Regional enteritis

ABSTRACT. Background: Low bone mineral density (BMD) is commonly reported in patients receiving home parenteral nutrition (HPN), but it remains unclear whether or not an accelerated bone loss occurs during HPN therapy. We evaluated the spinal, hip, and forearm bone mass density longitudinally in a cohort of 75 patients receiving HPN. Methods: A total of 943 regional dual-energy x-ray absorptiometry scans, 335 spinal, 318 hip, and 290 forearm, obtained between 1995 and 2003 in 75 patients receiving HPN, were used for the analysis of the annual changes in BMD. The average (SD) number of scans per patients was 4.4 (2.9), and follow-up time was 4.1 (1.9) years. Diagnoses were Crohn's disease (n = 35) and other conditions (non-Crohn's diseases; n = 40). Data were analyzed using a linear random coefficient model. Results: There was a statistically significant overall decline over time in spinal, hip, and forearm BMD, corresponding roughly to a 1% annual loss (p

Long-term parenteral nutrition self-administered in the home (HPN) has proved to be lifesaving for patients unable to manage on enteral feeding alone. The majority of patients with nonmalignant diseases requiring HPN had Crohn's disease, ischemic bowel infarction, radiation enteritis, abnormal gut motility, or complications after surgery. In these patients, a high prevalence of metabolic bone disease has been reported in several cross-sectional studies, either documented as histologic features of bone disease1-3 or as a diminished bone mineral density (BMD).4-11 Although some of the metabolic bone disease that is noted may be related to the patient's underlying illness and already present before entering the HPN program, longitudinal studies have shown that an accelerated bone loss occurs during HPN therapy, and mean rates of decline in BMD have been reported to be as high as 5% per year.7-11 However, these studies included only a small number of patients and data were not systematically adjusted data for the effect of age and sex, which is critical in assessing the true magnitude of bone loss associated with HPN therapy.

The current study was undertaken to characterize the annual changes in spine, hip, and forearm BMD in a large group of patients receiving HPN and to compare annual changes with that of age- and sex-matched healthy individuals. In addition, we investigated the effect of the diagnosis of the patients on bone health during HPN treatment.

MATERIAL AND METHODS

Patients

Since 1995, measurements of BMD by dual-energy x-ray absorptiometry (DXA) were routinely done at 1to 2-year intervals in the majority of our HPN patients. For this study, patients with nonmalignant diseases were selected from the register if they had received permanent HPN for more than 1 year and had at least 2 previous BMD scans with a follow-up period of more than 1 year. From a cohort of 160 HPN patients who had received HPN treatment during the period 1995 to 2002, 75 patients fulfilled the criteria and were included in the analysis. In 63 patients, the reason for exclusion was that the length of the period of receiving HPN was less than 1 year; of these, 22 died, 19 were weaned of HPN, and 2 moved to another HPN center. Twenty-two patients had been receiving HPN therapy for more than 1 year but had either never been scanned (n = 7) or had been scanned only once (n = 15). Data on the following clinical parameters were drawn from the case records and included sex, age, anthropometries, diagnosis, history of bowel resections, number of weekly days with HPN, average daily volume of HPN, IV dose of vitamin D, information about oral supplements of calcium and vitamin D, specific osteoporosis therapy (ie, bisphosphonates and hormone replacement therapy), and smoking habits. For all patients, we calculated the amount of energy provided with the HPN, as well as the individual metabolic rate (BMR) according to the Harris-Benedict equation.12 In the individual, the average daily energy provided with the HPN divided by the BMR was used as in indicator of the degree of HPN dependence.

The principles of administration and composition of parenteral nutrition at our center have previously been published.7

The Ethics Committee for Medical Research in Copenhagen, Denmark, approved the study protocol (no: KF 01-177/02), and the study was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 1983.

