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HPN-Associated Metabolic Bone Disease
Cynthia Hamilton, MS, RD, CNSD
Patients receiving long-term parenteral nutrition (PN) are at risk for developing abnormal bone metabolism or metabolic bone disease (MBD), which can result in osteoporosis or osteomalacia. Patients with MBD may complain of back, bone or joint pain; loss of height; or atraumatic fractures. They also may be asymptomatic. The exact cause of MBD in long-term parenterally fed patients is unknown, although several contributing factors have been identified, including various components of the PN solution and disease states for which PN is prescribed. All patients receiving long-term PN (over 1 year) should be monitored and treated for MBD.
MBD is associated with various disorders of bone metabolism, the most common of which are osteoporosis and osteomalacia. Osteoporosis is characterized by a normal ratio of bone matrix to bone mineral content, but the total amount of bone is decreased. Osteomalacia is characterized by inadequate calcification of bone matrix that leads to soft bones. Both forms of bone disease lead to increased risk of bone fracture.
Osteoporosis affects more than 20 million women in the United States, with 25 percent to 30 percent of women older than 65 years having symptomatic disease. Women are affected primarily, but men have one seventh of all vertebral fractures and one quarter of all hip fractures. The lesser incidence and prevalence in men are due to a greater peak bone mass, shorter life expectancy, and lack of menopause effect. Primary osteoporosis is further divided into postmenopausal, type I, or age-associated, type II (see Table 1). Type I osteoporosis primarily occurs in women and is associated with estrogen deficiency. Although rare, type I osteoporosis also can occur in men due to decreased androgen production. Type II osteoporosis is the normal loss of bone mass that occurs after age 25 to 35 years in both genders. The loss of height due to bone loss is approximately 1 cm per decade of life, but it is slower in men than women due to the postmenopausal effect.
A number of secondary factors contribute to MBD, including endocrine disorders, genetic disorders, malignancies, drugs, liver disease, renal failure, inflammatory bowel disease, immobilization, and nutrition-related factors.
Osteomalacia is characterized by defective mineralization of bone matrix that results in a decline of bone strength. It causes pain and fracture in adults. In children, it affects the bone and cartilage growth plate, resulting in the deformities seen with rickets (bowed legs). The most common cause of osteomalacia is vitamin D deficiency, which may be the result of inadequate dietary intake, inadequate ultraviolet light exposure, fat malabsorption (as seen in short bowel syndrome), jejunoileal bypass, inflammatory bowel disease, liver disease, and renal disease. Certain drugs, including anticonvulsants, fluoride, aluminum, furosemide and etidronate, inhibit bone mineralization and may cause osteomalacia.
Three types of cells continually interplay in the remodeling of bone. Osteoblasts promote bone formation, osteoclasts promote bone resorption or breakdown, and osteocytes are mature bone cells found within the bony matrix that transfer mineral from interior bone to growth surfaces. Bone also consists of two types of tissue: cortical and trabecular. Cortical bone represents about 80 percent of the total bone mass, is the outer layer of all bones, and forms the interior of long bones in the body. Cortical bone is very dense and provides the strength for weight bearing of long bones. Trabecular bone represents approximately 20 percent of the total bone bass and is the inner, fine, lace-like structure that surrounds the bone marrow and is found mostly in the vertebrae and the ends of long bones and the pelvis.
Bone tissue serves as a reservoir for calcium, phosphorus, and other minerals. Approximately 50 percent of the magnesium in the body is found in bone tissue, including bone fluids and bone crystals. Phosphate and calcium are the principle components involved in the miner phase of bone formation. Adequate amounts of these minerals must be supplied for bone mineralization. However, excess phosphate can alter the calcium/phosphate ratio, especially if calcium intakes are low, resulting in bone resorption.
Approximately 99 percent of the body’s calcium is found in the skeletal system, but the small percentage found in blood and extracellular fluids (1 percent) is critical to metabolic and cellular processes. The body maintains blood calcium at a narrow concentration (approximately 8.5 to 10 mg/dL), deriving calcium from the diet and bone fluids and tissue. A negative feedback system involving two antagonistic hormones, calcitonin and parathyroid (PTH), maintains the concentration of calcium in the blood which, in turn, affects the release or retention of calcium in bone. An increase in blood calcium levels induces the thyroid gland to secrete calcitonin, which stimulates calcium deposition in the bones, reduces calcium uptake in the gastrointestinal tract, and increases calcium losses via the kidneys. If blood calcium concentrations are low, PTH is secreted by the parathyroid glands to stimulate calcium release from the bones, increase calcium uptake in the gastrointestinal tract, and increase calcium uptake from the kidneys.
