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Therapy of osteogenesis imperfecta with synthetic salmon calcitonin
November 1979 TheJournalofPEDIATRICS
807
Therapy of osteogenesis imperfecta with synthetic salmon calcitonin We evaluated the long-term use of synthetic salmon calcitonin in the management of osteogenesis impelfecta tarda and congenita. Forty-eight children, ranging in ageJrom 6 months to 15years, and two young adults, received synthetic salmon ealcitonin 2 MRC units/kg three days a week and a daily oral calcium supplement of 230 to 345 rag. The annual fracture rate was decreased during calcitonin therapy as compared to the period preceding therapy. There was an increase in the ability of the patient to stand and move and in the subjective feeling of strength in the lower extremities during calcitonin therapy. There was also a significant improvement in radiographic bone density, as determined by the method of photodensitometry, in patients under 5 years of age. Long-term administration of synthetic salmon calcitonin mmJ be beneficial to young children with osteogenesis imperfecta.
S a l v a d o r Castells, M.D.,* B r o o k l y n , N . Y . , Charles Colbert, P h . D . , Yellow Springs, Ohio, C h h a y a C h a k r a b a r t i , M . D . , B r o o k l y n , N . Y . ,
R i c h a r d S. Baehtell, M . D . , Yellow Springs, Ohio,
E. G e o r g e Kassner, M . D . , and Seiichi Y a s u m u r a , Ph.D., B r o o k l y n , N. Y.
THE MOST DEVASTATING SEQUELAE ofosteogenesis imperfecta are due to generalized osteoporosis of the skeleton, which leads to frequent fractures and severe skeletal deformities. Tetracycline labeling techniques and radiocalcium turnover s t u d i e s ' ' have shown increased bone turnover with predominant bone resorption. Calcitonin, a peptide hormone secreted by the parafollicular cells of the thyroid gland, inhibits bone resorption in vitr@ and in vivo? In human beings, calcitonin seems to From the Departments of Pediatrics, Unit of Growth and Metabolism, Physiology, and Radiology, State University of New York, Downstate Medical Center," and the Radiological Researc h Laboratory, Greene Memorial Hospital. SupPorted by grants from the National Foundation-March of Dimes, the Osteogenesis Imperfecta Foundation, Grant RR-312, the General Clinical Research Centers Project of the Division of Research Resources, NIH, PHS Grants A M 16475, ES 000831, ES 01825, and the National Science Foundation, Grant D1-44068. *Reprint address: Director, Unit of Growth and Metabolism, 450 Ctarkson Ave., Brooklyn, NY 11203.
0022-3476/79/110807+05500.50/0 9 1979 The C. V. Mosby Co.
be effective in treating disease with an abnormally high rate of bone resorption. 7 We have reported that the administration of porcine calcitonin to two patients with osteogenesis imperfecta tarda caused a retention of calcium and a decrease in hydroxyproline excretion in one, ~ suggesting that calcitonin might be beneficial to children with osteogenesis imperfecta. Similar favorable responses to the administration of calcitonin in osteogenesis imperfecta have been reported? -~' Abbreviations used OI: ostengenesis imperfecta MRC: Metabolic Research Council BM: bone mineral mass BA: bone image area MC: mineral concentration rPMC: rate of MC change in patient rNMC: rate of MC change in normal subject In animal studies, '~ salmon calcitonin has been shown to be more potent and longer lasting than porcine calcitonin in its effects on serum calcium levels, suggesting that salmon calcitonin may provide a more convenient and more effective form for long-term therapy of osteo-
VoL 95, No. 5, part 1, pp, 807-811
808
Castells et aL
The Journal of Pediatrics November 1979
Table I. Clinical data
Osteogenesis imperfecta type
Period of treatment (mo)
Patient (n)'
Mean age (yr)
M
" F
9 6 4 6
2.9 7.8 13.2 12.5
4 4 3 3
5 2 1 3
20.6 18.8 16:0 18.5
2.9 2.8 2.8 1.7
12 9 4
1.8 7.4 7.8
7 5 2
5 4 2
19.4 20.8 15.3
4 . 0 - 0.9 3.7 _~ 0.7 2.0 = 1.0
Tarda I < 5 yr 5-10 yr > 10 yr Tarda II Congenita < 5 yr 5=10 yr > 10 yr
Sex
