December 1977 The Journal o f P E D I A T R I C S
1001
Calcitonin therapy of children with osteogenesis imperfecta Two children, ages 13 2/12 and 2 6/12 years, with osteogenesis imperfecta were treated with salmon calcitonin. During the course of therapy the older child developed calcitonin dose-related hypomagnesemia on two occasions. The younger child, coincident with otitis media and vomiting, developed hypomagnesemia, hypophosphatemia, hyponatremia, and hypokalemia. Since rib biopsies obtained before and after one year of treatment with salmon calcitonin failed to demonstrate any histologic changes, therapy was discontinued because of the induced metabolic consequences of calcitonin therapy.
Gilbert P. August, M.D.,* J a y S h a p i r o , M . D , , and W e l l i n g t o n Hung, M.D., W a s h i n g t o n , D. C.
OSTEOGENESIS IMPERFECTA is a congenital disease of varying severity that is characterized by bones which fracture easily; the repeated fractures may produce skeletal deformities. Other stigmata also are associated with this disease: blue sclera, lax joints, impaired hearing, thin skin, dental abnormalities, and hypermetabolic and hematologic disorders. '-e Abnormalities of the structural and physical chemical properties of collagen have been described in the bone, skin, and sclera of these patients? A variety of systemic therapeutic measures have been tried but have not been shown to be consistently effective. These have included sodium fluoride, ~.... magnesium oxide," and ascorbic acidY The results of these studies have been difficult to interpret because they are based upon a decreased fracture rate. Many other factors could decrease the fracture rate. These include more careful From the Department of Endocrinology and Metabolism of the Children's Hospital National Medical Center, the Greater Southeast Community Medical Center, and the Department of Child Health of the George Washington University School of Medicine. Supported by General Research Support Grant RR005515 and General Clinical Research Center Grant RR-00284, National Institutes of Health. *Reprint address: Children's Hospital National Medical Center, 2125 13th St., N. I'K, Washington, DIC. 20009.
handling of the infant and the tendency of children to become more careful as they mature. Morphologic changes in the bones were not seen in a small series of patients treated with sodium fluoride or magnesium oxide5 Castells and associates ':' reported that calcitonin therapy improved the clinical picture as reflected by a decreased fracture rate, These workers found that salmon calcitonin therapy was also associated with increased bone density as determined by densiometry. This initially favorable report impelled us to try calcitonin in the treatment of osteogenesis imperfecta. However, in the course of treatment two patients developed metabolic complications which are recorded here. Abbreviation used BUN: blood urea nitrogen
i
MATERIALS AND M E T H O D S Serum calcium, phosphate, magnesium, and alkaline phosphatase were quantified by our clinical chemistry laboratory. Total urinary hydroxyproline was determined by the method of Prockop and Undenfriend"; nondialyzable hydroxyproline, by the method of Haddad and coworkersY' Parathyroid hormone was quantified by BioScience Laboratories in a single radioin)munoassay run. In order to obtain a firm assessment of whether or not
Vol. 91, No. 6, pp. 1001-1005
10 0 2
August, Shapiro, and Hung
The Journal of Pediatrics December 1977
T a b l e I. S e r u m a n d u r i n a r y c h a n g e s d u r i n g c a l c i t o n i n t h e r a p y
Serum* Calcitonin dose (MRC units)
Patient A: Baseline 3 days 3 mo 6 mo 9 mo 12 rno 17 mo Normal for age
B:
32 32 20 12 8 20
Coefficient of variation (%) Baseline 3 days 3 mo 6 mo 12 mo
Ca (mg/dl)
PO~ (mg/dl)
Mg (mg/dl)
Alkaline phosphatase (mlU/ml)
10.4 10.5 9.2 9.3 10.2 10.8 9.2 9-11.5
4.7 4.5 4.5 4.1 4.5 5.0 4.3 4.5-6.5
1.7 2.2 1.7 1.2 2.0 1.8 1.3 1.9-2.4
128 63 112 166 134 152 -57-258
1.7
4.1
14.1
9.1 10.3 9.8 10.7
5.3 4.6 6.1
%11.5
4.5-6.5
8 8 8 8
Normal for age
Urinary hydroxyproline Total (l~moles/TV)
Nondialyzable (% of total)
794 558 912 827 976 841 -500-1,300 /~moles/m2/day
10 10.2 9.5 13.7 13.5 20.9 -9.85 _+ 0.46 (SE)
5.2
-
-
169
14.1
--
-
151
13.7
-
140
2.3
2.0 1.9-2.4
-
-
86 47-111
-
155 145 300-500 /~moles/m~/day
-
-
24.5 21.4 9.85 _+ 0.46 (SE)
*Serum samples were obtained 12 hours after calcitonin was given.
c a l c i t o n i n t h e r a p y was effective, histologic e v i d e n c e was c o n s i d e r e d essential. A n a d e q u a t e s p e c i m e n r e q u i r e d a surgical b i o p s y . T h e rib was c h o s e n as the b i o p s y site b e c a u s e o f its a d e q u a t e cortex, g o o d available t u r n o v e r d a t a w h i c h are m o r e c o n s i s t e n t t h a n t h o s e f r o m t h e iliac crest, a n d a c o n s t a n t ratio o f m o d e l i n g f r o m p e r s o n to p e r s o n ( e x c e p t for ribs 11 a n d 12)? ~ P a r t i c u l a r a t t e n t i o n was p a i d to a n y histologic e v i d e n c e o f i n c r e a s e d or decreased
bone
deposition
hyperparathyroidism,
and
or
resorption,
osteomalacia.
