CHAPTER II Osteoporosis: treatments. La Lettre du Rhumatologue Results of the FREEDOM study (open-label) at 5 years ● Effects of denosumab : BMD evaluation

CHAPTER IICHAPTER II

Osteoporosis: Osteoporosis: treatmentstreatments

La Lettre du Rhumatologue

Results of the FREEDOM study (open-label) at 5 years

● Effects of denosumab : BMD evaluation at 5 years

● After 3 years of treatment : 2 343 "long term" group

2 207 "de novo" group

BMD increase continues at 5 years of treatment

Tolerance: no ONJ or atypical fractures in the"long term" group; 2 ONJ cases in the « de novo » group

Incidence of new NVF

BL 1 2 3 4 5 BL 1 2 3 4 5

Treatment duration (years) Treatment duration (years)

02468

101214

-2

0

2

4

6

8Lumbar BMD Total hip BMD

BM

D v

aria

tion

(%, C

I 95)

Denosumab Placebo

*

**

*

**

**

** *

*

*p < 0,002 versus placebo and baseline values

1 2 3 4 50,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

Yea

rly in

cide

nce

ofno

nver

tebr

al fr

actu

res

(%)

3,1

2,6 2,7

2,0

2,3

1,9

1,2 1,1

FREEDOM Extension study

Placebo Denosumab

Var

iatio

n de

la D

MO

(%

, IC

95)

Yearss

ASBMR 2010 - D’après Papapoulos (1025)

20Osteoporosis: treatments

La Lettre du Rhumatologue ASBMR 2010 - D’après Jamal S et al., Toronto, Canada, abstr. 1068, actualisé

Denosumab : different efficacy by level of renal function ?

● Stratification in 4 subgroups according to creatinine clearance

Antifracture efficacity of denosumab is comparable with respect to renal function No differences in incidence of adverse events

BMD variation (%)

15-29ml/mn

(n = 73)

30-59ml/mn

(n = 2 817)

60-89ml/mn

(n = 4 069)

> 90ml/mn

(n = 842)

Lumbar5.0

(-0.8-10.8)8.9

(8.4-9.3)9.0

(8.6-9.4)8.1

(7.2-8.9)

Femoral neck5.9

(3.3-8.5)5.1

(4.7-5.5)5.2

(4.9-5.5)5.6

(4.9-6.3)

Total hip5.9

(3.0-8.7)6.4

(6.1-6.7)6.4

(6.2-6.7)5.8

(5.2-6.3)

N1 3 691 3 702 33 31 1 309 1 332 1 962 1 924 394 413

All patients 15-29ml/mn

30-59 ml/mn

60-89 ml/mn

> 90 ml/mn

0

1

2

3

4

5

6

7

8

9

10

7.2

2.3

9.1

3.2

7.0

2.9

7.0

1.8

8.1

3.1

Placebo (n = 3 906) Denosumab (n = 3 902)

Inci

denc

e of

ver

tebr

al f

ract

ures

(3

yea

rs, (

%)

BMD Variation within the 4 groups over 3 years

* *

*

*


*p < 0.05

Incidence of vertebral fractures


● Design: at the end of 3 years of the HORIZON study, female patients treated with zoledronic acid were randomly assigned to 2 groups : placebo (Z6 : n = 616) or continuation of treatment (Z3P3 : n = 617)

● Résultats– Difference of femoral BMD between the Z6 group and the Z3P3 placebo group = 1 %– No difference between the 2 groups for clinical fractures– Reduction of 52 % in the number of radiologic vertebral fractures (n = 14 versus n = 30) within the Z6/Z3P3 group

Zoledronic acid long-term treatment does not expose to an increased risk of side effects The question of the interest of prolonged treatment remains open

3 4,5 6

0

-0,5

-1

-1,5

0,5

2,5

2

1,5

1 Z6

Z3P3

Ans

Evo

lutio

n (%

)

1 %p < 0,001

Femoral neck BMD

0

5

10

15

Initial study (0-3 years)

Z3P3

Éxtension study(3-6 years)

Z6

PBO10,9 %

ZOL3,3 %

6,2 %(20/486)

3,0 %(14/469)

RR = 0,48IC95 (0,3 -0,9)

p = 0,03

Reduction : -52 %

New radiological vertebral fractures

Fem

ale

patie

nts

(%)

HORIZON study 6-year extension

ASBMR 2010 - D’après Black (1070)


La Lettre du Rhumatologue ASBMR 2010 - D’après Black D et al., San Francisco, États-Unis, abstr. 1028, actualisé

What is the efficacy of a single injection of zoledronic acid ?

