Parathyroid Hormone and the Hypercalcemia of Immobilization SAM LERMAN,* JANET M. CANTERBURY, AND ERIC REISS Division of Endocrinology, Department of Medicine, University of Miami School of Medicine, Miami, Florida 33152 ABSTRACT. Serial measurements of serum calcium and immunoreactive parathyroid hormone (PTH) were performed in two young patients with hypercalcemia of immobilization. Serum PTH was elevated in both patients. With mobilization, both serum PTH and serum calcium returned to normal levels
H
YPERCALCIURIA and hyperphosphaturia are well-recognized consequences of immobilization (1-3). The hypercalciuria may be severe and not infrequently is complicated by renal calculi. Hypercalcemia, especially elevation of the ionized fraction, occurs less commonly. It is usually mild, but in young patients may become severe and even life-threatening (4-14). Scanty and conflicting results have been reported concerning the role of parathyroid hormone (PTH) in the genesis of immobilization hypercalcemia. Hyman et al. (8), Claus-Walker et al. (13) and Heath (15) have reported circulating PTH levels in the normal range. Henke et al. (12) recorded elevation of serum PTH in one patient as did Arnstein et al. (16) in 8 of 17 patients with paralysis due to spinal cord trauma. Lawrence (14), on the other hand, noted decreased serum PTH in another patient. We report here long-term, sequential studies of circulating PTH levels in two immobilized patients in whom increased concentration of PTH were associated with severe hypercalcemia. Materials and Methods Serum calcium was measured by atomic absorption spectrophotometry or the SMA-12 colorimetric method (see legends to figures). Serum Received May 24, 1976. Supported in part by NIH Grant AM-16768. * Dr. Lerman is a Clinical and Research Fellow of the Medical Research Council of Canada. Reprint requests to: Dr. Eric Reiss, Dept. of Medicine, University of Miami School of Medicine, P.O. Box 520875, Biscayne Annex, Miami, Florida 33152.
and remained so during six months of follow-up. The hyperparathyroidism of immobilization is an unexplained, reversible disorder that should be treated by medical measures and aggresive attempts at early mobilization. (J Clin Endocrinol Metab 45:425, 1977)
PTH was immunoassayed using an antiserum (CH-824) whose affinity characteristics have been thoroughly described (17, 18). It reacts with both intact hormone and two smaller molecular weight forms of PTH, a carboxy terminal fragment and an amino terminal fragment. The antiserum has been found to be highly useful in distinguishing patients with normal parathyroid function from those with abnormal function under steady state conditions. The antiserum has been found less useful for the detection of rapid changes in PTH secretory rates. With calcium infusions in normal subjects, the overall half-time of immunoassayable hormone disappearance from the circulation approximates 3 h. Phase separation of the immunoassay was accomplished by a modification of the procedure described by Arnaud et al. (19). All calcium determinations were performed on fresh samples on the day of collection. PTH determinations were performed generally within a period of one week. In properly stoppled vials we have found that serum samples maintain unaltered PTH activity. Case Reports Patient No. 1, a previously healthy and active boy of 15, was admitted to another institution on September 2, 1973, after being struck by a truck. He sustained fractures of the pelvis, sacrum, and the third and fourth lumbar vertebrae. The bladder was contused, the sciatic nerve injured, and the rectum lacerated. There were extensive soft tissue injuries of the lower back and buttocks. Subsequently, massive soft tissue infection required extensive debridement. He was then transferred to the Rehabilitation Institute of lackson Memorial Hospital for further management and rehabilitation. On September 25, 1973, full-thickness skin grafts were applied to the buttocks. During the next five months, the patient remained almost
425
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LERMAN, CANTERBURY AND REISS
426
completely immobilized, lying prone. He experienced recurrent episodes of nausea and vomiting, ate poorly, and lost 50 pounds. The serum calciums on admission to our hospital ranged from 6.9-7.5 mg% (serum albumin 1.8-3.1 mg%). Mild hypercalcemia (11.5 mg%) was first noted in October of 1973, seven weeks after the accident. On March 3, 1974, serum calcium was 14.5 mg%. Serum creatinine was 1.6 mg% and BUN 19 mg%. PTH in relation to therapy and mobilization is shown in Fig. 1. Convalescence was slow. On March 24, 1974, a bladder calculus obstructing the right ureter was removed cystoscopically. Mobilization was difficult to accomplish because of the extent of the injuries. As shown in Fig. 1, serum calcium and PTH did not return to normal until the patient became fully mobile. Six months after discharge, serum calcium was 10.0 mg% and PTH 35 /ulEq/ml. He had resumed normal activities. Patient No. 2, an 11-year-old boy, dove into a shallow pool and sustained dislocation of the fourth and fifth cervical vertebrae on January 1, 1975. He was treated at another hospital for a flaccid quadriplegia with absence of sensation below the fifth cervical level. A month later, he was admitted to the Rehabilitation Institute. He had regained some motor function in the left upper extremity and sensation had returned to the T-10 level.
