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Once a Year? New Approaches to
Osteoporosis TreatmentBruce R. Troen, M.D.
Geriatrics InstituteDivision of Gerontology and Geriatrics Medicine
Geriatric Research, Education, and Clinical CenterMiami VA Medical Center
http://troelab.org
Learning ObjectivesTo 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)
> 50% of hip fractures occur in pts. with T-scores > –2.5
BMD is not the whole story!Wainwright SA 2005
No
. o
f h
ip f
ract
ure
cas
esN
o. o
f particip
ants
60
50
40
30
20
10
0
Total Hip T-Score
1800
1600
1400
1200
1000
800
600
400
200
0
Hip Fracture Cases
All Participants
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
Kanis et al. Osteoporos Int 2001
Age and BMD are the strongest predictors for hip fracture.
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
Ibandronate reduces vertebral fractures
Chesnut et al., Curr Med Res Opin 3/05
Ver
teb
ral
frac
ture
rat
e
12
10
8
6
4
2
0 Overall North America Europe
Placebo Daily IBN Intermittent IBN
Quarterly IV IBN is superior to daily oral IBN
Delmas et al. Arthritis & Rheumatism 54(6): 1838–1846 2006
Lumbarspine
Totalhip
Femoralneck
TrochanterCha
nge
from
bas
elin
e (%
)
2.5 mg daily2 mg q 2 months3 mg q 3 months
6
5
4
3
2
1
0
Osteoporosis - What’s New?
ONJ - how much of a problem is it?
Ruggiero SL. J Oral Maxillofac Surg. 2004;62:527-534.
Osteonecrosis of the Jaw
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
0.6
0.7
6
11
32
0 10 20 30 40 50 60 70 80 90 100
Death by Lighting in NM
ONJ - Osteoporosis Pt.
Death by Murder
Death by MVA
Anaphylaxis from PCN
Hip Fracture (1)
Any Fragility Fracture (1)
Risk per 100,000 People per Year
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
(1) Women age 65-69 (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.)
M. Lewiecki 2007
Osteoporosis - What’s New?
Bisphosphonate wars - is one better?
BMD Increases With Alendronate and Risedronate at 24 Months in FACT
Bonnick et al. JCEM 91(7):2631-2637, 2006
Total HipAlendronate (N=375)Risedronate (N=375) p < .001
3.0 %
1.3 %
BMD Increases With Alendronate and Risedronate at 24 Months in FACT
Bonnick et al. JCEM 91(7):2631-2637, 2006
Lumbar SpineAlendronate (N=372)Risedronate (N=379)
p < .001
5.2 %
3.4 %
Percent of Patients With Response by BMD Gains/Losses at 12 Months in FACT
0%40%60%80%100% 20% 40% 60% 80% 100%20%
84%16%
59%41%
Percent of patients who lost BMD at 24
months
Total HipPercent of patients who
maintained or gained BMD at 24 months
ALN 70 mg once-weekly RIS 35 mg once-a-week
P≤0.002 P≤0.002
Bonnick et al. JCEM 91(7):2631-2637, 2006
BMD (site) ALN RISHip Trochanter: 4.6% 2.5%Total Hip: 3.0% 1.3%Femoral Neck: 2.8% 1.0%Lumbar Spine: 5.2% 3.4%
Bone markers ALN RISBSAP: -40% -29%P1NP: -62% -46%NTX: -57% -44%CTX: -73% -53%
Bonnick et al. JCEM 91(7):2631-2637, 2006
Responses to Alendronate and Risedronate at 24 Months in FACT
Watts et al., JMCP 2004 10(2):142-151
RIS more effectively reduces non-vertebral fx’s than ALN or CT
Pat
ien
ts (
%)
Time to Fracture (Days)
6
5
4
3
2
1
0 0 30 60 90 120 150 180 210 240 270 300 330 360
RR = 0.41Risedronate
Alendronate
Calcitonin
% o
f co
hort
with
a h
ip f
ract
ure 0.58
0.50
0.40
0.30
0.20
0.10
0.00Baseline month 3 month 6 month 12 month 24
Silverman et al., Osteoporos Int (2007) 18:25–34
RIS more effectively reduces hip fractures than ALN
Alendronate
Risedronate
RR = 0.57
RIS more effectively reduces fractures than ALN
Silverman et al., Osteoporos Int (2007) 18:25–34
Osteoporosis - What’s New?
PTH - when should it be used?