● Post hoc analysis of antifracture efficacy after 3 years in patients having received a single injection of zoledronic acid

A single injection induces a reduction of 32 % of the risk of new fractures at 3 years The number of ‘lost to follow-up’ is significant in this group

0 10 20 30

0

5

10

15

20

0 10 20 30

0

5

10

15

20

Zoledronic acidPlacebo

p = 0.0389 p < 0.0001

1 367 858 368 294 6 904 6 904 6 904 6 662n =

1 single perfusion (n = 1 367)

3 perfusions (n = 6 904)

Follow-up duration : 3 years

Type of fracture

1 perfusion(n = 1 367)

3 perfusions(n = 6 904)

nfrac.

Reduction(%) p

nfrac.

Reduction(%) p

All fractures

105 32 % 0.04 466 34 % < 0.0001

Clinical vertebral fractures

14 56 %0.12(NS)

64 66 % < 0.0001

Nonvertebral fractures

93 24 %0.16 (NS)

414 27 % < 0.0001

Cum

ulat

ed e

vent

s (%

)

RR : 0.68 p = 0.04Follow-upduration: 3 years

RR : 0.66 p < 0.0001


Cum

ulat

ed e

vent

s (%

)

Months


Disintegration rate of alendronate generic versions is superior to the disintegration rate of alendronate, which raises tolerability and efficacy issues

Dis

inté

grat

ion

me

dian

(in

se

con

ds)

Comparison of disintegration rates

Novo-alendronate 70 mg

Apo-alendronate 70 mg

Actonel®

35 mgFosamax®

70 mgFosavance®

70 mg

0

50

100

150

200

250

300

350

400

450

500

Bisphosphonate generics : a rapid disintegration

ASBMR 2010 - D’après Olszynski (FR0390)



Diagnostic criteria for atypical femoral fracture

● Major criteria– Fracture line in a proximal site should be under the lesser trochanter and , in distal

site, over the femoral condyles– It should be a nontraumatic fracture, or following a low-energy trauma– Fracture line should be transversal or oblique, with a < 30° angle– It should be a noncomminuted fracture– Complete fractures involve the entire crossection of the bone, from one cortical to

the other, with a possible internal « thorn » – Incomplete fractures affect only the external cortical

Exclusion criteria: femoral neck fractures, intertrochanteric fractures with a subtrochanteric extension, periprosthetic or pathological fractures within the context of primary bone tumors or bone metastasis

All major criteria are required for diagnosis The minor criteria are not necessary (for diagnosis) but sometimes (we) come across their association

Minor criteria– Periosteal reaction on the external cortical– Increase of cortical thickness– Dull pain prodromes in thigh s and inner thighs– Bilateral fracture– Delayed cicatrization– Associated comorbidities : rheumatoid arthritis, vitamin D insufficiency, hypophosphatasia…– Associated therapies : bisphosphonates, corticoids, proton pump inhibitors …

Medial spine

Short-oblique configuration

Noncomminuted

ASBMR 2010 – Task Force concernant les fractures fémorales atypiques (16 octobre 2010)



Is the incidence of subtrochanteric fractures increasing?

● National data base (United States) on hip fractures between 1996 and 2007 coupled with a data base on the use of bisphosphonates

Hospitalizations for subtrochanteric fractures are rare, but they are increasing in menopausal women. The number of menopausal patients under bisphosphonate treatment has been increasing during the same period. But, at the same time, the number of classic hip fractures is decreasing.