secondary
Rib
biopsies
were o b t a i n e d b e f o r e a n d after 12 m o n t h s o f c a l c i t o n i n * t h e r a p y b y Dr. D o u g l a s M c K a y . t T h e o n e i n c h s e g m e n t s o f rib w e r e fixed in b u f f e r e d f o r m a l i n . Histologic e x a m i n a t i o n s w e r e m a d e o n b o t h u n d e c a l c i f i e d a n d decalcified m a t e r i a l by Dr. L e n t C. J o h n s o n . $ T h e s e studies w e r e r e v i e w e d a n d a p p r o v e d Institutional
Research
Committee.
The
by the
patients
were
h o s p i t a l i z e d in the Clinical R e s e a r c h C e n t e r . I n f o r m e d c o n s e n t was o b t a i n e d f r o m b o t h p a r e n t s a n d f r o m patient A. *Synthetic salmon calcitonin was the generous gift of Armour Laboratories. It contained 200 MRC units/ml. tDepartment of Orthopedics, Children's Hospital National Medical Center. $Chief of the Orthopedic Pathology Department of the Armed Forces Institute of Pathology.
CASE
R E P O R T S
Patient A. This boy was first seen at 13 2/12 years. He was born after a normal gestation. He had blue sclera and hyperextensible joints. The first fracture occurred at one year of age. He had numerous fractures throughout childhood; a diagnosis of osteogenesis imperfecta was made at nine years after a compression fracture of a vertebra. His height was 145 cm and he weighed 34.1 kg; blood pressure was 104/55. There was no axillary or pubic hair; external genitals were Tanner stage 2. His slcera were faintly blue; veins could be easily seen through his skin and his joints were hyperextensible. He had a mild thoracic scoliosis. Calcitonin therapy was initiated at an intramuscular dose of 32 M R C units every other day. The dose was reduced to 20 MRC units by six months of therapy and to 8 MRC units by 12 months because of recurrent nausea and vomiting that lasted 6 to 8 hours after each injection. A change to the subcutaneous route permitted an increase to 20 MRC units every other day after 15 months of therapy. Biochemical data are summarized in Table I. The serum parathyroid hormone concentrations did not change. The hypomagnesemia that developed after six months of therapy was associated with symptoms of fatigue and was treated by increasing his intake of magnesium,rich foods. The second episode of hypomagnesemia at 17 months of therapy occurred soon after the increase in calcitonin dose at 15 months to 20 MRC units every other day. There were no associated symptoms. No fractures occurred during the first nine months of therapy.
Volume 91 Number 6 In the next six months three fractures were associated with mild trauma. The rib biopsy before the onset of calcitonin therapy showed the development of lamellar bone but a decreased formation of osteones and was characterized by more osteocytes per unit area and closer spaced lamellae than normal. A comparison of the two rib biopsies failed to show any change that could be ascribed to calcitonin therapy. This histologic evidence combined with the recurrence of hypomagnesemia led to the discontinuance of calcitonin therapy. At 14 5/12 years of age he was 154.2 cm tall and weighed 43 kg; blood pressure was 110/70. He had no pubic or axillary hair; external genitals were Tanner stage 3. Patient B. She was first seen at 2 6/12 years of age, She was born after a nine-month gestation. Her mother had first trimester bleeding and was treated with medroxyprogesterone acetate, 10 mg daily, for the first four months of pregnancy. Patient B was delivered by breech extraction, and several fractures were noted at birth; the diagnosis of osteogenesis imperfecta was made at that time. She had numerous and seemingly spontaneous fractures wtih resultant deformities. Many surgical procedures had been performed and rods had been inserted through the long bones on several occasions. The girl was 72 cm in length and weighed 8.2 kg; her head circumference measured 46.5 cm. There were numerous operative scars on all extremities. Her sclera were blue and she had deformities of both upper and lower extremities. She received 8 MRC units of calcitonin every other day. Because of recurrent vomiting, the route was changed from intramuscular to subcutaneous with resultant toleration of the medication. During the year of therapy she had only two fractures. A rib biopsy before the onset of therapy showed a very thin cortex. Incremental periosteal bone was of the bundle bone type. There was an excess of osteocytes per unit area. Lamellae were numerous but poorly formed and irregular. The ability to form osteones was impaired, and those formed were incomplete. A comparison of the two rib biopsies, before and after one year of therapy, failed to show any change that could be ascribed to calcitonin therapy. Biochemical data are summarized in Table I. Serum parathyroid hormone levels did not change during therapy. Otitis media, associated with anorexia and vomiting, occured after 15 months of calcitonin treatment. She was admitted because of extreme lethergy and was seemingly dehydrated. Initial laboratory studies included: BUN, 8 mg/dl; sodium, 128 mEq/l; potassium 2.9 mEq/1; chloride, 95 mEq/l; CO._,, 11 mEq/l; glucose, 173 mg/dl. She received Isolyte M, 3,000 ml/ m~/day for 6 hours, to rehydrate her before the above serum values were known. Subsequent studies showed: BUN, 3 mg/dl; sodium, 128 mEq/1; potassium, 2.8 mEq/1; chloride, 101 mEq/l; CO~, 16 mEq/1; glucose, 277 mg/dl; calcium, 10.3 mg/dl; phosphate 1.6 mg/dl and magnesium, 1.3 mg/dl. Intravenous fluid administration was decreased to 2,000 ml/m-'/day; the fluid contained 5% dextrose, 75 mEq/1 of sodium chloride and 40 mEq/1 of potassium phosphate. She was treated with three intramuscular doses of 50% magnesium sulfate, 0.05 ml/kg/dose.
