Disclosures Dr. Schafer: grant support, Bariatric Advantage and - PDF document

4/13/2018 Challenging Cases in Metabolic Bone Disease and Mineral Metabolism UCSF Diabetes Update and Advances in Endocrinology and Metabolism April 13, 2018 Dolores Shoback, MD Professor of Medicine, UCSF Staff Physician, San Francisco VA Health Care System Anne Schafer, MD Associate Professor of Medicine, UCSF Staff Physician, San Francisco VA Health Care System Disclosures • Dr. Schafer: grant support, Bariatric Advantage and Tate & Lyle • Dr. Shoback: consultant, Radius Health, Inc. 1

4/13/2018 Case 1 70 year old woman referred by Orthopedic Surgery for management of osteoporosis Medical History: • Sciatica • 2 lumbar spinal fusions for spinal stenosis (2009, 2015) • Menopause age 51 (~1998), used hormone therapy x 5 years Family History: + hip fracture in her mother and grandmother • Osteoporosis diagnosed by DXA (2005): L-spine T-score -2.5 • Following the NOF Guidelines . . . • Consider pharmacologic therapy for T- score ≤ -2.5, or higher T-scores if risk factors present (+FH); she had no clinical fractures • Endocrinologist started weekly alendronate 70 mg (highly compliant) Case 1 - cont’d 70 year old woman referred by Orthopedic Surgery for management of osteoporosis • 8 years into treatment with alendronate (2013) she slipped in kitchen and fractured both wrists, requiring open reductions and internal fixations in separate surgeries 2

4/13/2018 Audience Question 70 year old woman with osteoporosis who is 8 years into therapy with alendronate and has sustained bilateral wrist fractures after a ground-level fall (2013) What would be your next step in management? A. Continue alendronate, as this event does not qualify as treatment failure B. Switch to zoledronic acid or denosumab C. Switch to an anabolic agent (teriparatide or abaloparatide) D. Initiate a drug holiday Case 1- Further Management • Continue alendronate 70 mg weekly for 2 more years (2013- 2015) DXA (2015) – 10 yrs ALN completed: • Lumbar spine (L1/L2): 0.969 g/cm 2 (T-score: -1.6 ) 0.736 g/cm 2 (T-score: -2.2 ) • Left femoral neck: 3

4/13/2018 FDA Analysis 2012 ** ** ** ** • Combined ALL morphometric and clinical vertebral and ALL nonvertebral fractures (% of pts) • Numbers – not large (all post-hoc) • FLEX/Alendronate – 1099 pts • Risedronate – 164 pts • Zoledronic acid – 1233 pts ** BENEFIT – clear in first 3-5 years - NOT AFTER Whitaker et al, NEJM 2012 FLEX Study Showed Reduction in Vertebral Fractures with 10 vs 5 years Alendronate: Clinical Subgroup Analyses GROUP RISK DIFF NNT* All women in study 2.9% 34 FN T < - 2.5 4.8% 21 FN T - 2.0 to - 2.5 3.0% 33 Her vertebral fracture status at the NO prevalent VFx time was unknown and FN T < - 2.5 4.2% 24 Prevalent VFx Underline = FN T < - 2.5 5.8% 17 best NNTs FN T - 2.0 to - 2.5 5.8% 17 * for 5 more years Black, Cummings et al, NEJM, 2012 4

4/13/2018 Case 1- Further Management DXA (2015): 0.969 g/cm 2 (T-score: -1.6 ) • Lumbar spine (L1/L2): 0.736 g/cm 2 (T-score: -2.2 ) • Left femoral neck: • Now, after 10 years treatment with alendronate, with increasing number of atypical fractures reported in the literature, the patient herself asked to stop alendronate Task Force Report on Managing Osteoporosis Patients After Long-Term Bisphosphonate Treatment. (Adler R, et JBMR, 2016 ) 5

4/13/2018 Case 1- Further Management DXA (2015): 0.969 g/cm 2 (T-score: -1.6 ) • Lumbar spine (L1/L2): 0.736 g/cm 2 (T-score: -2.2 ) • Left femoral neck: • Now, after 10 years treatment with alendronate, with increasing number of atypical fractures reported in the literature, the patient herself asked to stop alendronate • Her physician switched her to denosumab After 2 years - DXA (2017): • Lumbar spine (L1/L2): 1.007 g/cm 2 (T-score: -1.3 ) (+ 4%) • Left femoral neck: 0.758 g/cm 2 (T-score: -2.0 ) (+ 3%) Case 1 – More History • In 2017 - she retired from work, increased her exercise (vigorous daily walking) • 3 months prior to evaluation in our clinic: noted right leg pain, attributed to ‘sciatica’ (in radicular distribution), making ambulation difficult (started to use cane to walk), pain slowly intensified • 2 months prior: after a vigorous “power walk”, she developed more intense right leg pain the next day, and she went to see her internist 6

