Hypophosphatasia

ABSTRACT. The incidence of parenteral nutrition-- associated metabolic bone disease is unknown. Initial reports from the early 1980s suggested that both osteoporosis and osteomalacia were quite common in patients who receive long-term parenteral nutrition. The findings described in these early surveys provide a snapshot into the many factors that contribute to the development of metabolic bone disease. More recent evidence suggests that bone loss may not be as great with the initiation of parenteral nutrition as once was thought, and that most of the metabolic bone disease that is noted may be related to the patient's underlying illness. Although this recent

information is reassuring, it is of the utmost importance to provide parenteral nutrition that minimizes further bone loss and promotes the formation of new bone. This review will describe the general features of metabolic bone disease and the abnormalities noted with parenteral nutrition-associated metabolic bone disease, highlight the importance of preexisting illness and parenteral nutrition associated factors that contribute to the development of metabolic bone disease, and finally discuss an approach to avoid this debilitating complication of longterm parenteral nutrition. (Journal of Parenteral and Enteral Nutrition 26:S37-542, 2002)

BONE FUNCTION, METABOLISM, AND METABOLIC BONE DISEASES

Bone is the major structural component of the skeleton and provides a rigid frame for locomotion and protection of the vital organs of the body. Bone is also a site for hematopoiesis and provides a reservoir of calcium, phosphorus, and magnesium. There are two major types of bone, cortical and trabecular bone. Cortical bone is composed of densely packed layers of mineralized collagen and is the major component of the shafts of the long bones. Trabecular bone makes up the inner lace-like bone which surrounds the bone marrow and gives bone its compressive strength. Trabecular bone, which is also referred to as cancellous bone, makes up the major portion of the vertebrae, pelvis, and ends of long bones.

Bone responds to mechanical stress by undergoing continuous breakdown and renewal in a process referred to as bone remodeling.' New bone is initially laid down through the formation of osteoid, a protein matrix that is predominantly made up of collagen. Osteoid is then mineralized with calcium and phosphorus, a process that is carefully regulated by parathyroid hormone (PTH) and requires adequate blood levels of vitamin D, calcium, magnesium, and phosphorus. Old bone is removed by reabsorption of the mineral and organic components of the bone. At a cellular level, bone remodeling is directed by osteoclasts that resorb bone, osteoblasts that direct new bone formation, and osteocytes that regulate mineral metabolism. Bone mass increases through childhood and adolescence and peaks at the end of the second to third decade of life. Although bone mass remains fairly stable throughout adult life, there is a gradual decline with senescence that is most often of no clinical consequence. Although there are several types of metabolic bone disease (MBD), the two predominant forms are osteoporosis and osteomalacia.

Osteoporosis

Osteoporosis is the most common form of MBD and is responsible for over one million fractures in the United States each year. In osteoporosis, there is a decrease in the total amount of bone with a normal ratio of bone matrix to bone mineral. Although bone may appear to be histologically normal, microarchitecture damage to the trabecular bone has been demonstrated. Primary osteoporosis can be divided into "postmenopausal" or type I and "senile" or type II osteoporosis.1 Before menopause, bone loss is usually

Osteomalacia

The term osteomalacia means soft bones. It is characterized by defective calcification of osteoid that leads to a paradoxical increase in bone volume.1 This abnormality can be demonstrated on bone biopsy performed in conjunction with tetracycline labeling. It is primarily caused by vitamin D deficiency and poor calcium absorption. Osteomalacia can occur in gastrointestinal and hepatobiliary disease, with inadequate sun exposure, and disorders of vitamin D metabolism that occur in renal disease or vitamin D-dependent rickets, and vitamin D resistance. Drugs that inhibit bone mineralization can also cause osteomalacia and include anticonvulsants, fluoride, etidronate, and aluminum. Other rare causes include renal tubular acidosis, chronic hypophosphatemia, and hypophosphatasia. Although the clinical features of these disorders are similar, the biochemical defects are different and help differentiate the underlying causes of osteomalacia. The distinction between the different causes is necessary to institute therapy in a proper fashion. In children, the defect in mineralization predominantly involves the cartilage of the epiphysis, where bone growth occurs, resulting in the deformities seen with rickets.

