Transcript Osteoporosis - GRECC Audio Conferences

Once a Year? New
Approaches to
Osteoporosis Treatment
Bruce R. Troen, M.D.
Geriatrics Institute
Division of Gerontology and Geriatrics Medicine
Geriatric Research, Education, and Clinical Center
Miami VA Medical Center
http://troelab.org
Learning Objectives
To better understand and act
upon:
New and forthcoming
approaches to the treatment of
osteoporosis.
 The significant prevalence and
importance of vitamin D
insufficiency.

Osteoporosis Rx - 2007
• Treat all with a history of fragility
fractures.
• Rx benefits women with a fracture; less
so women with osteopenia or men.
• ALN, RIS, IBN, raloxifene, PTH, and
strontium reduce vertebral fractures.
• ALN, RIS, and HRT reduce hip
fractures in community-dwelling
women.
• Calcium + vit D reduce hip fractures in
the community and in institutions.
Male Osteoporosis





2 million men
13-25% lifetime fracture risk
exponential increase with age,
occurs ~10 years later in men
than in women
1/5 of all hip fractures; by age 90,
1/6 of men suffer hip fracture
vertebral fracture incidence: 12%
(same as in women)
60
50
Hip Fracture Cases
40
All Participants
30
20
10
0
1800
1600
1400
1200
1000
800
600
400
200
0
No. of participants
No. of hip fracture cases
> 50% of hip fractures occur
in pts. with T-scores > –2.5
Total Hip T-Score
BMD is not the whole story!
Wainwright SA 2005
BMD Contribution to Fracture
Risk Reduction
Alendronate 16 % Cummings AMJ 112:281, 2002
Risedronate 28 % Eastell JBMR 18: 1051, 2003
Raloxifene
4 % Sarkar JBMR 17:1, 2002
Risedronate 18 % Watts J Clin Dens 7:255, 2004
Teriparatide 40 % Chen JBMR 21:1785, 2006
BMD is not the whole story!
Both age and BMD alter fracture risk
Age and BMD are
the strongest
predictors for hip
fracture.
Kanis et al. Osteoporos Int 2001
Osteoporosis - What’s New?
•Ibandronate IV every 3 months
•ONJ - how much of a problem is it?
•Bisphosphonate wars - is one better?
•PTH - when should it be used?
•Under-diagnosis/treatment and poor
compliance
•Zoledronate 5 mg IV once a year
•Denosumab 60 mg SQ twice a year
•Vitamin D insufficiency is widespread
•Vitamin D 600,000 IU once a year
Osteoporosis - What’s New?
Ibandronate IV every 3
months
Vertebral fracture rate
Ibandronate reduces vertebral
fractures
Placebo
Daily IBN
Intermittent IBN
Overall
North America
12
10
8
6
4
2
0
Chesnut et al., Curr Med Res Opin 3/05
Europe
Change from baseline (%)
Quarterly IV IBN is superior
to daily oral IBN
2.5 mg daily
2 mg q 2 months
3 mg q 3 months
6
5
4
3
2
1
0
Lumbar
spine
Total
hip
Femoral
neck
Delmas et al. Arthritis & Rheumatism 54(6): 1838–1846 2006
Trochanter
Osteoporosis - What’s New?
ONJ - how much of a
problem is it?
Osteonecrosis of the Jaw
Ruggiero SL. J Oral Maxillofac Surg. 2004;62:527-534.
Osteonecrosis of the Jaw
(ONJ)



Osteonecrosis of the Jaw is a rare
condition that involves the loss, or
breakdown of the jaw bone1
Occurs usually after tooth extraction
Rather than healing post extraction,
indolent infection of the bone occurs
(osteomyelitis)
1National
Cancer Institute. Oral complications of chemotherapy and head/neck radiation (PDQ).2004
ONJ with oral BP





