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Joseph M. Lane, MD

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. Source:. Review:. Does have a financial interest or relationship with the manufacturers of products or services:

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Joseph M. Lane, MD

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  1. Effects of Bisphosphonates and PTH on Fracture Healing and Spine Fusion “Subtrochanteric Fractures”Joseph M. Lane, MDHospital for Special SurgeryNEW YORK

  2. Joseph M. Lane, MD Source: Review: 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 Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  3. Source: The Goal: Increased Bone Strength Review: NIH Consensus Statement 20001 Bone Strength Bone Quality Bone Mineral Density Reviewer Memo: and Architecture/Geometry Bone Remodeling Damage Accumulation Mineralization of Matrix 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  4. Risk of Vertebral Fracture Source: Review: 5x greater with prior vertebral fracture Vertebral fracture 2x risk of hip fracture Fracture more fractures Reviewer Memo: (Nevitt 1999) 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  5. Metabolic Bone DiseaseWorkup For Osteopenia Source: Review: 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 Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  6. Agents Against Osteoporosis Source: Review: Antiresorption (Experimental) Estrogen Calcitonin Bisphosphonates Serms Bone Stimulation PTH Strontium Renalate Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  7. Bisphosphonates Source: Review: Bone Mass (Spine/Hip) Fracture Risk (Vertebra/Long Bones) = Fracture Healing (animal/patients) Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  8. Animal Studies Source: Review: Remodeling Healing Callus =Biomechanics Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  9. Clinical Trials – Bisphosphonates in Fracture Healing Source: Review: 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) Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  10. PTH (1-34) Anabolic Agent Source: Review: Bone mass All fractures Enhances fracture healing Spine fusion In animal studies Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  11. Intermittent PTH (1-34)Rat Femoral Fracture Source: Review: 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 Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  12. Fracture Healing: PTH vs. Bisphosphonates Source: Review: Animal Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  13. Alendronate Source: Review: Long term effect unkown Theoretically dose with time Keep collagen breakdown products low Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  14. Subtrochanteric Fracture

  15. Prolonged Bisphosphonates Source: Review: Turnover Microfracture Frozen Bone Brittle Fracture (PAK) Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  16. Background Source: Review: • 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 Reviewer Memo: • Neviaser, et al J Orthop Trauma (2008) 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  17. Methods Source: Review: • 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 Reviewer Memo: 1. NIH Consensus Development Panel on Osteoporosis 2000. JAMA. 2001;285:785-795. Slide Modified: Memo:

  18. Rate of 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)

  19. 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

  20. ST/S Fracture 83 year old female with no history of alendronate use 60 year old female with no history of alendronate use

  21. Not for duplication 24

  22. Not for duplication 6

  23. Not for duplication 20

  24. Not for duplication 31

  25. Not for duplication 2

  26. Not for duplication Bis-24

  27. Not for duplication Bis-6

  28. Not for duplication No Bis-20

  29. Not for duplication Bis-31

  30. Not for duplication No Bis-2

  31. Simple With Thick Cortices Fracture • 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)

  32. Pattern vs. Absence of Pattern

  33. 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

  34. 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

  35. Osteoporosis Treatment Comparison Bone FormationRemodeling Normal Fx Healing ↑↑ ↑ Bisphosphonates ↓ ↓↓ PTH ↑↑ ↑

  36. Question Mechanism Treatment

  37. Mechanism Stress fracture 3 months pain Local ↑ diameter

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

  39. Treatment Stop bisphosphonate Correct Ca/VIT D Consider PTH 1-34 (anabolic)

  40. Patient with thigh pain History – bisphosphonate X-Ray → MRI / bone scan

  41. To Prevent Abnormal Bone Consider a Bone Holiday Old FxNew Fx No Pain Pain ↓ ↓ Anabolic Anabolic Consider nailing

  42. 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

  43. Fracture on Bisphosphonate Rule out secondary cause Stop bisphosphoate Correct calcium/vitamin D Consider PTH

  44. Clinical Studies Clinical characterization of fracture healing Evaluation of bone quality Histology - Doty Micro-Ct - Mayer-Kuckuk F-TIR - Boskey

  45. 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 HSS Osteoporosis Team

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