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Fractures in Active Patients With Transplanted Organs

Treatment and Exercise Recommendations

Javier Maquirriain, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 29 - NO. 1 - JANUARY 2021


In Brief: A 32-year-old tennis player had a kidney-pancreas transplant about 18 months before sustaining fractures in both feet. Fractures are common medical complications in patients who receive transplanted organs, primarily because immunosuppressive therapy using glucocorticoids can lead to osteoporosis. As more transplant survivors choose active lifestyles, their physicians need to be aware of special risks inherent in this unique population and provide sport-specific recommendations for safe participation. Low-impact, noncontact sports are deemed most appropriate.

Patients with transplants who participate in sports face an increased risk of musculoskeletal complications such as fractures. Immunosuppressive therapy using glucocorticoids seems to be the main cause of osteoporosis after transplantation; however, other conditions such as renal osteodystrophy, dialysis, diabetes mellitus, and physical activity should be considered in the clinical evaluation of this population. The possible multifactorial etiology of fractures in transplant patients is exemplified in the following case of nearly simultaneous, bilateral fifth metatarsal fractures.

Case Report

History. A 32-year-old recreational tennis player experienced sudden right midfoot pain during a training session. He had had a kidney-pancreas transplant 18 months earlier as treatment for chronic diabetic nephropathy with onset at 8 years of age. Prior to the transplant, he had been on hemodialysis three times per week for 5 years. Complications after the cadaveric-donor transplant procedure included recurrent hematuria, pneumonia by Pneumocystis carinii, four rejection episodes (treated with methylprednisolone pulses), and a left wrist fracture.

Physical exam and x-ray. Tenderness over the right fifth metatarsal with localized swelling was found at initial evaluation. X-ray exam confirmed an acute fifth metatarsal fracture through a well-delineated metaphyseal-diaphyseal oblique fracture line without intramedullary sclerosis or cortical hypertrophy (figure 1A). The patient had clinically normal lower-limb alignment, and physical examination failed to disclose any joint instability or overweight.

[Figure 1]

Laboratory. Results of tests performed 1 month before the fracture are shown in table 1. Bone mineral density (BMD), determined by dual-energy x-ray absorptiometry, indicated osteopenia at the right femoral neck and lumbar spine. At the time of injury, the patient's pharmacologic therapy consisted of prednisone (14 mg/day), cyclosporin A (350 mg/day), ranitidine (300 mg/day), nifedipine (40 mg/day), trimethoprim-sulfamethoxazole (640 mg/wk to 3,200 mg/wk), elemental calcium (1,500 mg/day), vitamin D supplements (800 IU/day), and alendronate (10 mg/day).


TABLE 1. Results of Lab Tests in a 32-Year-Old Renal Transplant Patient Obtained 1 Month Before Bilateral Foot Fracture

Test Result Normal Range

Hemoglobin 15.3 g/dL 13.0-18.0 g/dL

Urea 60 mg/dL 24-49 mg/dL

Creatinine 1.4 mg/dL 0.2-0.5 mg/dL

Calcium 9.6 mg/dL 8.4-10.6 mg/dL

Phosphate 3.7 mg/dL 3.0-4.5 mg/dL

Parathyroid hormone* 215.6 pg/mL 70-125 pg/mL



Bone mineral density**

   at right femoral neck -1.6

   at lumbar spine -1.17

*Radioimmune assay for intact parathyroid

**Determined by dual-energy x-ray absorptiometry (DEXA); listed as T-score


The left foot. Two weeks later, the athlete experienced acute pain in his left foot while attempting to board a bus. An acute Jones fracture was confirmed by x-ray exam, which showed a short line involving only the lateral cortex (figure 1B).

Treatment. Initial treatment for each fracture consisted of a short, non-weight-bearing leg cast. In addition, calcitonin was prescribed at 100 U/day following the second fracture. Both casts were removed 8 weeks later, although no consistent signs of healing were seen on the radiographs. The patient reported mild discomfort only, so physical therapy was performed to improve range of motion and proprioception. He returned gradually to daily activities with no symptoms.

