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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 6 2122-2126
Copyright © 2000 by The Endocrine Society

Special Articles

Osteoporosis: An Unusual Presentation of Childhood Crohn’s Disease1

M. Thearle, M. Horlick, J. P. Bilezikian, J. Levy, J. M. Gertner, L. S. Levine, M. Harbison, W. Berdon and S. E. Oberfield

Divisions of Pediatric Endocrinology (M.T., M.Ho., L.S.L., S.E.O.), Medicine and Pharmacology (J.P.B.), Pediatric Gastroenterology and Nutrition (J.L.), and Pediatric Radiology (W.B.), Columbia University College of Physicians and Surgeons, New York, New York 10032; and The Division of Pediatric Endocrinology (J.M.G., M.Ha.), Weill-Cornell University Medical College, New York, New York 10021

Address correspondence and requests for reprints to: Sharon E. Oberfield, M.D., Babies and Children’s Hospital of New York, Columbia University, 3959 Broadway, Box 50, New York, New York 10032. E-mail: seo8{at}columbia.edu


   Abstract
Top
 Abstract
Introduction
 Case Report
 Discussion
 References
 
Osteoporosis is known to be associated with Crohn’s disease. We report a 12-yr-old boy without a history of steroid use, in whom severe osteoporosis and multiple collapsed vertebrae were the presenting manifestations of Crohn’s disease. After treatment of the Crohn’s disease, he resumed normal growth and progressed through puberty. Concomitantly, he demonstrated a substantial recovery of vertebral bone mineral density and structure. Possible pathophysiological mechanisms underlying the osteoporosis and the subsequent improvement in bone density are discussed.


   Introduction
Top
 Abstract
 Introduction
Case Report
 Discussion
 References
 
OSTEOPOROSIS is a known extraintestinal complication of Crohn’s disease, both in children (1, 2, 3, 4, 5) and adults (6, 7, 8, 9, 10, 11, 12). The pathogenesis of decreased bone mass in Crohn’s disease is multifactorial, and the relative contribution of the primary disease process, as compared with secondary factors, has not been well defined. Corticosteroid use is often implicated as the major factor in the pathogenesis of osteopenia associated with Crohn’s disease (1, 2, 3, 5, 7, 8, 11, 13, 14). We report a pediatric patient whose extensive osteoporosis occurred before the diagnosis and treatment of Crohn’s disease, demonstrating that substantial bone loss in Crohn’s disease can occur in the absence of corticosteroid use.

Recovery from osteoporosis, in terms of increases in bone mineral density (BMD), does occur in adults (15, 16); but reconstitution of collapsed vertebrae and improvement in kyphosis, when it occurs in association with vertebral collapse, is not described. However, in children, substantial recovery of BMD, along with reconstitution of vertebral compression fractures, has been reported (17, 18, 19). The patient presented herein exhibited dramatic recovery of bone mass, restoration of vertebral height, and partial correction of kyphosis, once his underlying Crohn’s disease was treated. Potential mechanisms of bone loss and bone healing during the course of his illness are discussed in this report.


   Case Report
Top
 Abstract
 Introduction
 Case Report
Discussion
 References
 
The patient, a 12-yr-old male of Sephardic Jewish descent, presented with 2 yr of severely decreased growth velocity and 5 months of progressive nontraumatic back pain associated with 2 months of daily fevers, nausea, vomiting, and anorexia. His dietary intake was estimated to be less than 1000 calories per day. He had no abdominal pain, constipation, diarrhea, melena, or hematochezia. He was not receiving any medications, including oral or inhaled corticosteroids. There was no family history of inflammatory bowel disease (IBD) or osteoporosis. Physical examination revealed marked kyphosis, clubbing, and prepubertal genitalia. His height was 129 cm (51 in) (<<5 percentile), and his weight was 28.7 kg (63.1 lb.) (<5 percentile).

