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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

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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

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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

Treatment goals: Bone formation Bone turnover

Osteoclasts Osteocytes Calcified bone matrix Bone lining cells Osteoblasts

Resorbs bone Forms bone

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Current Treatments for Osteoporosis

Decrease Bone Turnover

• Hormone Therapy (HT)
• SERM/Raloxifene (Evista)
• Calcitonin (Miacalcin)
• Bisphosphonates

– Alendronate (Fosamax) – Risedronate (Actonel) – Ibandronate (Boniva) – Zoledronate (Reclast/Aclasta)

• (Strontium ranelate)
• RANKL inhibitors

– Denosumab (Prolia)

Increase Bone Formation

• Parathyroid hormone

(rPTH, Teriparatide)

• Weight bearing exercise

Key aspects to consider in transplant patients

• Pre-transplant factors
• Post-transplant factors
• Medications related to transplants
• Medication interactions post transplant

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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

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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
• Increased risk also observed in males
• Risk increases with time from first dialysis

Age Patient yrs Incidence per 1000 pt yrs in ESRD patients Rochester hip fracture incidence 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

Alem, et al., Kid. Int. 2000

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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

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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)

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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)

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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

• steoporosis (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

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Summary II: Post transplant risk factors for bone disease

Pre-transplant factors

• Age, low BMI
• Hypogonadism
• Vit D, Ca, PO4 deficiency
• Smoking, alcohol
• Organ failure
• Pancreatic insufficiency
• Physical inactivity
• Steroids
• Diabetes

Post-transplant factors

• High dose or prolonged

steroids

• Calcineurin inhibitors
• Post transplant

functionality (weight bearing, immobility)

• Diabetes

FRAX Scores: Check secondary

• steoporosis box

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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

Decrease Bone Turnover

• Hormone Therapy (HT)
• SERM/Raloxifene (Evista)
• Calcitonin (Miacalcin)
• Bisphosphonates

– Alendronate (Fosamax) – Risedronate (Actonel) – Ibandronate (Boniva) – Zoledronate (Reclast/Aclasta)

• (Strontium ranelate)
• RANKL inhibitors

– Denosumab (Prolia)

Increase Bone Formation

• Parathyroid hormone

(rPTH, Teriparatide)

• Weight bearing exercise

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Bisphosphates: FDA approved Indications

Agent Alendronate Risedronate Ibandronate Zolendronate

Post-menopausal osteoporosis Prevention* + + + + Treatment + + + + Glucocorticoid osteoporosis Prevention + + Treatment + + + Men with low BMD (Treatment) + + +

www.fda.gov Drugs@FDA database, analyzed for approved indications Accessed 2/7/2012

* Now moving towards use of fracture risk to determine management

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

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Denosumab

• Human monoclonal antibody that inhibits RANKL (required for
• steoclast function and survival)
• Given 60 mg sq every 6 months over 3 years reduces fracture risk

(FREEDOM) and Freedom extension

Vertebral Non- vertebral Hip N (Ref #) Alendronate

(10 mg qd)

0.55 (0.43-0.69) 0.84 (0.74-0.94) 0.60 (0.40-0.92) 12,068 (2) Zoledronate

(5 mg/yr iv)

0.30 (0.24-0.38) 0.75 (0.64-0.87) 0.59 (0.42-0.83) 7,765 (1) Denosumab

(60 mg/6 mo sq)

0.32* (0.26-0.41) 0.80* (0.67-0.95) 0.60 (0.37-0.97) 7868 (3) Relative risk of drug vs. placebo * Hazard ratios (secondary endpoints of study)

• 1. Black, et al. NEJM 2007 (HORIZON)
• 2. Wells, et al. Cochrane DB or Syst. Rev. 2008 (CD001155 Alendronate)
• 3. Cummings, et al. NEJM 2009 (FREEDOM)

Long-term Denosumab Use

• FREEDOM extension (total of 5 years) just reported, with

persistent gains in BMD and fracture risk (1)

• Transition from alendronate to 1 year of denosumab appears safe

and may have a slightly improved BMD (no fracture data) (2)