BMD Measurements

Assessment of BMD of the posterior-anterior spine, left femoral neck, and left distal forearm was performed by DXA with a Norland XR-36 DXA densitometer (Norland Corporation, Fort Atkinson, WI) according to the manufacturer's instructions. The BMD of spine and hip was also expressed as an SD score (z-score) and BMD T-score.12 The reference population consisted of 696 normal healthy Danish women who had taken part in the Copenhagen Female Study. Norland supplied normal BMD values for men from a normal white population. A reference material for forearm BMD was not available. In essentially all patients, each scan sequence included 1 spinal, 1 hip, and 1 forearm scan. Osteopenia was defined according to the WHO recommendation13 as a T-score of below -1.0 and above or equal to -2.5, and osteoporosis as a T-score below -2.5. The same densitometer was used for all measurements, and calibration (control for measurement drift) was performed daily prior to all DXA-scan procedures. In our laboratory, the precision error (spine phantom BMD coefficient of variation) was below 0.8%, and the short-term in vivo coefficients of variation of BMD measurements were 1.1% and 1.5% of the lumbar spine and femoral neck, respectively.

Statistics

The analysis strategy used a linear trend in time for changes in BMD. The SAS statistical program (version 8.02; SAS Institute, Inc, Cary, NC) was used to fit a random coefficient model to the data14 that involved a random intercept and slope for each subject and a variance-covariance model that incorporated correlations for all of the observations arising from the same person. The intercept term represented the model estimate of the BMD parameter on the initiation of HPN therapy, and the slope term represented the model estimate of change over time. The analysis was performed in 2 stages. A crude model containing only the time effect, evaluated as a fixed parameter, was fitted to the data to estimate the mean annual change in BMD over time. Second, the diagnosis of the patients, coded as a binary variable (Crohn's disease/non-Crohn's disease), was entered in the model as a fixed main effect along with the 2-way interaction term between time and diagnosis. Pairwise differences in the mean intercept and slope values between groups were tested by using t-statistics in the random coefficient model. The adequacy of the 2 models model was checked by the analysis of residuals and by the visual inspection of plots of predicted vs measured BMD values. For hip and spinal BMD data, the analysis was performed using the absolute BMD measurements and the adjusted BMD measures, ie, z-scores and T-scores. Results are expressed as means ± SEM unless otherwise indicated. All statistical tests were 2-tailed, and a p value of

RESULTS

Subject Characteristics

A total of 943 regional scans, 335 spinal, 318 hip, and 290 forearm, obtained between 1995 and 2003 in 75 patients receiving long-term HPN were used for the analysis of the annual changes BMD. The average (SD) number of scans per patients was 4.4 (2.9; range 2-15), and the mean (SD) follow-up time (ie, the time elapsed between the first and the last scan) was 4.1 (1.9) years. According to the data of the latest scan of each patient, the average spinal and hip z-scores were significantly below normal (p 0.05). All patients received HPN because of intestinal failure; the primary disorders were Crohn's disease (n = 35) and others (non-Crohn's disease; n = 40) including the following diagnoses: ischemic bowel infraction (n = 4), systemic scleroderma (n = 1), midgut volvulus with strangulation (n = 2), motility disorders (n = 3), intestinal pneumatosis (n = 1), gastrectomy (n = 3), unresponsive celiac disease (n = 1), intestinal lymphangiectasia (n = 2), radiation enteritis (n = 4), protein-loosing enteropathy (n = 1), postoperative intestinal complications (n = 14), and miscellaneous (n = 4). The clinical characteristics of the patients as a whole are detailed in Table I, together with the characteristics of patients grouped as Crohn's and non-Crohn's disease patients. Non-Crohn's disease patients were somewhat older than the Crohn's disease patients, and the distribution of men and pre- and postmenopausal women between groups differed significantly. Twelve of the 35 patients with Crohn's disease had a relapse during the observation period and were treated with steroids for short periods (less than 3 months).

Longitudinal Changes in BMD (Crude Model)

