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Bone Disease in Transplants Edward Hsiao, MD, PhD University of California, San Francisco Division of Endocrinology and Metabolism Metabolic Bone Clinic Institute for Human Genetics 2018 UCSF Advances in Internal Medicine Disclosures • Edward Hsiao receives research grant support from Clementia Pharmaceuticals for unrelated clinical trials. He has no conflicts of interest. • This presentation includes discussion of off- label, investigational use of a commercial product, or drugs that are not FDA approved. • Care should be guided by expert opinion and literature. As always, we encourage the application of sound clinical judgment on a case-by-case basis 1

Outline • Brief overview • Transplant bone loss – Pre-transplant factors – Post transplant factors • Medications – Management considerations • Cases – Liver (pre and post transplant) – Kidney (pre-transplant) Organ Transplants are Common Organdonor.gov Access 3/27/2018 2

Definition of Osteoporosis • Systemic skeletal disease – Low bone mass – Micro-architectural deterioration of bone • Leading to – Increased bone fragility – Increased fracture risk World Health Organization (WHO), 1994 Effective treatments require understanding bone remodeling Resorbs bone Forms bone Bone lining Osteoblasts Osteoclasts cells Osteocytes Calcified bone matrix Treatment goals: Bone formation Bone turnover 3

Current Treatments for Osteoporosis Increase Bone Formation Decrease Bone Turnover • Parathyroid hormone • Hormone Therapy (HT) (rPTH, Teriparatide) • SERM/Raloxifene (Evista) • Calcitonin (Miacalcin) • Bisphosphonates – Alendronate (Fosamax) • Weight bearing exercise – Risedronate (Actonel) – Ibandronate (Boniva) – Zoledronate (Reclast/Aclasta) • (Strontium ranelate) • RANKL inhibitors – Denosumab (Prolia) Key aspects to consider in transplant patients • Pre-transplant factors • Post-transplant factors • Medications related to transplants • Medication interactions post transplant 4

Bone fragility pre-transplant • Complex interactions of hormones, electrolytes, and functionality • Diseases generally associated with metabolic bone problems pre-transplant • All are generally associated with increased fracture risk post-transplant Factors contributing to bone disease prior to transplant • Kidney – PTH, calcium/phosphate abnormalities – Vitamin D deficiency – Hemodialysis • Lung – steroids, poor mobility – Chronic pulmonary insufficiency – Nutritional status • Liver – Steroids – Hypogonadism – poor mobility – Nutritional status – GI/malabsorptive state 5

Factors contributing to bone disease prior to transplant • Kidney – PTH, calcium/phosphate abnormalities – Vitamin D deficiency – Hemodialysis • Lung – steroids, poor mobility – Chronic pulmonary insufficiency – Nutritional status • Liver – Steroids – Hypogonadism – poor mobility – Nutritional status – GI/malabsorptive state Chronic kidney disease and fractures • High risk of hip fractures in ESRD females Age Patient yrs Incidence per Rochester hip 1000 pt yrs in fracture incidence ESRD patients per 1000 pt yrs < 45 70,672 2.96 0.03 45-54 40,009 5.60 0.28 55-64 59,174 9.79 0.96 65-74 73,420 20.28 3.18 75-84 35,101 32.88 13.11 >85 4,187 46.81 26.84 Total 282,563 13.63 7.40 • Increased risk also observed in males • Risk increases with time from first dialysis Alem, et al., Kid. Int. 2000 6

Renal Osteodystrophy Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD) • Osteitis fibrosa cistica – related to secondary hyperparathyroidism • Low bone turnover – osteomalacia, adynamic bone disease/aluminum toxicity, low Vitamin D, high phosphate, high FGF23 • Osteoporosis • Hypogonadism • Metabolic Acidosis • Medications Ebling, et al. 2013. Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism. Pre-transplant hemodialysis • Hemodialysis – Prevalence of fracture up to 21% – Older females, with complications like diabetes and peripheral vascular disease – Long duration • Bone turnover markers can sometimes be helpful – Upper half of normal pre-menopausal level to elevated is highest risk of fracture • Bone biopsy may be needed Nickolas, et al. 2011 J Am Soc Nephrol. Stehman-Breen, et al. 2000 Kidney Int. Ball, et al. 2002. JAMA 7