Radiographs of the spine showed diffuse osteopenia with multiple collapsed thoracic and lumbar vertebrae (T8-T11, L1-L5) (Fig. 1AGo). The kyphosis angle was 71 degrees. An upper gastrointestinal series was diagnostic of Crohn’s jejunitis with extensive nodularity, mucosal ulceration, and thickening of the jejunum; esophagoduodenogastroscopy and colonoscopy were grossly normal. Biopsies demonstrated duodenitis and gastritis; there was no active inflammation of the colon. An abdominal CT scan showed thickening of jejunal loops with enlargement of the draining mesenteric lymph nodes consistent with Crohn’s disease. Bone age was 10.5 yr. Pertinent laboratory values included an elevated erythrocyte sedimentation rate of 68 mm/h [normal (nl), <15 mm/h]; hemoglobin, 11.3 g/dL (nl, 12.3–15 g/dL) with a mean corpuscular volume of 74.8 fl (nl, 78–99 fl); calcium, 9.5 mg/dL (nl, 8.5–10.5 mg/dL); phosphorus, 5.1 (nl, 3.2–6.3 mg/dL); albumin, 3.6 g/dL (nl, 3–4.5 g/dL); and an alkaline phosphatase activity of 149 U/L (nl, 100–390 U/L). The urinary calcium-to-creatinine ratio was 0.14. The intact PTH level was 3.66 pmol/L (15 pg/mL) (nl, 2.44–15.86 pmol/L), and the urinary N-telopeptide (NTx) was 258 nmol/mmol creatinine [reference lab normal range for age, 429–902 nmol/mmol creatinine (Cr) (20)]. 1,25 dihydroxycholecalciferol was 93.6 pmol/L (39 pg/mL) (nl, 57.6–156.0 pmol/L), and 25 hydroxycholecalciferol D was 64.9 nmol/L (26 ng/mL) (nl, 42.4–134.8 nmol/L). Thyroid function tests were normal.



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  		Figure 1. A, Spinal radiograph at presentation. Note the thoracic and lumbar collapsed vertebrae (T8–T11, L1–L5). B, Spinal radiograph after 30 months of treatment. There is a striking reconstitution of the shape of the dorsolumbar vertebrae.

 
Treatment was begun with a semielemental diet (Peptamen, Clintec Nutrition Company, Deerfield, IL) containing hydrolyzed protein, maltodextrin, and a medium chain triglyceride/corn oil fat mixture plus 800 mg/L calcium and 700 mg/L phosphorus. Initial treatment also included Asacol (mesalamine 5-ASA) 800-mg bid and a multivitamin with 200 mg of calcium. During the first year of treatment, urinary calcium-to-creatinine levels were highly variable, secondary to dietary intake, but ranged from 0.07–0.43. Bone pain resolved within 3 months of initiation of therapy. 6-Mercaptopurine was added 6 months later with a maximum daily dose of 50 mg. Fifteen months after diagnosis, a therapeutic trial of 15-mg pamidronate infusions were given monthly for 4 months. Twenty four and a half months after diagnosis, three additional infusions of 30 mg of pamidronate were given at 2-week intervals (Fig. 2Go). Pamidronate was discontinued thereafter because of resulting severe abdominal pain. An abdominal CT scan, after 17 months of treatment, showed residual thickening of only a single loop of jejunum. Because of the jejunal involvement, after 17 months of treatment, Pentasa (mesalamine 5-ASA) 500-mg qid, which may be released earlier in the gastrointestinal tract, was substituted for Asacol. Budesonide (6 mg daily; Astra Zeneca, Wilmington, DE) was added 20 months after diagnosis.



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  		Figure 2. NTx and serum alkaline phosphatase activity levels over time. The boxes indicate the times of pamidronate treatment. The age at diagnosis was 12 yr. Normal NTx values were from Bollen and Eyre (20 ); 12-yr-old boy, 429–902 nmol/mmol Cr; 13-yr-old boy, 326–628 nmol/mmol Cr; 14-yr-old boy, 292–528 nmol/mmol Cr; 15-yr-old boy, 230–481 nmol/mmol Cr.

 
Fourteen months after treatment of his Crohn’s disease was initiated, the patient had progressed from prepubertal to pubertal status (Tanner Stage IV, genitalia and pubic hair). Both growth velocity (averaging 10.3 cm/yr) and weight increased significantly. After 2.5 yr of treatment, he had grown 22.9 cm (9 in) (5th–10th percentile for height) and gained 17.3 kg (38 lb.) (10th–25th percentile for weight). At age 14.3 yr, his bone age was 14 yr, yielding a predicted adult height of 163.8 cm (64.5 inches), within his target range of 158.8 cm (62.5 in) to 168.9 cm (66.5 in) [as calculated by the Roche-Wainer-Thissen method (21)].