As displayed in Figure 1, the individual longitudinal changes in spinal BMD z-scores were heterogeneous, with some subjects showing deterioration, others improvement, and still others no change. Similar patterns were seen with the longitudinal changes of hip and forearm BMD z-scores. Table II presents the regression coefficients for the annual change in spine, hip, and forearm BMD in the group as a whole. There was a highly statistically significant overall decline over time in BMD of the spine, corresponding to a 0.92% annual loss (that is, slope/intercept -0.009/0.956%). However, the annual rate of decline in spinal BMD expressed as z-scores (ie, BMD values adjusted for the normal changes seen in age- and sex-matched healthy subjects) was not significantly different from zero (95% CI -0.0653; 0.0246). There was also a highly significant mean annual decline in hip BMD, which represented roughly a 1.19% annual loss (that is, slope/intercept -0.009/0.780%), but analogously to the changes seen in spinal BMD z-scores, the annually mean changes in hip BMD z-scores did not reach statistical significance (95% CI -0.0675; 0.0026). Parallel to the changes seen in spinal and hip BMD, the mean annual change of the distal forearm was statistically significant from zero and corresponded to an approximate 1.04% loss in BMD (slope/intercept -0.003/0.308%).

The intercept values given in Table I represent the model estimate of mean BMD parameters on the initiation of HPN therapy. The intercepts for spinal and hip z-score were significantly below normal values (p

Effect of Diagnosis

Table III gives the annual changes in the BMD parameters according to the diagnosis of the patients when grouped as Crohn's disease patients and nonCrohn's disease patients. Consistently, across all regional skeletal sites, there were significantly greater losses in BMD over time in non-Crohn's disease patients than in Crohn's disease patients (p

There were highly significant differences in spinal, hip, and forearm intercept values between groups. Whereas non-Crohn's disease patients on average had spinal and hip BMD z-score intercept values not significantly different from normal, Crohn's disease patients had significantly reduced intercept values. Thus, spinal and hip BMD T-score values of around -1.6 indicated that the average Crohn's disease patients, on the initiation of HPN therapy, already had considerable osteopenia.

DISCUSSION

This study reports on the longitudinal changes in BMD over time in 75 long-term HPN patients. The results showed a moderate but statistically significant average annual decline in spinal, hip, and forearm BMD of about 1%. Notably, however, within narrow confidence intervals, the loss in BMD during HPN treatment in the group as a whole was not significantly greater than that seen in age- and sex-matched healthy individuals. It must be kept in mind that the results represent the average outcome in our HPN patients irrespective of the presence of renal impairment, metabolic acidosis, osteoporosis therapy, or any other factors that could likely affect bone health in the individual patient. Because many of these factors are uneasily assessed or did not remain fixed throughout the observation period, they are not included in the model. Furthermore, considering the retrospective nature of the study, we cannot fully preclude bias caused by the selection of patients, but given that >70% of all eligible patients of our HPN cohort were included in the analysis, we argue that the data are representative.

The results agree closely with the findings of Saitta et al10 but give somewhat smaller losses in BMD than previously reported in several other studies.7,8,11 Foldes et al8 found an approximate 3.5% annual decrease in forearm BMD, and Staun et al,7 using a dual-photon absorptiometry device, the predecessor of DXA, reported a 4.8% mean annual decrease in spinal bone mineral content. In a prospective intervention study in 10 placebo-treated patients selected from the same cohort as now studied, we recently saw a 1.6% spinal and 1.8% hip annual decrease in BMD.11 Somewhat conflicting results that showed an approximately 4% annual increase in spinal BMD were reported by Verhage et al9 in an uncontrolled intervention study with a complete withdrawal of vitamin D from the HPN solutions. However, the same study showed an annual decline in BMD of the trochanter region of a similar magnitude as the increase in spinal BMD.

Very recently, a French HPN center published interesting data on the longitudinal changes in BMD in a selection of their patient cohort.15 In accordance with our data, although the actual average annual change was not specified, they reported a moderate age- and sex-adjusted change in BMD over time.

In the present study, data on the BMD parameters on the initiation of HPN therapy were not exact measures but were based on model estimates calculated by extension of trends in the individual BMD values. Even with the limitations associated with such an approach, we believe that applicable results were obtained, given that the average annual changes in BMD were relatively small and that the first of the repeated series of DXA scans were performed within a mean of 4 years after the patients entered the HPN program. Our data strongly suggested that a considerable part of the metabolic bone disease was related to the underlying disease for which the HPN was indicated. Thus, non-Crohn's disease patients had calculated BMD values on initiation of HPN therapy very close to normal values, whereas Crohn's disease patients had significantly reduced values. This is likely explained by the fact that Crohn's disease patients ending up with a permanent need of HPN may typically have had several periods with glucocorticoid therapy, repeated small-intestinal resections, and malabsorption complications related to a relative short bowel, all of which are recognized risk factors for a low BMD. In contrast, non-Crohn's disease HPN patients typically had illnesses with no previous deleterious effects on bone health (eg, ischemic bowel infraction, midgut volvulus with strangulation, and complications after abdominal surgery).

