Episodes of acute graft rejection requiring bolus glucocorticoid therapy were recorded in both groups. Each subject in the trained group experienced an average of 2.5±1.5 rejection episodes, whereas subjects in the control group experienced an average of 1.8±1.6 rejection episodes. Although individual subjects in the trained group experienced nearly one more rejection episode during the course of the study, compared with the control group, the difference in rejection episodes between groups was not statistically significant (P ≥0.05).
The principal findings of this study are twofold as follows: First, LTR lost ∼15% BMD in the clinically significant lumbar vertebra within only 2 months after transplantation. These dramatic losses in lumbar BMD early in the postoperative period occurred despite the fact that study subjects met the World Health Organization criteria (BMD ≥2.5 SD less than norm) for established osteoporosis before transplantation (1). Second, an antiosteoporosis therapeutic regimen consisting of mechanical loading was efficacious in reversing glucocorticoid-induced osteoporosis of the lumbar spine in LTR. Six months of specific resistance exercise that isolated the lumbar spine was osteogenic and restored BMD in lumbar vertebra to within 5% of pretransplantation levels. In contrast, the control group of LTR that did not participate in lumbar extensor exercise continued to lose additional lumbar BMD throughout the control period. Lumbar BMD in the control group at the conclusion of the study was 19.5% less than baseline pretransplantation levels.
There is a substantial body of evidence supporting the role of mechanical loading in the regulation of the structure and quantity of bone (17–25). However, the mechanisms by which mechanical stimulation leads to new bone formation are not completely understood. Mechanical loading results in small but measurable deformation of the bone; this is expressed as a unit called strain. Animal studies have shown that unusual strain distributions and high strains seem to be particularly osteogenic (23–25). Application to human subjects implies that strength training, instead of endurance training programs such as running, should result in the greatest increase in skeletal density.
Recent evidence indicates that osteocytes, embedded within the calcified bony matrix, are involved in the transduction of mechanical stress into a biological response (18–21). Mechanical loading induces bone deformations that generate cell responses leading to the release of paracrine and autocrine factors. Osteocytes in mechanically stimulated vertebrae, for example, express insulin-like growth factor (IGF)-I shortly after stimulation, and levels reach a peak after 6 h and persist for 1 to 2 days (18). IGF-I is one of the most abundant growth factors secreted by bone cells. It induces proliferation and differentiation in osteoblastic cells in culture, and it has anabolic actions when administered to animals. The early expression of osteocyte IGF-1 is thought to diffuse along osteocytic channels to bone surfaces where it participates in the induction of IGF-1 production in bone lining cells (18). Expression of IGF-I in bone surface cells is subsequently followed by bone surface expression of bone matrix proteins, osteocalcin, and collagen (19). These increases in gene expression are accompanied by the induction of increased numbers of osteoblasts on bone surfaces and increases in mineralizing surfaces, as measured through the use of double tetracycline labels (19).
There are limited agents available that directly promote bone formation. Although emerging bisphosphonate drugs are effective inhibitors of bone resorption, there is little chance their use will restore BMD to normal values and radically prevent the occurrence of new fracture events (26). Therefore, there is an urgent need for the development of medications or therapies that stimulate osteoblast activity to such an extent that bone density can be brought back to values observed in normal subjects.
Sodium fluoride is clearly an osteogenic agent because it activates osteoblast precursors to form new trabecular bone. Mays et al. (27) treated heart transplant recipients for 24 months with calcium and calcidiol alone or calcium plus calcidiol plus 200 mg per day of monofluorophosphate. The calcium-calcidiol group did not lose bone mass over the 24 months, but the monofluorophosphate group had increases in lumbar spine BMD of 12.5% and 29.5% at 12 and 24 months, respectively. Significant side effects occurred in 16% of patients treated with monofluorophosphate. Dosage reductions are required in renal insufficiency, making this therapy less appealing in organ transplantation (28). Clearly, more therapies that increase bone mass are needed.
Unlike most solid organ transplant groups, LTR often have established osteoporosis before transplantation (8,9,11). Antecedent osteoporosis in LTR is caused, primarily, by years of glucocorticoid therapy to prevent airway inflammation associated with respiratory diseases. Despite growing awareness of the necessity for therapeutic interventions, LTR often receive no prophylactic treatment for osteoporosis after transplantation. Indeed, calcium and vitamin D supplementation may be the only postoperative antiosteoporosis therapy at many institutions, and those agents are known to be ineffective in preventing glucocorticoid-induced osteoporosis in LTR (29). Consequently, nearly 100% of LTR have BMD levels in the lumbar vertebra that are less than the osteoporosis threshold (10). Because the vertebral bodies contain approximately 35% cancellous bone by weight and approximately 70% by surface area, which greatly exceeds the cancellous component in other bones (30), lumbar compression fracture is the most debilitating sequelae of glucocorticoid therapy, leading to a downward spiral of lower back pain, inactivity, and continued loss of bone density. Half of the vertebral compression fractures in LTR occur without specific trauma and can be attributed to low BMD (10). Moreover, vertebral osteoporosis may compromise graft function by accelerating decreases in pulmonary function through structural chest wall changes (8).
Some transplant centers presently view established osteoporosis of the axial skeleton as a contraindication for lung transplantation (31). Thus, selected end-stage lung failure patients are denied this life-extending therapy. Clearly, therapeutic interventional strategies that halt further bone resorption and stimulate new bone growth in the axial skeleton, despite immunosuppression regimens consisting of bolus glucocorticoids, are necessary to improve the prognosis for lung transplant candidates diagnosed with established osteoporosis.
