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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
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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
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and BoneQualityBoneQuality Bone BoneStrength Strength Architecture/Geometry Bone Remodeling Damage Accumulation Mineralization of Matrix 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. BoneMineralDensityBoneMineralDensity NIH Consensus Statement 2000 1 The Goal: Increased Bone Strength
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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)
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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
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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
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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)
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1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Animal Studies Remodeling Healing Callus =Biomechanics
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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)
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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
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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
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1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Fracture Healing: PTH vs. Bisphosphonates BisphosphonatePTH Callus Size Maturation Biomechanics= Animal
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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
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Subtrochanteric Fracture
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1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Prolonged Bisphosphonates Turnover Microfracture Frozen Bone Brittle Fracture (PAK)
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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)
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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
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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)
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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
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ST/S Fracture 83 year old female with no history of alendronate use 60 year old female with no history of alendronate use
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24 Not for duplication
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6
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20 Not for duplication
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31 Not for duplication
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2
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Bis-24 Not for duplication
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Bis-6 Not for duplication
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No Bis-20 Not for duplication
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Bis-31 Not for duplication
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No Bis-2 Not for duplication
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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)
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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 Range55-8371-96 Race White %, Asian %90, 10100, 0 BMI (SD), kg/m 2 25.0 (4.1)23.4 (3.8).48 History of Osteoporosis, %100.99 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
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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
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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
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Osteoporosis Treatment Comparison Bone FormationRemodeling Normal Fx Healing ↑↑ ↑ Bisphosphonates ↓ ↓↓ PTH ↑↑ ↑
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Question Mechanism Treatment
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Stress fracture 3 months pain Local ↑ diameter Mechanism
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Bisphosphonates given to normal diaphyseal bone increased microdamage collagen aging >> fiber failure >> loss of toughness >> low energy spontaneous fracture Working Hypothesis
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Stop bisphosphonate Correct Ca/VIT D Consider PTH 1-34 (anabolic) Treatment
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Patient with thigh pain History – bisphosphonate X-Ray → MRI / bone scan
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Old Fx Old FxNew Fx No PainPain ↓ ↓ AnabolicAnabolic Consider nailing To Prevent Abnormal Bone Consider a Bone Holiday
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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
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Fracture on Bisphosphonate Rule out secondary cause Stop bisphosphoate Correct calcium/vitamin D Consider PTH
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Clinical Studies Clinical characterization of fracture healing Evaluation of bone quality Histology-Doty Micro-Ct-Mayer-Kuckuk F-TIR-Boskey
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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
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