Although primary interest was focused on determining the magnitude of trends in BMD over time on a group level, the model also provided information about the differences in trends associated with the diagnosis of the patients. Consistently, across all regional skeletal sites, the decline in BMD was significantly larger in non-Crohn's disease patients than in Crohn's disease patients, although part of the dissimilarity between groups could be attributed to differences in age and sex. The annual loss in spinal BMD of 1.6% in non-Crohn's disease patients was in the upper end but not significantly greater than normal, and the loss in hip BMD of 1.8% was only slightly larger than that expected in healthy individuals. In Crohn's disease patients, the annual losses in spinal and hip BMD were remarkably small (~0.5%) and not significantly different from normal. Regarding the individual trends over time in BMD, the study showed that some, in particular, Crohn's disease patients, might even improve bone health during HPN treatment. In Crohn's disease patients, a plausible explanation for this may be that HPN is often initiated in relation to the removal of an inflamed intestinal segment that presumably leads to a concurrent reduction in levels of circulating inflammatory cytokines with potent stimulatory effects on osteoclast-mediated bone resorption.16 This interpretation would be consistent with the results of studies in rats,17 which documented that an increased bone formation rate was followed by a healing in the experimentally induced colitis and in ulcerative colitis disease patients who improved bone health after resection of the inflamed colon.18 Additionally, in Crohn's dis ease patients with general malabsorption, the supply of minerals and nutrients provided with the HPN may also have beneficial effect on bone health.

The statistical analysis used a linear trend in BMD over time. Although in many disease states it is reasonable to assume linear changes in BMD over short time spans, there is some indication that this may not necessarily apply to HPN patients. Thus, Lipkin et al4,19 showed an accelerated calcium loss during the first months after initiation of total parenteral nutrition that could indicate an increased bone loss as well. Yet, so far, no BMD data are available to substantiate such assumption, and our data do not permit a detailed analysis on BMD changes at the beginning of HPN therapy.

Although the study showed no accelerated bone loss during HPN therapy, the BMD of many patients was substantially reduced, making them susceptible to fragility fractures, and in these patients specific therapy against osteoporosis must be considered. To date, prospective studies on the efficacy of treatment of HPN-associated bone disease are scarce. In a controlled study in HPN patients, we recently showed that bisphosphonate treatment significantly inhibited bone resorption, but although beneficial trends were observed, significant increases in BMD after 12 months were not achieved.11 Novel intestinotrophic drugs that enhance overall intestinal absorption in short bowel patients may also positively influence BMD,20 and such drugs may represent a new strategy for overall management of these patients. The dosing of parenteral vitamin D in HPN patients is currently a matter of controversy. At our center, we regularly monitor serum concentrations of calcium-regulating hormones and aim at providing the individual patients with parenteral vitamin D and calcium sufficient enough to retain normal levels of serum-calcium, 25-hydroxy-vitamin D and PTH.11

In conclusion, this study showed that the bone loss with the current HPN strategy is moderate and on a group level not statistically larger than normal. The current results substantiate other authors' findings9,10 that the present-day parenteral formulations low in aluminum and vitamin D2 do not necessarily cause worsening of bone health. Although the results are reassuring, some patients nonetheless developed severe and sometimes debilitating bone disease during HPN treatment, and further studies on bone metabolism and treatment in HPN-patients are needed.

ACKNOWLEDGMENTS

The technical assistance of Jette Christiansen, Dorte Christensen, and Bodil Petersen is greatly appreciated.

REFERENCES

1. Shike M, Harrison JE, Sturtridge WC, et al. Metabolic bone disease in patients receiving long-term total parenteral nutrition. Ann Intern Med. 1980;92:343-350.

2. Klein GL, Targoff CM, Ament ME, et al. Bone disease associated with total parenteral nutrition. Lancet. 1980;2:1041-1044.