Summary I: Pre-Transplant Management Strategies • Optimization of biochemical and hormonal abnormalities – Vitamin D deficiency (may need more replacement) – Electrolytes – Hyperparathyroidism (See CKDMB guidelines) – Hypogonadism • DEXA scan to document baseline – FRAX score – use secondary osteoporosis/steroid options • Early management of pre-transplant bone disease – (ie renal osteodystrophy) Other contributing factors • Aging • Low BMI/nutritional deficiency • Physical inactivity • Alcohol use • Smoking • Immobility (These are also traditional factors contributing to osteoporosis) 8

Post-transplant: Rapid early bone loss • Rapid bone loss in first 6-12 months – Regimen dependent • Thought to be steroid, immobility related – Fractures can affect both normal or low pre- transplant BMD patients – Typically occurs in first 1-3 years, but risk continues • (Sprague, et al. 2004 Semin Nephrol.) • Probably less severe now due to lower steroid use, but still bone loss will occur • Pre-transplant risk predicts post-transplant risk Medications: Glucocorticoids • Directly inhibits osteoblast proliferation and function • High doses used immediately post transplant • Known association with bone loss • (Van Staa, et al. 2000 JBMR) – Trabecular > Cortical • Early steroid reductions associated with fracture risk reduction – US Renal Data System • (Nikkel, et al. 2012. Am J Transplant) 9

Medications: Calcineurin Inhibitors • Cyclosporin A – Increases bone turnover in vitro • (Epstein, et al. 1996. JBMR) – Renal transplant patients receiving CsA alone do not seem to have increased fractures • (McIntire, et al. 1995. Clin Transplant) • Tacrolimus (FK506) – Trabecular bone loss in liver and heart transplant (Stempfle, et al. 1998 Transplant Proc.; Park, et al. 1996, Transplant Proc.) • Still useful as a way to decrease steroid exposure Other Medications • Sirolimus (rapamycin) – Like Tacrolimus, associated with bone loss in rats • (Rubert, et al. 2015. Bone Rep) – However, other reports suggest benefits for senile osteoporosis (Luo, et al. 2016 Osteoporosiss Int.). • Mycophenelate mofetil • Daclizumab • Azathioprine • Most have little data or unclear mouse/human data • Likely benefit from reduction of steroids 10

Summary II: Post transplant risk factors for bone disease Pre-transplant factors Post-transplant factors • Age, low BMI • High dose or prolonged • Hypogonadism steroids • Calcineurin inhibitors • Vit D, Ca, PO4 deficiency • Post transplant • Smoking, alcohol functionality (weight • Organ failure bearing, immobility) • Pancreatic insufficiency • Diabetes • Physical inactivity • Steroids • Diabetes FRAX Scores: Check secondary osteoporosis box 11

Management considerations • Prevention – Weight bearing – Calcium/vitamin D treatments • Bisphosphonates – Risk of renal toxicity • Coordinate with nephrology – Most have proven efficacy for steroid induced bone loss – Combination of bisphosphonates, Ca, and Vit D is useful after renal transplant • (Kovac,et al. 2001 Transplant Proc) Current Treatments for Osteoporosis Increase Bone Formation Decrease Bone Turnover • Parathyroid hormone • Hormone Therapy (HT) (rPTH, Teriparatide) • SERM/Raloxifene (Evista) • Calcitonin (Miacalcin) • Bisphosphonates – Alendronate (Fosamax) • Weight bearing exercise – Risedronate (Actonel) – Ibandronate (Boniva) – Zoledronate (Reclast/Aclasta) • (Strontium ranelate) • RANKL inhibitors – Denosumab (Prolia) 12

Bisphosphates: FDA approved Indications Agent Alendronate Risedronate Ibandronate Zolendronate Post-menopausal osteoporosis Prevention* + + + + Treatment + + + + Glucocorticoid osteoporosis Prevention + + Treatment + + + Men with low BMD (Treatment) + + + * Now moving towards use of fracture risk to determine management www.fda.gov Drugs@FDA database, analyzed for approved indications Accessed 2/7/2012 Using bisphosphonates in chronic kidney disease • Significant benefits for CKD and transplant patients in decreasing fracture risk • Manufacturers have indicated drug-specific cutoffs in the setting of renal failure – Likely safe for mild impairment (CKD1-3) – Unclear benefit for dose reduction • No bisphosphonates for GFR < 35 ml/min or CrCl < 30 ml/min (CKD 4-5/ESRD) – Risk of adynamic bone disease Jamal, et al. JBMR 2007 (FIT) Ott, et al. JBMR 2008 Amerling, et al. Blood Purif 2010 13