PN-ASSOCIATED MBD

Clinical Abnormalities

Patients with PN-associated metabolic bone disease (PN-MBD) may present with bone pain and fractures with minimal or no trauma; however, most will be asymptomatic. Biochemical parameters associated with bone formation and mineralization are often normal but may be subtly abnormal.3-5 These abnormalities have included an elevation in urinary calcium and an increase in serum calcium, phosphorus, and alkaline phosphatase. Although it is not entirely clear why the patients from these studies had such varied defects in bone metabolism, it is possible that the results reflect differences in the disease for which PN is indicated. In the study by Shike et al,3 bone turnover was noted to be increased with the initiation of PN; however, with time, the rate of bone turnover diminished and mineralization was impaired. Klein et al4 showed an increase in the amount of osteoid, similar to the defect seen with osteomalacia. Shike et al 5 later showed in a different cohort of patients that osteoporosis was present rather than osteomalacia. It has been speculated that the defect in bone mineralization noted in the earlier study may have been caused by low levels of PTH and 1,25-dihydroxyvitamin D.

Pathogenesis: Preexisting MBD

Nearly every condition requiring long-term PN can predispose a patient to MBD. Some of the mechanisms responsible for disease-associated MBD are listed in Table I. Patients with Crohn's disease are at risk for MBD if they have malabsorption of calcium and vitamin D or use corticosteriods to control their disease.6 The inflammatory process itself may promote bone resorption through the release of cytokines and other mediators of inflammation into the circulation. Patients with cancer may have decreased food intake and altered calcium and vitamin D metabolism-- associated with surgery or chemoradiotherapy. MBD may also develop in these patients as a result of therapy-induced amenorrhea or the elaboration of cytokines or PTH-like peptides.7 There is also evidence that renal wasting of calcium may occur in individuals with short bowel syndrome. In a rodent model of short bowel syndrome, animals subject to extensive small intestinal resection with bowel anastomoses developed hypercalciuria with negative calcium balance, whereas control animals who underwent a similar operation except that the transected bowel was left in situ did not develop this metabolic defect.8 These results suggest that the short bowel syndrome itself may be a risk factor for the development of MBD.

The impact of glucocorticoids on bone mineralization requires special mention because it is the most important determinant of MBD in patients with Crohn's disease.9 Glucocorticoids suppress osteoblast activity, inhibit vitamin D-independent intestinal calcium absorption, suppress pituitary function, decrease secretion of gonadal corticosteroids, and increase renal calciuria. Glucocorticoids may also increase the activity of osteoclasts. Most of the bone loss associated with glucocorticoids is of trabecular bone, although cortical bone mass also decreases. Bone loss is most rapid in the first 6 to 12 months of therapy, but accelerated bone loss seems to continue as long as therapy is continued. It is, therefore, best to minimize glucocorticoids use whenever possible.

Pathogenesis: PN and Hypercalciuria

Urinary excretion of calcium has been noted to be increased in patients on long-term parenteral nutrition.3-5,10 Normally, 10,000 mg of non-protein bound calcium is filtered by the kidney each day, with 99% of the filter load being reabsorbed by the renal tubules. Therefore, the daily excretion of calcium is between 100 and 300 mg. Several factors, listed in Table II, have been noted to contribute to the development of hypercalciuria in patients on PN. To best understand some of these factors, it is important to review the effect that nutrient metabolism has on the renal handling of calcium.