3. Lipkin EW, Ott SM, Klein GL. Heterogeneity of bone histology in parenteral nutrition patients. Am J Clin Nutr. 1987;46:673-680.

4. Lipkin EW, Ott SM, Chesnut CH 3rd, Chait A. Mineral loss in the parenteral nutrition patient. Am J Clin Nutr. 1988;47:515-523.

5. Goodman WG, Misra S, Veldhuis JD, et al. Altered diurnal regulation of blood ionized calcium and serum parathyroid hormone concentrations during parenteral nutrition. Am J Clin Nutr. 2000;71:560-568.

6. Pironi L, Labate AM, Pertkiewicz M, et al. Prevalence of bone disease in patients on home parenteral nutrition. Clin Nutr. 2002;21:289-296.

7. Staun M, Tjellesen L, Thaïe M, Schaadt O, Jarnum S. Bone mineral content in patients on home parenteral nutrition. J Clin Nutr. 1994;13:351-355.

8. Foldes J, Rimon B, Muggia-Sullam M, et al. Progressive bone loss during long-term home total parenteral nutrition. JPEN J Parenter Enteral Nutr. 1990;14:139-142.

9. Verhage AH, Cheong WK, Allard JP, Jeejeebhoy KN. Increase in lumbar spine bone mineral content in patients on long-term parenteral nutrition without vitamin D supplementation. JPEN J Parenter Enterai Nutr. 1995;19:431-436.

10. Saitta JC, Ott SM, Sherrard DJ, Waiden CE, Lipkin EW. Metabolic bone disease in adults receiving long-term parenteral nutrition: longitudinal study with regional densitometry and bone biopsy. JPEN J Parenter Enterai Nutr. 1993;17:214-219.

11. Haderslev KV, Tjellesen L, Sorensen HA, Staun M. Effect of cyclical intravenous clodronate therapy on bone mineral density and markers of bone turnover in patients receiving home parenteral nutrition. Am J Clin Nutr. 2002;76:482-488.

12. Long CL, Schaffei N, Geiger JW, Schiller WR, Blakemore WS. Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN J Parenter Enterai Nutr. 1979;3:452-456.

13. WHO Study Group. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis: WHO Technical Report Series, 843. Geneva, Switzerland: WHO Study Group; 1994.

14. SAS Institute. Random coefficient models. In: Littell RC, Milliken GA, Stroup WW, et al, eds. SAS Systems for Mixed Models. Gary, NC: SAS Institute; 1996:253-266.

15. Cohen-Solal M, Baudoin C, Joly F, et al. Osteoporosis in patients on long-term home parenteral nutrition: a longitudinal study. J Bone Miner Res. 2003; 18:1989-1994.

16. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling: emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 1995;332:305-311.

17. Lin CL, Moniz C, Chambers TJ, Chow JW. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology. 1996;111:1263-1271.

18. Abitbol V, Roux C, Guillemant S, et al. Bone assessment in patients with ileal pouch-anal anastomosis for inflammatory bowel disease. Br J Surg. 1997;84:1551-1554.

19. Lipkin EW. A longitudinal study of calcium regulation in a nonhuman primate model of parenteral nutrition [see comments]. Am J Clin Nutr. 1998;67:246-254.

20. Haderslev KV, Jeppesen PB, Hartmann B, et al. Short-term administration of glucagon-like peptide-2: effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon. Scared J Gastroenterol. 2002;37:392-398.

Kent Valentin Haderslev, MD, PhD; Lone Tjellesen, MDSc; Pernille Heldager Haderslev, MD; and Michael Staun, MDSc

From the Department of Gastroenterology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Received for publication January 28, 2004.

Accepted for publication June 7, 2004.

The work was performed at the Department of Medical Gastroenterology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

KH, LT, PHH, and MS were responsible for conception and design of the study. KH and MS were responsible for data interpretation and manuscript preparation. LT and PHH assisted in the data interpretation and manuscript preparation. None of the authors have personal or financial interests in any organization sponsoring the research.

Correspondence: Kent V. Haderslev, MD, Department of Medical Gastroenterology CA 2121, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic mail may be sent to khaderslev@dadlnet.dk.

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