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Aplastic Bone: A Nondisease of Medical Progress
Aplastic Bone: A Nondisease of Medical Progress Donald J. Sherrard Aplastic bone is characterized by a low bone formation rate, usually with no other histological abnormalities. Initially, it was thought to be caused by aluminum and was associated with a substantial morbidity. In the current milieu of dialysis, it is usually (>% of the time) not a result of aluminum toxicity. In the absence of large amounts of aluminum, aplastic bone is not an important cause of bone symptoms. It generally can be diagnosed by noninvasive means. Longer duration follow-up of such patients is needed, but up to now there is no evidence that this condition is a disease needing therapy.
© 1995 by the National Kidney Foundation, Inc. Index Words: Dialysis; aplastic bone renal osteodystrophy; aluminum; adynamic bone.
I
t is difficult to characterize and describe the aplastic (adynamic) bone lesion without first presenting something of the history and evolution of renal osteodystrophy. In the century before dialysis was developed, a connection was noted between kidney and bone disease.1,2 In addition, hyperparathyroidism was commonly noted in autopsies of patients who died of renal failure. In the first decade of dialysis (1960-1970), two calcium metabolic problems predominated: hyperparathyroidism and metastatic calcifications. 3 Both of these responded to phosphate control, which almost always required the administration of oral aluminum hydroxide as well as dietary restriction of phosphate. Aluminum was chosen, then, to be the primary phosphate binder because it was known to be not absorbed by the gastrointestinal tract, in contrast to calcium and magnesium. Of course, it is now known that aluminum is absorbed in the intestine. 4 Beginning in the 1970s, a second bone lesion, osteomalacia, appeared and was, for a time, even more common than the hyperparathyroid bone disease. 4 It was unclear for several years what caused this osteomalacia. Studies characterized the disorder as "vitamin 0 resistant," an important observation,s because the histologic picture strongly resembled the
From the Department of Medicine, the University of Washingtoll, Seattle. Supported by the General Medical Research Services of the Veterans Administration. Address correspondence to Donald ]. Sherrard, MD, the Veterans Administration, Nephrology (I11A), 1660 South Columbian Way, Seattle, WA 98108. © 1995 by the National Kidney Foundation, Inc. 1073-4449/ 95/ 0201-0005$3.00/ 0
20
osteomalacia seen with vitamin 0 deficiency. Subsequently, epidemiological data implicated aluminum as the cause. 6 This was then confirmed when a specific histological stain for aluminum showed the very high levels of bone aluminum in patients with dialysis osteomalacia. 4 Further support for bone aluminum toxicity was derived from aluminum exposure data, chelation treatment response, and a variety of animal studies. As these data accrued, it became apparent that another abnormality termed the aplastic lesion, could be seen with aluminum toxicity. This was characterized by low bone formation and high bone aluminum, both features of osteomalacia? However, these patients did not have an increased volume of osteoid, the defining characteristic of osteomalacia. When the aplastic lesion was first recognized, the initial impression was that this was the earliest form of aluminum bone disease, which probably evolved into overt osteomalacia with time. In some cases (but not all) the aluminumrelated aplastic bone lesion did progress to osteomalacia. In recent years aluminum usage has decreased and aluminum bone disease appears to be much less frequent. Certainly, the most overt form of aluminum bone disease, osteomalacia, occurs much less commonly.8Whether the aplastic form of aluminum toxicity has become less frequent is unclear because this lesion was only recently identified. What is almost certain is that the aplastic lesion in general has increased remarkably in frequency and it is usually not caused by aluminum. Not observed until the past 10 years, it now is seen in 50% of un selected dialysis patients and in two thirds of these it
Advances in Renal Replacement Therapy, Val 2, No 1 (January), 1995: pp 20-23
Aplastic Renal Osteodystrophy
does not appear to result from aluminum. In the remainder of this discussion, what is known about the causes, consequences, diagnosis, and management of this currently enigmatic disorder are assessed.