Excess dietary protein is known to lead to hypercalciuria. The precise mechanism for this effect is unknown; however, calcium resorption by the renal tubules has been shown to be decreased in response to a protein meal. Part of this effect may be related to sulfate excretion and insulin release, both of which occur with protein metabolism and are known to decrease renal calcium resorption.11,12 The amino acid dose in PN has also been shown to result in hypercalciuria. Bengoa et al13 infused a PN formula with 1 g/kg per day versus 2 g/kg per day and demonstrated a modest increase in urinary calcium from 287 +/- 46 to 455 +/- 58 mg/d. Concentrations of calcium, PTH, and 25-hydroxyvitamin D were normal and unchanged during the study. Amino acids seem to induce hypercalciuria by several means, including an increase in glomerular filtration rate and an increase in the levels of sulfate, titratable acid, and insulin. Other studies have confirmed the correlation between amino acid intake and calciuria.10

In addition, urinary calcium excretion has been shown to be positively correlated to calcium intake during PN with a threshold amount being required to maintain calcium balance. In a study of 151 patients receiving hospital-based PN, Sloan et al14 showed that at least 15 mEq of calcium is required to promote a positive calcium balance and 15 mmol of phosphorus is needed per day in patients receiving continuous PN infusion. It should be noted that these patients received 1000 IU of vitamin D per week and that nearly all of the patients had an underlying malignancy. Therefore, whereas the quantity of calcium and phosphorus provided may not be directly applicable to patients who need long-term PN, it points out the importance of providing an adequate amount of substrate for normal calcium metabolism.

Adequate amounts of phosphorus must also be provided in PN to promote a positive calcium balance. Wood et al15 studied calcium balance using a PN solution that contained a fixed dose of calcium (12 mEq/d) and a varied dose of phosphorus (22.7, 32.4, and 42.1 mmol/d). They showed that only the highest dose of phosphorus led to a positive calcium balance. It seems that phosphate enhances calcium reabsorption by the renal tubules independent of PTH, plasma calcium, and renal sodium handling.16 It must be kept in mind that whereas higher doses of phosphorus can diminish the amount of urinary calcium lost, a chronic excess of phosphorus can lead to bone loss as a result of secondary hyperparathyroidism.

Cyclic infusion of PN may also increase the renal loss of calcium. Wood et al17 reported an increase in urinary calcium excretion of 28% when PN was transitioned from a 24-hour to a cycled 12-hour infusion. Furthermore, approximately 80% of the daily urinary calcium loss occurred during the time of the cycled infusion. Lipkin et al18 also demonstrated an increased rate of urinary calcium excretion when the cycle length was decreased from 24 hours to 12 hours. However, total daily calcium excretion was unchanged over the course of the study. Although the exact cause of hypercalciuria during cycled infusion is not known, numerous factors are probably contributing to this effect because the rate of infusion for all PN components are typically doubled.

Other factors that have been shown to increase renal calcium excretion include higher quantities of sodium and dextrose. The former is related to an increase in glomerular filtration rate and the later is in part caused by an increase in serum insulin concentrations.

The extent of PN-induced hypercalciuria may not be as great as was once suspected. In a cross-sectional study comparing patients on long-term versus shortterm PN, Lipkin et al18 observed that the fraction of the infused calcium excreted in the urine was lower in the group receiving long-term therapy. The mechanism for this observation may be explained by a study performed in a primate model by the same investigators.19 In this study, the effect of PN on calciuria was positively correlated with the glomerular filtration rate, the urine filtration fraction for calcium, and the plasma PTH concentration. There was hyperfiltration of calcium with a more negative calcium balance after the first week of PN compared with measurements obtained at the end of the third week of the study. The initial hyperfiltration was believed to be caused by an increase in renal blood flow, whereas the conservation of calcium occurred with a diminution in filtered calcium load and an increase in the concentration of PTH. This adaptive response seems to favor the maintenance of normal calcium homeostasis and may minimize the development of PN-MBD.