The patient began teaching tennis at 7 months and running at 9 months, but x-rays performed at 12 months did not show that resolution criteria had been reached. The x-rays indicated incomplete union of both fractures and medullary sclerosis (figure 2). A left hallux amputation was performed during the fracture recovery period because of chronic microangiopathy.

[Figure 2]

Discussion

Complications. Treatment of end-stage renal failure involves dialysis or transplantation. Transplant recipients are likely to sustain several medical complications. Bone quality, immunosuppressive therapy, diabetic neuropathy, and renal osteodystrophy appear of interest in the pathogenic evaluation of this case, as do sports activity and overuse.

Bone quality. Both injuries sustained by this tennis player may be considered as insufficiency fractures, defined as stress fractures in individuals suffering medical conditions in which bone is abnormal and unable to withstand normal forces (1). Skeletal problems in renal transplant recipients, accounting for 16% of overall medical complications (2), consist primarily of osteonecrosis and fractures. Fractures are more likely to affect the foot and arm (3).

Jones fracture, a metaphyseal-diaphyseal junction injury, can be classified as acute or chronic. Initial treatment of Jones fractures is still controversial, the essential choice being between operative and nonsurgical management. Although surgical intervention for certain proximal fifth metatarsal fractures may speed up recovery time, most fractures heal with immobilization. Torg et al (4) suggested that acute fractures be treated with immobilization in a non-weight-bearing cast, whereas the chronic type are most effectively treated with curettage, bone grafting, and fixation. The vascular anatomy of the fifth metatarsal plays a role in the difficult healing of this fracture because the injury location corresponds to the site where the nutrient vessels enter the medial cortex, possibly rendering it avascular.

Immunosuppressive therapy using glucocorticoids seems to be the main cause of osteoporosis after renal transplantation. Renal transplant patients exhibit increased rates of trabecular bone fractures, probably due to glucocorticoid-induced osteopenia.

Glucocorticoids exert both direct and indirect effects on bone. The direct effects include inhibiting bone formation and enhancing bone resorption. The indirect effects include decreasing intestinal calcium absorption and increasing renal excretion, among others. Therefore, at least 50% of patients on long-term glucocorticoid therapy develop osteoporosis (5).

Short-term longitudinal studies have disclosed a strong decline in BMD after transplantation (6,7), but the long-term course of BMD has yet to be investigated. The lowest mean BMD values were measured 6 to 24 months posttransplantation. There was no loss after the second posttransplant year beyond the normal age- and sex-dependent decline. Mean daily prednisone doses were significantly higher during the first 2 years posttransplant compared with the later period (7). After such time, when the prednisone dose is below a 7.5 mg/day threshold, only a moderate normal loss of BMD is apparent. The use of drugs such as cyclosporin A or azathioprine, as well as metabolic causes such as parathyroid hormone level and graft function, fails to show significant additional differences before and after the second posttransplant year.

Long-term therapy trials for preventing glucocorticoid-induced osteoporosis have not yet been conducted, but reasonable recommendations include the use of a glucocorticoid with a short half-life at the lowest possible dose, maintenance of physical activity, adequate calcium and vitamin D intake, sodium restriction and use of chlorothiazide diuretics, and gonadal hormone replacement. In refractory cases, the use of calcitonin, bisphosphonates, sodium fluoride, or estrogen replacement should be considered.

Transplant patients interested in sports competition should be monitored with BMD tests, although BMD testing is known to underestimate the fracture risk in patients receiving corticosteroids (8). With the use of corticosteroids, bone strength may not be related to bone mass as directly as it is in primary osteoporosis. Nevertheless, therapy should be chosen to minimize bone loss.

Renal osteodystrophy is the main cause of initial osteopenia, but the transplant procedure may resolve the condition. The pathogenesis of spontaneous fractures occurring in 22% of a large group of renal transplant patients was found to be related to steroid-induced osteoporosis and not to renal osteodystrophy (9).

