Session Information
Date: Sunday, November 13, 2016
Title: Osteoporosis and Metabolic Bone Disease – Clinical Aspects and Pathogenesis - Poster
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Transplants increase risk of bone loss and fractures and reduce quality of life. Information on fracture incidence is important when making clinical decisions about initiating anti-osteoporotic treatment and when assessing treatment success. No existing fracture assessment tool accounts for the additional risk transplant patients may experience over time. With this study, we aimed to estimate fracture incidence rates in transplant patients and present them in a uniform way, which could aid clinicians in making personalized patient care decisions.
Methods: We searched MEDLINE and PubMed from inception to May 2016 for all observational studies and randomized controlled trials (RCTs) involving solid organ transplant recipients and reporting on osteoporotic fractures. We included RCT data from groups which received no anti-osteoporotic treatment or were treated with calcium and vitamin D. Studies involving >50% bisphosphonate users were excluded. Two independent reviewers extracted data on hip, vertebral (morphometric /clinical), non-vertebral, and total fractures. We calculated fracture incidence rates per 1000 patient-years (PY) for each study and combined them using a random effects meta-analysis model.
Results: We included 42 studies (N=280,066, 99% were kidney transplant) (Table 1). Time since transplantation varied across studies (3 months-11.5 years; median 1 year). A majority of transplant recipients were started on pulse IV steroids, followed by high dose oral corticosteroids, which were tapered within 3-6 months. Most incident fractures were reported within one year post-transplant across all studies. Kidney transplant recipients experienced high risk of hip fracture (4 per 1000 PY) (Table 2). We also found a very high risk of vertebral (morphometric/clinical) fracture (81 per 1000 PY) in heart transplant recipients. Liver transplant recipients experienced high risks of vertebral and non-vertebral fractures (86 and 31 per 1000 PY, respectively).
Conclusion: This study found a high fracture risk in transplant recipients, especially within the first post-transplant year. Our results will support informed decision-making regarding anti-osteoporotic treatment and will aid policy makers in formulating standards of care. Current evidence is heterogeneous in terms of variables such as patient characteristics and follow-up. Researchers studying post-transplant care should aim for a homogeneous study design, which will enable precise estimation of fracture rates and treatment effects, as well as investigation of factors relating to variability in fracture risk among transplant recipients.
| Table 1: Patient Characteristics | |||||||
| Author, year | N of patients, Female (%) | Mean age, years | Steroid regimen | Other Immunosuppressant use | Calcium and Vitamin D use | Bisphosphonate use (%) | Mean time from transplant, years |
|
Kidney |
|||||||
| Akaberi, 2008 | 238; 38.7 | 51 | Steroids in 98%; median long-term prednisolone dose 5 mg | Cyclosporine in 82%, Tacrolimus in 14% | Calcium and Vitamin D supplementation in 73.8% | 12.8 | Median 3.5 |
| Ball, 2002 | 59,944; 39.2 | 42% <40, 38% 40-54 | ND | ND | ND | ND | ND |
| Durieux, 2002 | 59; 45.8 | 49.6 | Prednisone 20 mg/day, tapered to 10 mg/day by 4-6 months after transplant; mean cumulative dose 37.7g | Azathioprine 92%, Cyclosporine 46% | ND (not excluded; mean dietary Calcium intake 906 mg) | 0 | 8.5 |