Causes Aluminum appears to be one cause of this lesion. When more than 25% of the bone surface is covered by aluminum in the aplastic lesion, the patient has all the features (see below) of aluminum-related osteomalacia. 8,9 Because these features reverse with aluminum removal, it seems most likely that aluminum is the cause. In patients with less than 25% bone surface aluminum, a variety of other factors is associated with an increased prevalence of the aplastic disorder. These factors may modulate this effect by lowering parathyroid activity (parathyroid hormone [PTH] is a major stimulus to osteoblasts), thereby reducing bone formation. These include peritoneal dialysis, with the use of supraphysiological dialysate calcium, and calcium carbonate therapy, which might be expected to maintain a higher calcium level. Curiously, parathyroidectomy, which should have lowered PTH more than any of the foregoing factors, was not seen as a risk factor except in the aplastic group with aluminum toxicity. Shorter dialysis duration, which is associated with lower PTH levels, was also more likely in patients with the aplastic disorder. Vitamin 0 treatment (particularly calcitrioPO) also suppresses PTH and might be expected to contribute to the lesion; however, the only large study of this possibility did not identify that as a risk factor.8 Two other conditions that seem to predispose to the development of the aplastic disorder are advanced age and diabetes. In both of these, lower bone formation is common in subjects with normal renal function,9 so it is hardly surprising that it occurs in patients on dialysis. In addition, diabetics on dialysis have an increased liklihood of having a low PTH level.
Consequences With excess aluminum (> 25% on bone surfaces), aplastic patients have a striking inci-
21
dence of proximal myopathy (69% of such patients), bone pain (42%), fractures (12%), and hypercalcemia (65%). In patients without excess aluminum, only hypercalcemia is seen with any increased frequency, and that occurs only in the patients with intermediate (6% to 24% of bone surface) aluminum levels. Patients with bone surface aluminum less than 6% have a lower incidence of hypercalcemia than dialysis patients with any other type of bone histology.8 Concerns have been expressed that the low bone formation in these patients could result in poor fracture healing or predispose to metastatic calcifications (Malluche H, personal communication; Hruska K, personal communication). So far, in those patients without excess aluminum, we have identified so few fractures that we cannot comment on the potential for poor fracture healing. We also have not noted an increase in metastatic calcifications, although further studies are being conducted to assess this issue.
Diagnosis The diagnosis of aplastic bone disease is dependent on assessment of PTH value and aluminum level (Fig 1). An intact PTH value of less than 100 pg/mL essentially identifies 90% of patients with low turnover bone disease and excludes 99% of patients with high turnover lesions. ll The distinction from the normal turnover ("mild") lesion is, however, less clear cut. No PTH value is particularly good in regards to incidence of false-positive and false-negative values in separating these two lesions. This may not be a particular problem because neither the mild nor the nonaluminumrelated aplastic lesion appears to confer any excess morbidity. Therefore, it is crucial for the clinician to identify those patients with low turnover bone who have aluminum toxicity. This group with aluminum bone disease will include both aplastic and osteomalacic subjects. Once a low PTH level « 100 pg/mL) is found, the next step in the evaluation of patients with important signs or symptoms (myopathy, bone pain, fracture, hypercalcemia) is to assess aluminum status with a deferoxamine challenge test.1 1 In
22
Donald]. Sherrard
< 100pg/ml
/
Measure Intact PTH
100-300
1
>500
1
Medical Rx (calcitrio1)
~
\
300-500
1
DFO test
+
~
Consider other bone disorders besides ROD
Medical Rx
Surgical Rx if necessary
Treat Aluminum Toxicity
Figure 1. Assessment of symptomatic renal osteodystrophy.
?bone biopsy
this test, serum aluminum is measured before dialysis. Deferoxamine (40 mg/ kg) is then administered intravenously during the last 2 hours of dialysis in hemodialysis patients, or intraperitoneally in patients on peritoneal dialysis. The serum aluminum is then remeasured 48 to 72 hours later. An increase in aluminum above baseline, greater than 150 ~g/ L, diagnoses aluminum bone disease in over (90%) of patients who have a PTH level less than 100 pg/ mL, while excluding 95% of patients who do not have aluminum bone disease. A bone biopsy can be performed for patients who have equivocal data or have persistent symptoms despite negative screening tests. Bone histology will not only identify the rare patient whose screening data are incorrect, but also may help detect patients who
have some other cause of bone disease (eg, amyloid bone disease or osteoporosis).
