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15 Νοε 2013 (πριν από 3 χρόνια και 7 μήνες)

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Effects of Bisphosphonates and
PTH on Fracture Healing and
Spine Fusion “Subtrochanteric
Fractures”


Joseph M. Lane, MD


Hospital for Special Surgery

NEW YORK

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Joseph M. Lane, MD

Does have a financial interest or relationship

with the manufacturers of products or

services:


Consulting Fees: Amgen, Arthrocare, Biomimetics, D’Fine,
Innovative Clinical Solutions, Kuros Biosurgery AG, Osteotech,
Orthovita, Soteira, Zelos, Zimmer


Speakers’ Bureaus: Eli Lilly, Novartis, Orthovita, Proctor and
Gamble, Roche, Sonofi
-

Aventis


Presentation will
not

include discussion of off

label or investigational use of products or

treatments


and


Bone

Quality



Bone

Strength

Architecture/Geometry

Bone Remodeling

Damage Accumulation

Mineralization of Matrix


1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Bone

Mineral

Density

NIH Consensus Statement 2000
1

The Goal: Increased Bone Strength

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Risk of Vertebral Fracture


5x greater with prior vertebral fracture


Vertebral fracture

2x risk of hip fracture


Fracture more fractures



(Nevitt 1999)

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Metabolic Bone Disease

Workup For Osteopenia

Bone Marrow CBC

Sed Rate

Immunoelectro
-
Phoresis

Endocrinopathy Hyper
Thyroid, Hyper PTH,
Cushings, Juvenile
Diabetes

Osteomalacia
-

Calcium, Phos, Alk
-
Ptase, PTH

25 Hydroxy Vit D

Osteoporosis


High vs. Low

Turnover NTX

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Agents Against Osteoporosis

Antiresorption

(Experimental)

Estrogen Calcitonin

Bisphosphonates

Serms

Bone Stimulation

PTH

Strontium Renalate

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Bisphosphonates


Bone Mass (Spine/Hip)


Fracture Risk

(Vertebra/Long Bones)

= Fracture Healing (animal/patients)

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Animal Studies


Remodeling



Healing



Callus


=Biomechanics

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Clinical Trials


Bisphosphonates
in Fracture Healing


Colles’ Fracture (Alendronate)

Tibia Shaft/Ankle (Alendronate)

Hip fractures (Zoledronic Acid)

↑ Bone Mass (DXA)

No Difference in Clinical Union

↓ Secondary Fracture

↓ Mortality






(Van der Poest JBMR 200, 2002)








(Lyles NEJM 2007)


1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

PTH (1
-
34) Anabolic Agent

Bone mass

All fractures


Enhances fracture healing


Spine fusion


In animal studies

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Intermittent PTH (1
-
34)

Rat Femoral Fracture


Bone Mineral Content

Bone Mineral Density

Bone Mineral Strength

Sustained Anabolic Effect

Large Cartilaginous Callus

No Chondrocyte Differentiation Delay







Alkhary






Einhorn
JBJS 2005






Nakazawa
-

Bone 2005

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Fracture Healing:

PTH vs. Bisphosphonates

Bisphosphonate

PTH

Callus Size

Maturation

Biomechanics

=

Animal

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Alendronate


Long term effect unkown

Theoretically dose with time

Keep collagen breakdown products low

Subtrochanteric Fracture

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Prolonged Bisphosphonates


Turnover

Microfracture

Frozen Bone

Brittle Fracture










(PAK)

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Background


Animal studies have linked bisphosphonate
use to microdamage accumulation


Case series have identified atypical
fractures



Odvina et al J Clin Endocrinol Metab
2005;90:1294



Goh et al JBJS Br 2007;89:349



Kwek et al Injury 2008;39:224


Neviaser, et al J Orthop Trauma (2008)

1. NIH Consensus Development Panel on Osteoporosis 2000.

JAMA
. 2001;285:785
-
795.

Methods

Retrospective case
-
control study 2000
-
2007


Cases: postmenopausal women with
subtrochanteric/shaft (ST/S) fractures


Low energy mechanism


Controls: postmenopausal women with
intertrochanteric (IT) or femoral neck (FN) fractures


Matched by age, race and BMI


X
-
ray confirmation of fracture type


Exclusion of any identifiable secondary causes of
bone loss

Rate of Alendronate Use

Subtrochanteric/Sha
ft Fracture Cases
(n=41)

Hip Fracture
Controls (n=82)

P Value

Alendronate Use (%)

15 (36.6)

9 (11)

.001


Subtrochanteric/Shaft


2 patients on 10 mg alendronate daily


Remaining 13 on 70 mg every week



Hip Fracture Controls


2 patients on 35 mg alendronate every week


1 took etidronate for 5 years then 70 mg alendronate for 2 years


1 patient was on 35 mg risedronate every week and was included in this
group


Remaining 5 on alendronate 70 mg every week



OR 4.68, 95% CI (1.83
-
11.89)



