Glucocorticoids are included in the standard immunosuppression regimen designed to prevent allograft rejection in most solid-organ transplant recipients. Cushingoid symptoms, including osteoporosis and skeletal muscle myopathy, are debilitating sequela of exogenous glucocorticoid therapy (1,2). Glucocorticoids act on bone tissue through a number of mechanisms including suppression of osteoblast function, activation of osteoclast activity, secondary hyperparathyroidism, and anabolic hormone deficiencies (1). These osteoporotic effects seem to be localized to cancellous bone found predominantly in the axial skeleton rather than cortical bone of the appendicular skeleton. Specifically, the lumbar vertebrae are particularly susceptible to glucocorticoid-induced osteoporosis with losses of 10% to 20% from pretransplant baseline recorded at only 2 months after transplantation (3–6). Accelerated bone resorption, coupled with diminished muscle strength, causes an increased incidence of vertebral compression fractures (7). Vertebral fractures are the most prevalent type of fracture in transplant recipients, representing approximately 35% of all fractures, and they can be the most debilitating and activity-restricting injuries in organ transplant recipients (7).
This study determined the therapeutic efficacy of a 6-month program of specific resistance exercise designed to reverse glucocorticoid-induced vertebral osteoporosis in lung transplant recipients (LTR). Because candidates for lung transplantation often have established osteoporosis engendered by years of glucocorticoid therapy to prevent airway inflammation (8–11), therapeutic regimens must incorporate two distinct but equally important components. Initially, antiosteoporosis therapy in LTR must attempt to inhibit further bone resorption caused by bolus glucocorticoids early in the postoperative period. Second, an efficacious antiosteoporosis therapy must also provide an osteogenic stimulus that alters the bone remodeling process to favor new bone accretion. Bisphosphonates have been used successfully to inhibit bone resorption in transplant recipients, but patients treated with these agents usually achieve only modest increases in bone mass that translate into a partial reduction of fractures (12–14). In contrast, we have demonstrated in heart transplant recipients that progressive resistance training programs, using specific rehabilitation machines that isolate the lumbar extensor muscles, are osteogenic and more effective in preventing glucocorticoid-induced osteoporosis than bisphosphonates alone (6,15). In this study, we hypothesized that the osteogenic stimulus of lumbar extensor training would effectively increase vertebral bone mineral density (BMD) in LTR who have established osteoporosis.
The descriptive characteristics of the LTR are presented in Table 1. Sixteen patients (n=16) listed with the United Network for Organ Sharing as lung transplant candidates were recruited. The indications for lung transplantation are presented in Table 2. The patients were randomly and prospectively assigned to a group that would participate in a 6-month program of resistance exercise training on a lumbar extensor machine (MedX; Ocala, FL) or to a control group that would not participate in resistance exercise training. Resistance training was initiated at 2 months after transplantation. All the LTR participated in postoperative walking programs that were comparable in intensity and duration. All subjects were receiving triple-drug immunosuppressive therapy with cyclosporine, prednisone, and azathioprine. The protocol was approved by the institutional review board for the protection of human subjects at the University of Florida College of Medicine, and all subjects provided written informed consent, before lung transplantation, to participate in the study.
LTR at our institution receive 500 mg of methylprednisolone (Solumedrol, Upjohn, Kalamazoo, MI) intravenously during the transplantation surgery and 125 mg per 12 h of methylprednisolone intravenously during the first two postoperative days. Oral prednisone (20 mg per 24 h) is initiated on the third postoperative day. The daily prednisone dose is tapered by 5 mg each 2 to 3 months during the first postoperative year in transplant recipients who remain rejection free. Thereafter, in the absence of rejection, the daily prednisone dose is decreased by 2.5 mg increments until a target dose of 5 mg per 24 h is achieved at approximately 2 years after transplantation. Episodes of acute rejection, as determined by routine surveillance biopsy, are treated with enhanced immunosuppression, including increased doses of intravenous methylprednisolone or oral prednisone.
