Osteoporosis Update : The Transplant Patient, Cases & Questions Bobo Tanner MD Director, Osteoporosis Clinic Marni Groves, NP Division of Rheumatology & Allergy Vanderbilt University Nashville TN Sept. 18, 2107
Disclosures Research,advisory panel and /or speakers bureau: Pfizer, BMS,GSK, AMGEN
69 yo w Case Age 26- TAH, BSO; Rx HT few years Age 33- DXA Bone Density test= low Failed treatments: SQ calcitonin-gi alendronate -GI raloxifene Hot flashes Age 50: Ischemic heart dz Age 55- DXA hip T-score= -3.5 Rx risedronate x 2yrs Age 57: Cardiomyopathy T plant list
#1. Why Are You Concerned About this Patient's Bone Density?
Relative BMD (%) Annual Fracture Incidence As BMD Decreases Fracture Risk Increases * Remember: Only ~1/3 of spine fractures are acutely painful 100 Forearm Colles' Spine 4000 Vertebrae 90 Hip and Heel Hip 3000 80 2000 70 1000 60 0 30 40 50 60 70 80 90 Age 35-39 Age 85+ Faulkner KG. J Clin Densitom. 1998;1:279 285. Cooper C. Baillières Clin Rheumatol. 1993;7:459 477.
The Osteoporotic Event: Hip Fracture
20% of females need assisted living or nursing home 80% of 75 yo preferred death to hip fx & nsg hm Cooper C, et al. Am J Epidemiol. 1993;137:1001 Hip Fracture: Devastating Event Mortality rate same as breast cancer 20% excess mortality in the first year 50% incapacitation
Awaiting Solid Organ Transplant: Low Bone Mineral Density Low BMD common in these pts. 2 yrs or more waiting t plant Long term survival after t plant BMD affected by: Organ disease: kidney, liver, lung Treatment: steroids, heparin, loop diuretics Negative calcium balance & bone loss Opportunity: prevent bone loss or restore before transplant
2. Questions about Osteoporosis When should DXA Bone Density testing be performed?
Bone Mass Measurement Act Federal Register 1997 for HCFA/CMS Medicare Osteoporosis Measurement Act 2003 1. Women with estrogen deficiency 2. Spine x-ray evidence of fracture or OP 3. Glucocorticoid therapy (3mos, 5 mg/d) 4. Primary Hyper-PTH 5. Follow-up treatment (23 months unless medical reason for sooner e.g. steroids)
3.How Do You Interpret a DXA Scan?
T- and Z-scores T-score: BMD compared to young adult reference Used for OSTEOPOROSIS diagnosis Post menopausal women, men >50 Z-score: BMD compared to age-matched reference Descriptive, especially children, premenopausal women and men <50; Z-score Not used for diagnosis
T-score T- & Z- scores & Osteoporosis World Health Organization (WHO) & ISCD Postmenopausal women, men>50 DXA Criteria > -1 Normal Classification < -1 and > -2.5 Osteopenia < -2.5 Osteoporosis < -2.5 & fracture Severe Osteoporosis Z-score Classification Premenopausal women, men<50 < -2 low bone density for age WHO Study Group JBMR 1994,1997; ISCD PDC www.iscd.org 2013
Spine Bone Density Report
Case (cont d) Age 59- cardiac transplant prednisone 5mg/day re-start risedronate => ibandronate Age 64 DXA FN = -2.4
4. When Do You Treat Osteopenia? Using FRAX
WHO Fracture Risk Prediction
Example of Applying the FRAX Tool Which Woman is at Higher Fracture Risk? 54 year old smoker with a T-score of -2.0 or 81 year old with no prior fracture with a T- score of -1.4 10 year risk of hip fracture = 2.5%; major osteoporotic fracture = 10% 10 year risk of hip fracture = 3.2%; major osteoporotic fracture = 26%
Initiate Pharmacologic Treatment: FRAX and NOF Guidelines 1. Patients w/ hip or vertebral fractures 2. PM women, men > 50,T-scores 2.5 femoral neck, total hip, lumbar spine,33% radius 3. Patients w/ Osteopenia (T-score < 1.0 & > 2.5) and FRAX = major fx risk 20 % or Hip fx risk 3 % Clinician s judgment and/or patient preferences may indicate treatment for people with 10-year fracture probabilities below these levels. www.nof.org and www.shef.ac.uk/frax