Before treatment, initial dual-energy x-ray absorptiometry scans (DXA; Lunar Corp. DPX) demonstrated a total body BMD of 0.753 g/cm2 (Z score, -2.97), a lumbar spine BMD of 0.314 g/cm2 (Z score, -6.65) and a total leg BMD of 0.581 g/cm2. Z scores for total body and lumbar spine BMD were derived by comparing BMD measurements with age-specific reference values, as proposed by Boot et al. (22). Because BMD in a growing child does not account for changes in bone size attributable to puberty or body size (23), we also report lumbar spine bone mineral content (BMC) with Z scores that were corrected for bone area, height, weight, and pubertal level, as recommended by Warner et al. (23) for children and adolescents (Fig. 3Go). Initial lumbar spine BMC was 8.88 g (Z score, -5.22). Fifteen months after treatment for Crohn’s disease, repeat DXA studies revealed a total body BMD of 0.735 g/cm2 (Z score, -2.63), lumbar spine BMD of 0.409 g/cm2 (Z score, -3.53), lumbar spine BMC of 12.79 g (Z score, -4.49), and a total leg BMD of 0.649 g/cm2. Whole-body DXA, 30 months after the initial test, demonstrated a 5.4% increase in total body BMD, to 0.794 g/cm2 (Z score, -2.62), and a 30.8% increase in total leg BMD to 0.760 g/cm2. After 3 yr of treatment, the lumbar spine BMD had increased 69.1% over the initial value to 0.531 g/cm2 (Z score, -2.62), the lumbar spine BMC had increased 137.4%, to 21.08 g (Z score, -3.68) (Fig. 3Go); and the combined lumbar (L1–L4) vertebral height had increased from 8.88 cm to 11.40 cm.



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  		Figure 3. Bar graph of absolute BMD at the lumbar spine and Z scores for BMC corrected as per Warner et al. (23 ) over 3 yr of treatment.

 
Additionally, 30 months after treatment, a lumbar spine radiograph showed a decrease in kyphosis, to 56 degrees, and a striking reconstitution of the height of the thoracic and lumbar vertebrae, although diffuse osteopenia of the lumbar spine and pelvis persisted (Fig. 1BGo). Current treatment for the bone disease is 400 U vitamin D and 1000 mg calcium carbonate daily.

After 15 months, as BMD and growth velocity increased, both the serum alkaline phosphatase activity and urinary NTx rose to maximum levels of 410 (2.8-fold) and 1135 (4.4-fold), respectively; but then, by 30 months, they decreased to 103 and 151, respectively (Fig. 2Go). Calcium, phosphorus, PTH, 1,25 dihydroxycholecalciferol, and 25 hydroxycholecalciferol remained normal throughout his course.


   Discussion
Top
 Abstract
 Introduction
 Case Report
 Discussion
References
 
Osteopenia is associated with Crohn’s disease in childhood, with a reported prevalence as high as 41% (3). Though osteopenia has been detected at presentation of Crohn’s disease (4, 6, 9), we found no reports of the symptoms of bone loss (severe bone pain, vertebral collapse, kyphosis) as the initial presentation of Crohn’s disease. The etiology of osteoporosis in Crohn’s disease is often attributed, in large part, to corticosteroids (1, 2, 3, 5, 7, 8, 11, 13, 14); however, this patient makes it clear that substantial bone loss can occur in Crohn’s disease in the absence of corticosteroid use. His course also demonstrates the remarkable capacity of the growing skeleton to reconstitute itself, with major gains in bone mass and vertebral height. Such increases are rarely seen in the fully formed adult skeleton.

Cowan et al. (4) described a 16-yr-old boy with osteopenia when the diagnosis of Crohn’s disease was made but who did not develop symptomatic osteoporosis with vertebral compression fractures until he was treated with high-dose steroids for 3 months. In contrast, our patient’s exposure to steroids occurred 20 months after diagnosis. The severity of our patient’s osteoporosis before any steroid use suggests that primary disease factors are important in the pathophysiology of osteoporosis in Crohn’s disease.

This suggestion is supported by in vitro data demonstrating decreased dry weight and calcium content, as well as disorganized histology of fetal rat parietal bone cultured in serum from children with Crohn’s disease who had not received steroids for at least 12 months (24). These findings were attributed to an imbalance of inflammatory cytokines, which are elevated in patients with active IBD (12, 25) and are known to inhibit bone formation and enhance bone resorption (26, 27).

Other possible contributing factors to reduced bone mass in Crohn’s disease are deficiencies of calories (2, 8) or specific nutrients related to particular areas of intestinal involvement. Although, in our patient, it was difficult to assess what role, if any, specific nutrient deficiencies had in the development of osteoporosis, there has been no uniform correlation between intestinal site of Crohn’s disease and low BMD (3, 9, 11, 28). Patients with chronic IBD and caloric deficiency secondary to decreased oral intake, decreased absorption, and increased loss of nutrients (29) often have associated pubertal and growth delay (29, 30, 31, 32) with decreased insulin-like growth factor 1 (IGF1) that improves with increased caloric intake (33). IGF1 is anabolic, with respect to bone. Estrogen and testosterone are also important for normal bone mineral accumulation, as shown by the osteopenia found in estrogen (34) and androgen (35, 36) -resistant syndromes and by the late pubertal peak bone mineral accumulation that follows peak statural growth (37, 38, 39, 40). Boot et al. (2) found that decreased BMD in IBD is associated with nutritional status. Therefore, decreased caloric intake may contribute to reduced bone acquisition by causing relative growth-factor and sex-steroid deficiencies.