JCE & M • 1977 Vol 45 • No 3
Serum calcium on admission was 16.3 mg% (SMA-12). BUN was 40 mg% and serum creatinine 1.7 mg%. Serum calcium and PTH in relation to therapy and activity are shown in Fig. 2. Convalescence was slow but steady with gradually returning function and, eventually, full mobilization. On discharge, the patient walked without assistance. One month after discharge, the serum calcium was 0.3 mg% and serum PTH 30 /zlEq/ml. Discussion The hypercalcemia of immobilization is largely confined to patients with rapid bone turnover, notably children. In the first full description of the syndrome of immobilization hypercalcemia, Albright et al. (10) arrived at the erroneous diagnosis of primary hyperparathyroidism; normal parathyroid glands were described at surgery. Serum calcium in Albright's patient returned to normal when full mobilization was achieved. The recorded data applying the immunoassay of PTH in the study of immobilization hypercalcemia are inconsistent and confusing. This is understandable since much of the information was obtained before the problems of heterogeneity of circulating
300
16.0 250 15.0 200 14.0 SERUM
13.0
150
P T H
100
. _ «
CALCIUM (mg%)
12.0
o-~o 11.0
50 10.0
9.0 FLUIDS •FLUIDS P.O.P.O. & I.V. TREATMENT • FLEET PHOSPHO-SODA-
FIG. 1. Patient No. 1. Serum calcium was measured by SMA-12 Colorimetric method. The average value for November to February followed by weekly values are plotted. Normal range, 8.5-10.5 mg%. PTH represents individual assays. Normal range for PTH, 10-60 julEq/ml. Mobility: 0, immobile; +, up in chair or tilt table once daily; + + , tilt table and use of parallel bars; + + + , walking with assistance but infrequently; + + + + walking without assistance at least three times daily.
MOBILITY
NOV-FEB. MARCH
APRIL
MAY
JUNE
JULY DISCHARGE
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427
PARATHYROID HORMONE IN IMMOBILIZATION 300 16.0
250
15.0 200
14.0
FIG. 2. Patient No. 2. Serum calcium was measured by atomic absorption spectrophotometry. The weekly average values are plotted. Normal range, 9.1-10.6 mg%. For mobility, see legend of Fig. 1. Treatment: 1—Intravenous and oral fluids; la—Oral fluids only; 2—Furosemide; 3— Steroids; 4—Fleet Phospho-Soda.
SERUM CALCIUM
13.0
(mg%)
12.0
150
PTH MEq/ml]
100
•
•
11.0 50
10.0
0
9.0 TREATMENT
1 -2-H H3H 1-4-1
MOBILITY FEB.