Osteogenesis imperfecta and calcitonin therapy
10 0 3
The serum values 24 hours later were: BUN, 5 mg/d]; sodium, 133 mEq/1; potassium, 3.8 mEq/l; chloride, 100 mEq/1; CO~, 21 mEq/1; glucose, 71 mg/dl; calcium, 9.4 mg/dl; phosphate, 3.0 mg/dl and magnesium, 1.9 mg/dl. She was greatly improved symptomatically. Calcitonin therapy was discontinued after this episode in view of the lack of histologic evidence of a calcitonin effect. DISCUSSION Each of these children experienced episodes o f severe mineral i m b a l a n c e d u r i n g therapy with s a l m o n calcitonin. The dose of calcitonin used in o u r patients was h a l f that used by Castells a n d associates TM in their larger study o f children with osteogenesis imperfecta. T h e effects of the acute a d m i n i s t r a t i o n o f calcitonin include not only a fall in serum calcium b u t also in m a g n e s i u m a n d phosphate57 Sorenson a n d associates '~ also reported o n the lack o f effect o f calcitonin u p o n the urinary excretion o f calcium, m a g n e s i u m , a n d p h o s p h a t e . They pointed out, though, that others h a d f o u n d an increased excretion o f these substances. However, Sorenson a n d associates f o u n d an increased urinary excretion o f sodium. O f particular i m p o r t a n c e to c h i l d r e n is their reference to the more p r o f o u n d h y p o m a g n e s e m i c effect of calcitonin, in y o u n g rats c o m p a r e d with that in older animals. Recent evidence indicates that calcitonin induces a net secretion of water into the j e j u n u m which is associated with a net loss of sodium, potassium, chloride, calcium, and p h o s p h a t e . '~ Calcitonin m a y thus cause a loss o f electrolytes a n d minerals from the body t h r o u g h both the kidney and the gut. A large body of experience is n o w available r e g a r d i n g the long-term effects of calcitonin t h e r a p y in adults with Paget disease. In a report o f the effects o f either procine or salmon calcitonin in 178 patients followed serially for one to 18 months, Bastian a n d coworkers'" f o u n d a fall in serum m a g n e s i u m but n o changes in s e r u m calcium, phosphate, sodium, or potassium. M e a s u r e m e n t by total body e l e m e n t a l analysis after long-term calcitonin therapy o f adults with Paget disease revealed a decrease in b o d y stores o f p h o s p h o r u s a n d s o d i u m ; -'~' Most of the loss a p p e a r e d to be skeletal a n d a m o u n t e d to a significant m e a n loss o f 6% for p h o s p h o r u s and of 14% for sodium. Total body calcium declined 4%. Neither chloride n o r potassium a p p e a r e d to c h a n g e and m a g n e s i u m was not measured. Evidence from a n i m a l a n d h u m a n e x p e r i m e n t a t i o n cited above '~ '~ as well as from clinical experience with calcitonin'" ~'' indicates that its use is associated with h y p o m a g n e s e m i a a n d skeletal depletion o f p h o s p h o r u s a n d sodium. Increased urinary excretion o f these e l e m e n t s may play a role in the losses '~ but a m a j o r role in these
10 0 4
August, Shapiro, and Hung
losses may also be ascribed to net secretion by the gut under the influence of calcitonin.TM The development of hypomagnesemia in Patient A was probably related to the combined effects of calcitonin and of a diet which was minimally adequate in magnesium intake in this adolescent boy. In Patient B, adequate dietary intake of magnesium was sufficient to prevent hypomagnesemia until the episode of otitis media which was associated with anorexia. If we assume that chronic calcitonin therapy had depleted her body reserves, the occurrence of hypomagnesemia, hypophosphatemia, hyponatremia, and hypokalemia is understandable in terms of the susceptibility of young children to develop imbalances of fluids and electrolytes when subjected to stresses such as diarrhea, vomiting, or anorexia. We feel that calcitonin therapy must have played a role in the electrolyte and mineral imbalance displayed by Patient B, since hypomagnesemia and hypophosphatemia together would not be expected to occur in children with otitis media. A further biochemical change that occurred in both children during calcitonin therapy was the increase in the excretion of the nondialyzable hydroxyproline moiety in the urine (Table I). Previous studies by Haddad and co-workers 1~ established 9.85 ___ 0.46 as the mean for the nondialyzable percent of hydroxyproline excretion in the urine. The percent of the total hydroxyproline ranged from 5.8 to 18.1 in our measurements of nondialyzable hydroxyproline excretion in growth hormone deficient children?' In Patient A the increase in the percent nondialyzable hydroxyproline excretion was progressive with length of treatment, and in each child the percent exceeded what has previously been reported. The increase is also opposite to what had been reported to occur in a patient with Paget disease who had been treated with calcitoninY' It is difficult to draw conclusions from small numbers of patients but the changes we found in the nondialyzable fraction may represent a pharmacologic effect of calcitonin and may be associated with new collagen synthesis. 