PTH + concurrent bisphosphonate?
Finkelstein et al., NEJM 9/03
NO
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
Treatment / Prevention of Osteoporosis - PTH
Fracture Risk Reduction in Women with PMO
Agent Vertebral Fx New First
Hip Fracture
Nonvertebral Fracture
Ca+2/Vit D Calcitonin No effect demonstrated
Raloxifene No effect demonstrated
Ibandronate No effect demonstrated
Alendronate Risedronate Teriparatide 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
Ettinger et al., Arthritis & Rheumatism 2004
Bisphosphonate Persistence:Weekly vs. Daily (newly started)
Ettinger et al., Arthritis & Rheumatism 2004
Bisphosphonate Persistence:Weekly vs. Daily (previous)
Danese et al. ASBMR, Philadelphia, 2006
All-cause hospitalization rate in osteoporosis pts. by adherence level
Re
lati
ve
Rat
e o
f H
os
pit
aliz
ati
on
Adherence (medication possession over time)
1.60
1.50
1.40
1.30
1.20
1.10
1.00
0.90> 90% 80-90% 50-80% < 50%
IBN vs. RIS: ?compliance
Gold et al., Current Medical Research and Opinion 12(22):2383-2391, 2006Cooper et al. Int. J. Clinical Practice 2006
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%
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 T-
score < -2.5 or fracture plus T-score < -1.5
calcium 1000-1500 mg/day vit D (400-1200 IU/day)
zoledronic acid IV infusion 5 mgBlack et al. NEJM 356:1809-1822, 2007
ZOL reduces hip fracture
*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007
P = .0024
1
2
3
0
Placebo (n = 3861) ZOL 5 mg (n = 3875)
Cu
mu
lati
ve I
nci
den
ce (
%)
Time to First Hip Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 36
41%*(17%, 58%)
P < .0001
Cu
mu
lati
ve I
nci
den
ce (
%)
Time to First Clinical Vertebral Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 36
77%(63%, 86%)
Placebo (n = 3861) ZOL 5 mg (n = 3875)
1
2
3
0
ZOL reduces vertebral fx
*Relative risk reduction (95% confidence interval) vs placeboBlack et al. NEJM 356:1809-1822, 2007
P = .0002
Time to First Clinical Non-vertebral Fracture (months)
2
4
6
8
10
12
0 3 6 9 12 15 18 21 24 27 30 33 36
25%(13%, 36%)
Placebo (n = 3861) ZOL 5 mg (n = 3875)
0
Cu
mu
lati
ve I
nci
den
ce (
%)
ZOL reduces non-vertebral fx
*Relative risk reduction (95% confidence interval) vs placeboBlack 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
(receptor activator of NFB ligand)
RANKLVit D
PTH
PGE2
IL-11
Stromal cellsOsteoblasts
Osteoclast(mature)
CTSK
OPG
RANK
Osteoclastprecursor
RANK Ligand (RANKL) is a Key Mediator of Osteoclast Activity
OPGRANKL
growth factors
hormones
PTH
cytokines
drugs
vitamins
gravity
aging
The RANKL / OPG Balance
RANKL Expression Is Increased in Postmenopausal Women
No
rmal
ized
flu
ore
sce
nc
e in
ten
sit
y fo
r O
PG
-Fc
-la
be
led
FIT
C
Premenopausal Untreated postmenopausal
Postmenopausal + ERT (n=12/group)
*vs postmenopausal + ERT; †vs premenopausal.ERT = estrogen replacement therapy.Eghbali-Fatourechi et al. J Clin Invest. 2003;111:1221.
60
Marrow stromal cells
90
P<0.001
0
30
B cells
P<0.001
T cells
P=0.003
Total
P<0.001**†
*†
*†
Vit D
PTH
PGE2
IL-11
Stromal cellsOsteoblasts
Osteoclastprecursor
Antibody to RANKL prevents OC precursor differentiation
RANKL denosumabRANK
Inhibition ofmature OC formation
X CTSKX
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
Months
Me
an
ch
an
ge
fro
m b
as
elin
e (
%)
-2
-1
0
1
2
3
4
5
6
0 2 4 6 8 10 12
McClung et al. N Engl J Med. 2006;354:821.
