Once a Year? New Approaches to Osteoporosis Treatment Bruce R. Troen, M.D. Geriatrics Institute...

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


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


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


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


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%


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


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


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?


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


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


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


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


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


ALN 70 mg/wk

Denosumab 14 mg

Denosumab 210 mg


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


Placebo


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


ALN 70 mg/wk

Denosumab 14 mg

Denosumab 210 mg


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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Once a Year? New Approaches to Osteoporosis Treatment Bruce R. Troen, M.D. Geriatrics Institute...

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