1~ In this study, however, there was no histologic evidence, on review of the rib biopsies, of any calcitonin-induced hyperparathyroidism nor any effect of calcitonin on new bone formation. Rosenberg and co-workers ~ recently reported on the effects of salmon calcitonin given to ten children with osteogenesis imperfecta over a period of 14 to 35 months. The results of earlier studies with calcitonin were also reviewed. These investigators felt that they obtained a therapeutic effect which was evidenced by a trend toward increased bone density. They pointed out the need for long-term studies in a larger number of patients. Calcitonin may yet prove to be an effective treatment for this disease. Clinical trials appear justified. However,
The Journal of Pediatrics December 1977
care must be taken to recognize that children may be susceptible to hypomagnesemia during therapy; during illness associated with intestinal malfunction they may be additionally prone to develop hypophosphatemia, hypokalemia, and hyponatremia. An effort should be made to ensure an adequate dietary intake of magnesium during calcitonin therapy. REFERENCES
1. McKusick,VA: Heritable disorders of connective tissue, ed 4, St Louis, 1972, The CV Mosby Company, p 390. 2. Solomons CC, and Millar EA: Osteogenesis imperfecta: New prospectives, Clin Orthop 96:299, 1973. 3. Riley FC, and Jowsey J: Osteogenesis imperfecta: Morphologic and biochemical studies of connective tissue, Pediatr Res 7:757, 1973. 4. Teitelbaum SL, Kraft WJ, Lang R, and Avioli LV: Bone collagen aggregation abnormalities in osteogenesis imperfecta, Calcif Tissue Res 17:75, 1974. 5. Penttinem RP, Lichtenstein JR, Martin GR, and McKusick VA: Abnormal collagen metabolism in cultured cells in osteogenesis imperfecta, Proc Natl Acad Sci USA 72:586, 1975. 6. Smith R, Francis MJO, and Bauze RJ: Osteogenesis imperfecta: a clinical and biochemical study of a generalized connective tissue disorder, Q J Med 44:555, 1975. 7. Lancaster G, Goldman H, Scriver CR, Gold RJM, and Wong I: Dominantly inherited osteogenesis imperfecta in man: an examination of collagen biosynthesis, Pediatr Res 9:83, 1975. 8. Aeschlimann MI, Grunt JA, and Crigler JF Jr: Effects of sodium fluoride on the clinical course and metabolic balance of an infant osteogenesis imperfecta congenita, Metabolism 15:905, 1966. 9. Albright JA, and Grunt JA: Studies of patients with osteogenesis imperfecta, J Bone Joint Surg [Am] 53:1415, 1971. 10. Kuzemko JA: Osteogenesis imperfecta tarda treated with Sodium fluoride, Arch Dis Child 45:581, 1970. 11. Solomons CC, and Styner J: Osteogenesis imperfecta: Effect of magnesium administration on pyrophosphate metabolism, Calcif Tissue Res 3:318, 1969. 12. Kurz D, and Eyring EJ: Effects of vitamin C on osteogenesis imperfecta, Pediatrics 54:56, 1974. 13. Castells S, Reddy CM, and Hashemi SE: Long-term therapy of osteogenesis imperfecta with synthetic salmon calcitonin, Pediatr Res 9:2880, 1975 (Abstr 190). 14. ProckopDJ, and Udenfriend SA: A specific method for the analysis of hydroxyproline in tissues and urine, Anal Biochem 1:228, 1960. 15. Haddad HG Jr, Couranz S, and Avioli LV: Nondialyzable urinary hydroxyproline as an index of bone collagen formation, J Clin Endocrinol Metab 30:282, 1970. 16. Frost HM: Tetracycline-based histological analysis of bone remodeling, Calcif Tissue Res 3:21l, 1969. 17. Sorenson OH, Friis T, Hindberg I, and Nielsen SP: The effect of calcitonin injected into hypercalcemic and normocalcemic patients, Acta Med Scand 187:283, 1970. 18. Juan D, Liptak P, and Gray TK: Absorption of inorganic phosphate in the human jejunum and its inhibition by salmon calcitonin, J Clin Endocrinol Metab 43:513, 1976.
Volume 91 Number 6
19. Bastian JW, Aldred JP, Lesh JB, and Klaszynski RR: Clinical experience in Paget's disease with porcine and salmon calcitonin, International Symposium La Maladie de Paget, Le Mas D'Artigney, St Paul de Vence, June 20, 1973 p 270. 20. Wallach S, Avramides A, Flores A, Bellavia J, and Cohn S: Skeletal turnover and total body elemental composition during extended calcitonin treatment of Paget's disease, Metabolism 24:745, 1975.
Osteogenesis imperfecta and calcitonin therapy
10 0 5
21. August GP, Hung W, and Houck JC: The effects of growth hormone therapy on collagen metabolism in children, J Clin r Endocrinol Metab 39:1103, 1974. 22. Rosenberg E, Lang R, Boisseau V, Rojanasathit S, and Avioli LV: Effect of long-term calcitonin therapy on the clinical course of osteogenesis imperfecta, J Clin Endocrinol Metab 44:346, 1977.