Placebo
Denosumab 60 mgDenosumab 100 mg
ALN 70 mg/wk
Denosumab 14 mg
Denosumab 210 mg
Denosumab SC q6mo enhances total hip BMD
Months0 1 2 3 4 5 6 7 8 9 10 11 12
-2
-1
0
1
2
3
4
Me
an
ch
an
ge
fro
m b
as
elin
e (
%)
*Placebo
Denosumab 60 mgDenosumab 100 mg
ALN 70 mg/wk
Denosumab 14 mg
Denosumab 210 mg
McClung et al. N Engl J Med. 2006;354:821.
Months
-3
-2
0
1
2
3
-1
120 1 2 3 4 5 6 7 8 9 10 11
Me
an
ch
an
ge
fro
m b
as
elin
e (
%)
Denosumab SC q6mo maintains distal third radius BMD
McClung et al. N Engl J Med. 2006;354:821.
Placebo
Denosumab 60 mgDenosumab 100 mg
ALN 70 mg/wk
Denosumab 14 mg
Denosumab 210 mg
Denosumab suppresses serumc-telopeptide
Months
-100
-80
-60
-40
-20
0
20
0 2 4 6 8 10 12
Me
an
ch
an
ge
fro
m b
as
elin
e (
%)
Adapted from McClung et al. N Engl J Med. 2006;354:821.
Placebo
Denosumab 60 mgDenosumab 100 mg
ALN 70 mg/wk
Denosumab 14 mg
Denosumab 210 mg
Osteoporosis - What’s New?
Vitamin D insufficiency is widespread and
plays a critical role in fractures
The 25(OH)D Continuum: Controversy
“insufficiency” “normal”
0 10 20 30 40 50 ng/ml
0 25 50 75 100 125 nmol/l
“deficiency”
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.
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P = NS for test of trend.
Hypovitaminosis D (<30 ng/mL) is prevalent across latitudes in North America
Holick et al. J Clin Endocrinol Metab. 2005;90:3215–3224.
25 (OH) D Winter Summer(N=212) (N=99)
Men 24.9 ± 8.7 31.0 ± 11.0 14.8%Women 22.4 ± 8.2 25.0 ± 9.4 13%
Vitamin D deficiency (< 20 ng/ml)Men 38 %Women 40 %
Vitamin D deficiency in South Florida
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
90% < 32 ng/ml
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
20.5
52.5
80.8
96.2 97.4
0
10
20
30
40
50
60
70
80
90
100
<9 <15 <20 <25 <30Cutoff Points for Serum 25(OH)D, ng/mL
Pat
ien
ts,
%
N = 78
Prevalence of Low Vitamin D Levels in a Minimal Trauma Fracture Population
Simonelli et al. Curr Med Res Opin. 2005:21:1069-1074.
Of 78 patients hospitalized with an osteoporotic fracture (76 hip fractures), 97% had vitamin D levels <30 ng/mL
Bischoff-Ferrari, H. A. et al. JAMA 2004;291:1999-2006.
Vitamin D supplementation reduces falls
Primary analysisOR: 0.69 (0.53-0.88)
Secondary analysisOR: 0.84 (0.73-0.98)
Flicker et al. JAGS 2005;53:1881-1888.
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
Dawson-Hughes et al.
NEJM 1997
500 mg Ca+2 &
700 IU vit D
Calcium + vitamin D reduces non-vertebral 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
Calcium plus vitamin D reduces hip fractures
400
1.01.0
Hip Fx Non-vert Fx
700-800
1.0 1.0
700-800 IU/d vitamin D reduces fractures, but 400 IU/d does not
Bischoff-Ferrari et al. JAMA 2005;293:2257-2264.
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.
Diamond et al. MJA 2005; 183: 10-12
Test Baseline 4 months 12 months
Calcium 2.40 ± 0.11 2.40 ± 0.12 2.45 ± 0.10
25(OH)D 32 ± 8.4 114 ± 35* 73 ± 13*
Creatinine 0.08 ± 0.02 0.07 ± 0.02 0.08 ± 0.03
PTH 7.4 ± 4 6 ± 3 5.2 ± 3*
2° urine Ca+2/cr 0.24 ± 0.2 0.29 ± 0.3 0.40 ± 0.3*
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
Vit D Supplementation
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 References1. 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.
5. Sambrook, P, Olver, I, Goss, A, Bisphosphonates and osteonecrosis of the jaw. 2006 Australian Family Physician 35(10), October 2006.
6. Troen, BR, Osteoporosis in older people: a tale of two studies (and three treatments). J Am Geriatr Soc. 2006 54(5):853-5.
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