MARCH
APRIL
MAY
DISCHARGE
PTH were appreciated (20,21). In Hyman's report (8) the antiserum used is not specified. Heath et al. (15) provide no information about the PTH assay. Similarly, ClausWalker et al. (13) and Lawrence (14) provide no information about the specificity of the assay used. Thus, the available information is difficult to interpret, and discrepancies in results are not surprising. During immobilization, calcium is mobilized from the skeleton as a result of stillundefined factors (22). In this context, one would anticipate a tendency toward hypercalcemia with a suppression of PTH secretion. Hence, our observation of elevated levels of circulating PTH is surprising. Neither of the patients studied by us had any evidence of the common clinical types of hypercalcemic (primary) hyperparathyroidism. It would appear that the marked increase in PTH secretion was caused by some non-ionic stimulus. Several such nonionic stimuli have been reported (23-25); catecholamines, for example, have been shown to be powerful PTH secretagogues (23). It is not clear to what extent increased PTH secretion can account for the hypercalcemia in our two patients. The observed
elevations of PTH were moderate, and we rarely have noted severe hypercalcemia in adults with such moderate hyperparathyroidism. Perhaps children with their normally increased bone turnover are more sensitive. Increased levels of immunoreactive PTH have been generally attributed to increased secretion of the hormone. This may be a false interpretation since both metabolism (17) and renal excretion (26) may be determining factors of steady-state hormone concentrations. So far, however, these theoretical possibilities have not been explored in clinical practice. There is some indirect evidence supporting the notion that PTH contributes to the mobilization of bone mineral during immobilization. Heany demonstrated by means of calcium kinetic studies that immobilization is associated with increased bone resorption (27). Burkhardt and Jowsey demonstrated that in parathyroidectomized animals the osteoporosis of immobilization does not occur (28). The present study is deficient in that we have no systematic data on calcium excretion and no biologic marker, such as excretion of nephogenic cyclic AMP, to correlate with immunoassay results. Despite this
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428
LERMAN, CANTERBURY AND REISS
limitation and the obvious gaps in the understanding of the relationship between PTH secretion and immobilization, the present report has clear practical implications. The hypercalcemia of immobilization associated with increased circulating levels of PTH is a medical rather than a surgical problem. The hyperparathyroidism is reversible by mobilization. References 1. Deitrick, J. E., G. D. Whedon, and E. Shorr, Effects of immobilization upon various metabolic and physiologic functions of normal men, Am J Med 4: 3, 1948. 2. Whedon, G. D., and E. Shorr, Metabolic studies in paralytic acute anterior poliomyelitis. II. Alterations in calcium and phosphorus metabolism, J Clin Invest 36: 966, 1957. 3. Issekutz Jr., B., J. J. Blizzard, N. C. Birkhead, and K. Rodahl, Effect of prolonged bed rest on urinary calcium output, J Appl Physiol 21: 1013, 1966. 4. Heath III,H., J. M. Earll, M. Schaaf, J. T. Piechocki, and T.-K. Li, Serum ionized calcium during bed rest in fracture patients and normal men, Metabolism 21: 633, 1972. 5. Halvorsen, S., Osteoporosis, hypercalcemia and neophropathy following immobilization of children, Ada Med Scand 149: 401, 1954. 6. Mason, A. S., Acute osteoporosis with hypercalcemia, Lancet 1: 911, 1957. 7. Winters, J. L., A. G. Kleinschmidt Jr., J. J. Frensilli, and M. Sutton, Hypercalcemia complicating immobilization in the treatment of fractures, J Bone Surg 48A: 1182, 1966. 8. Hyman, L. R., G. Boner, J. C. Thomas, and W. E. Segar, Immobilization hypercalcemia, Am J Dis Child 124: 723, 1972. 9. Dodd, K., H. Graubarth, and S. Rapoport, Hypercalcemic neophropathy and encephalopathy following immobilization, Pediatrics 6: 124, 1950. 10. Albright, F., C. H. Burnett, O. Cope, and W. Parson, Acute atrophy of bone (osteoporosis) simulating hyperparathyroidism, J Clin Endocrinol Metab 1: 711, 1941. 11. Levine, C., R. B. Greer, III, and S. L. Gordon, Hypercalcemia complicating fracture immobilization: A report of three cases, J Trauma 15: 70, 1975. 12. Henke, J. A., N. W. Thompson, and H. Kaufer, Immobilization hypercalcemic crisis, Arch Surg 110: 321, 1975. 13. Claus-Walker, J., R. E. Carter, R. J. Campos, and W. A. Spencer, Hypercalcemia in early traumatic quadriplegiaj Chronic Dis 28: 81, 1975.