Vitamin D plays an important roll in calcium homeostasis. Vitamin D ingested from the diet or derived from the skin via sunlight activation is metabolized in the liver to 25-hydroxyvitamin D and then in the kidney to its active for, 1,25-dihydroxyvitamin D which, in turn, enhances calcium absorption in the intestines.
MBD is diagnosed by the radiologic presence of fracture (atraumatic) or by measurement of bone mineral density. Low bone mineral density is an important determinant of susceptibility to osteoporotic fractures. The most common method used to measure bone mineral density is dual energy x-ray absorptiometry (DXA). This technique has low radiation exposure (less than chest radiography), has a short examination time (20 min), is highly accurate (1 percent to 2 percent reproducibility), and relatively low cost. DXA measures bone density of the lumbar spine, femoral neck, and radius. The bone density of an individual is compared with a control group comprised of gender-matched young adults, and deviation from this value is expressed in standard deviations (SD) above or below the mean as a T-score. The T-score is a classification of osteoporosis fracture risk. The World Health Organization has defined a T-score of –1 SD or above as normal, a T-score between –1 and –2.5 as representative of osteopenia (the precursor state to the more serious osteoporosis), and a T-score at or below –2.5 SD as osteoporosis.
Biochemical tests can also be used to help detect MBD and include blood and urine studies. Blood tests that document decreased amounts of serum calcium, phosphorus, 25-hydroxyvitamin D and osteocalcin (a marker of bone growth) or increased amounts of alkaline phosphatase and PTH may be indicative MBD. Urine tests documenting decreased amounts of calcium and magnesium or increased amounts of n-telopeptide (a collagen marker reflective of bone resorption) can also be predictive of MBD.
Parenteral Nutrition-Associated MBD
MBD associated with long-term PN initially was described in the early 1980’s. Among 38 patients who were receiving home total parenteral nutrition (TPN) for more than 3 months, 11 had severe debilitating bone pain and hypercalcuria, and 7 iliac crest bone biopsies documented patchy osteomalacia in patients who had pain. Another early report documented increased bone turnover without calcification (by bone biopsy) within 1 to 4 months of starting PN among 12 of 16 patients, with progression to osteomalacia within 12 to 16 months. Seven of the 16 patients had hypercalcemia, and 10 patients had hypercalcuria. Vitamin D was removed from the PN solution, despite the presence of normal serum levels in the patients, and resulted in decreased urinary calcium excretion and normalization of serum calcium concentrations.
A number of studies were undertaken after an early report of improvement of MBD when vitamin D was removed from PN solutions, with conflicting results. One study found that early on patients showed improved bone histology when vitamin D was removed from their solutions; but abnormal bone histology was evident at a 6-month follow-up. In a study by Verhage and colleagues, they found that there was improved bone mineral content of the lumber spine among long-term PN patients in which vitamin D was removed for an average of 4.5 years.
Current usual practice is not to remove vitamin D from PN formulas because bone disease is known to be associated with chronic vitamin D deficiency. The recommended parenteral dose of the vitamin is 200 IS/d for adults.
Initial investigations of MBD in long-term PN patients also examined the role of aluminum (Al). Early PN solutions contained protein as casein hydrolysates, which contained significant amounts of Al; 3,400 mcg/3 L of PN verses 33 mcg/3 L of PN solution made with free amino acids. In several studies, patients who received casein hydrolysate solutions had significantly detectable amounts of Al in plasma, urine, and bone compared with patients receiving free amino acid solutions. Discontinuation of the casein hydrolysate solution resulted in reduction of bone pain, reduction of hypercalcuria, improved bone formation, and normal serum concentrations of 1,25-dihydroxyvitamin D.