Management For patients with aluminum bone disease, whether aplastic or osteomalacic, aluminum chelation is still indicated. Deferoxamine will bind significant amounts of aluminum that can then be removed via dialysis. Because deferoxamine is extremely toxic, dosage is generally between 500 and 1,000 mg once weekly; the drug is administered for 2 to 3 months. Little toxicity has been noted with this regimen, although no definitive reports confirm this. Early reports recommended 40 mg/ kg intravenously administered once weekly for 6 to 12 months.12 Generally this was curative. How-
Aplastic Renal Osteodystrophy
ever, a high incidence (perhaps 10% of patients), developed a serious infection, usually the fungus mucormycosis. 13 Over 90% of such patients died. For this reason, we now use the much lower doses noted above. In addition, aluminum usage has markedly diminished in dialysis patients resulting in a considerable reduction in the prevalence of aluminum toxicity. What should be done for patients with low turnover bone disease without aluminum toxicity? Probably nothing! As noted, other than a modest tendency to develop hypercalcemia, few clinical problems occur. By carefully titrating vitamin 0, oral calcium and dialysate calcium the hypercalcemia can be easily managed and is rarely symptomatic. Recently we have reported on the potential of using low-calcium dialysate to stimulate PTH secretion, which in turn increases bone formation rates. Although this is feasible, after 1 year of such treatment we were unable to identify any benefit in the patients so treated.
Note Added in Proof Although the foregoing assessment was valid when written, more recent analyses of our data suggest that aplastic/adynamic bone disease may not be as benign as we thought. In information presented by Hercz et al and Sherrard et al at the meeting of the American Society of Nephrology, October 26-29, 1994, we described an apparent increase in fractures and in mortality with the aplastic lesion. This, together with the potential increase in fractures in renal transplant patients with aplastic bone disease, makes further long-term studies of this lesion imperative. For now, an intact PTH value in this population of less than 100
23
pg/mL, which is highly predictive of this lesion, must be viewed with concern.
References 1. Virchow R: Kalk-metastasen. Arch Pathol Anat Physiol 8:103-107,1877 2. Follis RH Jr, Jackson DB: Renal osteomalacia and osteitis fibrosa in adults. Bull Johns Hopkins Hosp 72:232-242,1943 3. Sherrard DJ: Aluminum toxicity-Much ado about something. N Engl J Med 324:558-559, 1991 4. Ott SM, Maloney NA, Coburn JW, et al: The prevalence of bone aluminum deposition in renal osteodystrophy and its relation to the response to calcitriol therapy. N Engl J Med 307:709-714, 1982 5. Coburn JW, Brickman AS, Massry SG, et al: Altered vitamin D metabolism in the pathogenesis of uremic osteodystrophy. Opuscula Medico-Technica Ludensia 6:51-78-5125, 1975 6. Parkenson IS, Ward MK, Feest TG, et al: Fracturing osteodystrophy and dialysis encephalopathy; an epidemiological survey. Lancet 1:406-409, 1979 7. Andress DL, Maloney NA, Coburn JW, et al: Osteomalacia and aplastic bone disease in aluminum-related osteodystrophy. J Clin Endocrinol Metab 65:11-16, 1987 8. Sherrard DJ, Hercz G, Pei Y, et al: The spectrum of bone disease in end-stage renal failure-An evolving disorder. Kidney Int 43:436-442,1993 9. Hercz G, Pei Y, Greenwood C, et al: Aplastic osteodystrophy without aluminum: The role of "suppressed" parathyroid function. Kidney Int 44:860-866,1993 10. Slatopolsky EA, Weerts C, Thielan J, et al: Marked suppression of secondary hyperparathyroidism (SH) by intravenous 1,25 (OHh D3 in uremic patients. J Clin Invest 74:2136-2142,1984 11. Pei Y, Hercz G, Greenwood C, et al: Non-invasive prediction of aluminum bone disease in hemo- and peritoneal dialysis patients. Kidney Int 41:1374-1382, 1992 12. Andress DL, Nebeker HG, Ott SM, et al: Bone histologic response to deferoxamine in aluminum-related bone disease. Kidney Int 31:1344-1350,1987 13. Windus DW, Stokes TJ, Julian BA, et al: Fatal rhizopus infections in hemodialysis patients receiving deferoxamine. Ann Intern Med 107:678-680, 1987
© 1995 by the National Kidney Foundation, Inc. Index Words: Dialysis; aplastic bone renal osteodystrophy; aluminum; adynamic bone.