5. What are The Treatment Choices For Osteoporosis?
Normal Bone Remodeling: A Coupled Homeostatic Process Lining cells Osteoclast precursors Activated Osteoclasts Osteoblasts Lining cells Bone remodeling unit Resting Stage Activation Resorption Reversal Phase Formation Remodeling Completed 2 4 weeks 3 4 months 1. Marcus R. In: Hardman JG et al. Goodman & Gillman s The Pharmacologic Basis of Therapeutics. 10 th ed. McGraw-Hill; 2001:1715 1743. 2. Tanaka Y et al. Curr Drug Targets Inflamm Allergy. 2005;4:325 328. 3. Rosen CJ. Available at: http://www.endotext.org/parathyroid/index.htm. Accessed March 15, 2006.
FDA Approved Osteoporosis Medications Drug Post Menopausal OP Steroid OP Male OP Prevention Treatment Prevention Treatment Alendronate Risedronate Ibandronate Zoledronate Raloxifene Estrogen Calcitonin * Denosumab Teriparatide
Questions about Osteoporosis 6. Are Bisphosphonates safe? -Renal Excretion -Esophageal irritation - ONJ -Atypical fractures
#6. What is the Clinical Presentation of Osteonecrosis of the Jaw (ONJ)? Signs &Symptoms: 1 Asymptomatic or Facial pain, jaw pain Soft-tissue swelling,drainage Exposed,necrotic bone Cultures: actinomyces 2 Risk factors Cancer & concomitant therapies Poor oral hygiene Smoking Pre-existing dental disease, anemia, coagulopathy, and infection Management Povidone-iodine & 0.12% chlorhexidine mouthwash Oral antibiotics and anti-inflammatory drugs Conservative debridement for necrotic tissue Ruggiero SL, Hehrotra B, Rosenberg TJ, et al. J Oral Maxillofac Surg. 2004;62:527-34. 1. Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004 2. Naveau A. Joint Bone Spine 2005. Melo MD, Obeid G. J Can Dent Assoc 2005;71: 11-3.
ONJ Comparative Risks Any Fragility Fracture (1) Hip Fracture (1) 2668 387 Anaphylaxis from Penicillin Shot 32 Death by MVA 11 Death by Murder ONJ- Osteoporosis Patient Death by Lighting Strike (1) Women age 65-69 (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.) 6 0.7 0.6 0 10 20 30 40 50 60 70 80 90 100 Risk per 100,000 People per Year Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf. 2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150. www.nssl.noaa.gov/papers/techmemos/nws-sr-193/techmemo-sr193-4.html
American Dental Association Recommendations 2011 Dentists generally should not modify routine dental treatment solely because of the use of anti-resorptive agents All patients should receive routine dental examinations Patients for whom anti-resorptive agents have been prescribed likely would benefit from a comprehensive oral examination before or early in their treatment Anti-resorptive therapy places them at low risk of developing ARONJ (the highest prevalence estimate in a large sample is about 0.10 percent) Hellstein, et al., JADA 2011; 142: 1243-1251
#6. Can Bisphosphonates Cause Atypical Femoral Fractures? JBMR 2010
Features of Atypical Femoral Fractures Rare Low energy or spontaneous Subtrochanteric Thickened lateral cortex (often bilat.) Transeverse or spiral fracture beak assoc. with stress fracture Thigh pain before fracture After 5-10 years of bisphos. use Goh JBJS 2007, Nevaiser J Ortho Truama 2008, Somford JBMR 2009, Capeci JBJS 2009, Lenart Osteoporosis International 2009, Koh J Ortho Trauma 2010 Bukata S ISCD Ann Mtg San Antonio 2010
Sub Trochanteric Fractures 250,000 hip fractures /year US 25-80,000 subtrochanteric femoral shaft fractures (SFSF) Atypical SFSF, rare: 5 cases /10,000 patient-years ASBMR Task Force report to FDA: 50% have premonitory thigh or hip pain 25% bilateral involvement Black et al NEJM 2010 Girgis et al NEJM 2010, JBMR 2010
Goh SK. JBJS 2007;89:349
Goh SK. JBJS 2007;89:349
Bisphosphonates & Atypical Femoral Fractures Mechanism: Loss of bone turnover & repair? Similar appearance to hypophosphatasia or sclerosing bone disorders (osteopetrosis, pycnodysostosis) Asian heritage; bowed femur Is this result of a bone condition that has erroneously been diagnosed and treated as osteoporosis or a side effect of the medication? Whyte JBMR 2009 ; 5 Dell RM, J Bone Miner Res, 2012;27:2544-50
Atypical Femoral Fractures: X-ray both femurs What to do??tetracycline labeled bone biopsy labs: Vit D level, phos, other metabolic bone parameters Prophylactic nail? Consider teriparatide treatment Bukata S ISCD Ann Mtg 2010 San Antonio
What about a bisphosphonate holiday? Does the patient need more than 5 years? DXA Bone Turnover Markers Consider switch to teriparatide for drug holiday from bisphosphonates FDA advisory committee,9/9/11 no clear evidence of benefit or harm in continuing the drugs beyond 3-5 years. Ott Clev Clin J Med 2011 Laster, Tanner Rheum Dis Clin of NA 2011 www.fda.gov