None seen in all clinical trial data
(>100,000 patients ≥ 3 years)
Postmarketing anecdotal reports: ALN
~75 cases, RIS ~10
FDA labeling on ONJ caution (especially
for oral BPs) is not based on any sound
science
Oral BP cumulative ONJ may be ≤
0.0005% of all persons taking oral BPs
(10 x more oral BP exposure than IV BPs)
ONJ would never have been detected
without high-dose IV BP use
Dr. Paul Miller
ONJ Comparative Risks
Any Fragility Fracture (1)
Hip Fracture (1)
Anaphylaxis from PCN
32
Death by MVA
11
Death by Murder
6
ONJ - Osteoporosis Pt.
0.7
Death by Lighting in NM
0.6
0
10
20
30
40
50
60
70
80
90
100
Risk per 100,000 People per Year
(1) Women age 65-69 (from Swedish
National Bureau of Statistics and
database of Olmsted County, MN, USA.)
M. Lewiecki 2007
Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf.
2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150.
www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html
Osteoporosis - What’s New?
Bisphosphonate wars is one better?
BMD Increases With Alendronate and
Risedronate at 24 Months in FACT
Total Hip
Alendronate (N=375)
Risedronate (N=375)
p < .001
3.0 %
1.3 %
Bonnick et al. JCEM 91(7):2631-2637, 2006
BMD Increases With Alendronate and
Risedronate at 24 Months in FACT
Lumbar Spine
Alendronate (N=372)
Risedronate (N=379)
5.2 %
p < .001
3.4 %
Bonnick et al. JCEM 91(7):2631-2637, 2006
Percent of Patients With Response by
BMD Gains/Losses at 12 Months in FACT
Total Hip
Percent of patients
who lost BMD at 24
months
Percent of patients who
maintained or gained
BMD at 24 months
16%
84%
P≤0.002
P≤0.002
41%
100% 80%
60%
40%
59%
20% 0%
ALN 70 mg once-weekly
Bonnick et al. JCEM 91(7):2631-2637, 2006
20%
40%
60%
80% 100%
RIS 35 mg once-a-week
Responses to Alendronate and
Risedronate at 24 Months in FACT
BMD (site)
Hip Trochanter:
Total Hip:
Femoral Neck:
Lumbar Spine:
ALN
4.6%
3.0%
2.8%
5.2%
RIS
2.5%
1.3%
1.0%
3.4%
Bone markers
BSAP:
P1NP:
NTX:
CTX:
ALN
-40%
-62%
-57%
-73%
RIS
-29%
-46%
-44%
-53%
Bonnick et al. JCEM 91(7):2631-2637, 2006
RIS more effectively reduces nonvertebral fx’s than ALN or CT
6
Patients (%)
5
Calcitonin
4
3
Alendronate
2
Risedronate
RR = 0.41
1
0
0
30
60
90
120 150 180 210 240 270 300 330 360
Time to Fracture (Days)
Watts et al., JMCP 2004 10(2):142-151
% of cohort with a hip fracture
RIS more effectively reduces
hip fractures than ALN
0.58
0.50
Alendronate
0.40
0.30
Risedronate
RR = 0.57
0.20
0.10
0.00
Baseline
month 3
month 6
Silverman et al., Osteoporos Int (2007) 18:25–34
month 12 month 24
RIS more effectively reduces
fractures than ALN
Treatment Time Cohort Percent Adjusted C.I.
psize fractures
ratio
value
Non-vertebral
ALN
6
21,615
1.31
0.650.81
0.05
RIS
mo. 12,215
1.14
1.00
ALN
12 21,615
2.30
0.680.82
0.03
RIS
mo. 12,215
1.99
0.98
Hip
ALN
6
21,615
0.29
0.320.54
0.02
RIS
mo. 12,215
0.17
0.91
ALN
12 21,615
0.58
0.370.57
0.01
RIS
mo. 12,215
0.37
0.87
Silverman et al., Osteoporos Int (2007) 18:25–34
Osteoporosis - What’s New?
PTH - when should it be
used?
PTH + concurrent bisphosphonate?
NO
Finkelstein et al., NEJM 9/03
Treatment / Prevention of
Osteoporosis - PTH