Pathogenesis: Inhibitors of Normal Bone Metabolism Chronic metabolic acidosis can impair the metabolism of vitamin D and lead to the development of MBD with features of osteomalacia.20 Acidosis can also lead to direct loss of bone because it is involved in buffering nonvolatile acids. There are several factors that may contribute to the development of.acidosis with PN. Amino acid metabolism produces weak phosphate and sulfate acids that the kidney must excrete. Excessive amino acids or renal disease may contribute to the development of metabolic acidosis. Patients with the short bowel syndrome and enterocutaneous fistulas can develop metabolic acidosis as a result of diarrheal losses of bicarbonate. Patients on long-term PN are also at risk for developing bacterial overgrowth. In some cases these bacteria produce D-lactate, which has also been shown to contribute to the development of PN-MBD.21 Therefore, it is important to provide a sufficient amount of acetate in the parenteral nutrition prescription to help metabolize the titratable acid produced from protein metabolism and balance bicarbonate losses from the gastrointestinal tract. When it is difficult to correct an underlying metabolic acidosis, then D-lactate should be measured in the blood, and if found, appropriate antibiotics and diet should be prescribed.

A modest number of the initial cases of PN-MBD were likely because of aluminum contamination of amino acid solutions prepared from protein hydrolysates.22 Aluminum toxicity impairs PTH secretion, decreases serum levels of 1,25-dihydroxyvitamin D, and has been shown to result in a MBD similar to osteomalacia.23 The frequency of PN-MBD secondary to aluminum toxicity should now be lower because amino acids solutions contain negligible amounts of aluminum. Aluminum is still present in calcium gluconate, phosphate salts, vitamins, and trace element solutions; however, the amounts are far less than those encountered in casein hydrolysates, and they are not believed to make a significant contribution to PN-MBD. This has been corroborated by a report of PN-MBD that did not find the marked hypercalciuria, hypercalcemia, and low 1,25-dihydroxyvitamin D previously attributable to aluminum.24,25

Anecdotal reports of improvement of PN-MBD on withdrawal of vitamin D suggest that vitamin D in amounts considered normal for maintenance of bone health in patients receiving PN may lead to the development of MBD.26,27 In these studies, the short-term withdrawal of vitamin D led to correction of hypercalcemia, hypercalciuria, and osteomalacia. Excessive vitamin D may also suppress PTH secretion and directly promote bone resorption.28 It is also possible that relatively high concentrations of 1,25-dihydroxyvitamin D resulted in an increase in bone resorption.28 In a study of 9 patients on long-term PN in whom vitamin D was withdrawn for an average of 4.5 years, Verhage et al29 demonstrated improvement in bone mineral content of the lumbar spine and normalization of blood PTH and 1,25-hydroxyvitamin D. Calcium, phosphorus, magnesium, and 25-hydroxyvitamin D was found to be in the normal range at the start of the study and remained so during the time that vitamin D was withheld. Although it seems that this approach would be ideal for patients with low levels of PTH and PN-MBD, it is presently impractical because the parenteral multiple vitamin preparation used in the study is no longer available.

EVALUATION, PREVENTION, AND MANAGEMENT OF PN-MBD

Evaluation

Evaluation for MBD should include a thorough history, physical examination, and laboratory assessment. Although most patients with osteoporosis are asymptomatic, some may report a history of bone fractures with minimal trauma or back pain from spinal compression fractures. Osteomalacia can present with a history of diffused skeletal pain, proximal muscle weakness, and a tendency to develop fractures with little trauma. The medication history should include questions about the use of vitamin and mineral supplements, estrogens, glucocorticoids, and loop diuretics. Physical signs are only occasionally present. Kyphosis of the spine is strongly suggestive of past compression fractures of the thoracic spine. Signs of Cushing's syndrome, hyperparathyroidism, and hypogonadism in men may be found in patients with secondary osteoporosis caused by these conditions. Laboratory studies should include a complete blood count, serum chemistry panel to exclude kidney and liver disease, and a thyroid-stimulating hormone study (TSH) to evaluate for hyperthyroidism. An intact parathyroid hormone (iPTH) and 25-hydroxyvitamin D level in the serum should be checked when there is a strong suspicion for underlying MBD or an abnormal bone mineral density study (see below). An increased iPTH with a low serum calcium may indicate inadequate calcium intake or absorption, whereas primary hyperparathyroidism should be considered with an increased iPTH and high serum calcium. Osteomalacia may be present if 25-hydroxyvitamin D is low and iPTH is elevated and should prompt measurement of 1,25-dihydroxyvitamin D and a blood aluminum level or a desferoxamine test to exclude aluminum toxicity. In aluminum toxicity, 1,25-dihydroxyvitamin D is low or unmeasurable. N-teliopeptide collagen is a breakdown product of bone collagen and can be measured in the blood or urine. An increased N-teliopeptide collagen level suggests high bone turnover and loss.30 If elevated values are found, therapy should be given to maintain the levels of these markers near the midrange of normal. A baseline dual-energy absorptiometry (DEXA) should be considered in most patients who will receive home PN. An exception to this would be the patient without any risk factors or conditions that result in MBD who might only need home PN for 6 months or less. A suggested strategy for testing is outlined in Table III.

