Lucarelli, Sandra*; Borrelli, Osvaldo*; Paganelli, Massimiliano*; Capocaccia, Paolo†; Frediani, Tullio‡; Ferri, Federica*; Cucchiara, Salvatore*
*Pediatric Gastroenterology Division, †Pediatric Radiology Division, and ‡Pediatric Allergology and Immunology Division, "La Sapienza" University of Rome, Italy
Received July 28, 2005; accepted March 29, 2006.
Address correspondence and reprint requests to Sandra Lucarelli, MD, Department of Pediatrics, Division of Pediatric Gastroenterology, University of Rome "La Sapienza," Viale Regina Elena 324, Rome 00161, Italy (e-mail: firstname.lastname@example.org).
Increased risk of osteoporosis and fractures has been reported in patients with inflammatory bowel disease (IBD) primarily because of the inflammatory process itself and corticosteroid therapy (1,2). Vertebral fractures (VF) have rarely been reported in children with IBD, and only in the case of Crohn disease (CD) (3). We describe a case of vertebral compression fractures complicating the course of ulcerative colitis (UC) in a 7-year-old girl with increased sensitivity to corticosteroids.
A 7-year-old girl with a 13-month-long history of relapsing UC was referred to our unit for severe back pain associated with weakness and functional limitation of the lower limbs beginning 1 month before admission. The patient had undergone three 2-month cycles of oral corticosteroid therapy (dosage, 2 mg/kg/day) alternated with 5-aminosalicylates and salazopirin from the onset of the illness up to the time of our initial examination, but without achieving any lasting remission of the symptoms. One month before our first examination, during admission to a different hospital center, a radiographic result of the lumbar spine proved normal, and electromyography revealed features attributed to a nonspecific polyradiculopathy. There were marked Cushing-like features and severe back pain in the lumbar region. The lower limbs were hypotonic and extremely weak, and stretch tendon reflexes were absent. The girl was confined to bed and could not move her legs. The Babinski sign was present bilaterally.
The girl also complained of bloody stools, tenesmus and abdominal pain. Colonoscopy revealed active diffuse UC. The medication used on admission was 40 mg/d of methylprednisolone. Azathioprine (dosage, 50 mg/d) and sulfasalazine (dosage, 2.5 g/d) were introduced and the use of corticosteroids tapered. Although there was slow improvement regarding the abdominal complaints, the back pain was unchanged. Antibiotics were administered on day 18 because of fever and pulmonary opacity revealed by a radiograph of the chest. As the back pain persisted, another radiograph of the lumbar spine was performed, which revealed multiple vertebral compression fractures (Fig. 1). Osteoporosis was suspected because of the IBD and corticosteroid therapy. A dual-energy x-ray absorptiometry scan of the lumbar spine was performed, revealing a severe reduction in bone mineral density (BMD; z score, −3.5 SD). The corticosteroid dosage of 2 mg/kg/day, which is typical for pediatric patients with IBD, was not to account for the severity of the clinical conditions, even in view of the duration of the treatment. This suggested the possibility of increased sensitivity to corticosteroids. A study of glucocorticoid cytotoxicity was thus carried out on lymphocytes from the patient with the use of dexamethasone and methylprednisolone. The concentration of the drug with a lethal effect on 50% of the cells proved much lower in both cases than with the controls (dexamethasone, 0.251 mmol/L, vs controls, 0.8 ± 0.15 mmol/L; methylprednisolone, 0.691 mmol/L, vs controls, 1.1 ± 0.2 mmol/L). The girl refused an orthopedic corset because of pain, and physical, manual or exercise therapies were precluded because of low compliance. A slow intravenous infusion of pamidronate (dose, 1 mg/kg) was therefore administered 2 weeks after admission for 3 consecutive days. There were no adverse effects during the first day, and then a slight temperature and headache, which disappeared with acetaminophen, on the second and third days. Intravenous pamidronate was preferred to oral alendronate; oral alendronate is not recommended for recumbent patients because of severe esophageal adverse effects. Treatment was also commenced with calcium (dosage, 1 g/d) and 25-OH-D3 (dosage, 30 μg/d) per os.
The back pain began to improve 10 days after starting infusion. Four days later, the patient started to move her legs and accepted the corset. Five days later, she was able to remain in an almost seated position; 1 week later, she could use a wheelchair with no pain. She was then referred to the rehabilitation unit, where she stayed for 1 month. The girl was then readmitted to our unit. She could walk and had no back pain at all. Slight tenderness was noted on compression of the lumbar vertebrae. Ulcerative colitis was in remission. She was discharged with a prescription of sulfasalazine, azathioprine, oral calcium and vitamin D. Three months after treatment with pamidronate, she exhibited no difficulties in locomotion and no trace of the back pain and intestinal symptoms. A second dual-energy x-ray absorptiometry scan revealed a 30.5% increase in BMD (z score, −2.3), and a spine x-ray showed improved mineralization with sclerosis of vertebral bodies (Fig. 2). A course of oral alendronate (dosage, 5 mg/d) was planned for 3 months. She was discharged after 5 days.
Low BMD is a widely recognized complication of IBD in both adults and children (1). The estimated prevalence of low BMD in IBD varies greatly among the studies, ranging from 5% to 70%, in relation to the definition used, the methods of assessing BMD and the nature of the study population (5-7). Frank osteoporosis is observed in approximately 15% of patients (8). The prevalence of low BMD in children with IBD is reported to be as high as 70% (5).