Casein hydrolysates have not been used in PN solutions for many years, virtually eliminating Al toxicity as a risk factor for the development of MBD. While there may be small amounts of Al in other additive to PN, the amount can vary among manufacturers, the United States Food and Drug Administration made new rules to attempt to regulate the amount of Al in PN solution. Effective July 26, 2004, all large volume parenterals, such as dextrose, saline solutions and crystalline amino acids must contain no more than 25 mcg/L of Al. In addition, small volume additive, including calcium gluconate, phosphate salts, and vitamin and mineral solutions, must have the Al content note on their labels.
Incidence of MBD
The incidence of MBD in long-term PN patients is unknown. One review of several studies reported a 42 percent to 100 percent prevalence of MBD. A recent study documented a prevalence of 84 percent among patients receiving PN for more than 6 months. Although the exact cause of MBD in parenterally fed patients is not known, several factors may contribute to altered bone metabolism, including inadequate provision of calcium and phosphorus, excess amounts of protein and vitamin D, cyclic infusion, and metabolic acidosis.
Conditions for which patients are placed on PN include disorders that may contribute to MBD, such as severe malnutrition, Crohn’s disease with malabsorption of calcium and vitamin D, and short bowel syndrome. Cancer may contribute to MBD through decreased intake of calcium and vitamin D from the diet or from surgery and chemotherapy.
The use of glucocorticoids for inflammatory bowel disease can be a major contributor to MBD. Glucocorticoids suppress osteoblast activity, inhibit vitamin D and calcium absorption in the gastrointestinal tract, and increase the activity of osteoblasts that leads to suppressed bone formation. Abitbol and associates evaluated bone disease in 84 patients with Crohn’s disease and ulcerative colitis. Patients had no complaints of bone pain and exhibited normal serum levels of calcium, phosphorus, and vitamin D. However, bone mineral density by DXA showed osteopenia among 43 percent of the patients, 52 percent of whom were receiving glucocorticoid therapy and 7 percent of whom had vertebral fractures. A statistically significant correlation with age and cumulative glucocorticoid doses was also observed. Other medications used to treat inflammatory disorders that can contribute to MBD include methotrexate, cyclosporine, and tacrolimus.
Calcium and Phosphorus
The single most important contributor to bone disease is a negative calcium balance, characterized by decreased intake and increased urinary calcium losses. The kidney filters 10,000 mg of non-protein-bound calcium each day, with greater than 98 percent reabsorbed by the renal tubules. The normal daily excretion of urinary calcium is 100 to 300 mg. Phosphate, also a major component of bone formation, is filtered by the kidneys. Approximately 7,000 mg of phosphate are filtered by the kidneys daily, and 87 percent is reabsorbed by the renal tubules.
Inadequate provision of calcium and phosphorus in PN can lead to nutrition-related MBD. Many of the early studies suggested that hypercalcuria may be the result of abnormal renal tubular function or disruption of PTH regulation, and adaptation appeared to occur with time, resulting in calcium conservation.
Hypercalcuria generally parallels urinary phosphate excretion. Adequate amounts of both calcium and phosphorus are necessary to promote maximal retention of calcium and phosphorus.
Recommended amounts of daily electrolytes for normal organ function have been suggested by the American Society for Parenteral and Enteral Nutrition, but electrolytes need to be individualized to the patient based on disease state and excess losses. Increasing the amount of phosphate and calcium in the parenteral nutrition formula can be a challenge and must be done cautiously. Excess amounts of phosphate and calcium can form a precipitate that makes TPN unsafe for administration.
High amino acid concentrations in PN have been shown to cause hypercalciuria. Patients receiving PN often require high doses of amino acids, especially at the initiation of therapy, to promote surgical wound healing and to replace losses, but protein doses should be reduced as serum protein concentrations normalize. Additional calcium should be added to the TPN while the amino acid provision remains high.
Metabolic acidosis in patients receiving long-term PN may contribute to MBD. Patients with renal insufficiency and renal failure and those with chronic diarrhea and malabsorption due to short bowel syndrome frequently experience chronic acidosis.
Patients who develop metabolic acidosis require substantial amounts of acetate in their PN to prevent mobilization of calcium carbonate stores from bone to buffer the acid load.
Treatment of MBD
Because of the many factors contributing to the development of MBD in long-term PN patients, treatment can be challenging. Adequate amounts of calcium, vitamin D, magnesium, and phosphorus in the PN solution are the foremost considerations. Supplemental doses may be indicated for severely depleted patients. Underlying conditions or diseases such as those that involve inflammatory responses should be treated because the release of cytokines in stress promotes bone resorption. Glucocorticoids or medications that worsen calcium wasting should be eliminated or reduced substantially.