Annual fracture fate Before -:- 0.5 ~- 1.0 ~ 1.1 -~ 0.5
On 0.8 0.4 0.4 0.2
z 0.3 ~- 0.3 ~ 0.3 -+ 0.1
1.1 z 0.5 0.5 --- 0.2 0.3 z 03
qP < 0.002)
(P<0.03) (P < 0.01) (P
Improvement of paiients on therapy Activity (n)
[ Leg strength I (n)
9 5 3 6
9 6 3 5
3 2 3
9 5 4
Individual 16atient data are available upon request. genesis imperfecta, la Short-term administration of synthetic salmon calcitonin to children with osteogenesis tmperfecta seems capable of reducing the increased bone resorption of osteogenesis imperfecta2 This study was undertaken to evaluate long-term therapy with synthetic salmon calcitonin in a large number of patients With osteogenesis imperfecta. MATERIALS
AND METHODS
We treated 48 children, ages 6 months to 15 years, and two young adults (20 and 22 years of age) with osteogenesis imperfecta, with synthetic salmon calcitonin for up to 48 months (Table I). In each patient the clinical diagnosis was substantiated by radiographic findings, a history of multiple fractures, a n d / o r the presence of blue sclera. The patients were classified as having osteogenesis lmperfecta congenita or tarda (types l and 2) according to the clinical classification of Falvo et al. x" N o n e of the patients had received any other specific therapy for osteogenesis imperfecta for at least six months before entry i n t o the study. On admission into the study, each patient was hospitalized for 7 to 10 days. Several baseline evaluations were made: (1) annual fracture (ate (the average n u m b e r of fractures during the two years preceding calcitonin therapy); (2) functional activity level (the ability of the pauent to stand and move); (3) subjective feeling of strength in the lower extremities in patients old enough to provide this information. Complete blood count, urinalysis, and laboratory studies with the SMA-12 Technicon AutoAttal'~zer (serum sodium, potassium, chloride, bicarbonate.~,calcium, alkaline phosphamse, glutamic oxaloacetic transammase, total protein, albumin, bilirubin, glucose, and blood urea nitrogem, were normal initially and remained normal during synttaetic salmon calcitonin therapy. Standard
screening tests for inborn errors of metabolism (horizontal paper chromatography for amino acids. Clinitest for reducing substances. Phenistix for keto acids, nitroprusside test for sulfur-containing amino acids, cetyltrimethyla m m o n i u m bromide test for mucopolysaccharidesl were normal.i~. 16 Serum concentrations of parathyroid horm o n e were determined by immunoassay* before and during calcitonifa therapy. 17 Antibodies to synthetic salmon calcitonin were assayed at intervals during the course of the treatment, according to a method previously describedY Fourteen patients were followed in our clinic. No attempt was made to influence various factors that might affect the fracture rate, such as level of activity, exposure to accidents, use of physical therapy, or degree of parental supervision. The remaining 36 patients received basic medical care (which often included orthopedic treatment and physical therapy) in their own communities and were only seen in our clinic at monthly intervals to regulate their calcitonin therapy and to perform the necessary investigations. ,~:, Synthetic salmon calcitonin (AL0977) was supplied by A r m o u r Pharmaceutical Company. Prior to administration of the drug, intradermal testing was done with 0.5 ml of salmon calcitonin solution ~equivalent to 0.5 M R C units) and with veliicle control, using separate sites on the ventral surface of the forearm. N o patient had cutaneous hypersenslovity. The patients were hospitalized for baseline studies and initiation of treatment. The treatment regimen consisted of subcutaneous rejection of satmon calcitonin (2 M R C units/kg) three days a week and a daily oral calcium supplement (10 to l 5 ml o f Neocalglu*The annserum used for serum parathyroid hormone determlnanons was Ch-12. kindly provided and partially ct~aracterized by reaction with several defined molecular fragments of human PTH by Dr. C.D. Arnaud.