7. Questions about Osteoporosis Are calcium & Vitamin D supplements needed?
Calcium Essential for prevention and treatment regimens Institute of Medicine of the National Academy of Sciences Recommendations: Over age 50 1200 mg daily Institute of Medicine. 1997. Washington, DC, Academy Press Fracture reduction in some but not all studies Recker RR, et al. J Bone Miner Res. 1996;11:1961
But are calcium supplements safe? Meta analysis: Conclusion: 30% increased MI risk But: no sig increase in mortality or stroke Independent of age, sex, type of ca. suppl. Caveats: Not 1 outcome Dietary Calcium appears to be safe
Dietary Calcium: About 800mg a Day? Warensjö E et al. BMJ 2011;342:bmj.d1473 2011 by British Medical Journal Publishing Group
7. What about Vitamin D? Optimal 25-OH Vit D for bone health >32ng/ml IOM: for general pop =20ng/ml Vit D Deficiency= falls, 3.4 X CHF death Possibly cancer, DM, autoimmune disease,etc., remember Vit E? Supplements: assoc with decreased mortality 1000 IU daily increase level~ 10ng/ml Too much at once? 500,000 IU and falls Toxicity? Liu et all Heart Failure Society of America San Diego Sept 2010 Binkley et al,endocrinol Metab Clin N Am 2010 Bischoff-Ferrari H. et al. JAMA. 2005;293(18):2257-2264 Janssen HCJP, et al. Am J Clin Nutr. 2002;75:611
Treatment: vitamin D Calcium and Vit D are insufficient to prevent transplant related bone loss Calcitriol (1,25 dihydroxy D)may be required by kidney and SPKT patients for a brief period at doses lower than used during dialysis All patients required vitd 400-1000 IU at least. Patients with malabsorption, cystic fibrosis or PBC may have higher vit D requirements. Monitor 25 D levels to assess replacement adequacy
#8: Questions About Osteoporosis What about the newest treatment: denosumab for osteoporosis?
Monoclonal antibody for Osteoporosis:RANKL-Inhibition OPG RANKL RANK Denosumab CFU-M Prefusion osteoclast OPG Multinucleated osteoclast Active Osteoclast Stromal cells BONE Adapted from Boyle et al. Nature. 2003;423:337.