I
t is difficult to characterize and describe the aplastic (adynamic) bone lesion without first presenting something of the history and evolution of renal osteodystrophy. In the century before dialysis was developed, a connection was noted between kidney and bone disease.1,2 In addition, hyperparathyroidism was commonly noted in autopsies of patients who died of renal failure. In the first decade of dialysis (1960-1970), two calcium metabolic problems predominated: hyperparathyroidism and metastatic calcifications. 3 Both of these responded to phosphate control, which almost always required the administration of oral aluminum hydroxide as well as dietary restriction of phosphate. Aluminum was chosen, then, to be the primary phosphate binder because it was known to be not absorbed by the gastrointestinal tract, in contrast to calcium and magnesium. Of course, it is now known that aluminum is absorbed in the intestine. 4 Beginning in the 1970s, a second bone lesion, osteomalacia, appeared and was, for a time, even more common than the hyperparathyroid bone disease. 4 It was unclear for several years what caused this osteomalacia. Studies characterized the disorder as "vitamin 0 resistant," an important observation,s because the histologic picture strongly resembled the
From the Department of Medicine, the University of Washingtoll, Seattle. Supported by the General Medical Research Services of the Veterans Administration. Address correspondence to Donald ]. Sherrard, MD, the Veterans Administration, Nephrology (I11A), 1660 South Columbian Way, Seattle, WA 98108. © 1995 by the National Kidney Foundation, Inc. 1073-4449/ 95/ 0201-0005$3.00/ 0
20
osteomalacia seen with vitamin 0 deficiency. Subsequently, epidemiological data implicated aluminum as the cause. 6 This was then confirmed when a specific histological stain for aluminum showed the very high levels of bone aluminum in patients with dialysis osteomalacia. 4 Further support for bone aluminum toxicity was derived from aluminum exposure data, chelation treatment response, and a variety of animal studies. As these data accrued, it became apparent that another abnormality termed the aplastic lesion, could be seen with aluminum toxicity. This was characterized by low bone formation and high bone aluminum, both features of osteomalacia? However, these patients did not have an increased volume of osteoid, the defining characteristic of osteomalacia. When the aplastic lesion was first recognized, the initial impression was that this was the earliest form of aluminum bone disease, which probably evolved into overt osteomalacia with time. In some cases (but not all) the aluminumrelated aplastic bone lesion did progress to osteomalacia. In recent years aluminum usage has decreased and aluminum bone disease appears to be much less frequent. Certainly, the most overt form of aluminum bone disease, osteomalacia, occurs much less commonly.8Whether the aplastic form of aluminum toxicity has become less frequent is unclear because this lesion was only recently identified. What is almost certain is that the aplastic lesion in general has increased remarkably in frequency and it is usually not caused by aluminum. Not observed until the past 10 years, it now is seen in 50% of un selected dialysis patients and in two thirds of these it
Advances in Renal Replacement Therapy, Val 2, No 1 (January), 1995: pp 20-23
Aplastic Renal Osteodystrophy
does not appear to result from aluminum. In the remainder of this discussion, what is known about the causes, consequences, diagnosis, and management of this currently enigmatic disorder are assessed.
