to 0.86)*
RR 0.47 (95% CI,
0.25 to 0.88)†
% of Women
6
5
4
3
2
1
0
30
Placebo
14
14
rhPTH 20
rhPTH 40
(n=544)
(n=541)
(n=552)
Number of women who had ≥1 nonvertebral fracture
*P=0.01 vs placebo. †P=0.02 vs placebo.
Adverse Events With Teriparatide
No. of Adverse Events (% of total) Reported
Placebo
PTH 20
PTH 40
≥1 elevated sCa
8 (2)
60 (11)‡
153 (28)‡
Confirmed high sCa
1 (0)
16 (3 )‡
53 (10)‡
Nausea
41 (7)
51 (9)
98 (18)‡
Headache
45 (8)
44 (8)
72 (13)†
6 (1)
17 (3)*
13 (2)
32 (6)
35 (6)
59 (11)§
Leg cramps
Withdrawn for AE
*P=0.02 vs placebo. †P = 0.01 vs placebo.
‡P< 0.001 vs placebo. §P=0.004 vs placebo.
Denosumab: The Freedom Trial
► 7868
postmenopausal women aged 60 to
90 years randomized to denosumab 60 mg
subq or PBO q6months for 3 years
► Inclusion criteria
– Femoral neck BMD T score < -2.5
► Primary
endpoints
– New vertebral fractures
► Secondary
–
–
–
–
endpoints
Time to 1st non-vertebral fracture
Time to 1st hip fracture
Change in bone mineral density
Change in bone turnover markers
Cummings SR et al: NEJM 2009;361:756-65.
Denosumab: The Freedom Trial
Relative risk
Percent w/
fractures
8
6
Spine 0.32 (0.26,0.41)
Hip
0.60 (0.37,0.97)
Nonvert 0.80 (0.67,0.95)
4
2
0
PBO
Deno
Treatment group
Vertebral
Nonvertebral
Hip
Cummings SR et al: NEJM 2009;361:756-65.
Evidence-Based Review
of Osteoporosis Trials
►
Several drugs reduce
the risk of vertebral
fractures
–
–
–
–
–
–
–
–
–
Calcitonin
Raloxifene
Hormone Rx
Alendronate
Risedronate
Ibandronate
Zoledronic acid
Teriparatide
Denosumab
►
Some drugs reduce
the risk of non-spine
fractures
–
–
–
–
–
–
–
Hormone Rx*
Alendronate*
Risedronate*
Ibandonate (?)
Zoldedronic acid*
Teriparatide
Denosumab*
*Also reduce the risk of hip fracture
Safety and Tolerability Issues
► Bisphosphonates
– GI tolerability, ONJ, Atypical femur fractures
► Hormone
therapy
– CV thrombotic events, Breast Ca, others
► Raloxifene
– Venous thrombotic events
► Teriparatide
– Hypercalcemia
► Denosumab
– Increased risk of infections
Treatments Under Development

SERMs
 Bazedoxifene, lasofoxifene





Oral calcitonin
Transdermal PTH
Cathepsin K inhibitors
Sclerostin monoclonal antibody
rhIGF-1
Kawai M et al: Nat Rev Drug Discov 2011;10:141-56
Recommendations: 2011
►
For postmenopausal women with osteoporosis
– Oral bisphosphonate (alendronate or risedronate)
– Zoledronic acid (if contraindication to or intolerant of oral
BP)
– Teriparatide (“severe OP” or contraindication to, failure of
or unable to tolerate BPs)
– Denosumab (as above plus contraindication to or unable to
tolerate TPTH)
All pharmacologic agents should be added to a background of
calcium and vitamin D supplementation and education in nonpharmacologic treatment strategies.
Thank you for your attention!