NTx, a measure of bone resorption, was initially low in this patient, compared with reported pediatric reference values (20), suggesting decreased age-appropriate new bone formation rather than increased bone resorption. Growth and pubertal delay alone cannot explain his severe osteoporosis, because this is not seen with either GH deficiency or constitutional delay of puberty (41). As suggested by the work of Hyams et al. (24), a process unique to Crohn’s disease may be the driving force for such osteoporosis as that seen in our patient.

The mainstay of his treatment was the semielemental diet. Improved nutrition was associated with rapid growth and progression through puberty (Tanner stage I to IV within 14 months). At the same time, he had a 2.8-fold increase of serum alkaline phosphatase followed by a 4.4-fold increase in urinary NTx (Fig. 2Go), reaching levels above published normal reference values (20). The concomitant rise of these two bone markers indicated not only rapid new bone modeling seen in a growing child but also remodeling of impoverished bone. As expected, during Pamidronate treatment, markers of bone resorption and bone formation decreased (Fig. 2Go). After Pamidronate, these markers did not return to the previous elevated levels, suggesting normalized bone dynamics with reduction of the accelerated phase of bone deposition.

The result of his rapid bone formation was a dramatic recovery in vertebral height and in bone mass (Figs. 1BGo and 3Go). We recognize the limitations of areal bone density measurement (DXA technology) in growing children and adolescents. However, this is a widely available, noninvasive, low-radiation technique that, when used in one patient over time, may be informative (42). His second DXA study demonstrated a small decrease in total body BMD, although the age-matched Z score and the other measures of BMD improved. This is likely attributable to a more rapid initial increase in bone area during his growth spurt, relative to bone mineral accretion, which occurred later (37, 43, 44). Over 3 yr, the BMD of his lumbar spine increased by 69.1%, and the BMD of his lower extremities increased by 30%. Moreover, recovery of normal vertebral shape was associated with a gain of 2.52 cm of lumbar vertebral height (L1–L4). Even more striking, his kyphosis decreased from a debilitating 71 degrees to 56 degrees. The greater involvement and improvement of his lumbar spine, as compared with his total body, suggests that trabecular bone was affected more than cortical bone.

Such dramatic reversal is rare in adults, but almost complete spinal recovery has been described after disease treatment in children with acute lymphoblastic lymphoma (17), Cushing’s syndrome (18), and idiopathic juvenile osteoporosis (19). In adults, bone density improvements have been reported in hypercalciuric, osteoporotic men treated with hydrochlorothiazide (15) and in osteitis fibrosa cystica after parathyroidectomy (16). However, in the latter study, the most marked improvements occurred in a 17-yr-old girl who probably still had potential for bone mineral acquisition (16). The ability of children, but not adults, to evince dramatic improvement of osteoporosis, vertebral collapse, and kyphosis indicates that, while bone is still in the acquisition stage, there is tremendous capacity for reconstitution.

Although deficiencies of sex steroids and growth factors may not have been the major cause of our patient’s low BMD, the surge of anabolic factors, once the Crohn’s disease was controlled, probably contributed significantly to bone recovery. A report of adult men with idiopathic osteoporosis treated with GH or IGF1 demonstrated increased rates of bone formation and resorption, although this study was not long enough to document increased BMD (45). Men with decreased bone density secondary to hypogonadotropic hypogonadism have shown increased BMD with androgen therapy (36). These increases were most pronounced in men with immature skeletons (36). In addition, PTH, an anabolic agent for cancellous bone, led to an increase in BMD in men with idiopathic osteoporosis (46). Therefore, anabolic agents can improve BMD, even in adults. However, as our patient demonstrates, the growth potential of children, combined with the high concentration of anabolic factors, allows for accelerated bone acquisition and more significant recovery after diffuse bone injury.


   Footnotes
 
1 Supported in part by NIH Grant NIH-DK-37352. Back

Received November 9, 1999.

Revised February 9, 2000.

Accepted February 29, 2000.


   References
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 Introduction
 Case Report
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals