Effects of Bisphosphonates and PTH on Fracture Healing and Spine Fusion “Subtrochanteric Fractures” Joseph M. Lane, MD Hospital for Special Surgery NEW

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

Joseph M. Lane, MD

Hospital for Special SurgeryNEW 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

andBoneBoneQualityQualityBoneBone

QualityQuality BoneBone

StrengthStrength BoneBone

StrengthStrength

Architecture/GeometryBone RemodelingDamage AccumulationMineralization of Matrix


BoneBoneMineralMineralDensityDensity

BoneBoneMineralMineralDensityDensity

NIH Consensus Statement 20001

The Goal: Increased Bone Strength


Risk of Vertebral Fracture

5x greater with prior vertebral fracture

Vertebral fracture2x risk of hip fracture

Fracture more fractures

(Nevitt 1999)


Metabolic Bone DiseaseWorkup 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


Agents Against Osteoporosis

Antiresorption

(Experimental)

Estrogen Calcitonin

Bisphosphonates

Serms

Bone Stimulation

PTH

Strontium Renalate


Bisphosphonates

Bone Mass (Spine/Hip)

Fracture Risk (Vertebra/Long Bones)

= Fracture Healing (animal/patients)


Animal Studies

Remodeling

Healing

Callus

=Biomechanics


Clinical Trials – Bisphosphonates Clinical Trials – Bisphosphonates in Fracture Healingin 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)


PTH (1-34) Anabolic Agent

Bone mass

All fractures

Enhances fracture healing

Spine fusion

In animal studies


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


Fracture Healing: PTH vs. Bisphosphonates

Bisphosphonate PTH

Callus Size

Maturation

Biomechanics =

Animal


Alendronate

Long term effect unkown

Theoretically dose with time

Keep collagen breakdown products low

Subtrochanteric Fracture


Prolonged Bisphosphonates

Turnover

Microfracture

Frozen Bone

Brittle Fracture

(PAK)


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)


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/Shaft 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/m2 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)

Nu

mb

er o

f p

atie

nts

SubtrochantericIntertrochantericFemoral Neck

*

**

Conclusions

Long-term bisphosphonate use decreases risk of hipfractures at IT/FN (94%) regions but may increase at ST/Sregions (6%)

A small subgroup of patients may be more susceptible tothe effects of prolonged therapy

Further studies are needed to confirm whether prolongeduse increases the risk of ST/S fractures and tocharacterize 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 FxOld 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 D3 [2 – 6,000 units/day]

Short half-life bisphosphonate/lower dose

PTH → bisphosponate

Bone turnover determines TX: right in themiddle

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/PhDAdele Boskey

Richard BockmanEdward DicarloSteven DotySteve GoldringDean LorichLinda RussellRobert SchneiderDave Zackson

FELLOWSJaimo AhnPadhraig O’LaughlinPhilipp Mayer-KuckukAlana SerotaAasis Unnanuntana

STUDENTS/RESIDENTSCharles ChangLily BogunovichBrian GladnickFlo Edobor-Osula Brett LenartDennis MeridethAndy NeviaserBarbara Schreck

RN’S/NP’SJanet CurtinPatricia DonnellyDiana LapianoLisa Shindle

Documents

Effects of Bisphosphonates and PTH on Fracture Healing and Spine Fusion “Subtrochanteric Fractures” Joseph M. Lane, MD Hospital for Special Surgery NEW