19950

1998 2000 2002 2004 2008 1995 1998 2000 2002 2004 2008

15

20

25

30

35

40

200

400

600

800

1 000

1 200

Inci

de

nce

Inci

de

nce

(%

) Women

Men

Women

Men

Subtrochanteric fractures Hip fractures

ASBMR 2010 - D’après Wang (1029)



For these atypical femoral fractures,

● no association with alendronate in the New Zealand study

● an apparent association between BP and atypical fractures in the Australian study, but with a very weak frequency of the latter

● treatment benefits prevail over potential risk

● 2 retrospective monocenter 5-year studies : radiographic analysisNew Zealand study : 71 subtrochanteric and diaphyseal fractures, of which 11 atypical fractures

Alendronate median duration not specified

All BP : RR = 2.1 (0.5-8.2), p = 0.16

Australian study : 152 subtrochanteric and diaphyseal fractures, of which 20 atypical fractures

Alendronate median duration 5.1 years

All BP : RR = 37.4 (12.9-119), p < 0.001

Atypical (11) Typical (60)

Age (years) 81 (66-96) 81 (44-100)

Men/Women 1/10 11/49

Alendronate 4 8

Etidronate 0 5

Calcium 6 18

Vitamin D 6 14

Glucocorticoïds 2 5

IPP 0 4

Fracture background 6 28

Total Diaphyse Subtrochanter Distal

Atypical 20 15 5 0

Typical 132 15 65 52

BisphosphonatesAlendronate

(median duration)Risedronate

(median duration)

Atypical(n = 20)

17 (85 %)15

(5.1 ans)2

(3 ans)

Typical(n = 132)

3 (2.3 %) 2 (3.5 ans) 1 (1 an)

ASBMR 2010 - D’après Warren (1030) et Girgis (1071)


Are patients who received long acting bisphosphonates at risk for atypical fractures ?


What is the incidence of subtrochanteric and diaphyseal fractures before and after treatment against osteoporosis ?

● National Danish registry, matched-centrals study● Each user of an antiosteoporosis treatment between 1996 and 2006 (n = 103 562) was matched,

after adjustment for age and sex, with 3 controls (n = 310 683)

There was an increased risk for subtrochanteric and diaphyseal fractures before starting the treatment against osteoporosis. This increased risk was especially high in the year preceding start of treatment.

With alendronate, such increased risk diminishes progressively with treatment.

Alendr

onat

e

Clodro

nate

Étidro

nate

Iban

dron

ate

Pamidr

onat

ePTH

Raloxif

ene

Risedr

onat

e

Stront

ium

Zoledr

onat

e0

4

8

12

16

20

IRR

(IC

95)

0

1

2

3

4

5

6

7

> 10

year

s

5-10

year

ss

1-5

year

s

< 1y

earn

< 1

year

1-5

year

s

> 5

year

ss

Before and after periods

IRR

(IC

95) Before

After

Subtrochanteric fractures and alendronate

ASBMR 2010 - D’après Vestergaard (1072)


La Lettre du Rhumatologue ASBMR 2010 - D’après Kelly (FR0355)

Incidence of subtrochanteric fractures in the SOF cohort

● 1 396 hip fractures, 45 of which were subtrochanteric fractures

Subtrochanteric fractures represent less than 2 % of hip fractures The incidence of subtrochanteric fractures increases with patient age, with a same pattern as

for hip fractures

Femoral

→ 58,1/10 000

Intertrochanteric

→ 49,1/10 000

Subtrochanteric

→ 3,1/10 000

0

50

100

150

65-69 70-74 75-79 80-84 85+

Age (years)

Inci

denc

e fo

r10

000

pe

rso

ns-y

ear



Breast cancer risk is reduced with alendronate

● Cohort study from a Danish national registry● Women > 50 years,without cancer history that have been treated with alendronate from 1996 to 2005

– 30 606 users– 4 centrals matched for to age and sex (n = 122 424)

This national registry, based on a cohort study, shows a significant reduction of the risk of developping and dying from breast cancer in postmenopausal women treated with alendronate

0

1

2

3

Co

mb

ine

d I

nci

de

nce

(%

)

0 2 4 6 8 Years

Controls

Alendronate

Diagnostic of breast cancerRR = 0.74 (0.66-0.84) ; p < 0.001

Death due to breast cancerRR = 0,52 (0,40-0,68) ; p < 0,001

ASBMR 2010 - D’après Abrahamsen (SU0128)



Comparison of transdermal and subcutaneous pharmacokinetic and

pharmacodynamic profiles

Transdermal teriparatide has a pharmacokinetic and a pharmacodynamic profile on the bone remodeling markers comparable to subcutaneous teriparatide 20 g profile.