• Likely cost effective, particularly for patients with low compliance to

bisphosphonates (3,4)

• Main complications:

– skin infection, urinary tract infection; dermatitis/eczema/rash – ONJ reported in cancer patients receiving high doses (120 mg every 4 weeks)

• f denosumab (5, 6) and was seen in 2 patients in the FREEDOM extension (1)

– Likely occurs at same rate as bisphosphonates, during clinical trials

1. Papapoulos, et al. JBMR 2011 2. Kendler, et al. JBMR 2010 3. Jonsson, et al. Ost. Int 2011 (Sweden) 4. Hiligsmann, et al. Pharmacoeconomics 2011 (Belgium) 5. Smith, et al., Lancet 2012 (Prostate cancer) 6. Stopeck, et al. J Clin Oncol 2010 (Breast cancer)

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New Considerations for Denosumab

• Fracture risk increase in spine

– Multiple clinical case series

• Rapid bone loss with discontinuation of denosumab

– FREEDOM and FREEDOM Extension

• Cummings, et al. 2018 JBMR

– Occurs within 1-2 years after stopping

• 6 fold increased risk of vertebral fractures
• 2 fold higher risk of multiple vertebral fractures

Patients who stop denosumab show increased vertebral fracture risk

– Odds ratio of multiple vertebral fractures in patient with prior fracture = 3.9 – Non-vertebral fracture rates were similar

• Unclear what to do – chase with bisphosphonate?

Cummings, et al. 2018 JBMR

Any Vertebral Fracture Multiple Vertebral Fractures

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Combination Therapy Teriparatide & bisphosphonates

• Bone mass is lost after teriparatide stopped
• Bisphosphonates help maintain bone mass and reduce

fracture risk

• Teriparatide + bisphosphosphonate

– Less bone increase than either teriparatide or ALN alone (1) – Teriparatide+zoledronate may increase spine and hip BMD (4)

• Bisphosphonates then teriparatide

– Blunted response to teriparatide (2) – 1 year washout prior to teriparatide may not be necessary (3)

• Risk of bone cancer (osteosarcoma)

– Not recommended for prior X-ray therapy; known or prior bone mets; history of skeletal malignancies

• 1. Black, et al. NEJM 2003
• 2. Finkelstein, et al. NEJM 2003 (men with osteoporosis)
• 3. Keel, et al. JBMM 2010
• 4. Cosman, et al. JBMR 2011

Other transplants

• Hematopoietic stem cells

– Often done for cancer – May complicate use of anabolics (teriparatide)

• Lung Transplant

– Often complicated by multiple infections, poor mobility, poor oxygenation

• Heart

– Often complicated by poor mobility, perfusion problems

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Summary III: Transplant

• steoporosis
• Common
• Pre- and post-transplant risk factors
• Early intervention/diagnosis/treatment is

critical

• May involve a balance of risk with

immunosuppressants

• Bisphosphonates remain the mainstay
• Denosumab has promise but also newly

identified risks with vertebral fractures

CASE 1: LIVER TRANSPLANT CANDIDATE

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Pre-transplant

• 62 yo M

– Liver cirrhosis (alcohol related) – Esophageal bleeding – No fractures – Awaiting transplant – Prior history of atrial fibrillation

• Brother with osteoporosis

Medication

• Lactulose
• Cholecalciferol
• Amiodarone
• Magnesium, Zinc
• What assessments do you want?

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Data

• DEXA at presentation
• Spine: T=-2.7 Total Femur -1.4

Femoral Neck -1.9

• PTH =44, Ca=9.7, PO4=2.2
• Testosterone = 537
• 25 OH VitD=23
• 24 hr Urine Ca=637 mg/day

Management considerations

• Oral bisphosphonate may be

contraindicated

– History of varices, with bleeding

• Elevated urine calcium excretion

– Started on HCTZ – 24 hr urine calcium down to 150s

• New DEXA 2 years later:

– Spine: T=-2.2; Total femur = -1.9; Fem Neck: T=-2.2

• Improved spine; others slight decrease.