| Grotz, 1994 | 100; 46 | 44 | ND | ND | 0% for Vitamin D, 6% took Calcium (500 mg/day) | ND | 5.25 |
| Marcen, 2007 | 40; 40 | 41.8 | Prednisone in 100% | Cyclosporine | ND | ND | 10.8 |
| Nair, 2014 | 69,740; 39 | 51 | Steroids in 91% | Cyclosporine: 26% Tacrolimus: 64%, Mofetil Mycophenolate: 82% | ND | ND | 2.2 |
| Nikkel, 2009 | 68,814; 39.7 | 43.6 | ND | ND | ND | ND | 5 |
| Nikkel, 2012 | 77,430; 39.7 | 49.0 | Compared patients with (n=11,164) and without (n=66,266) early corticosteroid withdrawal | ND | ND | ND | 4 |
| Pichette, 1996 | 70; 34.3 | 46.1 | Prednisone mean dose 0.19 mg/kg every other day or 0.11 mg/kg/day | Cyclosporine or Azathioprine | Vitamin D in 26% and Vitamin D and Calcium in 16% | ND | 8.1 |
| Vautour, 2004 | 86; 31 | 38.3 | Steroids in 100% | Cyclosporine, Tacrolimus, or Azathioprine | ND | ND | Median 10.6 |
| Coco, 2012 (RCT) | 22; 28 | 48 | All patients received prednisone 20 mg/day tapered to 5 mg/day by 90 days post-transplant | Tacrolimus (or Cyclosporine, <10% patients), Rapamycin, and Mofetil Mycophenolate | Calcium (as needed) and Calcitriol (0. 25 μg/day) |
0 (Patients received an oral placebo) | Immediately post-transplant, 1 year follow-up |
| Cueto-Manzano, 2000 (RCT) | 30; 47 | 48 | All patients received prednisone 20 mg/day for 90 days tapered to 5-10 mg/day (mean dose 6.1 mg/day for Calcium and D patients and 4.6 mg/day for Control patients) | Cyclosporine: 43% Azathioprine: 40% Cyclosporine and Azathioprine: 17% | Calcium (500 mg/day) and Calcitriol (0.25 μg/day) in 53% of patients | 0 | 10.5 |
| De Sevaux, 2002 (RCT) | 111; 41 | 47 | 100 mg/day IV prednisone for first 3 days post-transplant, 0.35 mg/kg/day for the first month, then tapered to 0.10 mg/kg/day at 3 months (mean daily dose 7.2 mg) | Cyclosporine (or Azathioprine for select patients) and Mofetil Mycophenolate | Calcium (1000 mg/day) and Alfacalcidol (0.25 μg/day) in 41% of patients | 0 | Immediately post-transplant, 6 month follow-up |
| Smerud, 2012 (RCT) | 63; 19 | 52.6 | All patients received prednisolone. Mean cumulative dose over one year: 5,315 mg | Cyclosporine or Tacrolimus and Mofetil Mycophenolate | Calcium (500 mg twice a day) and Calcitriol (0.25 μg/day) | 0 (Patients received an IV placebo) | 0.051 |
| Torregrosa, 2007 (RCT) | 45; 51 | 55 | All patients received prednisone: 5-7.5 mg/day | Cyclosporine or Tacrolimus with or w/o Mofetil Mycophenolate | Calcium (2500 mg/day) and Vitamin D (800 IU/day) | 0 | 1.75 |
| Torregrosa, 2010 (RCT) | 49; 29 | 50.7 | 500 mg/day immediately post-transplant; then 1 mg/kg/day tapered to 10 mg/day over 1 month, then to 5 mg/day from 3 to 12 months | Tacrolimus with or w/o Mofetil Mycophenolate | Calcium (1500 mg/day) and Vitamin D (400 IU/day) | 0 | Immediately post-transplant, 1 year follow-up |
| Trabulus, 2009 (RCT) | 21; 38 | 33.9 | Mean cumulative dose of 13.6 g | Cyclosporine or Tacrolimus with Azathioprine or Mofetil Mycophenolate | Calcium (1000 mg/day) and Alfacalcidol (0.5 μg/day) | 0 | 3.11 |
|
Liver |
|||||||
| Eastell, 1991 | 20; 100 | ND | ND | ND | ND | ND | 2 |
| Giuchelaar, 2007 | 360; 61 | 49.54 | All patients received prednisone; mean dose in fractured patients (4 months post-transplant)= 45.7mg/day | Tacrolimus or Cyclosporine with or w/o Azathioprine or Mofetil Mycophenolate | 1.5g Cal/day with Vitamin D supplements | 4.4 | 5.3 |