Volume 95 Number 5, part 1
cagon solution, equivalent to 230 to 345 mg of calcium). One or both parents were taught to administer subcutaneous injections. Before initiation of treatment each patient or parents signed a statement of informed consent. This investigation was approved by the institution's human research committee. Radiographic bone density was determined bY the method of radiographic photodensitometry (absorptiometry) of Colbert et al? 9' 20 This method automatically compares the minimal value of the patient's middle phalanges with that of age and sex-matched peer norms. A computer controlled microdensitometer* scans 1 mm "slices" of the image of each phalanx on a conventional nonscreen radiograph of the 9 and wrist. For the baseline study and each subsequent determination, a pair of radiograph s (exposed at 50 to 60 KVP) is obtained with an aluminum alloy reference wedge included in the field to permit correction for day-to-day variation in radiographic exposure and energy spectrum. The ratio of bone mineral mass to bone image area is the mineral concentration, expressed in computer units. We compared MC of calcitonin-treated patients with that of 308 normal subjects of both sexes (age range one to 20 years). In a normal population, values of MC at any age are symmetrically distributed about the mean (SD T 15%): We graphed serial values of MC for treated patients and normal subjects at various ages and measured the slope of the regression liner to determine the average annual rate of change in MC for treated patients and normal subjects of comparable age; ~R. the difference in these rates (npMC-RNMC) was used as a simple measure of efficacy of calcitonin treatment. &R > 0 indicates effective treatment. and AR _< 0 indicating treatment failure, although &R in untreated patients with OI is not known. RESULTS General. Most of the patients tolerated the therapeutic regimen of thrice weekly injections with minimal inconvenience. After the first injection, 25% Of the patients experienced flushing in the hands and feet. and 20% had nausea. These symptoms usually resolved after the second or third injection. In three patien m. nausea and vomiting persisted for several months and it was necessary to discontinue therapy. Two patients hacl urticarial reactions that required discontinuation of therapy. Many patients experienced subjective improvement as early as the second week of therapy; these panents also
*Mark III Microdensitometer connected on line to a Digital Equipment Company LINC-8 computer 9 +Determined by the method of least squares regression.
809
Osteogenesis treated with calcitonin
Table II. Density difference in patients with osteogenesis imperfecta treated with calcitonin Patiem classification
No. o f patients
Mean
AR for entire treatment period* )8 -1.09 All patient s OI type 19 0.51 Congenital 19 1.67 Tarda Sex 21 -0.79 Male 17 -1.46 Female Age range (yr) 17 + 1.26 0.5-5 12 -3.00 5-10 10120 9 --2.99 AR during first year of treatmentt 38 + 1.44 All patients Age range (yr) 17 +6.14 0.5-5 12 --2.25 5-10 9 --2.50 i0-20
SD
SE
3.83
0.62
3.64 4.03
0.84 0.92
3.68 4.10
0.80 0.99
2.97 2.69 4.37
0 72 0.78 1.46
7.48
1.21
6.99 6.22 4.79
!.70 1.80 1.60
*AR = a P M C aNMC, where AR is the difference in annual rate of change in treated patien!s (~PMC) a n d aged-matched normal subjects (RNMC). t T o determine AR for first year of treatment, the slope of the plot of the patients first three densitometric studies (before and following after six and 1Zmonths of treatment ) was used for RPMC.
had objective evidence of increased mobility and increased strength in the extremities, which in general was sustained throughout the course of treatment. Most of the patients were able to increase their physical activity (Table I). Both adult patients reported that their chronic back pain decreased during the three-month treatment period. Some patients complained of aching bone pain during treatment, and radiographic evidence of stress fractures (usua!ly in the tibia or femur) was occasionally observed. I n some patients, persistent pain in the lower extremities appeared to be related to degenerative changes of the hips and knees. There was a decrease in the fracture rate per year during synthetic salmon calcitonin (3.2 fractures per year before therapy, 0.6 fractures per year during therapy)9 The decrease in the fracture rate was similar in the congenita and tarda types of osteogenesis imperfecta. In the 25 patients with OI tarda, the fracture rate before therapy was 2.7 and after, 0.5; in the 25 patients with the congenital type, the fracture rate before calcitonin was 3.6. and after therapy, 0.8. Although the average annual fracture rate during the three years prior to treatment was slightly higher in patient s with OI congenita than in patients with Ol tarda, the decrease in annual fracture rate was similar in both
810
Castells et al,