Causes Aluminum appears to be one cause of this lesion. When more than 25% of the bone surface is covered by aluminum in the aplastic lesion, the patient has all the features (see below) of aluminum-related osteomalacia. 8,9 Because these features reverse with aluminum removal, it seems most likely that aluminum is the cause. In patients with less than 25% bone surface aluminum, a variety of other factors is associated with an increased prevalence of the aplastic disorder. These factors may modulate this effect by lowering parathyroid activity (parathyroid hormone [PTH] is a major stimulus to osteoblasts), thereby reducing bone formation. These include peritoneal dialysis, with the use of supraphysiological dialysate calcium, and calcium carbonate therapy, which might be expected to maintain a higher calcium level. Curiously, parathyroidectomy, which should have lowered PTH more than any of the foregoing factors, was not seen as a risk factor except in the aplastic group with aluminum toxicity. Shorter dialysis duration, which is associated with lower PTH levels, was also more likely in patients with the aplastic disorder. Vitamin 0 treatment (particularly calcitrioPO) also suppresses PTH and might be expected to contribute to the lesion; however, the only large study of this possibility did not identify that as a risk factor.8 Two other conditions that seem to predispose to the development of the aplastic disorder are advanced age and diabetes. In both of these, lower bone formation is common in subjects with normal renal function,9 so it is hardly surprising that it occurs in patients on dialysis. In addition, diabetics on dialysis have an increased liklihood of having a low PTH level.
Consequences With excess aluminum (> 25% on bone surfaces), aplastic patients have a striking inci-
21
dence of proximal myopathy (69% of such patients), bone pain (42%), fractures (12%), and hypercalcemia (65%). In patients without excess aluminum, only hypercalcemia is seen with any increased frequency, and that occurs only in the patients with intermediate (6% to 24% of bone surface) aluminum levels. Patients with bone surface aluminum less than 6% have a lower incidence of hypercalcemia than dialysis patients with any other type of bone histology.8 Concerns have been expressed that the low bone formation in these patients could result in poor fracture healing or predispose to metastatic calcifications (Malluche H, personal communication; Hruska K, personal communication). So far, in those patients without excess aluminum, we have identified so few fractures that we cannot comment on the potential for poor fracture healing. We also have not noted an increase in metastatic calcifications, although further studies are being conducted to assess this issue.
Diagnosis The diagnosis of aplastic bone disease is dependent on assessment of PTH value and aluminum level (Fig 1). An intact PTH value of less than 100 pg/mL essentially identifies 90% of patients with low turnover bone disease and excludes 99% of patients with high turnover lesions. ll The distinction from the normal turnover ("mild") lesion is, however, less clear cut. No PTH value is particularly good in regards to incidence of false-positive and false-negative values in separating these two lesions. This may not be a particular problem because neither the mild nor the nonaluminumrelated aplastic lesion appears to confer any excess morbidity. Therefore, it is crucial for the clinician to identify those patients with low turnover bone who have aluminum toxicity. This group with aluminum bone disease will include both aplastic and osteomalacic subjects. Once a low PTH level « 100 pg/mL) is found, the next step in the evaluation of patients with important signs or symptoms (myopathy, bone pain, fracture, hypercalcemia) is to assess aluminum status with a deferoxamine challenge test.1 1 In
22
Donald]. Sherrard
< 100pg/ml
/
Measure Intact PTH
100-300
1
>500
1
Medical Rx (calcitrio1)
~
\
300-500
1
DFO test
+
~
Consider other bone disorders besides ROD
Medical Rx
Surgical Rx if necessary
Treat Aluminum Toxicity
Figure 1. Assessment of symptomatic renal osteodystrophy.
?bone biopsy
this test, serum aluminum is measured before dialysis. Deferoxamine (40 mg/ kg) is then administered intravenously during the last 2 hours of dialysis in hemodialysis patients, or intraperitoneally in patients on peritoneal dialysis. The serum aluminum is then remeasured 48 to 72 hours later. An increase in aluminum above baseline, greater than 150 ~g/ L, diagnoses aluminum bone disease in over (90%) of patients who have a PTH level less than 100 pg/ mL, while excluding 95% of patients who do not have aluminum bone disease. A bone biopsy can be performed for patients who have equivocal data or have persistent symptoms despite negative screening tests. Bone histology will not only identify the rare patient whose screening data are incorrect, but also may help detect patients who
have some other cause of bone disease (eg, amyloid bone disease or osteoporosis).