| Krol, 2014 | 201; 29 | 53 (median) | IV MP 500mg given peri-operatively, then oral GC 20mg/day for 1 week, 10mg/day for 3 months, tapered to discontinue 3-6 months post-transplant. Maintenance= 2.5-10 mg/day. | Cyclosporine or Tacrolimus, with or w/o Mofetil Mycophenolate or Sirolimus | Calcium (500 mg/day) and Vitamin D (400 IU/day) | Patients taking bisphosphonate at baseline or initiating bisphosphonate during study (32%) were excluded | 1 |
| Leidig-Bruckner, 2001 | 130; 42 | 44.9 | ND | Tacrolimus: 15% Cyclosporine and Azathioprine: 68% | Calcium and Vitamin D supplementation in 77% | 0 | 3.3 |
| Monegal 2001 | 45; 36 | 50.8 | 1 g of IV MP, tapered to 20 mg/day of prednisone after the first week, 15 mg after 2 months. | Cyclosporine and Azathioprine | Dietary Calcium intake of 1000 mg/day recommended, not enforced or supplemented | 0 | 3 |
| Ninkovic, 2002 | 37; 46 | 51.3 | 10mg/kg IV MP, then oral GC 1mg/kg/day tapered to max 30 mg/day at 1 month and 5-10 mg/day at 3 months | Cyclosporine | ND | ND | 0.25 |
| Premaor, 2011 | 531; 38.4 | 51.7 | Pulse MP in 20.3%; Presdnisolone in 97.8%, with a median regimen duration of 3 months | Tacrolimus: 90.7% Azathioprine: 92.8% Sirolimus: 25.9% Mofetil Mycophenolate: 11.4% | Calcium and Vitamin D supplementation in 37.8% | 27 | 5.12 |
| Atamaz, 2006 (RCT) | 49; 26.5 | 45 | 500 mg IV prednisone peri-operatively, then 100 mg/day tapered to 20 mg over 8 days, further tapered from 20 mg to 10 mg/day over 2 months, ultimately discontinued between 6-12 months | Cyclosporine or Tacrolimus | Calcium (1000 mg/day) and Calcitriol (0.25 μg/day) | 0 | Immediately post-transplant, 2 year follow-up |
| Bodingbauer, 2007 (RCT) | 49; 24. 5 |
52 | 40 mg dexamethasone on the day of transplant, tapered to 4 mg/day by day 5, then substituted with 20 mg methylprednisolone per day, discontinued within 3 months | Cyclosporine: 63.6% Tacrolimus: 36.4% | Calcium (1000 mg/day) and Vitamin D (800 IU/day) | 0 | Immediately post-transplant, 2 year follow-up |
| Crawford, 2006 (RCT) | 30; 23 | 49 | 500 mg IV MP on day 1, then 20 mg prednisone/day by day 12. Mean daily prednisone dose was 16.4 mg/day at 1 month, tapered to 9.5 mg/day by 3 months, and tapered to 3.8 mg/day by month 12 | Cyclosporine or Tacrolimus and Azathioprine | Calcium (600 mg/day) and Vitamin D (1000 IU/day) | 0 (Patients received an IV placebo) | Immediately post-transplant, 1 year follow-up |
| Guadalix, 2011 (RCT) | 44; 14 | 54.6 | 500 mg IV MP peri-operatively, then 20 mg prednisone/day, tapered to withdrawal after 3 months | Tacrolimus (Cyclosporine or Mofetil Mycophenolate in select patients) | Calcium (1000 mg/day) and Vitamin D (800 IU/day) | 0 | Immediately post-transplant, 1 year follow-up |
| Kaemmerer, 2010 (RCT) | 40; 30 | 50.9 | 500 mg IV MP peri-operatively, then tapered based on body weight. Mean cumulative dose after 12 months: 2,426 mg | Cyclosporine, Mofetil Mycophenolate, and Anti-thymocyte globulin | Calcium (1000 mg/day) and Vitamin D (800-1000 IU/day) | 0 | Immediately post-transplant, 2 year follow-up |
|
Heart |
|||||||
| Dalle Carbonare, 2011 | 180; 13 | 53.2 | Steroids 100%; mean dose 15.3 mg/day; in 40% mean cumulative dose ≥10 g | Cyclosporine and Azathioprine | No Calcium/Vitamin D supplementation. Mean daily Calcium intake =887.5 mg | 0 | 3.91 |
| Glendenning, 1999 | 32; 15.6 | 50 | 87.5% receiving steroids; 5-15 mg/day | Cyclosporine and Azathioprine | 2 patients were taking Calcium/Vitamin D or estrogen supplementation | ND | Median 2.58 |
| Hariman, 2014 | 105; 16 | 55.5 (median, non-fracture); 61 (median, fracture) | 68.6% receiving steroids | ND | Calcium and Vitamin D supplementation in 89% | 40 | 1-5 |