JCE & M • 1977 Vol 45 • No 3
14. Lawrence, G. D., R. G. Loeffler, L. G. Martin, and T. B. Connor, Immobilization hypercalcemia. Some new aspects of diagnosis and treatment, J Bone Joint Surg 55A: 87, 1973. 15. Heath III, H., M. Schaaf, H. L. Wray, J. M. Monchik, and J. M. Earll, In Frame, B., A. M. Parfitt, and H. Duncan (eds.), Clinical Aspects of Metabolic Bone Disease, Excerpta Medica, Amsterdam, 1973, p. 257. 16. Arnstein, A. R., D. S. McCann, F. S. Blumenthal, and J. Prunty, In Frame, B., A. M. Parfitt, and H. Duncan (eds.), Clinical Aspects of Metabolic Bone Disease, Excerpta Medica, Amsterdam, 1973, p. 253. 17. Canterbury, J. M., and E. Reiss, Multiple immunoreactive molecular forms of parathyroid hormone in human serum, Proc Soc Exp Biol Med 140: 1393, 1972. 18. Canterbury, J. M., L. A. Bricker, G. S. Levey, P. L. Kozlovskis, E. Ruiz, J. E. Zull, and E. Reiss, Metabolism of bovine parathyroid hormone. Immunological and biological characteristics of fragments generated by liver perfusion, J Clin Invest 55: 1245, 1975. 19. Arnaud, C. D., H. S. Tsao, and T. Littledike, Radioimmunoassay of human parathyroid hormone in serum,/ Clin Invest 50: 21, 1971. 20. Berson, S. A., and R. S. Yalow, Immunochemical heterogeneity of parathyroid hormone in plasma, J Clin Endocrinol Metab 28: 1037, 1968. 21. Reiss, E., and J. M. Canterbury, Emerging concepts of the nature of circulating parathyroid hormones: Implications for clinical research, Recent Prog Horm Res 30: 391, 1974. 22. Donaldson, C. L., S. B. Hulley, J. M. Vogel, R. S. Hahner, J. H. Bayers, and D. E. McMillan, Effect of prolonged bed rest of bond mineral, Metabolism 19: 1071, 1970. 23. Fischer, J. A., J. W. Blum, and U. Binswanger, Acute parathyroid hormone responses to epinephrine in vivoj Clin Invest 52: 2434, 1973. 24. Fischer, J. A., S. B. Oldham, G. W. Sizemore, and C. D. Arnaud, Calcitonin stimulation of parathyroid hormone secretion in vitro, Horm Metab Res 3: 223, 1971. 25. Abe, M., and L. M. Sherwood, Regulation of parathyroid hormone secretion by adenyl cyclase, Biochem Biophy Res Commun 48: 369, 1972. 26. Hruska, K. A., R. Kopelman, E. Rutherford, S. Klahr, and E. Slatopolsky, Metabolism of immunoreactive parathyroid hormone in the dog: The role of the kidney and the effects of chronic renal disease, J Clin Invest 56: 39, 1975. 27. Heany, R. P., Radiocalcium metabolism in disuse osteoporosis in man, Am J Med 33: 188, 1962. 28. Burkhart, J. M., and J. Jowsey, Parathyroid and thyroid hormones in the development of immobilization osteoporosis, Endocrinology 81: 1053, 1967.
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H
YPERCALCIURIA and hyperphosphaturia are well-recognized consequences of immobilization (1-3). The hypercalciuria may be severe and not infrequently is complicated by renal calculi. Hypercalcemia, especially elevation of the ionized fraction, occurs less commonly. It is usually mild, but in young patients may become severe and even life-threatening (4-14). Scanty and conflicting results have been reported concerning the role of parathyroid hormone (PTH) in the genesis of immobilization hypercalcemia. Hyman et al. (8), Claus-Walker et al. (13) and Heath (15) have reported circulating PTH levels in the normal range. Henke et al. (12) recorded elevation of serum PTH in one patient as did Arnstein et al. (16) in 8 of 17 patients with paralysis due to spinal cord trauma. Lawrence (14), on the other hand, noted decreased serum PTH in another patient. We report here long-term, sequential studies of circulating PTH levels in two immobilized patients in whom increased concentration of PTH were associated with severe hypercalcemia. Materials and Methods Serum calcium was measured by atomic absorption spectrophotometry or the SMA-12 colorimetric method (see legends to figures). Serum Received May 24, 1976. Supported in part by NIH Grant AM-16768. * Dr. Lerman is a Clinical and Research Fellow of the Medical Research Council of Canada. Reprint requests to: Dr. Eric Reiss, Dept. of Medicine, University of Miami School of Medicine, P.O. Box 520875, Biscayne Annex, Miami, Florida 33152.