1001
Calcitonin therapy of children with osteogenesis imperfecta Two children, ages 13 2/12 and 2 6/12 years, with osteogenesis imperfecta were treated with salmon calcitonin. During the course of therapy the older child developed calcitonin dose-related hypomagnesemia on two occasions. The younger child, coincident with otitis media and vomiting, developed hypomagnesemia, hypophosphatemia, hyponatremia, and hypokalemia. Since rib biopsies obtained before and after one year of treatment with salmon calcitonin failed to demonstrate any histologic changes, therapy was discontinued because of the induced metabolic consequences of calcitonin therapy.
Gilbert P. August, M.D.,* J a y S h a p i r o , M . D , , and W e l l i n g t o n Hung, M.D., W a s h i n g t o n , D. C.
OSTEOGENESIS IMPERFECTA is a congenital disease of varying severity that is characterized by bones which fracture easily; the repeated fractures may produce skeletal deformities. Other stigmata also are associated with this disease: blue sclera, lax joints, impaired hearing, thin skin, dental abnormalities, and hypermetabolic and hematologic disorders. '-e Abnormalities of the structural and physical chemical properties of collagen have been described in the bone, skin, and sclera of these patients? A variety of systemic therapeutic measures have been tried but have not been shown to be consistently effective. These have included sodium fluoride, ~.... magnesium oxide," and ascorbic acidY The results of these studies have been difficult to interpret because they are based upon a decreased fracture rate. Many other factors could decrease the fracture rate. These include more careful From the Department of Endocrinology and Metabolism of the Children's Hospital National Medical Center, the Greater Southeast Community Medical Center, and the Department of Child Health of the George Washington University School of Medicine. Supported by General Research Support Grant RR005515 and General Clinical Research Center Grant RR-00284, National Institutes of Health. *Reprint address: Children's Hospital National Medical Center, 2125 13th St., N. I'K, Washington, DIC. 20009.
handling of the infant and the tendency of children to become more careful as they mature. Morphologic changes in the bones were not seen in a small series of patients treated with sodium fluoride or magnesium oxide5 Castells and associates ':' reported that calcitonin therapy improved the clinical picture as reflected by a decreased fracture rate, These workers found that salmon calcitonin therapy was also associated with increased bone density as determined by densiometry. This initially favorable report impelled us to try calcitonin in the treatment of osteogenesis imperfecta. However, in the course of treatment two patients developed metabolic complications which are recorded here. Abbreviation used BUN: blood urea nitrogen
i
MATERIALS AND M E T H O D S Serum calcium, phosphate, magnesium, and alkaline phosphatase were quantified by our clinical chemistry laboratory. Total urinary hydroxyproline was determined by the method of Prockop and Undenfriend"; nondialyzable hydroxyproline, by the method of Haddad and coworkersY' Parathyroid hormone was quantified by BioScience Laboratories in a single radioin)munoassay run. In order to obtain a firm assessment of whether or not
Vol. 91, No. 6, pp. 1001-1005
10 0 2
August, Shapiro, and Hung
The Journal of Pediatrics December 1977
T a b l e I. S e r u m a n d u r i n a r y c h a n g e s d u r i n g c a l c i t o n i n t h e r a p y
Serum* Calcitonin dose (MRC units)
Patient A: Baseline 3 days 3 mo 6 mo 9 mo 12 rno 17 mo Normal for age
B:
32 32 20 12 8 20
Coefficient of variation (%) Baseline 3 days 3 mo 6 mo 12 mo
Ca (mg/dl)
PO~ (mg/dl)
Mg (mg/dl)
Alkaline phosphatase (mlU/ml)
10.4 10.5 9.2 9.3 10.2 10.8 9.2 9-11.5
4.7 4.5 4.5 4.1 4.5 5.0 4.3 4.5-6.5
1.7 2.2 1.7 1.2 2.0 1.8 1.3 1.9-2.4
128 63 112 166 134 152 -57-258
1.7
4.1
14.1
9.1 10.3 9.8 10.7
5.3 4.6 6.1
%11.5
4.5-6.5
8 8 8 8
Normal for age
Urinary hydroxyproline Total (l~moles/TV)
Nondialyzable (% of total)
794 558 912 827 976 841 -500-1,300 /~moles/m2/day
10 10.2 9.5 13.7 13.5 20.9 -9.85 _+ 0.46 (SE)
5.2
-
-
169
14.1
--
-
151
13.7
-
140
2.3
2.0 1.9-2.4
-
-
86 47-111
-
155 145 300-500 /~moles/m~/day
-
-
24.5 21.4 9.85 _+ 0.46 (SE)
*Serum samples were obtained 12 hours after calcitonin was given.
c a l c i t o n i n t h e r a p y was effective, histologic e v i d e n c e was c o n s i d e r e d essential. A n a d e q u a t e s p e c i m e n r e q u i r e d a surgical b i o p s y . T h e rib was c h o s e n as the b i o p s y site b e c a u s e o f its a d e q u a t e cortex, g o o d available t u r n o v e r d a t a w h i c h are m o r e c o n s i s t e n t t h a n t h o s e f r o m t h e iliac crest, a n d a c o n s t a n t ratio o f m o d e l i n g f r o m p e r s o n to p e r s o n ( e x c e p t for ribs 11 a n d 12)? ~ P a r t i c u l a r a t t e n t i o n was p a i d to a n y histologic e v i d e n c e o f i n c r e a s e d or decreased
bone
deposition
hyperparathyroidism,
and
or
resorption,
osteomalacia.
