Oley Research Symposium Part II: Bone Disease
Under the auspices of the American Society of Parenteral and Enteral Nutrition, the Oley Foundation recently sponsored a symposium to discuss the association between parenteral nutrition and liver and bone disease. The symposium provided clinicians an opportunity to focus on pertinent research issues, with the goal of defining practical strategies for further study of these serious PN complications. An account of the group’s discussion of PN associated liver disease was presented to Oley members in the last issue of the LifelineLetter. This issue continues with an overview of metabolic bone disease (MBD) and parenteral nutrition as described at the Oley symposium.
The discussion of bone disease included presentations by Dr. Dan Hurley of the Mayo Clinic, Minnesota, and Dr. Doug Seidner of the Cleveland Clinic. It was moderated by Dr. Lyn Howard of the Albany Medical Center.
What is metabolic bone disease?
Metabolic bone disease results from an impairment of bone remodeling, the process by which the body replaces old bone and repairs bone fractures. In normal bone remodeling, damaged or weakened bone is dissolved, or, ‘resorbed’, and the constituent minerals are recycled through the blood stream as calcium and phosphate available to form new bone or for other bodily functions. Bone remodeling depends upon an adequate supply of these minerals via the bloodstream. When serum calcium levels fall below a specific threshold, parathyroid hormone (PTH) is secreted, triggering increased calcium absorption from the gut and also calcium resorption from old bone. These metabolic processes raise the level of serum calcium to enable new bone formation.
The metabolic processes associated with the conservation of calcium occur primarily in the kidney. Under normal circumstances, approximately ninety-nine per cent of the calcium that filters through the kidney is restored to the blood. The remaining one percent, roughly 100-300 mg/day, is lost through urinary excretion. Complex metabolic activities ensure that this balance is preserved. PTH, calcitonin, and vitamin D are among the substances involved in limiting renal loss of calcium and preserving positive levels of serum calcium. Any defect or dysfunction at any point in this intricate metabolic process can undermine healthy bone remodeling and lead to MBD.
There are many forms of MBD, but those most commonly encountered are osteoporosis and osteomalacia. Osteoporosis is characterized by bones with a normal protein matrix/bone crystal ratio, but abnormally low total bone mass. This makes osteoporotic bones susceptible to stress and compression fractures. Broadly speaking, osteoporosis results either from an increased rate of bone resorption, or less commonly from a decreased rate of bone formation. In contrast, osteomalacia is an abnormality of bone formation resulting in excessive accumulation of bone matrix which is very poorly mineralized. Osteomalacia can lead to bone pain, fractures, skeletal deformity and muscle weakness, especially of the thighs.
The reduced bone mineral mass of osteoporosis and osteomalacia can generally be diagnosed by radiological measurement of bone mineral density. The underlying pathological processes are distinguished by blood tests or bone biopsy. There are several means of measuring bone density, but the method most commonly employed is dual energy absorptiometry (DEXA). DEXA is preferred over other techniques because it is a simple, rapid procedure that is low in cost and involves the lowest level of exposure to radiation (about 1/4 the exposure of a chest x-ray).
How is PN associated with MBD?
Parenteral nutrition solutions contain many nutrients that influence serum calcium levels. Some of these, such as phosphorous and magnesium, promote positive calcium balance by reducing the urinary excretion of calcium. Others, such as amino acids, dextrose, sodium and possibly even some forms of vitamin D, may promote a net calcium loss. Parenteral vitamin D, for example, has been associated with a form of MBD similar to osteomalacia. It is thought that excess levels of this vitamin suppress the production of PTH, interfering both with release of calcium from old bone and with preservation of calcium by the kidney. The impact of PN solutions on serum calcium levels is especially pronounced during the initial period of PN therapy, when most patients experience a marked increase in the urinary excretion of calcium, a condition known as hypercalciuria. Hypercalciuria does not generally persist past the first several weeks of PN therapy, but during this period it may precipitate rapid and potentially lasting deterioration in bone health.
Aspects of PN therapy other than parenteral solutions have been considered as possible risk factors for MBD. A study completed in the late 1980’s concluded that urinary calcium loss is increased by the practice of infusing in cycles of twelve hours on/twelve hours off, as compared to a continuous twenty-four hour infusion. Subsequent studies have questioned this finding, suggesting that while cycled infusions may increase calcium loss during the infusion period, net loss over twenty-four hours is not greater.