Exercise is one component of treatment for osteoporosis. Although its effects have not been studied in patients receiving long-term PN therapy, one investigation documented that a low-impact exercise routine for Crohn’s patients increased bone mineral density.
Pharmacologic Treatments for Osteoporosis
A variety of pharmacologic agents may be helpful for patients who have PN-associated MBD. Treatment options for osteoporosis include vitamin D and calcium supplements, hormone replacement therapy (estrogen for women, testosterone for men), selective estrogen receptor modulators, antiresorptive drugs such as bisphosphonates, calcitonin, and bone-forming drugs.
The most widely used pharmacologic treatment for osteoporosis is the drug class of bisphosphonates (e.g. etidronate, alendronate, risedronate), which inhibit osteoclastic activity and decrease bone resorption. However, these medications can have undesirable gastrointestinal adverse effects and may not be well absorbed in patients with malabsorption or short bowel syndrome. Some of the bisphosphonates are available as weekly doses or in intravenous form. Calcitonin is available as a nasal spray.
To date, only one study has been performed in long-term PN patients using pharmacologic treatment. In a prospective, double-blind, randomized, controlled trial, Haderslev and colleagues compared the effects of clodronate, a bisphosphonate (available in Europe), with those of placebo in patients receiving long-term PN ( >1 year) who had evidence of abnormal bone mineral density (DXA T-score, <-1). Biochemical markers of bone resorption were statistically lower in the bisphosphonate group, and there was a significant increase in bone mineral density in the forearm. Bone mineral density was also increased in the spine and hip, but not significantly.
The bone-forming drug recently approved by the FDA for treatment of osteoporosis is teriparatide (Forteo-Eli Lilly, Indianapolis, Ind.) recombinant human parathyroid hormone. This drug increases osteoblast activity and has been shown to increase bone mineral content significantly and reduce the risk of fracture in patients with osteoporosis. Teriparatide has been shown to increase bone mineral content significantly in postmenopausal women, men with idiopathic osteoporosis, and patients with glucocorticoid-induced osteoporosis. It may be effective treatment for long-term PN patients with MBD, and clinical trials in this population are indicated.
Guidelines for Monitoring and Managing PN-Associated MBD
Several clinical studies have identified the prevalence of MBD and the contributing factors in long-term PN patients. Routine assessment and monitoring for MBD should be a standard of care for patients receiving long-term PN (>1 yr). Suggested guidelines for monitoring and managing these patients are listed on Table 2.
Routine blood and urine studies can aid in detecting MBD and evaluating the adequacy of minerals supplied in the PN solution, which are critical for bone remodeling. Protein concentration in PN may need to be adjusted and adequate amounts of acetate included to prevent mobilization of calcium carbonate from the bones. DXA should be used to assess bone mineral density, with referral to an endocrinologist, if necessary, for appropriate pharmacologic treatment.
Bone resorption medications should be minimized. Patients can be encouraged to incorporate exercise and cease smoking.
Patients receiving long-term PN are at risk of developing MBD, which can lead to severe bone pain, fracture, loss of height, and debilitation. The cause of MBD in patients receiving PN is not known, but several factors have been identified that contribute to its development. Clinicians who manage long-term PN patients should establish a standard of care for routine assessment and monitoring for MBD. PN solutions should be adjusted for adequate amounts of calcium, phosphorus, magnesium, and acetate, and protein should be limited after normalization of serum protein concentrations. Routine laboratory evaluation and 24-hour urine measurements of calcium and magnesium can help determine the adequacy of minerals supplied in the PN. DXA, which provides a definitive measure of bone mineral density and risk of fracture, should be obtained every 1 to 2 years. Patients with low bone mineral density should be referred to the endocrinologist for specific treatment. Pharmacologic agents, including bisphosphonates and bone-forming agents, have not been well studied in long-term PN patients, and clinical trials are indicated.
This article was adapted with permission from Support Line, a publication of Dietitians in Nutrition Support Dietetic Practice Group. For a copy of the complete article or references you may contact Jenifer Lefton, Support Line Editor at Jcannon390@aol.com.