Bone Mineral Density Measurements
BMD was assessed noninvasively using a dual-energy X-ray absorptiometer (DXA) (Lunar; GE Medical, Madison, WI). Lateral lumbar spine scans were performed with the subject lying on their left side against a cushion that kept the hips flexed at a 90 degree angle while the X-ray scanner performed a series of traverse scans at 1-cm intervals, moving from the top of the L2 vertebra to the bottom of the L3 vertebra. Quality control of the DXA machine was performed daily by scanning an anthropomorphic phantom supplied by the manufacturer. We demonstrated (16) that lumbar BMD, bone mineral content, and total body calcium measurements with this technique are highly reliable and are associated with <5% variability when subject positioning is carefully standardized.
All subjects completed a total of three DXA scans. A pretransplantation scan was performed while subjects were lung transplant candidates. The second DXA scan was performed 2 months after transplantation and just before initiation of the lumbar resistance-training program or control period. The DXA bone scans were repeated after 6 months of resistance training or control period. Thus, the final DXA scan was performed at approximately 8 months after lung transplantation.
Lumbar Strength Measurements
Maximum voluntary isometric lumbar extension strength was measured with the MedX clinical lumbar extension machine at seven positions through a 72 degrees range of motion (ROM). The seven positions measured were 0, 12, 24, 36, 48, 60, and 72 degrees of lumbar flexion. The testing positions were standardized by using an electronic goniometer interfaced to the microprocessor of the testing machine. Lumbar extension strength was measured at 2 months after transplantation and immediately after a 6-month resistance-training program or control period.
Resistance Exercise Training
The resistance-training group began supervised resistance exercise at 2 months after transplantation and continued to train for 6 months. The training regimen consisted of lumbar extensor training 1 day per week on the MedX clinical lumbar extension machine. Through pelvic stabilization using both a thigh restraint and knee restraint, the lumbar extensor muscles are effectively isolated on the MedX machine and optimally stimulated to respond to training (Fig. 1). For each training session, the subjects were required to perform one set of variable resistance lumbar extensions through a 72 degree ROM with a weight load that allowed 15 to 20 repetitions to volitional muscle fatigue. The positive (concentric) portion of the lift was completed in 2 sec, and after a brief pause (1 sec), the negative (eccentric) portion of the lift was completed in 4 sec. Progressive resistance exercise was achieved by increasing the weight by approximately 5% when 20 repetitions could be completed. All training sessions were supervised by a technician certified in the proper use of the MedX clinical lumbar extension machine.
Lumbar Spine BMD
The period of time between the pretransplantation bone scan and transplantation surgery was 16±5 weeks. Absolute values (g/cm2 of hydroxyapatite) of lumbar spine BMD in the trained and control groups are presented in Table 3. Lumbar vertebra BMD (L2-3) did not differ (P ≥0.05) between the two groups at study entry. Both the trained (0.63–0.54 g/cm2 of hydroxyapatite) and control groups (0.62–0.53 g/cm2 of hydroxyapatite) lost significant (P ≤0.05) BMD between study entry and 2 months posttransplantation and the magnitude of lumbar BMD decrease (−14.5%) early in the postoperative period was similar (P ≥0.05) in both groups. The control group experienced further significant (P ≤0.05) losses of lumbar BMD (−5.6%) between 2 and 8 months posttransplantation (0.53–0.50 g/cm2 of hydroxyapatite) and decreased to values that were 19.5% less than pretransplantation BMD. In contrast, lumbar BMD in the trained group increased significantly (+9.2%; P ≤0.05) during the 6-month program of specific lumbar extension exercises (0.54–0.60 g/cm2 of hydroxyapatite) and returned to values that were within 5% of pretransplantation BMD. Relative changes in lumbar BMD are presented in Figure 2.
Lumbar Extensor Muscle Strength
Absolute lumbar strength values are presented in Table 4. Absolute values were determined from the amount of weight lifted and expressed in kilogram per meters. The trained group increased (P ≤0.05) maximal lumbar isometric strength at all seven testing positions (degrees of lumbar flexion). In contrast, the control group experienced increases (P ≤0.05) in lumbar strength at only 48, 60, and 72 degrees of lumbar flexion. The magnitude of lumbar strength gains in the trained group at 48, 60, and 72 degrees of lumbar flexion were significantly greater (twofold; P ≤0.05) than the control group. Relative changes (%) in lumbar extensor strength during the resistance training program or control period are shown in Figure 3.
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.
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