secondary
Rib
biopsies
were o b t a i n e d b e f o r e a n d after 12 m o n t h s o f c a l c i t o n i n * t h e r a p y b y Dr. D o u g l a s M c K a y . t T h e o n e i n c h s e g m e n t s o f rib w e r e fixed in b u f f e r e d f o r m a l i n . Histologic e x a m i n a t i o n s w e r e m a d e o n b o t h u n d e c a l c i f i e d a n d decalcified m a t e r i a l by Dr. L e n t C. J o h n s o n . $ T h e s e studies w e r e r e v i e w e d a n d a p p r o v e d Institutional
Research
Committee.
The
by the
patients
were
h o s p i t a l i z e d in the Clinical R e s e a r c h C e n t e r . I n f o r m e d c o n s e n t was o b t a i n e d f r o m b o t h p a r e n t s a n d f r o m patient A. *Synthetic salmon calcitonin was the generous gift of Armour Laboratories. It contained 200 MRC units/ml. tDepartment of Orthopedics, Children's Hospital National Medical Center. $Chief of the Orthopedic Pathology Department of the Armed Forces Institute of Pathology.
CASE
R E P O R T S
Patient A. This boy was first seen at 13 2/12 years. He was born after a normal gestation. He had blue sclera and hyperextensible joints. The first fracture occurred at one year of age. He had numerous fractures throughout childhood; a diagnosis of osteogenesis imperfecta was made at nine years after a compression fracture of a vertebra. His height was 145 cm and he weighed 34.1 kg; blood pressure was 104/55. There was no axillary or pubic hair; external genitals were Tanner stage 2. His slcera were faintly blue; veins could be easily seen through his skin and his joints were hyperextensible. He had a mild thoracic scoliosis. Calcitonin therapy was initiated at an intramuscular dose of 32 M R C units every other day. The dose was reduced to 20 MRC units by six months of therapy and to 8 MRC units by 12 months because of recurrent nausea and vomiting that lasted 6 to 8 hours after each injection. A change to the subcutaneous route permitted an increase to 20 MRC units every other day after 15 months of therapy. Biochemical data are summarized in Table I. The serum parathyroid hormone concentrations did not change. The hypomagnesemia that developed after six months of therapy was associated with symptoms of fatigue and was treated by increasing his intake of magnesium,rich foods. The second episode of hypomagnesemia at 17 months of therapy occurred soon after the increase in calcitonin dose at 15 months to 20 MRC units every other day. There were no associated symptoms. No fractures occurred during the first nine months of therapy.
Volume 91 Number 6 In the next six months three fractures were associated with mild trauma. The rib biopsy before the onset of calcitonin therapy showed the development of lamellar bone but a decreased formation of osteones and was characterized by more osteocytes per unit area and closer spaced lamellae than normal. A comparison of the two rib biopsies failed to show any change that could be ascribed to calcitonin therapy. This histologic evidence combined with the recurrence of hypomagnesemia led to the discontinuance of calcitonin therapy. At 14 5/12 years of age he was 154.2 cm tall and weighed 43 kg; blood pressure was 110/70. He had no pubic or axillary hair; external genitals were Tanner stage 3. Patient B. She was first seen at 2 6/12 years of age, She was born after a nine-month gestation. Her mother had first trimester bleeding and was treated with medroxyprogesterone acetate, 10 mg daily, for the first four months of pregnancy. Patient B was delivered by breech extraction, and several fractures were noted at birth; the diagnosis of osteogenesis imperfecta was made at that time. She had numerous and seemingly spontaneous fractures wtih resultant deformities. Many surgical procedures had been performed and rods had been inserted through the long bones on several occasions. The girl was 72 cm in length and weighed 8.2 kg; her head circumference measured 46.5 cm. There were numerous operative scars on all extremities. Her sclera were blue and she had deformities of both upper and lower extremities. She received 8 MRC units of calcitonin every other day. Because of recurrent vomiting, the route was changed from intramuscular to subcutaneous with resultant toleration of the medication. During the year of therapy she had only two fractures. A rib biopsy before the onset of therapy showed a very thin cortex. Incremental periosteal bone was of the bundle bone type. There was an excess of osteocytes per unit area. Lamellae were numerous but poorly formed and irregular. The ability to form osteones was impaired, and those formed were incomplete. A comparison of the two rib biopsies, before and after one year of therapy, failed to show any change that could be ascribed to calcitonin therapy. Biochemical data are summarized in Table I. Serum parathyroid hormone levels did not change during therapy. Otitis media, associated with anorexia and vomiting, occured after 15 months of calcitonin treatment. She was admitted because of extreme lethergy and was seemingly dehydrated. Initial laboratory studies included: BUN, 8 mg/dl; sodium, 128 mEq/l; potassium 2.9 mEq/1; chloride, 95 mEq/l; CO._,, 11 mEq/l; glucose, 173 mg/dl. She received Isolyte M, 3,000 ml/ m~/day for 6 hours, to rehydrate her before the above serum values were known. Subsequent studies showed: BUN, 3 mg/dl; sodium, 128 mEq/1; potassium, 2.8 mEq/1; chloride, 101 mEq/l; CO~, 16 mEq/1; glucose, 277 mg/dl; calcium, 10.3 mg/dl; phosphate 1.6 mg/dl and magnesium, 1.3 mg/dl. Intravenous fluid administration was decreased to 2,000 ml/m-'/day; the fluid contained 5% dextrose, 75 mEq/1 of sodium chloride and 40 mEq/1 of potassium phosphate. She was treated with three intramuscular doses of 50% magnesium sulfate, 0.05 ml/kg/dose.