Management For patients with aluminum bone disease, whether aplastic or osteomalacic, aluminum chelation is still indicated. Deferoxamine will bind significant amounts of aluminum that can then be removed via dialysis. Because deferoxamine is extremely toxic, dosage is generally between 500 and 1,000 mg once weekly; the drug is administered for 2 to 3 months. Little toxicity has been noted with this regimen, although no definitive reports confirm this. Early reports recommended 40 mg/ kg intravenously administered once weekly for 6 to 12 months.12 Generally this was curative. How-
Aplastic Renal Osteodystrophy
ever, a high incidence (perhaps 10% of patients), developed a serious infection, usually the fungus mucormycosis. 13 Over 90% of such patients died. For this reason, we now use the much lower doses noted above. In addition, aluminum usage has markedly diminished in dialysis patients resulting in a considerable reduction in the prevalence of aluminum toxicity. What should be done for patients with low turnover bone disease without aluminum toxicity? Probably nothing! As noted, other than a modest tendency to develop hypercalcemia, few clinical problems occur. By carefully titrating vitamin 0, oral calcium and dialysate calcium the hypercalcemia can be easily managed and is rarely symptomatic. Recently we have reported on the potential of using low-calcium dialysate to stimulate PTH secretion, which in turn increases bone formation rates. Although this is feasible, after 1 year of such treatment we were unable to identify any benefit in the patients so treated.
Note Added in Proof Although the foregoing assessment was valid when written, more recent analyses of our data suggest that aplastic/adynamic bone disease may not be as benign as we thought. In information presented by Hercz et al and Sherrard et al at the meeting of the American Society of Nephrology, October 26-29, 1994, we described an apparent increase in fractures and in mortality with the aplastic lesion. This, together with the potential increase in fractures in renal transplant patients with aplastic bone disease, makes further long-term studies of this lesion imperative. For now, an intact PTH value in this population of less than 100
23
pg/mL, which is highly predictive of this lesion, must be viewed with concern.
References 1. Virchow R: Kalk-metastasen. Arch Pathol Anat Physiol 8:103-107,1877 2. Follis RH Jr, Jackson DB: Renal osteomalacia and osteitis fibrosa in adults. Bull Johns Hopkins Hosp 72:232-242,1943 3. Sherrard DJ: Aluminum toxicity-Much ado about something. N Engl J Med 324:558-559, 1991 4. Ott SM, Maloney NA, Coburn JW, et al: The prevalence of bone aluminum deposition in renal osteodystrophy and its relation to the response to calcitriol therapy. N Engl J Med 307:709-714, 1982 5. Coburn JW, Brickman AS, Massry SG, et al: Altered vitamin D metabolism in the pathogenesis of uremic osteodystrophy. Opuscula Medico-Technica Ludensia 6:51-78-5125, 1975 6. Parkenson IS, Ward MK, Feest TG, et al: Fracturing osteodystrophy and dialysis encephalopathy; an epidemiological survey. Lancet 1:406-409, 1979 7. Andress DL, Maloney NA, Coburn JW, et al: Osteomalacia and aplastic bone disease in aluminum-related osteodystrophy. J Clin Endocrinol Metab 65:11-16, 1987 8. Sherrard DJ, Hercz G, Pei Y, et al: The spectrum of bone disease in end-stage renal failure-An evolving disorder. Kidney Int 43:436-442,1993 9. Hercz G, Pei Y, Greenwood C, et al: Aplastic osteodystrophy without aluminum: The role of "suppressed" parathyroid function. Kidney Int 44:860-866,1993 10. Slatopolsky EA, Weerts C, Thielan J, et al: Marked suppression of secondary hyperparathyroidism (SH) by intravenous 1,25 (OHh D3 in uremic patients. J Clin Invest 74:2136-2142,1984 11. Pei Y, Hercz G, Greenwood C, et al: Non-invasive prediction of aluminum bone disease in hemo- and peritoneal dialysis patients. Kidney Int 41:1374-1382, 1992 12. Andress DL, Nebeker HG, Ott SM, et al: Bone histologic response to deferoxamine in aluminum-related bone disease. Kidney Int 31:1344-1350,1987 13. Windus DW, Stokes TJ, Julian BA, et al: Fatal rhizopus infections in hemodialysis patients receiving deferoxamine. Ann Intern Med 107:678-680, 1987