Diabetes mellitus is associated with low bone turnover and cortical osteopenia. Combined pancreas-kidney transplantation has proven successful in the treatment of diabetic complications in patients requiring kidney transplants for renal failure. Smets et al (10) studied the incidence of fractures after successful pancreas-kidney transplantation and concluded that, contrary to the predominant trabecular bone loss expected with cortico- steroid excess, cortical bone loss was prevalent, possibly due to preexisting diabetic status and persistent hyperparathyroidism. Furthermore, stress fractures of the fifth metatarsal are commonly seen in patients with neuropathic disorders such as diabetes because of their decreased protective sensation of the foot. Diabetic transplant recipients, especially those who have undergone dialysis, are at a high risk of foot disease or injury leading to amputation (11).

Level of activity. Stress fractures have been associated with a wide spectrum of sports and physical activities. Such fractures seem more frequent in weight-bearing activities, especially when they involve a running or jumping component. However, scanty epidemiologic data render it troublesome to compare the incidence of stress fracture in various sports or to identify the activity posing the greatest risk. Tennis and ballet have been mentioned as posing the greatest risk of fifth metatarsal stress fracture (12). Overuse sports injuries are more common during peak-performance training.

Renal transplant patients have achieved a better quality of life during the last few years, and their sports participation has increased significantly. Today, physical activity is considered essential for the well-being of transplanted organs and thus for the recipient. Originally, athletes with transplants were kidney recipients who competed on a recreational level; however, gradually the recipients of other organs (heart, liver, lung, bone marrow) were admitted to competitive events, which has meant a larger number of participants and a higher level of performance.

The level of performance is also affected by the particular kind of grafting. Most kidney and liver transplant recipients are able to regain their former physical condition, but this is not true for heart and lung transplant subjects. The latter continue to be affected by heart denervation and altered lung function, which often keeps them out of competition.

Recommendations

Preventive medical therapy and follow-up measures as well as sport-specific recommendations are needed to allow transplant patients safe athletic participation. Until reliable clinical and epidemiologic studies are performed, low-impact, recreational, noncontact sports are recommended, and high-level competition by transplant patients should be discouraged.

References

  1. Markey KL: Stress fractures. Clin Sports Med 120217;6(2):405-425
  2. Nixon JE, Hughes SP, Castro JE: Orthopaedic complications of renal transplantation. J Bone Joint Surg (Br) 120210;62(4):526
  3. Ramsey-Goldman R, Dunn JE, Dunlop DD, et al: Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res 1999;14(3):456-463
  4. Torg JS, Balduini FC, Zelko RR, et al: Fractures of the base of the fifth metatarsal distal to the tuberosity: classification and guidelines for non-surgical and surgical management. J Bone Joint Surg (Am) 120214;66(2):209-214
  5. Lukert BP, Raisz LG: Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990;112(5):352-364
  6. Grotz WH, Mundinger FA, Gugel B, et al: Bone mineral density after kidney transplantation: a cross-sectional study in 190 graft recipients up to 20 years after transplantation. Transplantation 1995;59(7):20212-20216
  7. Horber FF, Casez JP, Steiger U, et al: Changes in bone mass early after kidney transplantation. J Bone Miner Res 1994;9(1):1-9
  8. Adachi JD, Olszynski WP, Hanley DA, et al: Management of corticosteroid-induced osteoporosis. Semin Arthritis Rheum 2021;29(4):228-251
  9. Takeo Y, Tominaga K, Tsuji H, et al: Spontaneous fracture and osteoporosis following renal transplantation, abstracted (in Japanese). Nippon Seikeigeka Gakkai Zasshi 120219;63(5):507-513
  10. Smets YF, van der Pijl JW, de Fijter JW, et al: Low bone mass and high incidence of fractures after successful simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant 192021;13(5):1250-1255
  11. Kalker AJ, Pirsch JD, Heisey D, et al: Foot problems in the diabetic transplant recipient. Clin Transplant 1996;10(6 pt 1):503-510
  12. Brukner PD, Khan KM: Clinical Sports Medicine. Sydney, Australia, McGraw-Hill, 1993, p 17

Dr Maquirriain is a surgeon in the orthopedic department at Centro Nacional de Alto Rendimiento Deportivo in Buenos Aires, Argentina. Address correspondence to Javier Maquirriain, MD, Centro Nacional de Alto Rendimiento Deportivo, Orthopedic Dept, Simbron 2958, Capital Federal 1417, Argentina; e-mail to [email protected].


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