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The serum values 24 hours later were: BUN, 5 mg/d]; sodium, 133 mEq/1; potassium, 3.8 mEq/l; chloride, 100 mEq/1; CO~, 21 mEq/1; glucose, 71 mg/dl; calcium, 9.4 mg/dl; phosphate, 3.0 mg/dl and magnesium, 1.9 mg/dl. She was greatly improved symptomatically. Calcitonin therapy was discontinued after this episode in view of the lack of histologic evidence of a calcitonin effect. DISCUSSION Each of these children experienced episodes o f severe mineral i m b a l a n c e d u r i n g therapy with s a l m o n calcitonin. The dose of calcitonin used in o u r patients was h a l f that used by Castells a n d associates TM in their larger study o f children with osteogenesis imperfecta. T h e effects of the acute a d m i n i s t r a t i o n o f calcitonin include not only a fall in serum calcium b u t also in m a g n e s i u m a n d phosphate57 Sorenson a n d associates '~ also reported o n the lack o f effect o f calcitonin u p o n the urinary excretion o f calcium, m a g n e s i u m , a n d p h o s p h a t e . They pointed out, though, that others h a d f o u n d an increased excretion o f these substances. However, Sorenson a n d associates f o u n d an increased urinary excretion o f sodium. O f particular i m p o r t a n c e to c h i l d r e n is their reference to the more p r o f o u n d h y p o m a g n e s e m i c effect of calcitonin, in y o u n g rats c o m p a r e d with that in older animals. Recent evidence indicates that calcitonin induces a net secretion of water into the j e j u n u m which is associated with a net loss of sodium, potassium, chloride, calcium, and p h o s p h a t e . '~ Calcitonin m a y thus cause a loss o f electrolytes a n d minerals from the body t h r o u g h both the kidney and the gut. A large body of experience is n o w available r e g a r d i n g the long-term effects of calcitonin t h e r a p y in adults with Paget disease. In a report o f the effects o f either procine or salmon calcitonin in 178 patients followed serially for one to 18 months, Bastian a n d coworkers'" f o u n d a fall in serum m a g n e s i u m but n o changes in s e r u m calcium, phosphate, sodium, or potassium. M e a s u r e m e n t by total body e l e m e n t a l analysis after long-term calcitonin therapy o f adults with Paget disease revealed a decrease in b o d y stores o f p h o s p h o r u s a n d s o d i u m ; -'~' Most of the loss a p p e a r e d to be skeletal a n d a m o u n t e d to a significant m e a n loss o f 6% for p h o s p h o r u s and of 14% for sodium. Total body calcium declined 4%. Neither chloride n o r potassium a p p e a r e d to c h a n g e and m a g n e s i u m was not measured. Evidence from a n i m a l a n d h u m a n e x p e r i m e n t a t i o n cited above '~ '~ as well as from clinical experience with calcitonin'" ~'' indicates that its use is associated with h y p o m a g n e s e m i a a n d skeletal depletion o f p h o s p h o r u s a n d sodium. Increased urinary excretion o f these e l e m e n t s may play a role in the losses '~ but a m a j o r role in these
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August, Shapiro, and Hung
losses may also be ascribed to net secretion by the gut under the influence of calcitonin.TM The development of hypomagnesemia in Patient A was probably related to the combined effects of calcitonin and of a diet which was minimally adequate in magnesium intake in this adolescent boy. In Patient B, adequate dietary intake of magnesium was sufficient to prevent hypomagnesemia until the episode of otitis media which was associated with anorexia. If we assume that chronic calcitonin therapy had depleted her body reserves, the occurrence of hypomagnesemia, hypophosphatemia, hyponatremia, and hypokalemia is understandable in terms of the susceptibility of young children to develop imbalances of fluids and electrolytes when subjected to stresses such as diarrhea, vomiting, or anorexia. We feel that calcitonin therapy must have played a role in the electrolyte and mineral imbalance displayed by Patient B, since hypomagnesemia and hypophosphatemia together would not be expected to occur in children with otitis media. A further biochemical change that occurred in both children during calcitonin therapy was the increase in the excretion of the nondialyzable hydroxyproline moiety in the urine (Table I). Previous studies by Haddad and co-workers 1~ established 9.85 ___ 0.46 as the mean for the nondialyzable percent of hydroxyproline excretion in the urine. The percent of the total hydroxyproline ranged from 5.8 to 18.1 in our measurements of nondialyzable hydroxyproline excretion in growth hormone deficient children?' In Patient A the increase in the percent nondialyzable hydroxyproline excretion was progressive with length of treatment, and in each child the percent exceeded what has previously been reported. The increase is also opposite to what had been reported to occur in a patient with Paget disease who had been treated with calcitoninY' It is difficult to draw conclusions from small numbers of patients but the changes we found in the nondialyzable fraction may represent a pharmacologic effect of calcitonin and may be associated with new collagen synthesis. 