those who continue to fracture or lose
BMD after bisphosphonates x 2 years
severe loss of BMD (T ≤ -3.5)
prevalent fractures and T ≤ -2.5
20 µg subcutaneously daily
treat for no longer than two years
do NOT combine with anti-resorptive
treat with anti-resorptive after PTH
Fracture Risk Reduction in
Women with PMO
Agent
Ca+2/Vit D
Calcitonin
Raloxifene
Ibandronate
Alendronate
Risedronate
Teriparatide
Vertebral Fx
New







First
Hip
Fracture
Nonvertebral
Fracture


No effect demonstrated

No effect demonstrated
No effect demonstrated




No effect demonstrated



Osteoporosis - What’s New?
Under-diagnosis,
Under-treatment, and
Non-compliance
Osteoporosis: underdetected
and undertreated
• 14/16 studies on fragility fractures
• < 32% had a BMD test
• 8-62% (median 18%) were on
calcium or vitamin D
• 0.5-38% were on bisphosphonates
Elliot-Gibson et al., Osteoporosis Int 15:767-778, 2004
Osteoporotic nonvertebral fractures are
often not diagnosed or treated
Bisphosphonate Persistence:
Weekly vs. Daily (newly started)
Ettinger et al., Arthritis & Rheumatism 2004
Bisphosphonate Persistence:
Weekly vs. Daily (previous)
Ettinger et al., Arthritis & Rheumatism 2004
Relative Rate of Hospitalization
All-cause hospitalization rate in
osteoporosis pts. by adherence level
1.60
1.50
1.40
1.30
1.20
1.10
1.00
0.90
> 90%
80-90%
50-80%
< 50%
Adherence (medication possession over time)
Danese et al. ASBMR, Philadelphia, 2006
IBN vs. RIS: ?compliance

Preference (depends how you ask!)
– monthly > weekly
– weekly > monthly

Persistence (depends on the study!)
– RIS vs. IBN: 144.3 vs. 100.1
days
– IBN vs. RIS: 57% vs. 39%

Adherence
RIS: 72.7 ± 26.4% (p < 0.0001)
– IBN: 52.8 ± 31.5%
–
Gold et al., Current Medical Research and Opinion 12(22):2383-2391, 2006
Cooper et al. Int. J. Clinical Practice 2006
Osteoporosis:
Bottom Line
• Any treatment is better
than no treatment!
• How can we improve
treatment compliance
and persistence?
Osteoporosis - What’s New?
Zoledronic acid 5 mg IV
once a year
Once Yearly Zoledronic Acid
Reduces Fractures
HORIZON Pivotal Fracture Trial
 multi-national, multi-center, RCT
 7,736 women age 65-89 with Tscore < -2.5 or fracture plus Tscore < -1.5
 calcium 1000-1500 mg/day vit D
(400-1200 IU/day)
 zoledronic acid IV infusion 5 mg

Black et al. NEJM 356:1809-1822, 2007
Cumulative Incidence (%)
ZOL reduces hip fracture
3
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
41%*
(17%, 58%)
P = .0024
2
1
0
0
3
6
9
12
15
18
21
24
27
30
33
Time to First Hip Fracture (months)
*Relative risk reduction (95% confidence interval) vs placebo
Black et al. NEJM 356:1809-1822, 2007
36
ZOL reduces vertebral fx
Cumulative Incidence (%)
3
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
77%
(63%, 86%)
P < .0001
2
1
0
0
3
6
9 12 15 18 21 24 27 30 33 36
Time to First Clinical Vertebral Fracture (months)
*Relative risk reduction (95% confidence interval) vs placebo
Black et al. NEJM 356:1809-1822, 2007
Cumulative Incidence (%)
ZOL reduces non-vertebral fx
12
25%
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
10
(13%, 36%)
P = .0002
8
6
4
2
0
0
3
6
9
12 15 18 21 24 27 30 33 36
Time to First Clinical Non-vertebral Fracture (months)
*Relative risk reduction (95% confidence interval) vs placebo
Black et al. NEJM 356:1809-1822, 2007
Once Yearly Zoledronic Acid
Reduces Fractures