Reduced BMD in patients with IBD is multifactorial and thought to result from vitamin D deficiency, malabsorption, restriction diets and the inflammatory process itself (1,2), whereas conflicting data have been reported on the effects of corticosteroid therapy (9,10). Other variables, such as genetic predisposition, reduced physical activity, growth failure and alteration of sex hormones, have been implicated in the occurrence of BMD reduction in patients with IBD (4).
The patient, on admission to our unit, exhibited severe back pain with functional limitation and negative emotional impact, and was found to have severe osteoporosis and VF. Severe osteoporosis and VF are the most commonly reported pathological fractures from osteoporosis in patients with IBD and have been mainly described in adult patients with CD, with a prevalence of 22% (11). Their association with UC is not as well documented (7,12). Vertebral fractures have rarely been described in pediatric patients with IBD, and only in children with CD (8,11). Attention has been given to the increased duration of systemic corticosteroid use and higher daily doses among the various risk factors for the occurrence of fractures in patients with IBD and osteoporosis (10). The patient was subjected to three 2-month-long cycles of oral corticosteroid therapy during the 13 months between the onset of the illness and the time of our examination. The dose administered was not, however, sufficient to account for the onset of severe osteoporosis with multiple fractures. The hypothesis of increased individual sensitivity to corticosteroids was borne out by laboratory tests.
The patient's VF healed after the administration of intravenous pamidronate, and full locomotion was recovered in a few weeks. No significant adverse effects were observed after the use of the drug. Antiresorptive agents, such as bisphosphonates (including alendronate and pamidronate), are frequently used in adults with osteoporosis of different etiology. These drugs irreversibly inhibit bone resorption by becoming incorporated into the mineralized bone matrix, especially at the sites of osteoclastic activity. Their use in pediatrics is, however, still rare and debated because there is no evidence for their efficacy and long-term effect in children. They are mostly used for osteogenesis imperfecta, in which they serve to reduce fracture frequency and improve bone mass and locomotion (13-15). To the best of our knowledge, there have been no reports on the use of bisphosphonate in children with osteoporosis and IBD.
Our case shows that bisphosphonates can be suggested as treatment for the critical reduction in BMD in children with IBD, particularly if osteoporosis is complicated by fractures. Controlled trials with these drugs in this population are therefore warranted. It also provides further proof that BMD evaluation is warranted in every patient with IBD and that spinal radiography should be performed in the presence of low BMD and clinical symptoms such as back pain. At the same time, it bears out the view that although corticosteroids do not seem to alter the course of IBD (16), their use may be associated with troublesome and dangerous complications, especially when there is increased sensitivity to these drugs.
The authors are grateful to I. Drigo, MD, Biomedical Sciences Department, University of Trieste, Italy, for laboratory support with the glucocorticoid cytotoxic test.
1. Abreu MT, Geller JL, Vasiliauskas EA, et al. Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease. J Clin Gastroenterol
2. Fuller K, Murphy C, Kirstein B, et al. TNF alpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology
3. Semeao EJ, Stallings VA, Peck SN, et al. Vertebral compression fractures in pediatric patients with Crohn's disease. Gastroenterology
4. Harpavat M, Keljo DJ. Perspectives on osteoporosis in pediatric inflammatory bowel disease. Curr Gastroenterol Rep
5. Bernstein CN, Blanchard JF, Leslie W, et al. The incidence of fracture among patients with inflammatory bowel disease: a population-based cohort study. Ann Intern Med
6. Loftus EV, Crowson CS, Sandborn WJ, et al. Long-term fracture risk in patients with Crohn's disease: a population-based study in Olmsted County, Minnesota. Gastroenterology
7. Vestergaard P, Krogh K, Rejnmark L, et al. Fracture risk is increased in Crohn's disease, but not in ulcerative colitis. Gut
8. Gokhale R, Favus M, Karrison T, et al. Bone mineral density assessment in children with inflammatory bowel disease. Gastroenterology
9. Bernstein CN, Blanchard JF, Metge C, et al. The association between corticosteroid use and development of fractures among IBD patients in a population-based database. Am J Gastroenterol
10. Leonard MB, Feldman HI, Shults J, et al. Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephritic syndrome. N Engl J Med
11. Klaus J, Armbrecht G, Steinkamp M, et al. High prevalence of osteoporotic vertebral fractures in patients with Crohn's disease. Gut
12. Loftus EV, Achenbach SJ, Sandborn WJ, et al. Risk of fractures in ulcerative colitis: a population-based study in Olmsted County, Minnesota. Clin Gastroenterol Hepatol
13. Steelman J, Zeitler P. Treatment of symptomatic pediatric osteoporosis with cyclic single-day intravenous pamidronate infusions. J Pediatr
14. Noguera A, Ros JB, Pavia C, et al. Bisphosphonates, a new treatment for glucocorticoid-induced osteoporosis in children. J Pediatr Endocrinol Metab
15. Srivastava T, Alon US. The role of bisphosphonates in diseases of childhood. Eur J Pediatr
16. Kim SC, Ferry GD. Inflammatory bowel diseases in pediatric and adolescent patients: clinical, therapeutic, and psychosocial considerations. Gastroenterology
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