Both central catheters and the use of heparin to maintain line patency have been cited as factors contributing to MBD. Central lines may cause the growth of bacteria, and their production of toxins could adversely affect bone remodeling. However, a 1997 animal study addressing this point found that Macaque monkeys provided with central lines, but maintained on a normal oral diet, experienced no change in their urinary calcium output, serum calcium levels, or other MBD markers such as PTH values. The use of heparin in high doses (greater than 10,000 units) has been linked to MBD in some patient groups. Although this issue has not been studied in PN patients, it is generally assumed that the substantially lower doses of heparin used in PN therapy have no consequence for bone remodeling. This question perhaps deserves further investigation.
Does PN cause MBD?
Despite the many connections between PN and MBD, it is extremely difficult to isolate the impact of parenteral nutrition on the bone health of any given patient. There are several reasons for this.
Many people who begin PN therapy already have some form of MBD. Parenteral nutrition is typically required by those suffering from inflammatory bowel disease, radiation enteritis, short gut, cancer and other medical disorders which are associated with a variety of risk factors for bone disease independent of infusion therapy. Such disorders are associated with malnourishment, malabsorption of key nutrients such as calcium and vitamin D, prolonged bedrest or inactivity, bowel surgery and other conditions that adversely affect bone. In addition, these disorders frequently involve forms of treatment, such as steroids, that also increase the risk of MBD.
Under these circumstances, it is obviously very difficult to attribute MBD to parenteral nutrition therapy rather than some antecedent condition. Routine screening of patients for bone disease prior to commencing PN therapy would go far toward clarifying this issue. Such tests, however, are not presently standard of care except where clinical symptoms are present. This is rarely the case, as most patients with early MBD are asymptomatic. In consequence, it is generally not known if patients have underlying bone disease prior to beginning PN therapy.
Patient response to PN therapy further complicates the task of identifying the specific mechanisms through which parenteral nutrition might affect bone remodeling. PTH levels often vary significantly from one consumer to another. Some show marked decreases in PTH, others remain in the normal range, while still others show increased PTH levels. Much the same is true of many other indicators of MBD, including bone density measurements. A study completed in l993 followed fourteen long term PN patients for two years with DEXA scans. The results were random: Some patients showed normal bone density, others were mildly below normal, still others were well below normal. Some patients had below normal bone density before beginning PN therapy and showed improvement after starting parenteral nutrition. Some showed no change, while others got worse. Such findings tend to muddy the water, but since they are based on limited data, it may be that a very different picture will emerge given more extensive and more standardized use of diagnostic testing.
Where do we go from here?
The dynamics of bone remodeling are largely known and provide a conceptual framework that elucidates the potential links between parenteral nutrition and metabolic bone disease. However, any actual adverse effects of PN on bone metabolism are typically camouflaged both by the heterogeneity of patient response to PN and by the fact that PN therapy often occurs alongside a host of other risk factors that affect bone remodeling in similar ways. Again and again, discussion at the Oley symposium returned to the problem of sorting through this mix of risk factors in order to identify the specific impact of PN, target treatment accordingly and evaluate outcomes. It was equally clear that the way out of this difficulty begins with detailed patient data on a large number of subjects.
Following the expert presentation, a workgroup met to identify the kind of data that is presently most needed. The group looked for test protocols that were low in cost, that could extend to multicenter studies, and could detect rapid changes in bone remodeling during the initial period of PN therapy. The burden of discussion fell on ways of structuring the use of such tests to generate maximum data. Many ideas were discussed with an eye toward striking a balance between the ideal and the feasible. For example, ideally a large study group of several hundred patients would enable correlations between PN therapy and disease subgroups, but finding such a large number of suitable patients, especially prior to their having commenced PN therapy, poses obvious problems. Conversely, other options seemed highly practical. DEXA scans, for example, are reliable, inexpensive and covered by most insurers. Such scans could be used to follow patients over a two-year period, taking bone density values at the start of PN therapy and then again during the fourth, eighth, twelfth, eighteenth and twenty-fourth months. This strategy, used in conjunction with other tests, such as the measurement of urinary calcium and creatinine, PTH levels and other markers of MBD, would help stratify patients into high, medium and low risk groups, and would assess which markers need continuous monitoring and at what intervals. These studies will lead to screening protocols that do not simply identify PN-MBD, but offer a means of studying its progression, providing insight into such issues as its prevalence and interaction with other risk factors.
The more PN consumers know about the nature of MBD, the better able they are to discuss their circumstances and options with their physicians. Similarly, the more physicians and other clinicians learn from their patients about Oley’s attempt to focus existing resources on the study of PN-MBD, the greater the likelihood of collaborative efforts against this serious complication of parenteral nutrition therapy.
The Oley Foundation thanks the many individuals who made this research symposium possible, including the organizers, presenters and participants. The Foundation would also like to recognize the volunteer efforts of those who wrote and reviewed the articles covering the symposium.
Copyright © 1995 The Oley Foundation