1~ In this study, however, there was no histologic evidence, on review of the rib biopsies, of any calcitonin-induced hyperparathyroidism nor any effect of calcitonin on new bone formation. Rosenberg and co-workers ~ recently reported on the effects of salmon calcitonin given to ten children with osteogenesis imperfecta over a period of 14 to 35 months. The results of earlier studies with calcitonin were also reviewed. These investigators felt that they obtained a therapeutic effect which was evidenced by a trend toward increased bone density. They pointed out the need for long-term studies in a larger number of patients. Calcitonin may yet prove to be an effective treatment for this disease. Clinical trials appear justified. However,
The Journal of Pediatrics December 1977
care must be taken to recognize that children may be susceptible to hypomagnesemia during therapy; during illness associated with intestinal malfunction they may be additionally prone to develop hypophosphatemia, hypokalemia, and hyponatremia. An effort should be made to ensure an adequate dietary intake of magnesium during calcitonin therapy. REFERENCES
1. McKusick,VA: Heritable disorders of connective tissue, ed 4, St Louis, 1972, The CV Mosby Company, p 390. 2. Solomons CC, and Millar EA: Osteogenesis imperfecta: New prospectives, Clin Orthop 96:299, 1973. 3. Riley FC, and Jowsey J: Osteogenesis imperfecta: Morphologic and biochemical studies of connective tissue, Pediatr Res 7:757, 1973. 4. Teitelbaum SL, Kraft WJ, Lang R, and Avioli LV: Bone collagen aggregation abnormalities in osteogenesis imperfecta, Calcif Tissue Res 17:75, 1974. 5. Penttinem RP, Lichtenstein JR, Martin GR, and McKusick VA: Abnormal collagen metabolism in cultured cells in osteogenesis imperfecta, Proc Natl Acad Sci USA 72:586, 1975. 6. Smith R, Francis MJO, and Bauze RJ: Osteogenesis imperfecta: a clinical and biochemical study of a generalized connective tissue disorder, Q J Med 44:555, 1975. 7. Lancaster G, Goldman H, Scriver CR, Gold RJM, and Wong I: Dominantly inherited osteogenesis imperfecta in man: an examination of collagen biosynthesis, Pediatr Res 9:83, 1975. 8. Aeschlimann MI, Grunt JA, and Crigler JF Jr: Effects of sodium fluoride on the clinical course and metabolic balance of an infant osteogenesis imperfecta congenita, Metabolism 15:905, 1966. 9. Albright JA, and Grunt JA: Studies of patients with osteogenesis imperfecta, J Bone Joint Surg [Am] 53:1415, 1971. 10. Kuzemko JA: Osteogenesis imperfecta tarda treated with Sodium fluoride, Arch Dis Child 45:581, 1970. 11. Solomons CC, and Styner J: Osteogenesis imperfecta: Effect of magnesium administration on pyrophosphate metabolism, Calcif Tissue Res 3:318, 1969. 12. Kurz D, and Eyring EJ: Effects of vitamin C on osteogenesis imperfecta, Pediatrics 54:56, 1974. 13. Castells S, Reddy CM, and Hashemi SE: Long-term therapy of osteogenesis imperfecta with synthetic salmon calcitonin, Pediatr Res 9:2880, 1975 (Abstr 190). 14. ProckopDJ, and Udenfriend SA: A specific method for the analysis of hydroxyproline in tissues and urine, Anal Biochem 1:228, 1960. 15. Haddad HG Jr, Couranz S, and Avioli LV: Nondialyzable urinary hydroxyproline as an index of bone collagen formation, J Clin Endocrinol Metab 30:282, 1970. 16. Frost HM: Tetracycline-based histological analysis of bone remodeling, Calcif Tissue Res 3:21l, 1969. 17. Sorenson OH, Friis T, Hindberg I, and Nielsen SP: The effect of calcitonin injected into hypercalcemic and normocalcemic patients, Acta Med Scand 187:283, 1970. 18. Juan D, Liptak P, and Gray TK: Absorption of inorganic phosphate in the human jejunum and its inhibition by salmon calcitonin, J Clin Endocrinol Metab 43:513, 1976.
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19. Bastian JW, Aldred JP, Lesh JB, and Klaszynski RR: Clinical experience in Paget's disease with porcine and salmon calcitonin, International Symposium La Maladie de Paget, Le Mas D'Artigney, St Paul de Vence, June 20, 1973 p 270. 20. Wallach S, Avramides A, Flores A, Bellavia J, and Cohn S: Skeletal turnover and total body elemental composition during extended calcitonin treatment of Paget's disease, Metabolism 24:745, 1975.
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21. August GP, Hung W, and Houck JC: The effects of growth hormone therapy on collagen metabolism in children, J Clin r Endocrinol Metab 39:1103, 1974. 22. Rosenberg E, Lang R, Boisseau V, Rojanasathit S, and Avioli LV: Effect of long-term calcitonin therapy on the clinical course of osteogenesis imperfecta, J Clin Endocrinol Metab 44:346, 1977.