side effects: fever (15%), myalgia (8%),
flu-like symptoms, headache, and bone
pain - majority resolved within 3 days
ONJ - 1 Rx, 1 placebo (resolved w/ RX)
atrial fibrillation 1.2% Rx, 0.4% placebo
bone markers: decreased CTX, BSAP,
and P1NP (to mid premenopausal
range)
Black et al. NEJM 356:1809-1822, 2007
Osteoporosis - What’s New?
Denosumab 60 mg SQ
twice a year
RANK Ligand (RANKL) is a Key
Mediator of Osteoclast Activity
(receptor activator of NFkB ligand)
OPG
Vit D
PTH
PGE2
IL-11
RANKL
Stromal cells
Osteoblasts
RANK
CTSK
Osteoclast
precursor
Osteoclast
(mature)
The RANKL / OPG Balance
growth factors
hormones
PTH
cytokines
RANKL
gravity
vitamins
drugs
aging
OPG
Normalized fluorescence
intensity for OPG-Fclabeled FITC
RANKL Expression Is Increased
in Postmenopausal Women
P<0.001
90
*†
60
P=0.003
*
P<0.001
*†
P<0.001
*†
30
0
Marrow
stromal cells
B cells
T cells
Premenopausal
Total
Untreated postmenopausal
Postmenopausal + ERT
*vs postmenopausal + ERT; †vs premenopausal.
ERT = estrogen replacement therapy.
Eghbali-Fatourechi et al. J Clin Invest. 2003;111:1221.
(n=12/group)
Antibody to RANKL prevents
OC precursor differentiation
RANKL
RANK
Vit D
PTH
PGE2
IL-11
denosumab
X
Stromal cells Osteoclast
Osteoblasts precursor
X
CTSK
Inhibition
of
mature OC
formation
Denosumab increases BMD
and decreases bone resorption
 RCT, dose ranging
 412 women, mean age 63 with
T-scores: LS < -1.8 to -4.0 or
FN/hip < -1.8 to -3.5
 calcium 1000 mg/day, vit D 400
IU/day
 denosumab SC, q 3mo. & q 6
mo.
McClung et al. N Engl J Med. 2006;354:821.
Denosumab SC q6mo
enhances lumbar spine BMD
6
Mean change
from baseline (%)
5
4
3
2
Placebo
Denosumab 14 mg
Denosumab 60 mg
Denosumab 100 mg
Denosumab 210 mg
ALN 70 mg/wk
1
0
-1
-2
0
2
4
6
Months
McClung et al. N Engl J Med. 2006;354:821.
8
10
12
Denosumab SC q6mo
enhances total hip BMD
Mean change
from baseline (%)
4
3
2
*
Placebo
Denosumab 14 mg
Denosumab 60 mg
Denosumab 100 mg
Denosumab 210 mg
ALN 70 mg/wk
1
0
-1
-2
0
1
2
3
4
5
6
7
Months
McClung et al. N Engl J Med. 2006;354:821.
8
9
10 11 12
Denosumab SC q6mo maintains
distal third radius BMD
Placebo
Denosumab 14 mg
Denosumab 60 mg
Denosumab 100 mg
Denosumab 210 mg
ALN 70 mg/wk
Mean change
from baseline (%)
3
2
1
0
-1
-2
-3
0
1
2
3
4
5
6
Months
McClung et al. N Engl J Med. 2006;354:821.
7
8
9
10
11
12
Denosumab suppresses serum
c-telopeptide
20
Mean change
from baseline (%)
0
-20
Placebo
Denosumab 14 mg
Denosumab 60 mg
Denosumab 100 mg
Denosumab 210 mg
ALN 70 mg/wk
-40
-60
-80
-100
0
2
4
6
8
Months
Adapted from McClung et al. N Engl J Med. 2006;354:821.
10
12
Osteoporosis - What’s New?
Vitamin D insufficiency
is widespread and
plays a critical role in
fractures
The 25(OH)D Continuum:
Controversy
“deficiency”
“insufficiency”
“normal”
0
10
20
30
40
50
0
25
50
75
100
125 nmol/l
1. Boonen S et al. Osteoporos Int. 2004;15:511–519.
2. Lips P. Endocr Rev. 2001;22:477–501.
3. Heaney RP. Osteoporos Int. 2000;11:553–555.
4. Heaney RP. Am J Clin Nutr. 2004;80(suppl):1706S-1709S.
5. Thomas MK et al. N Engl J Med. 1998;338:777–783.
ng/ml
Hypovitaminosis D (<30 ng/mL) is prevalent
across latitudes in North America
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P = NS for test of trend.
Holick et al. J Clin Endocrinol Metab. 2005;90:3215–3224.
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Vitamin D deficiency in South
Florida
25 (OH) D
Men
Women
Winter
Summer
(N=212)
(N=99)
24.9 ± 8.7
22.4 ± 8.2
31.0 ± 11.0
25.0 ± 9.4
14.8%
13%
Vitamin D deficiency (< 20 ng/ml)
Men
Women
38 %
40 %
90% < 32 ng/ml
Hypovitaminosis observed across age and
racial groups, and independently of sunlight
exposure or vitD/calcium supplementation
Levis et al. J Clin Endocrinol Metab 2005;90:1557-1562
Vitamin D and African Americans



