Effects of Bisphonates and PTH on Fracture Healing

Effects of Bisphonates 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 5 x greater with prior vertebral fracture Vertebral fracture 2 x 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 Bone Stimulation (Experimental) PTH Estrogen Calcitonin Strontium Renalate Bisphonates Serms 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001; 285: 785 -795.

Bisphonates 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 – Bisphonates 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. Bisphonates Animal Bisphonate 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 Bisphonates 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 bisphonate 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 Age, y Mean (SD) Range Race White %, Asian % BMI (SD), kg/m 2 History of Osteoporosis, % Duration of time on alendronate (SD), y Ratio of cortical thickness to diameter 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 . 99 7. 3 (1. 8) 2. 8 (1. 3) <. 001 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 *1 pt on risedronate, **1 pt on etidronate for 5 years, then alendronate for 2 • Fem Neck vs. Intertroch P=0. 3

Conclusions Long-term bisphonate 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 ↑↑ ↑ Bisphonates ↓ ↓↓ PTH ↑↑ ↑

Question Mechanism Treatment

Mechanism Stress fracture 3 months pain Local ↑ diameter

Working Hypothesis Bisphonates given to normal diaphyseal bone increased microdamage collagen aging >> fiber failure >> loss of toughness >> low energy spontaneous fracture

Treatment Stop bisphonate Correct Ca/VIT D Consider PTH 1 -34 (anabolic)

Patient with thigh pain History – bisphonate X-Ray → MRI / bone scan

To Prevent Abnormal Bone Consider a Bone Holiday Old Fx New Fx No Pain ↓ ↓ Anabolic Consider nailing

Osteoporosis New Fracture Treatment Calcium (Citrate) [1, 000 mg Ca] Vitamin D 3 [2 – 6, 000 units/day] Short half-life bisphonate/lower dose PTH → bisphosponate Bone turnover determines TX: right in the middle

Fracture on Bisphonate Rule out secondary cause Stop bisphoate 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/Ph. D 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