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 JAMA. 2001;285: 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 BoneQualityBoneQuality Bone BoneStrength Strength Architecture/Geometry Bone Remodeling Damage Accumulation Mineralization of Matrix 1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: BoneMineralDensityBoneMineralDensity NIH Consensus Statement The Goal: Increased Bone Strength

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: 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 JAMA. 2001;285: 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 JAMA. 2001;285: Agents Against Osteoporosis Antiresorption (Experimental) Estrogen Calcitonin Bisphosphonates Serms Bone Stimulation PTH Strontium Renalate

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: Bisphosphonates Bone Mass (Spine/Hip) Fracture Risk (Vertebra/Long Bones) = Fracture Healing (animal/patients)

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: Animal Studies Remodeling Healing Callus =Biomechanics

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: 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 JAMA. 2001;285: PTH (1-34) Anabolic Agent Bone mass All fractures Enhances fracture healing Spine fusion In animal studies

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: 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 JAMA. 2001;285: Fracture Healing: PTH vs. Bisphosphonates BisphosphonatePTH Callus Size Maturation Biomechanics= Animal

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: Alendronate Long term effect unkown Theoretically dose with time Keep collagen breakdown products low

Subtrochanteric Fracture

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: Prolonged Bisphosphonates Turnover Microfracture Frozen Bone Brittle Fracture (PAK)

1. NIH Consensus Development Panel on Osteoporosis JAMA. 2001;285: 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 JAMA. 2001;285: Methods Retrospective case-control study 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 ( )

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

20 Not for duplication

31 Not for duplication

2

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 ( )

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 Race White %, Asian %90, 10100, 0 BMI (SD), kg/m (4.1)23.4 (3.8).48 History of Osteoporosis, % Duration of time on alendronate (SD), y7.3 (1.8)2.8 (1.3)<.001 Ratio of cortical thickness to diameter0.36 (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

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 FormationRemodeling 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 Old FxNew Fx No PainPain ↓ ↓ AnabolicAnabolic 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