Bone density can be assessed by several techniques including single-photon absorptiometry (SPA), DEXA, and quantitative computer tomography (QCT). DEXA is currently preferred over the other methods because it is associated with the lowest level of radiation exposure (= -2.5 below the lower limit of normal. A T-score between -1.0 and -2.5 SD below normal is considered to represent osteopenia. If results are normal, then repeat measurement may be considered in 2 to 3 years in patients on long-term PN to determine the effect of time on bone mineral content. Patients with risk factors for the development of MBD can be measured again in 1 year. Treatment is advised for patients with osteoporosis or a decrease in bone mass of 2% to 3% per year. Finally, it should be pointed out that most individuals with a decrease in bone mass have osteoporosis as opposed to osteomalacia; however, only a bone biopsy can distinguished osteoporosis from osteomalacia with certainty.

Prevention and Management

Providing adequate amounts of minerals and vitamins form the foundation for maintaining the integrity of bone. This is of great importance in the formulation of PN solutions for patients who need long-term nutrition support. Calcium gluconate should be provided at a dose of 15 mEq/d (approximately 3 g of salt or 300 mg of elemental calcium) to most patients on long-term PN.31 Serum values should be maintained in the normal range with correction for the presence of hypoalbuminemia. When dosing is adequate, the amount of calcium in a 24-hour urine collection should be within the normal range of 100 to 300 mg. A low value suggests that the infused calcium is being excreted in the stool and a higher dose is necessary to maintain normal calcium homeostasis. Magnesium, at a dose of 15 to 20 mEq, is given each day to meet losses that occur with large volume diarrhea. A 24-hour urine magnesium is a good way to see if dosing is adequate because, like calcium, normal urinary losses are seen with adequate dosing, and low values are seen when more magnesium needs to be added to the PN.32 Phosphate is provided as a sodium or potassium salt to maintain blood levels near the midrange of normal. It has been suggested that calcium and phosphate be given in a ratio of 1:2.31 An example would be to add 15 mEq of calcium and 30 mmol of phosphorus to the PN solution each day. Blood levels of phosphorus must be closely monitored, especially in patients with renal insufficiency. An adequate amount of acetate should be provided to avoid metabolic acidosis and to maintain serum bicarbonate near the midrange of normal. The moderately high doses of amino acids (1.5 g/kg per day) needed to normalize visceral proteins and reach a desired weight when PN is begun should be reduced to a maintenance levels (0.8 to 1.0 g/kg per day) once the patient is stable. Sodium should not exceed the amount needed to meet gastrointestinal, renal, and cutaneous losses. Multiple vitamins for injection (MVI) provide 200 IU of vitamin D each day. Currently, there is not enough data to support the use of a two-in-one dextrose based formula versus a total nutrient admixture (TNA) for the prevention or management of PN-MBD. The distribution of non-protein calories should therefore be based on other metabolic requirements.