Variations of bone remodeling markers

PT

H m

ea

n v

alu

e

(pg

/ml)

Hours

Va

riatio

ns

(%)

ASBMR 2010 - D’après Kenan Y et al., Lod, Israël, abstr. FR0376, actualisé

0 1 2 3 4 5 6 7 80

50

100

150

200SC20

TD50

TD80

0 48 72 96 0 48 72 96

0

50

100

150

200

250

300

0

50

100

150

200

250

300PINP CTX

DaysDays


Effect of transdermal teriparatide on bone remodeling

*B

*A

*

*B

*A

*

*

**A

*

**

*

**

**

*A

*p < 0,05 versus baseline ; Ap< 0,05 TD50 versus TD80 ; Bp < 0,01 SC20 versus TD80

La Lettre du Rhumatologue ASBMR 2010 - D’après Gee AH et al., Cambridge, Royaume-Uni, abstr. 1250, actualisé

What is the impact of teriparatide on the cortical bone of women with osteoporosis?

● In vivo study using High Resolution Cortical Thickness mapping● 65 women (median age: 67.5 years) from the EUROFORS study, treated with teriparatide for 2 years

At 24 months teriparatide increases the cortical thickness of

● Tension zones involved in walking (muscle insertion sites)

● Upper part of the cortical, critical zone for the susceptibility to hip fracture risk

Mapping and significance of cortical thickness modifications (besides the femoral head)

24 months - baselineThickness variations (%)

-2 0 2 4 6 8 0,05 0,025 0p for topographic distribution(a) p = 0,00000004(b) p = 0,00007 (c) p = 0,00007



Are the vibrations beneficial for bone ? ● Randomized , placebo controlled, ITT trial, with evaluation on the BMD at 12 months

● 202 menopausal women with osteopenia and controls (n = 67)

● Vertical acceleration : 0.3 g (90 Hz [n = 67], 30 Hz [n = 68])

● Similar demographic parameters (age, menopause duration, weight, BMI, ethnics)

Beneficial effect in ITT vibrations on BMD has not been demonstrated Lack of data on muscle evaluation, weight at one year, quality of life, etc.

Densitometry data characteristics, vitaminD-calcium contribution

Initial caracteristics Type 90 Hz 30 Hz Witnesses

Mean BMD (g/cm-2),(SD) Femoral neck 0.686 (0,049) 0.676 (0,060) 0.687 (0.054)

Total hip 0.851 (0,066) 0.836 (0,083) 0.845 (0.068)

Lumbar spince 0.904 (0,090) 0.890 (0,069) 0.902 (0.080)

Mean vBMD (mg:cm-3), (SD) Trabecular tibial bone 149 (36) 144 (29) 145 (30)

Calcium (mg), mean + ET (SD) Total 1 538 (677) 1 399 (656) 1 352 (642)

Vitamin D (UI), mean+ ET (SD) Total 866 (582) 778 (583) 808 (584)

Phisycal activity (kcal/j), mean (SD) Metabolic index 352 (224) 337 (237) 383 (227)

ASBMR 2010 - D’après Slatkovska (1027)


La Lettre du Rhumatologue ASBMR 2010 - D’après Jamal S et al., Toronto, Canada, abstr. 1252, actualisé

NTG seems to have beneficial effects on bone remodeling and BMD at 24 months

BMD variations at 24 months Markers variations at 12 months


An explosive treatment… nitroglycerin (NTG) !

Var

iatio

ns (

%)

Lumbar spine

Femoral neck

Var

iatio

ns (

%)Urinary NTX

Var

iatio

ns (

%)

Var

iatio

ns (

%) PAL osseuses

0 3 12

0 3 12 240

50

100

150

80

100

120

140

160

50,8 %(43,7 à 60,2)

21,3 %(21,6 à 22,1)

-2

0

2

4

6

8

10

10

8

6

4

2

0

-2

12 24

12 24

Months

Months

Mois

Months

7,0 %(5,5 à 8,5)

6,7 %(5,2 à 8,2)

Placebo NTG ointment

Documents

CHAPTER II Osteoporosis: treatments. La Lettre du Rhumatologue Results of the FREEDOM study (open-label) at 5 years ● Effects of denosumab : BMD evaluation