and remained so during six months of follow-up. The hyperparathyroidism of immobilization is an unexplained, reversible disorder that should be treated by medical measures and aggresive attempts at early mobilization. (J Clin Endocrinol Metab 45:425, 1977)
PTH was immunoassayed using an antiserum (CH-824) whose affinity characteristics have been thoroughly described (17, 18). It reacts with both intact hormone and two smaller molecular weight forms of PTH, a carboxy terminal fragment and an amino terminal fragment. The antiserum has been found to be highly useful in distinguishing patients with normal parathyroid function from those with abnormal function under steady state conditions. The antiserum has been found less useful for the detection of rapid changes in PTH secretory rates. With calcium infusions in normal subjects, the overall half-time of immunoassayable hormone disappearance from the circulation approximates 3 h. Phase separation of the immunoassay was accomplished by a modification of the procedure described by Arnaud et al. (19). All calcium determinations were performed on fresh samples on the day of collection. PTH determinations were performed generally within a period of one week. In properly stoppled vials we have found that serum samples maintain unaltered PTH activity. Case Reports Patient No. 1, a previously healthy and active boy of 15, was admitted to another institution on September 2, 1973, after being struck by a truck. He sustained fractures of the pelvis, sacrum, and the third and fourth lumbar vertebrae. The bladder was contused, the sciatic nerve injured, and the rectum lacerated. There were extensive soft tissue injuries of the lower back and buttocks. Subsequently, massive soft tissue infection required extensive debridement. He was then transferred to the Rehabilitation Institute of lackson Memorial Hospital for further management and rehabilitation. On September 25, 1973, full-thickness skin grafts were applied to the buttocks. During the next five months, the patient remained almost
425
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LERMAN, CANTERBURY AND REISS
426
completely immobilized, lying prone. He experienced recurrent episodes of nausea and vomiting, ate poorly, and lost 50 pounds. The serum calciums on admission to our hospital ranged from 6.9-7.5 mg% (serum albumin 1.8-3.1 mg%). Mild hypercalcemia (11.5 mg%) was first noted in October of 1973, seven weeks after the accident. On March 3, 1974, serum calcium was 14.5 mg%. Serum creatinine was 1.6 mg% and BUN 19 mg%. PTH in relation to therapy and mobilization is shown in Fig. 1. Convalescence was slow. On March 24, 1974, a bladder calculus obstructing the right ureter was removed cystoscopically. Mobilization was difficult to accomplish because of the extent of the injuries. As shown in Fig. 1, serum calcium and PTH did not return to normal until the patient became fully mobile. Six months after discharge, serum calcium was 10.0 mg% and PTH 35 /ulEq/ml. He had resumed normal activities. Patient No. 2, an 11-year-old boy, dove into a shallow pool and sustained dislocation of the fourth and fifth cervical vertebrae on January 1, 1975. He was treated at another hospital for a flaccid quadriplegia with absence of sensation below the fifth cervical level. A month later, he was admitted to the Rehabilitation Institute. He had regained some motor function in the left upper extremity and sensation had returned to the T-10 level.
JCE & M • 1977 Vol 45 • No 3
Serum calcium on admission was 16.3 mg% (SMA-12). BUN was 40 mg% and serum creatinine 1.7 mg%. Serum calcium and PTH in relation to therapy and activity are shown in Fig. 2. Convalescence was slow but steady with gradually returning function and, eventually, full mobilization. On discharge, the patient walked without assistance. One month after discharge, the serum calcium was 0.3 mg% and serum PTH 30 /zlEq/ml. Discussion The hypercalcemia of immobilization is largely confined to patients with rapid bone turnover, notably children. In the first full description of the syndrome of immobilization hypercalcemia, Albright et al. (10) arrived at the erroneous diagnosis of primary hyperparathyroidism; normal parathyroid glands were described at surgery. Serum calcium in Albright's patient returned to normal when full mobilization was achieved. The recorded data applying the immunoassay of PTH in the study of immobilization hypercalcemia are inconsistent and confusing. This is understandable since much of the information was obtained before the problems of heterogeneity of circulating
300
16.0 250 15.0 200 14.0 SERUM
13.0
150
P T H
100
. _ «
CALCIUM (mg%)
12.0
o-~o 11.0
50 10.0
9.0 FLUIDS •FLUIDS P.O.P.O. & I.V. TREATMENT • FLEET PHOSPHO-SODA-
FIG. 1. Patient No. 1. Serum calcium was measured by SMA-12 Colorimetric method. The average value for November to February followed by weekly values are plotted. Normal range, 8.5-10.5 mg%. PTH represents individual assays. Normal range for PTH, 10-60 julEq/ml. Mobility: 0, immobile; +, up in chair or tilt table once daily; + + , tilt table and use of parallel bars; + + + , walking with assistance but infrequently; + + + + walking without assistance at least three times daily.