Approved medications for perimenopausal osteoporosis include conjugated estrogens, selective estrogenreceptor modulators (SERMS), calcitonin, and bisphosphonates. These drugs primarily maintain bone by decreasing the rate of bone resorption by inhibit osteoclast activity. They can decrease the rate of bone turnover and thus minimize the rate of decline of bone mineralization. When these drugs are used, bone mass can only increase through the normal osteoblast activity. On the other hand, PTH stimulates both bone formation and resorption. A recent clinical trial has shown that daily subcutaneous injection of PTH can lead to an increase in bone density and a decreased rate of bone fractures.33 Unfortunately, PTH is not available for use outside of a clinical trial. Conjugated estrogens should be considered as the first line of therapy for perimenopausal women to prevent the development of type I osteoporosis. A history of breast and endometrial cancer, thromboembolic disease, and acute liver failure are contraindications to this therapy. Alternatively, calcitonin can be used when estrogens are not appropriate or are contraindicated. It should be noted that calcitonin can increase urinary calcium loss. Bisphosphonates are approved for the treatment and prevention of primary osteoporosis and glucocorticoid induced bone loss. Parenteral preparations of bisphosphonates may be most appropriate for patients with short bowel syndrome and active Crohn's disease because oral forms of these medications are poorly absorbed, and they can lead to ulceration of the gastrointestinal tract. As previously discussed, corticosteroids should be decreased and whenever possible discontinued in patients with inflammatory bowel disease to minimize bone loss. It should be noted that none of these medications have been formally studied in patients with osteoporosis who are on long-term PN. A management approach for PN-MBD is listed in Table IV.

CONCLUSION

Osteoporosis and osteomalacia are potential complications of PN. Medical conditions for which long-term PN is required are often associated with these MBDs. The preparation of PN can be optimized to avoid the development of a negative calcium balance and thus minimize the risk of developing or exacerbating underlying MBD. Future research should be directed toward determining the true incidence of MBD in patients on long-term PN, clarifyng the biologic response to PN as it relates to calcium homeostasis and bone metabolism and toward developing the most optimal approach to diagnosis and treatment of MBD.

REFERENCES

1. Fitzgerald PA: Endocrinology. IN Current Medical Diagnosis and Treatment 2000, 39th ed., Tierney LM, McPhee SJ, Papadakis MA (eds). Lange Medical Books/McGraw-Hill, New York, 2000, pp 1079-1151

2. Manolagas SC, Jilka RL: Bone marrow, cytokines, and bone remodeling. N Engl J Med 332:305-311, 1995

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

4. Klein GL, Ament ME, Bluestone R, et al: Bone disease associated with TPN. Lancet 2:1041-1044, 1980

5. Shike M, Shils ME, Heller A, et al: Bone disease in prolonged parenteral nutrition: Osteopenia without mineralization defect. Am J Clin Nutr 44:89-98, 1986

6. Abitbol V, Roux C, Chaussade S, et al: Metabolic bone assessment in patients with inflammatory bowel disease. Gastroenterology 108:417-422, 1995

7. Harvey HA: The management of hypercalcemia of malignancy. Support Care Cancer 3:123-129, 1995

8. Chu RC, Barkowski SM, Buhac J: Small bowel resection associated urinary calcium loss in rats on long term TPN. JPEN 14:64-67, 1990

9. Silvennoinen JA, Karttunen TJ, Niemela SE, et al: A controlled study of bone mineral density in patients with inflammatory bowel disease. Gut 37:71-76, 1995

10. DeVernejoul MC, Messing B, Modrowski D, et al: Multifactorial low remodeling bone disease during cyclic TPN. J Clin Endocrinol Metab 60:109-113, 1985

11. Zemel MB, Schuette SA, Hegsted M, et al: Role of sulfur-containing amino acids in protein-induced hypercalciuria in men. J Nutr 11:545-552, 1981

12. DeFronzo RA, Cooke CR, Andes R, et al: The effect of insulin on renal handling of sodium, potassium, calcium and phosphorous in man. J Clin Invest 55:845-855, 1975

13. Bengoa JM, Sitrin MD, Wood RJ, et al: Amino acid induced hypercalciuria in patients on TPN. Am J Clin Nutr 83:264-269, 1983