Denosumab 60 mg q 6 months Decreased Incidence of New Vertebral, Nonvertebral, & Hip Fractures 65% reduction new spine fractures 20% reduction new Non-spine fractures 40% reduction new hip fractures Cummings SR et al. N Engl J Med 2009;361:756-765
Densoumab (Prolia ) Men & postmenopausal osteoporosis with high fracture risk or failed, or intolerant of other therapies Has been given to renal impairment pts. (including ESRD) single dose, without affecting pharmacodynamics or pharmokinetics of the drug; May drop serum calcium, verify nml Flare ups of Cellulitis? Eczema? Block et al National Kidney Foundation Mtg, Orlando, FL; April 13-17, 2010
#9. What Lab Tests Should I Order Before Treatment? CBC Creat., LFTS Calcium, Phos, Mg 25-OH Vit D TSH, PTH Bone Specific Alk Phos Bone Turnover Marker :P1NP (Procollagen-1 N-terminal Peptide) Serum Free Light Chains 24 hour urine : calcium, creatinine, phos, magnesium, sodium, protien immunoelectropheresis
#10: Transplantation- Induced Osteoporosis (TIOP) 3-11% bone loss 1 st yr. post transplant 14-36% increase incidence of fragility fxs. Most fracture occur at relatively normal Bone Mineral Density: Bone Quality? Pre-transplant: chronic disease & GCS Post-transplant : GCS & calcineurin inhib. Controversy: cyclosporine A & tacrolimus tacrolimus better?, may allow less GCS Carbonare et al Transplantation 2011
Post transplant Immunosuppression Simultaneous high dose GC initially and simultaneous administration of CsA, tacrolimus, azathioprine or mycophenolate mofetil Sorting out independent effects difficult since given simultaneously Immunosuppressant doses higher in liver and cardiac transplants than renal transplants contributeing to greater bone loss
T plant Medications: CsA Causes severe and rapid trabecular bone loss Results in accelerated bone turnover wit both increased formation and resorption Lowers serum testosterone Prevented by Bisphoshonates
T plant medications: Tacrolimus Causes high bone turnover loss even greater than CsA More potent immunosuppressant than CsA
#10: TIOP :Organ Specific Issues Kidney Bone loss: greatest in 1 st 6-18 months, 4-9% Assoc. with low estradiol & testosterone, not always gender, age, GCS, rjxn, PTH Fractures: higher early, diabetics, more in hips, long bones, feet than spine & ribs. Post transplant 34% increase in hip fractures compared to continued dialysis pts. Treatment: increase BMD, reduce fx, adjust bisph dose, consider Dmab,PTH for low cal,lowpth
#10: TIOP :Organ Specific Issues Heart Transplant Bone loss: 3-11% in first year Fractures: 14-36% in first year, 22-35% longterm fractures occur at T-score of -1.5 Treatment: 92% vitamin D deficient
#10: TIOP :Organ Specific Issues Lung - 37% osteoporosis at txp Bone loss: 2-5% in first year Fractures: 18-37% in first year, fractures occur at T-score of -1.5; pre txp low BMD & GCS = more fx
#10: TIOP :Organ Specific Issues Liver- Bone loss: 3.5-24% in first year, worse in older pt, post menopause, & less time since txp Fractures: Highest in 1 st 6-12 months, 24-65%, highest in women with PBC Ribs and spine most common, pre txp vert fx predict increased risk post txp Yadav et al Nutr Clin Pract 2013 28: 52
#10: TIOP :Organ Specific Issues Bone Marrow Usually younger, shorter time from dz onset to txp, less bed rest vs. solid organ txp Bone loss: 2-9% 1 st year, recovers after 12 mos, baselinbe at 48 mos., GVHD and GCS contributes to loss Vitamin D: marked decline pots txp,? Low sun exposure to avoid GVHD
Treatment Counsel all patients with low bone mass or fx prior to transplant re: increased risk of fracture Even a nml BMD does not protect against post Transplant fx Can prevent post transplant bone loss with bisphosphonates (zoledronic acid) Should prophylaxis against bone loss should be give to all transplant recipients without regard to BMD? (Cohen 2004) Avoid cigarette smoking and heavy alcohol consumptions Adequate nutrition Exercise to provide a mechanical load to bone
Osteoporosis Drugs in Development Anabolic drugs antibody to sclerostin- romosozumab PTH related peptide -abaloparatide (SQ or patch) Cat K inhibitor odanacatib: withdrawn
Long term monitoring Annual BMD assessments Bone Turnover Markers (PINP, NTx, CTx) Radiographs/MRI if suggestion of fx Bone bx occasionally required in renal transplant patients to evaluate for adynamic bone prior to bisphosphonate therapy
Learn More About Osteoporosis Management Know How to Read DXA Scans Know How to Treat Your Patients The International Society for Clinical Densitometry www.iscd.org
When Should I Refer A Patient To The Osteoporosis Clinic? When you do not feel comfortable treating with osteoporosis medications When a patient has already been taking an oral bisphosphonate such as Fosamax or Boniva for 5 years When a patient has chronic renal insufficiency When a patient continues to have fractures
Reasons why patients object to taking Osteoporosis Medications Cost Fear of side effects Fear of needles/injecting themselves
Questions For Us?