Now considering iv bisphosphonate

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CASE 1B: LIVER TRANSPLANT

Post transplant

• 59 yo F
• Orthotopic liver transplant 11 years ago

for primary sclerosing cholangitis

• Course complicated by

– ulcerative colitis (GI confirmed) – Primary hyperparathyroidism s/p resection 3 years ago – calcium pyrophosphate crystal deposition disease (CPPD), 5 years ago

• What assessments do you want?

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Medications

• FK506 (Tacrolimus)
• Acyclovir
• Adalimumab
• Vitamin D 2000 IU/day
• Colace
• Estradiol
• Ferrous sulfate
• Lansoprazole
• Levothyroxine
• Magnesium
• Mycophenolate

Labs/Imaging

• DEXA at initial visit

– L1-L4 T=-2.1, Femur T= -1.2, Femoral neck T=-2.2 – Prior history of broken Wrist x 2; Hand x 1 within past 10 years (post transplant)

• Labs

– CBC=normal – Na=137, K=3.6. Ca=9.7, Tacrolimus=4.2 (Nl), TSH=1.6, FT4=1.37, PTH=66.5, 25 OH VitD=46.2 – Aspirate of joint fluid = CPPD crystals (not gout)

https://openi.nlm.nih.gov/detailedresult.php?img=PMC2625400_b716791a-f3&req=4

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CPPD

• Can result from hypomagnesemia (ie in short

gut or malabsorption)

– (Hahn, et al. 2012)

• Cyclosporine and FK506

– Associated with CPPD (Mg wasting) – Unclear if calcineurin inhibition contributes

• (Guerne, et al., in Gout and other Crystal Deposition

Arthropathies 2011)

• (Perez-Luiz, et al. 2002)

– Also associated with gout

• (Lin et al NEJM 1989)
• Associated with risk of osteoporosis

– (Abstract AB0895, Vladimirov, Annals of the Rheumatic Diseases 2017)

Management

• CPPD:

– Magnesium supplementation

• Mild hyperparathyroidism

– Secondary to GI calcium malabsorption – Calcium supplementation (1500 mg/day) – Maintenance of high normal VitD level – Work with GI to optimize UC management

• Transplant

– Continued immunosuppressants

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2 Years Later

• Improved DEXAs:

– L1-L4 T=-2.1, Femur T= -1.2, Femoral neck T=-2.2  – L1-L4: T=-1.9; Femur T=-0.9, Femoral Neck T=-1.8

• Cr=0.8, Mg=2.1, iCA=4.2 (normal), Ca=9.5,

Alb=4.3, TSH=3.364, CRP >0.4. PTH=112.6

– At time of labs – massive diarrhea, active UC – Returned to normal – Continues to fluctuate depending on diet, Ca compliance, and UC activity – Current PTH=42

CASE 2: KIDNEY TRANSPLANT

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Pre-transplant

• 33 yo M with chronic renal failure

– Hemodialysis x 5 years – Recent foot fracture – PTH noted to be >1500 – Ca=8; PO4 = 5; 25OH VitD=10

• Diffuse bony pain

– DEXA: L1-L4: T=-5.6, Femoral neck = -5.7

• Wants stabilization of bone disease so

he will be a candidate for transplant

Hyperparathyroidism Secondary to Renal Disease

• US/sestamibi: 4 prominent glands

– Surgical resection of 3.75 glands – PTH now 200s.

• Weight bearing exercise
• Calcium/vitamin D replacement, as

tolerated (including calcitriol)

• Considering denosumab once calcium

stabilizes (currently 6.7-7.0)

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Metabolic Bone Clinic / Institute for Human Genetics Division of Endocrinology and Metabolism University of California, San Francisco P: (415)353-2350 F: (415)353-2337 Edward.hsiao@ucsf.edu / http://www.tiny.ucsf.edu/hsiaolab

Thank you! Additional Resources

• Ebling, PR. “Transplantation

Osteoporosis.” Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. Edited by Clifford J. Rosen.