14. Sloan GM, White DE, Brennan MF: Calcium and phosphorous metabolism during TPN. Ann Surg 197:1-6, 1983

15. Wood RJ, Sitrin MD, Cusson GJ, et al: Reduction of TPN induced urinary calcium loss by increasing the phosphorous in the TPN prescription. JPEN 10:188-190, 1996

16. Lau K, Goldfarb S, Goldberg M, et al: Effects of phosphate administration on tubular calcium transport. J Lab Clin Med 99:317-324, 1982

17. Wood RJ, Bengoa JM, Sitrin MD, et al: Calciuretic effect of cyclic versus continuous TPN. Am J Clin Nutr 41:614-619, 1985

18. Lipkin EW, Ott SM, Chestnut CH, et al: Mineral loss in parenteral nutrition patients. Am J Clin Nutr 47:515-523, 1988

19. Lipkin EW: A longitudinal study of calcium regulation in a nonhuman primate model of parenteral nutrition. Am J Clin Nutr 67:246-254, 1988

20. Cunningham J, Fraher LJ, Clemens TL, et al: Chronic acidosis in metabolic bone disease: Effective alkali on bone density and vitamin D metabolism. Am J Med 73:199-204, 1982

21. Karton MA, Rettmer R, Lipkin EW, et al: D-lactate and metabolic bone disease in patients receiving long term parenteral nutrition. JPEN 13:132-135, 1989

22. Ott SM, Maloney NA, Klein GL, et al: Aluminum is associated with low bone formation in patients receiving chronic parenteral nutrition. Ann Intern Med 99:910-914, 1983

23. Goodman WG, Henry DA, Horst R, et al: Parenteral aluminum administration in the dog: II, Induction of osteomalacia and effect on vitamin D metabolism. Kidney Int 25:270-275, 1984

24. Klein GL: Aluminum in parenteral products: Medical perspective on large and small volume parenterals. J Parenter Sci Technol 43:120-124, 1989

25. Koo WWK, Kaplan LA, Horn J, et al: Aluminum in parenteral nutrition solutions: Sources and possible alternatives. JPEN 10:591-595, 1986

26. Shike M, Sturtridge WC, Tam CS, et al: A possible role of vitamin D in the genesis of parenteral nutrition induced metabolic bone disease. Ann Intern Med 95:560-568, 1981

27. Seligman JV, Basi SS, Deitel M, et al: Metabolic bone disease in a patient on long-term TPN: A case report with review of literature. JPEN 8:722-727, 1984

28. Vieth R: The mechanisms of vitamin D toxicity. Bone Miner 11:267-272, 1990

29. Verhage AH, Cheong WK, Allard JP, et al: Increase in lumbar spine bone mineral content in patients on long term parenteral nutrition without vitamin D supplementation. JPEN 19:431436, 1995

30. Bikle DD: Biochemical markers in the assessment of bone disease. Am J Med 103:427-436, 1997

31. Steiger ES, Seidner DL, McAdams MP, et al: Parenteral nutrition. IN: The Cleveland Clinic Foundation: Nutrition Support Handbook, Matarese LM (ed). The Cleveland Clinic Foundation, Cleveland, OH, 1997, pp 45-62

32. Fleming CR, Georg L, Stoner GL, et al: The importance of urinary magnesium values in patients with gut failure. Mayo Clinic Proc 71:21-24, 1996

33. Neer RM, Arnaud CD, Zanchetta JR, et al: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:14341441,2001

Douglas L. Seidner, MD, FACG, CNSP

From the Ohio State University Medical School and The Cleveland Clinic Foundation

Correspondence and reprint requests: Douglas L. Seidner, MD, Department of Gastroenterology/A30, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Electronic mail may be sent to seidned@ccf.org.

Copyright American Society for Parenteral and Enteral Nutrition Sep/Oct 2002
Provided by ProQuest Information and Learning Company. All rights Reserved