4/13/2018 Xray of Pelvis and Right Femur • Negative for fracture • No clear etiology for her pain Case 1 - Additional History • While walking around at home the very next morning, right leg pain intensified, and she could not get up from the bathroom • Taken to emergency room by family • Xray right hip/femur showed an acute subtrochanteric fracture 7

4/13/2018 Atypical Femur Fractures • Subtrochanteric or femoral diaphyseal fractures in pts on BP’s or denosumab • “Stress” or insufficiency fractures • 3-50 cases/100,000 person-yrs; long-term use  ~100/100,000 person-yrs • Duration of BP treatment: > 3 years, median ~7 years • Lower limb geometry, Asian ethnicity may contribute • Most studies found association with glucocorticoid use Shane E et al, JBMR, 2010 and 2014 At least 4/5: Shane E et al, JBMR, 2014 8

4/13/2018 Case 1 - Management • Open reduction and internal fixation, with intramedullary rod/nail • Discharged home with ongoing physical therapy • Slow recovery, continued pain with weight bearing and unable to participate in physical therapy • Thought to have delayed healing by Xray (per orthopedist) • Referred to clinic to discuss medical management of non-healing fracture, now 8 weeks after initial trauma In Clinic Evaluation • Physical Exam: petite woman, height 5’5” (165.1 cm), weight 120 lbs (54.4 kg), normal vital signs; pain with internal and external rotation of right hip, using a wheelchair • Labs: normal chemistries, Ca, PTH, phosphate, 25- OH vitamin D, TSH, free T4, tissue transglutaminase Ab, complete blood count - all normal 9

4/13/2018 Current Management Strategies: Atypical Femur Fractures • Pain in thigh or groin in pt on BP or denosumab  should be investigated • Modalities: X-ray, MRI, CT; assess both sides • Extended DXA of femur • If you diagnose an AFF, BP or D-Mab should be stopped • Surgery (femoral rod) - recommended for complete fractures and for painful incomplete fractures • Minimal pain and incomplete fracture  can try non-weight bearing x 2-3 months, then surgery if not healed • Delayed healing – not uncommon • Anabolic therapy? Several reports of enhanced healing, but others with no effects on healing (teriparatide) • No RCT’s Bone Biopsies Before and After 12 Months Treatment with TPTD in 15 Patients with AFF’s • Average 7 years of ALN • Bone histomorphometry – bone formation rates • AT BASELINE: 7/15 pts had unmeasurable parameters (e.g., BFR/BV) and 8/15 had measurable parameters but below control population • Responses to 12 months of teriparatide Miller PD, McCarthy EF, Sem Arth Rheum, 2014 10

4/13/2018 Case 1 – Further Evaluation CT Scan – right and left femur (9-10 weeks post-trauma): - healing abundant bridging callus formation noted at proximal right femoral diaphysis - nail in satisfactory alignment - NO CT evidence for “stress reactive changes” or cortical thickening involving left femur • Was now able to participate in physical therapy, and deferred pharmacologic intervention • Being followed with plan to monitor BMD and clinical status Case 2 74 year old man referred for evaluation of history of fractures Present Illness : • + h/o multiple fractures beginning in childhood (very active, lived on ranch, did heavy labor) • Fractures stopped as an adolescent • Deployed to Viet Nam where he sustained a painful vertebral compression fracture in combat exercise, took a desk job until the war ended • Sustained L femur fracture in 2000 with mild fall, rod placed Orthopedic surgeon told him  “. . . you may have osteogenesis imperfecta” 11

4/13/2018 Case 2 – cont’d 74 year old man referred for evaluation of history of fractures Review of systems: • + bilateral hearing loss; + poor dentition; no joint laxity, chest pain Past medical history: • L2 superior endplate fracture noted on 6/2001 xray • New T12 compression fracture detected on surveillance CT for following thoracic aortic aneurysm in 2017 • Aortic aneurysm: no change in size since 2014 Case 2 – cont’d Social history: • Smoked cigars (1968-73) in Army • Quit heavy drinking ~age 34; beer drinker until ~age 64 • Works as ranch hand, does horseshoeing, no riding horses Medications: • amlodipine 10 mg • lisinopril 5 mg bid • metoprolol succinate 25 mg • vit D3 1,000 IU qd 12

4/13/2018 Case 2 – cont’d Family history: • No aneurysms, joint laxity, or sudden cardiac death • Mother died of cancer (age 57), father – old age (age 93) • 1 brother – alcoholism, had fractures but traumatic Age 74 proband Age 50, multiple frxs broken hip at age 1, other med problems Age 14 Age 25 Age 13 Case 2 – Physical Exam • Ht: 67 in [170.2 cm]; weight: 201.4 lbs, nl VS • NAD, well developed and well appearing • HEENT: +blue sclerae; lower teeth dysplastic, small and translucent. • CV: no murmurs • Lungs: clear, barrel chested • Bones/Joints: +kyphosis, no joint laxity or deformity • Skin: sun damage to forearms bilaterally, no skin laxity • Neuro: intact, slight limp 13