| Lee, 1994 | 31; 0 | 56 | 500 mg peri-operatively, 3 doses 125 mg every 8 hours, then tapered to 30 mg/day. Reduced to 5-10 mg/day by 6 months. Mean cumulative dose 6.8 g | Cyclosporine and Azathioprine | Calcium (1000 mg) and Vitamin D (250 IU) per day | ND | 2.17 |
| Leidig-Bruckner, 2001 | 105; 16 | 51.4 | ND | Cyclosporine | Calcium and Vitamin D supplementation in 94% | 0 | 3.7 |
| Shane, 1993 | 40; 25 | 52 | Mean 9.7 mg/day; mean cumulative dose 11.3 g | Cyclosporine | Cal (1000mg/day) and Vitamin D (50,000 IU/week) in 95% | ND | 2.33 |
| Shane, 1996 | 47; 28 | ND | ND | ND | Calcium (1000mg/day and Vitamin D (400 IU/day) | ND | 1 |
| Fahrleitner-Pammer, 2009 (RCT) | 17; 0 | 43.4 | IV MP 1 g at the time of transplantation, then 750 mg on day 1 post-transplant, followed by oral prednisolone starting at 15 mg/day for 6 months, tapered until a lifetime maintenance dose of 5 mg/day was reached | Cyclosporine and Mofetil Mycophenolate | Calcium (500 mg/day) and Vitamin D (400 IU/day) | 0 (Patients received an IV placebo) | Immediately post-transplant, 1 year follow-up |
|
Lung |
|||||||
| Aris, 1996 | 45; 53 | 35 | Prednisone started 0.5 mg/kg decreased to 15 mg every other day by 7months | Cyclosporine . | Calcium (1200 mg/day) and Ergocalciferol (800 IU/day) | ND | ND |
| Ferrari, 1996 | 14; 57 | 47 | Prednisone 0.2 mg/kg/day for 1 week, 0.5 mg/kg/ per day for 3 months, then taper to 0.2 mg/kg/day | Cyclosporine and Azathioprine | Calcium (1000mg/day) and Vitamin D (1000 IU/day) | 0 | 1 |
| Hariman, 2014 | 210; 48 | 56 (median, non-fracture); 58 (median, fracture) | 91% receiving steroids | ND | Calcium and Vitamin D supplementation in 91% | 50 | 1-5 |
| Spira, 2000 | 28; 43 | 53.5 (median) | IV MP 500 mg pre-transplant, followed by 0.5 mg/kg/day for the first 4 days. Day 4 post-transplant, prednisone 40 mg/day, tapered to 5 mg every 5 days until a dose of 20 mg during first 3 months | Cyclosporine and Azathioprine | Calcium and Vitamin D supplementation in 100% | 0 | 1 |
| ND= No data; RCT= Randomized Controlled Trial; IV= Intravenous administration; IU= International Units; MP= Methylprednisolone; GC= Glucocorticoid | |||||||
| Table 2: Incidence of Fractures in Transplant Patients per 1000 Patient-years (95%CI) | |||||
| Median age, years | % Female, median | Hip Fracture | Vertebral Fracture | Non-Vertebral Fracture | Total Fracture |
|
Heart Transplant (8 Observational Studies, 1 RCT*, 1001 Patients) |
|||||
|
53 |
16 |
3 (-28 to 33) |
81 (57 to 106) |
10 (-15 to 35) |
85 (57 to 114) |
|
Kidney Transplant (10 Observational Studies, 9 RCTs*, 276,851 Patients) |
|||||
|
46 |
40 |
4 (1 to 7) |
13 (8 to 18) |
38 (28 to 47) |
41 (37 to 45) |
|
Lung Transplant (4 Observational Studies, 327 Patients) |
|||||
|
47 |
50 |
4 (-167 to 175) |
87 (-22 to 196) |
68 (-43 to 179) |
126 (2 to 250) |
|
Liver Transplant (7 Observational Studies, 5 RCTs*, 1,887 Patients) |
|||||
|
51 |
33 |
10 (-22 to 41) |
86 (62 to 111) |
31 (10 to 52) |
107 (80 to 133) |
| Statistically significant results are shown in bold. 95% CI= 95% Confidence Interval *Randomized trial data was included only from study arms in which patients were receiving either no anti-osteoporotic treatment or were treated with Calcium and Vitamin D alone | |||||
To cite this abstract in AMA style:
Bannuru RR, Vaysbrot E, Osani M, Buckley L, Fink H, McAlindon TE. Fracture Incidence Rates in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/fracture-incidence-rates-in-solid-organ-transplant-recipients-a-systematic-review-and-meta-analysis/. Accessed .« Back to 2016 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/fracture-incidence-rates-in-solid-organ-transplant-recipients-a-systematic-review-and-meta-analysis/