<50 nmol/l: 53-76% NHB, 8-33%
NHW
many do not achieve optimal
25OHD at any time of the year
median vitamin D intakes are low
–6-31% lower than other groups
–decreased intake of dairy products
and fortified cereals
Harris, J. Nutrition 136: 1126-1129, 2006
Prevalence of Low Vitamin D Levels in
a Minimal Trauma Fracture Population
Of 78 patients hospitalized with an osteoporotic fracture (76 hip fractures),
97% had vitamin D levels <30 ng/mL
100
90
96.2
97.4
<25
<30
80.8
Patients, %
80
70
52.5
60
50
40
30
20.5
20
10
0
<9
<15
<20
Cutoff Points for Serum 25(OH)D, ng/mL
Simonelli et al. Curr Med Res Opin. 2005:21:1069-1074.
N = 78
Vitamin D supplementation reduces falls
Primary analysis
OR: 0.69 (0.53-0.88)
Secondary analysis
OR: 0.84 (0.73-0.98)
Bischoff-Ferrari, H. A. et al. JAMA 2004;291:1999-2006.
Vitamin D reduces falls in older people in
residential care
 Mean age - 83.4, 25(OH)D - 25-90
nmol/L
 1767 assessed: 579 <25 nmol, 39 >90
nmol
 Ergocalciferol 10,000/week 
1,000/day
 Falls OR - 0.73 (.57-.95)
 Fall OR (compliant) - 0.63 (.48-.82)
 NNT 12 (8 for first year)
 Fracture rates not reduced
Flicker et al. JAGS 2005;53:1881-1888.
Calcium + vitamin D reduces nonvertebral fractures
DawsonHughes et al.
NEJM 1997
500 mg Ca+2 &
700 IU vit D
Calcium plus vitamin D
reduces hip fractures