Simple With Thick Cortices
Fracture

83 year old female with a 9 year
history of alendronate use


77 year old female with a 5 year
history of alendronate use


ST/S Fracture

83 year old female with no
history of alendronate use


60 year old female with no
history of alendronate use

24

Not for duplication

6

Not for duplication

20

Not for duplication

31

Not for duplication

2

Not for duplication

Bis
-
24

Not for duplication

Bis
-
6

Not for duplication

No Bis
-
20

Not for duplication

Bis
-
31

Not for duplication

No Bis
-
2

Not for duplication

Simple With Thick Cortices
Fracture

ST/S on
Alendronate
(n=15)

ST/S Not on
Alendronate
(n=26)

P
Value

X
-
ray Pattern
(%)

10 (66.6)

3 (11.5)

<.001


X
-
ray Pattern Definition: simple transverse or oblique
with cortical thickening and beaking of the cortex on one
side



OR 15.33, 95% CI (3.06
-
76.90)

Pattern vs. Absence of Pattern



ST/S on Alendronate
With Xray Pattern
(n=10)

ST/S on Alendronate
Without Xray Pattern
(n=5)

P
Value

Age, y








Mean (SD)

70.4 (10.6)

82.5 (9.3)

.05


Range

55
-
83

71
-
96



Race








White %, Asian %

90, 10

100, 0

BMI (SD), kg/m
2

25.0 (4.1)

23.4 (3.8)

.48

History of Osteoporosis, %

100

100

.99

Duration of time on alendronate
(SD), y

7.3 (1.8)

2.8 (1.3)

<.001

Ratio of cortical thickness to
diameter

0.36 (0.048)

0.20 (0.034)

<.001

Distribution by Fracture Type


Kruskal Wallis one
-
way
variance analysis on the
duration of alendronate
use in patients in all
three groups yielded
P
=0.001



Subtroch/shaft vs.
Intertroch
P
=0.01



Subtroch/shaft vs. Fem
Neck
P
=0.001



Fem Neck vs. Intertroch
P
=0.3

*1 pt on risedronate, **1 pt on etidronate for 5
years, then alendronate for 2

0
1
2
3
4
5
6
7
1-3
4-6
>6
Duration of bisphosphonate use (yrs)
Number of patients
Subtrochanteric
Intertrochanteric
Femoral Neck
*
**
Conclusions

Long
-
term bisphosphonate use decreases risk of hip

fractures at IT/FN (94%) regions but may increase at ST/S

regions (6%)


A small subgroup of patients may be more susceptible to

the effects of prolonged therapy


Further studies are needed to confirm whether prolonged

use increases the risk of ST/S fractures and to

characterize this subgroup of patients



Osteoporosis Treatment
Comparison







Bone


Formation

Remodeling

Normal Fx Healing


↑↑ ↑

Bisphosphonates






↓↓

PTH





↑↑ ↑

Question





Mechanism




Treatment

Stress fracture

3 months pain

Local
↑ diameter


Mechanism

Bisphosphonates given to normal diaphyseal

bone


increased microdamage


collagen aging >> fiber failure


>> loss of toughness >> low energy


spontaneous fracture



Working Hypothesis

Stop bisphosphonate

Correct Ca/VIT D

Consider PTH 1
-
34 (anabolic)




Treatment

Patient with thigh pain

History


bisphosphonate


X
-
Ray


MRI / bone scan















Old Fx



New Fx




No Pain



Pain












Anabolic


Anabolic


Consider nailing

To Prevent Abnormal Bone
Consider a Bone Holiday

Osteoporosis New Fracture
Treatment


Calcium (Citrate) [1,000 mg Ca]


Vitamin D
3
[2


6,000 units/day]


Short half
-
life bisphosphonate/lower dose


PTH


bisphosponate


Bone turnover determines TX: right in the

middle


Fracture on Bisphosphonate

Rule out secondary cause

Stop bisphosphoate

Correct calcium/vitamin D

Consider PTH


Clinical Studies




Clinical characterization of fracture
healing



Evaluation of bone quality



Histology

-

Doty


Micro
-
Ct

-

Mayer
-
Kuckuk



F
-
TIR

-

Boskey


HSS Osteoporosis Team

MD/PhD


Adele Boskey



Richard Bockman


Edward Dicarlo


Steven Doty


Steve Goldring


Dean Lorich


Linda Russell


Robert Schneider


Dave Zackson


FELLOWS


Jaimo Ahn


Padhraig O’Laughlin


Philipp Mayer
-
Kuckuk


Alana Serota


Aasis Unnanuntana

STUDENTS/RESIDENTS


Charles Chang


Lily Bogunovich


Brian Gladnick


Flo Edobor
-
Osula


Brett Lenart


Dennis Merideth


Andy Neviaser


Barbara Schreck




RN’S/NP’S


Janet Curtin


Patricia Donnelly


Diana Lapiano


Lisa Shindle