MOBILITY
NOV-FEB. MARCH
APRIL
MAY
JUNE
JULY DISCHARGE
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427
PARATHYROID HORMONE IN IMMOBILIZATION 300 16.0
250
15.0 200
14.0
FIG. 2. Patient No. 2. Serum calcium was measured by atomic absorption spectrophotometry. The weekly average values are plotted. Normal range, 9.1-10.6 mg%. For mobility, see legend of Fig. 1. Treatment: 1—Intravenous and oral fluids; la—Oral fluids only; 2—Furosemide; 3— Steroids; 4—Fleet Phospho-Soda.
SERUM CALCIUM
13.0
(mg%)
12.0
150
PTH MEq/ml]
100
•
•
11.0 50
10.0
0
9.0 TREATMENT
1 -2-H H3H 1-4-1
MOBILITY FEB.
MARCH
APRIL
MAY
DISCHARGE
PTH were appreciated (20,21). In Hyman's report (8) the antiserum used is not specified. Heath et al. (15) provide no information about the PTH assay. Similarly, ClausWalker et al. (13) and Lawrence (14) provide no information about the specificity of the assay used. Thus, the available information is difficult to interpret, and discrepancies in results are not surprising. During immobilization, calcium is mobilized from the skeleton as a result of stillundefined factors (22). In this context, one would anticipate a tendency toward hypercalcemia with a suppression of PTH secretion. Hence, our observation of elevated levels of circulating PTH is surprising. Neither of the patients studied by us had any evidence of the common clinical types of hypercalcemic (primary) hyperparathyroidism. It would appear that the marked increase in PTH secretion was caused by some non-ionic stimulus. Several such nonionic stimuli have been reported (23-25); catecholamines, for example, have been shown to be powerful PTH secretagogues (23). It is not clear to what extent increased PTH secretion can account for the hypercalcemia in our two patients. The observed
elevations of PTH were moderate, and we rarely have noted severe hypercalcemia in adults with such moderate hyperparathyroidism. Perhaps children with their normally increased bone turnover are more sensitive. Increased levels of immunoreactive PTH have been generally attributed to increased secretion of the hormone. This may be a false interpretation since both metabolism (17) and renal excretion (26) may be determining factors of steady-state hormone concentrations. So far, however, these theoretical possibilities have not been explored in clinical practice. There is some indirect evidence supporting the notion that PTH contributes to the mobilization of bone mineral during immobilization. Heany demonstrated by means of calcium kinetic studies that immobilization is associated with increased bone resorption (27). Burkhardt and Jowsey demonstrated that in parathyroidectomized animals the osteoporosis of immobilization does not occur (28). The present study is deficient in that we have no systematic data on calcium excretion and no biologic marker, such as excretion of nephogenic cyclic AMP, to correlate with immunoassay results. Despite this
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 24 November 2015. at 01:00 For personal use only. No other uses without permission. . All rights reserved.
428
LERMAN, CANTERBURY AND REISS
limitation and the obvious gaps in the understanding of the relationship between PTH secretion and immobilization, the present report has clear practical implications. The hypercalcemia of immobilization associated with increased circulating levels of PTH is a medical rather than a surgical problem. The hyperparathyroidism is reversible by mobilization. References 1. Deitrick, J. E., G. D. Whedon, and E. Shorr, Effects of immobilization upon various metabolic and physiologic functions of normal men, Am J Med 4: 3, 1948. 2. Whedon, G. D., and E. Shorr, Metabolic studies in paralytic acute anterior poliomyelitis. II. Alterations in calcium and phosphorus metabolism, J Clin Invest 36: 966, 1957. 3. Issekutz Jr., B., J. J. Blizzard, N. C. Birkhead, and K. Rodahl, Effect of prolonged bed rest on urinary calcium output, J Appl Physiol 21: 1013, 1966. 4. Heath III,H., J. M. Earll, M. Schaaf, J. T. Piechocki, and T.-K. Li, Serum ionized calcium during bed rest in fracture patients and normal men, Metabolism 21: 633, 1972. 5. Halvorsen, S., Osteoporosis, hypercalcemia and neophropathy following immobilization of children, Ada Med Scand 149: 401, 1954. 6. Mason, A. S., Acute osteoporosis with hypercalcemia, Lancet 1: 911, 1957. 7. Winters, J. L., A. G. Kleinschmidt Jr., J. J. Frensilli, and M. Sutton, Hypercalcemia complicating immobilization in the treatment of fractures, J Bone Surg 48A: 1182, 1966. 8. Hyman, L. R., G. Boner, J. C. Thomas, and W. E. Segar, Immobilization hypercalcemia, Am J Dis Child 124: 723, 1972. 9. Dodd, K., H. Graubarth, and S. Rapoport, Hypercalcemic neophropathy and encephalopathy following immobilization, Pediatrics 6: 124, 1950. 10. Albright, F., C. H. Burnett, O. Cope, and W. Parson, Acute atrophy of bone (osteoporosis) simulating hyperparathyroidism, J Clin Endocrinol Metab 1: 711, 1941. 11. Levine, C., R. B. Greer, III, and S. L. Gordon, Hypercalcemia complicating fracture immobilization: A report of three cases, J Trauma 15: 70, 1975. 12. Henke, J. A., N. W. Thompson, and H. Kaufer, Immobilization hypercalcemic crisis, Arch Surg 110: 321, 1975. 13. Claus-Walker, J., R. E. Carter, R. J. Campos, and W. A. Spencer, Hypercalcemia in early traumatic quadriplegiaj Chronic Dis 28: 81, 1975.