1200 mg Ca+2, 800 IU vit D3
3270 healthy ambulatory women
18 months & 36 months
BMD: Rx-2.7%, C-4.6% (p=.001)
non-vertebral fxs - 32 % (p=.015)
hip fractures - 43 % (p=.043)
25(OH)D 162%, PTH 44%
Chapuy et al. NEJM 1992 and BMJ 1994; Chapuy et al. Osteoporos Int. 2002
700-800 IU/d vitamin D reduces
fractures, but 400 IU/d does not
Hip Fx
Non-vert Fx
700-800
1.0
1.0
400
1.0
Bischoff-Ferrari et al. JAMA 2005;293:2257-2264.
1.0
Vitamin D and disease
Bone - osteoporosis
 Neuromuscular - falls
 Cancer - prostate, breast, ovary,
colon
 Cardiovascular - BP, CHF
 Inflammation - CRP, TNF, IL-6
 Autoimmune - multiple sclerosis
 Metabolic - glucose / insulin
sensitivity

Once-yearly I.M. cholecalciferol
(600000 IU) is effective therapy for
vitamin D deficiency.
Test
Calcium
25(OH)D
Creatinine
PTH
2° urine Ca+2/cr
Baseline
4 months 12 months
2.40 ± 0.11 2.40 ± 0.12 2.45 ± 0.10
32 ± 8.4
114 ± 35*
73 ± 13*
0.08 ± 0.02 0.07 ± 0.02 0.08 ± 0.03
7.4 ± 4
0.24 ± 0.2
Diamond et al. MJA 2005; 183: 10-12
6±3
5.2 ± 3*
0.29 ± 0.3 0.40 ± 0.3*
Vit D Supplementation


Measure 25-OH D
Many healthy: 800-1200 IU/day
– diet (1-2 glasses milk) plus 400-800 units

Elderly / impaired mobilty / little sunlight:
1,500 - 5,000 IU per day
– ergocalciferol (D2): 50,000 each month
– cholecalciferol (D3): 2,000 - 5,000 per day


No evidence of adverse effects at doses
less than 10,000 IU/day
Monitor 25-OH D every 3 months
Fall Prevention Checklist





Check glasses: correct prescription and
worn correctly
Check for factors that impair walking and
balance: peripheral neuropathy, arthropathy
Check for postural hypotension, arrhyrthmias
Check for excessive use of tranquilizers,
sedatives, hypnotics, & anti-depressants
Pay attention to home environments:
– nonslip floors; good lighting; hand rails; no
obstacles; beds/seating - easy in & out





WHI
Trial
“… we must conclude that calcium
with vitamin D supplementation is not
an effective means of preventing hip
fracture in this population.” (Wrong!)
Ca+2 - 500 mg, vit D - 200 IU: BID
>50% HRT, 64% placebo taking 800
mg Ca+2 & 400 IU vit D
25(OH)D levels: hip fracture
46.0±22.6 nmol, controls 48.4±23.5
nmol
Hip fracture reduced in adherent
subjects: OR - 0.71 (0.52 to 0.97)
“I had come to an entirely
erroneous conclusion, which
shows my dear Watson, how
dangerous it always is to
reason from insufficient data.”
Sherlock Holmes in “The speckled band”
Monitoring treatment






Total or bone specific alkaline phosphatase
before initiating Rx, repeat 3-6 months later
NTX or CTX before Rx, repeat 6-12 weeks
Estradiol levels in women receiving
replacement therapy
Testosterone in men receiving replacement
Vitamin D before initiating Rx, repeat in 3
months
?BMD infrequently needed, requires
minimum 1 year interval
Selected References
1. Black, et al., Once-Yearly Zoledronic Acid for Treatment of
Postmenopausal Osteoporosis. N Engl J Med, 346(18): 1809-1822.
2. McClung MR et al., Denosumab in Postmenopausal Women with
Low Bone Mineral Density. 2006 N Engl J Med 354;8:821-831.
3. Ott, S, Osteoporosis and Bone Physiology.
http://courses.washington.edu/bonephys/.
4. Silverman, SL, Effectiveness of bisphosphonates on nonvertebral
and hip fractures in the first year of therapy: The risedronate and
alendronate (REAL) cohort study. 2007 Osteoporos Int 18:25-34.
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