The purpose of this study was to determine the therapeutic efficacy of a 6-month program of specific resistance exercise designed to reverse glucocorticoid-induced vertebral osteoporosis in a small cohort of LTR. Subjects in both the control and exercise groups lost dramatic (∼14%) amounts of BMD in the lumbar vertebra at only 2 months after transplantation. The control group lost further significant amounts of lumbar BMD between 2 and 8 months posttransplantation and decreased to values that were 19.5% less than pretransplantation levels. In contrast, lumbar BMD in the trained group increased significantly during the 6-month program of specific lumbar extension exercises and returned to values that were within 5% of pretransplantation BMD. Our data indicate that specific resistance exercise that isolates the lumbar spine is effective in reversing glucocorticoid-induced vertebral osteoporosis in LTR.
1. Lukert B. Glucocorticoid-induced osteoporosis. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego, Academic Press 1996.
2. Epstein S, Shane E. Transplantation osteoporosis. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego, Academic Press 1996.
3. Julian BA, Laskow DA, Dubovsky J, et al. Rapid loss of vertebral density after renal transplantation. N Engl J Med 1991; 325: 544–550.
4. Muchmore JS, Cooper KC, Ye Y, et al. Prevention of loss of vertebral bone density in heart transplant patients. J Heart Lung Transplant 1992; 11: 959–964.
5. Sambrook P, Birmingham J, Kelly P, et al. Prevention of corticosteroid osteoporosis: A comparison of calcium, calcitrol, and calcitonin. N Engl J Med 1993; 328: 1747–1752.
6. Braith RW, Mills RM, Welsch MA, et al. Resistance exercise training restores bone mineral density in heart transplant recipients. J Am Coll Cardiol 1996; 28: 1471–1477.
7. Shane E, Rivas MC, Silverberg SJ, et al. Osteoporosis after cardiac transplantation. Am J Med 1993; 94: 257–264.
8. Aris RM, Neuringer IP, Weiner MA, et al. Severe osteoporosis before and after lung transplantation. Chest 1996; 109: 1176–1183.
9. Ferrari S, Rizzoli R, Nicod L. Osteoporosis in patients undergoing lung transplantation. Chest 1997; 11: 257–258.
10. Schulman LL, Addesso V, Staron RB, et al. Insufficiency fractures of the sacrum: A cause of low back pain after lung transplantation. J Heart Lung Transplant 1997; 16: 1081–1085.
11. Braith RW, Gagnon SD, Musto T, et al. Resistance exercise restored bone mineral density in an osteoporotic patient before lung transplantation. J Cardiopulm Rehabil 1998; 36: 18–23.
12. Lieberman U, Weiss SR, Broll J. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995; 333: 1437–1443.
13. Black DM, Cummings SR, Karpf DB. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535–1541.
14. Braith RW, Magyari PM, Aranda JM, et al. Nasal calcitonin spray does not prevent glucocorticoid-induced vertebral osteoporosis in heart transplant recipients. J Cardiopulm Rehabil 2002; 22 ( 5): 351.
15. Braith RW, Magyari PM, Fulton MN, et al. Resistance exercise training and alendronate reverse glucocorticoid-induced osteoporosis in heart transplant recipients. J Heart Lung Transplant (in press).
16. Carpenter D, Tucci J, Pollock M, et al. Effect of repositioning on intraday reliability of lateral lumbar spine bone measurements using dual energy x-ray absorbtiometry. Med Sci Sports Exerc 1992; 24: S65.
17. Rubin CT, Lanyon LE. Regulation of bone formation by applied dynamic loads. J Bone Joint Surg Am 1984; 66: 397–402.
18. Chow JWM. Role of nitric oxide and prostaglandins in the bone formation response to mechanical loading. Exerc Sport Sci Rev 2000; 28: 185–188.
19. Lean JM, Mackay AG, Chow JWM, et al. Osteocytic expression of mRNA for c-fos and IGF-I: An immediate early gene response to an osteogenic stimulus. Am J Physiol 1996; 270: E937–E945.
20. Raab-Cullen DM, Thiede MA, Peterson DN, et al. Mechanical loading stimulates rapid changes in periosteal gene expression. Calcif Tissue Int 1994; 55: 473–478.
21. Marie PJ, Jones D, Vico L, et al. Osteobiology, strain, and microgravity. I: Studies at the cellular level. Calcif Tissue Int 2000; 67: 2–9.
22. Duncan RL, Turner CH. Mechanotransduction and the functional response of bone to mechanical strain. Calcif Tissue Int 1995; 57: 344–358.
23. Lanyon LE. Using functional loading to influence bone mass and architecture: Objectives, mechanisms, and relationship with estrogen of the mechanically adaptive process in bone. Bone 1996; 18 (Suppl): S37–S43.
24. O’Conner JA, Lanyon LE. The influence of strain rate on adaptive bone remodeling. J Biomech 1982; 15: 767–781.
25. Rubin CT, Lanyon LE. Regulation of bone mass by mechanical strain magnitude. Calcif Tissue Int 1985; 37: 411–417.
26. Russell RG, Rogers MJ, Frith JC. The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res 1999; 14: 53–65.
27. Mays E, Terreaux D, Beaume-Six T, et al. Bone loss after cardiac transplantation: Effects of calcium, calcidiol and monofluorophosphate. Osteoporos Int 1993; 3: 322–329.
28. Moe SM. The treatment of steroid-induced bone loss in transplantation. Curr Opin Nephrol Hypertens 1997; 6: 544–549.
29. De Boer WJ. Preoperative corticosteroids: A contraindication to lung transplantation. Chest 1995; 105: 1905–1908.
30. Snow-Harter C, Marcus R. Exercise, bone density and osteoporosis. Exerc Sport Sci Rev 1991; 19: 351–388.
31. Spira A, Gutierrez C, Chaparro C, et al. Osteoporosis and lung transplantation: A prospective study. Chest 2000; 117: 476–481.