JCE & M • 1977 Vol 45 • No 3
14. Lawrence, G. D., R. G. Loeffler, L. G. Martin, and T. B. Connor, Immobilization hypercalcemia. Some new aspects of diagnosis and treatment, J Bone Joint Surg 55A: 87, 1973. 15. Heath III, H., M. Schaaf, H. L. Wray, J. M. Monchik, and J. M. Earll, In Frame, B., A. M. Parfitt, and H. Duncan (eds.), Clinical Aspects of Metabolic Bone Disease, Excerpta Medica, Amsterdam, 1973, p. 257. 16. Arnstein, A. R., D. S. McCann, F. S. Blumenthal, and J. Prunty, In Frame, B., A. M. Parfitt, and H. Duncan (eds.), Clinical Aspects of Metabolic Bone Disease, Excerpta Medica, Amsterdam, 1973, p. 253. 17. Canterbury, J. M., and E. Reiss, Multiple immunoreactive molecular forms of parathyroid hormone in human serum, Proc Soc Exp Biol Med 140: 1393, 1972. 18. Canterbury, J. M., L. A. Bricker, G. S. Levey, P. L. Kozlovskis, E. Ruiz, J. E. Zull, and E. Reiss, Metabolism of bovine parathyroid hormone. Immunological and biological characteristics of fragments generated by liver perfusion, J Clin Invest 55: 1245, 1975. 19. Arnaud, C. D., H. S. Tsao, and T. Littledike, Radioimmunoassay of human parathyroid hormone in serum,/ Clin Invest 50: 21, 1971. 20. Berson, S. A., and R. S. Yalow, Immunochemical heterogeneity of parathyroid hormone in plasma, J Clin Endocrinol Metab 28: 1037, 1968. 21. Reiss, E., and J. M. Canterbury, Emerging concepts of the nature of circulating parathyroid hormones: Implications for clinical research, Recent Prog Horm Res 30: 391, 1974. 22. Donaldson, C. L., S. B. Hulley, J. M. Vogel, R. S. Hahner, J. H. Bayers, and D. E. McMillan, Effect of prolonged bed rest of bond mineral, Metabolism 19: 1071, 1970. 23. Fischer, J. A., J. W. Blum, and U. Binswanger, Acute parathyroid hormone responses to epinephrine in vivoj Clin Invest 52: 2434, 1973. 24. Fischer, J. A., S. B. Oldham, G. W. Sizemore, and C. D. Arnaud, Calcitonin stimulation of parathyroid hormone secretion in vitro, Horm Metab Res 3: 223, 1971. 25. Abe, M., and L. M. Sherwood, Regulation of parathyroid hormone secretion by adenyl cyclase, Biochem Biophy Res Commun 48: 369, 1972. 26. Hruska, K. A., R. Kopelman, E. Rutherford, S. Klahr, and E. Slatopolsky, Metabolism of immunoreactive parathyroid hormone in the dog: The role of the kidney and the effects of chronic renal disease, J Clin Invest 56: 39, 1975. 27. Heany, R. P., Radiocalcium metabolism in disuse osteoporosis in man, Am J Med 33: 188, 1962. 28. Burkhart, J. M., and J. Jowsey, Parathyroid and thyroid hormones in the development of immobilization osteoporosis, Endocrinology 81: 1053, 1967.
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