Effects of Bisphosphonates and
PTH on Fracture Healing and
Spine Fusion “Subtrochanteric
Fractures”
Joseph M. Lane, MD
Hospital for Special Surgery
NEW YORK
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
1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795.
The Goal: Increased Bone Strength
NIH Consensus Statement 20001
Bone
Strength
Bone
Quality
and
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
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
ImmunoelectroPhoresis
Endocrinopathy Hyper
Thyroid, Hyper PTH,
Cushings, Juvenile
Diabetes
OsteomalaciaCalcium, Phos, AlkPtase, 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
Bone Stimulation
(Experimental)
PTH
Estrogen Calcitonin
Strontium Renalate
Bisphosphonates
Serms
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
1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795.
JBJS 2005
Einhorn
Nakazawa - Bone 2005
Fracture Healing:
PTH vs. Bisphosphonates
Animal
Bisphosphonate
Callus Size
Maturation
Biomechanics
=
1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795.
PTH
Alendronate
Long term effect unkown
Theoretically dose with time
Keep collagen breakdown products low
1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795.
Subtrochanteric Fracture
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
1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795.
Rate of Alendronate Use
Subtrochanteric/Sha
ft Fracture Cases
(n=41)
Hip Fracture
Controls (n=82)
P Value
15 (36.6)
9 (11)
.001
Alendronate Use (%)
• 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
Not for duplication
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
Simple With Thick Cortices
Fracture
X-ray Pattern
(%)
ST/S on
Alendronate
(n=15)
ST/S Not on
Alendronate
(n=26)
P Value
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
70.4 (10.6)
82.5 (9.3)
.05
55-83
71-96
90, 10
100, 0
25.0 (4.1)
23.4 (3.8)
.48
100
100
.99
7.3 (1.8)
2.8 (1.3)
<.001
0.36 (0.048)
0.20 (0.034)
<.001
Age, y
Mean (SD)
Range
Race
White %, Asian %
BMI (SD), kg/m2
History of Osteoporosis, %
Duration of time on alendronate
(SD), y
Ratio of cortical thickness to
diameter
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
Number of patients
7
6
Subtrochanteric
Intertrochanteric
Femoral Neck
5
4
3
*
2
**
1
• Subtroch/shaft vs.
Intertroch P=0.01
0
1-3
4-6
Duration of bisphosphonate use (yrs)
*1 pt on risedronate, **1 pt on etidronate for 5
years, then alendronate for 2
>6
• Subtroch/shaft vs. Fem
Neck P=0.001
• Fem Neck vs. Intertroch
P=0.3
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
Normal Fx Healing
Bisphosphonates
PTH
↑↑
↓
↑↑
Remodeling
↑
↓↓
↑
Question
Mechanism
Treatment
Mechanism
Stress fracture
3 months pain
Local ↑ diameter
Working Hypothesis
Bisphosphonates given to normal diaphyseal
bone
increased microdamage
collagen aging >> fiber failure
>> loss of toughness >> low energy
spontaneous fracture
Treatment
Stop bisphosphonate
Correct Ca/VIT D
Consider PTH 1-34 (anabolic)
Patient with thigh pain
History – bisphosphonate
X-Ray → MRI / bone scan
To Prevent Abnormal Bone
Consider a Bone Holiday
Old Fx
No Pain
↓
Anabolic
New Fx
Pain
↓
Anabolic
Consider nailing
Osteoporosis New Fracture
Treatment
Calcium (Citrate) [1,000 mg Ca]
Vitamin D3 [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
STUDENTS/RESIDENTS
Charles Chang
Lily Bogunovich
Brian Gladnick
Flo Edobor-Osula
Brett Lenart
Dennis Merideth
Andy Neviaser
Barbara Schreck
FELLOWS
Jaimo Ahn
Padhraig O’Laughlin
Philipp Mayer-Kuckuk
Alana Serota
Aasis Unnanuntana
RN’S/NP’S
Janet Curtin
Patricia Donnelly
Diana Lapiano
Lisa Shindle