groups. We had anticipated that increased activity in patients whose mobility and strength had improved might lead to an increased fracture rate; this was not seen. Serum parathyroid hormon e levels were within normal range in all patients before therapy and there was no increase of serum parathyroid hormone levels during administration of synthetic salmon calcitonin. Serum antibodies to synthetic salmon calcitonin rose slightly in 30% of the patients. One patient who had received porcine calcitonin one year earlier had serum antibodies to salmon calcitonin on the baseline assay (Patient 1). DenSitometrie studies. The total number of radiographs suitable for radiographic absorptiometry were 214 (0 to 11 per patient); 12 patients with fewer than three usable radiographs were excluded from analysis. Statistical analysis of radiographic bone density was performed for 38 patiems (21 males, 17 females) of whom 19 had OI congenita, and 19 had OI tarda (Table II). The mean duration of treatment was 17 months (range 6 to 48 months) in these patients. AR was determined for the entire treatment group and for various subgroups. The statistical evaluation is summarized in Table II. For the entire treatment group (38 patients) AR was 1.09. indicating that treated patients did not gain bone mineral as rapidly as age-matched normals. AR varied with type of OI ~--0151 in the congenita form. 1.67 in the tarda form~ and sex ~-0.79 in males. -1.46 in femalesl, but these differences were not significant al the 5% level. We divided the patients into three age groups and determined AR for each: 0.5-5 years (+1.26), 5-10 years I 3.00), 10-20 yea1:s ~-2.99). Using a one-way analysis of variance. AR was significantly greater in the 0.5 to 5-year age group than in the others, and the 0.5 to 5-year age group was the only one in which the rate of bone mineral deposition exceeded the norm. The tendency for MC to "catch up" with the norm was maximal during the first year of treatment: AR during the first year of treatment Idetermined by measuring ~'PMC for the first year 0nly) was + 6.14. significantly greater than k R for the entire treatment period ( + i.26) IP < 0.01). During the first year of treatment, the tendency for MC to "catch up" with that of age matched controls was highly significant (P < 0.0025). DISCUSSION It appears from the present study that thrice weekly subcutaneous injections of synthetic saloaon calcitonin with daily oral supplementation of calcium was well tolerated. Nausea and vomiting were frequently found at the start of calcitonin administration, but these symptoms generally subsided during the first week of treatment. Flushing of the skin of the hands and feet (observed in
The Journal of Pediatrics November 1979
25% of the patients) was probably a manifestation of vasodiiation and increased peripheral c!rculatiom Early increase in mobility and muscle strength in the extremities, frequently noted during the second week, was probably due to improved peripheral circulation, but may have reflected decreased osseous and articular pain due to the direct effect of calcitonin on bone. The marked improvement in radiographic bone density in patients under 5 years of age correlated Well with our clinical impression that young patients with osteogenesis imPerfecta respond better to salmon calcitonin than do older ones. However, the mean rate of increase observed during the first year of treatment was not sustained during the full cour, se of therapy. To evaluate the efficiency of calcitonin to promote bone density changes in older children, it would have been more appropriate to compare bone densltometry values of our treated patients to a control group of children with osteogenesis imperfecta rather than to compare it with a normal population. A control group of patients with osteogenesis imperfecta was not available. This lack of densitometric norms for untreated patients with OI did not enable us to determine whether calcitonin slowed down the rate of bone mineral loss in patients over 5 years of age. No consistent abnormalities of biochemical values in osteogenesis imperfecta can be followed to evaluate the response to the administration of calcitonin. Plasma alkaline phosphatase has been reported to be either normal -'1 or high, TM and urinary excretion of hydroxyproline has also been reporte d to be normal ~2or high. 23 In the present study there were no significant changes in these two measurements during therapy. Hypocalcemia or hypophosphatem!a was never observed in these patients. The lack of sustained hypocalcemia might explain why parathyroid activity remained normal during calcito.nin treatment. August et al -'~ h~We reported hypomagnesemia in two children treated with salmon calcitonin. Although there is evidence to suggest that calcitonin induces a net secretion of water, sodium, potassiumi chloride, calcium, and phospha*e into the jejunum, -~ the hypomagnesemia described in two children reported by August et ar -'~ might have been related to inadequate dietary intake of magnesium and in{erm'ittent, infections. In our study, there were no detectable symptoms of hypomagnesemia, but plasma levels of magnesium were not c!osely monitored. Salmon calcitonin differs by amino acid substitution along the polypeptide chain from human calcitonin; treatment with the former is recognized by the body as a foreign protein and stimulates formation of antibodies.,~.._,6 The data presented in this study indicate that
Volume 95 Number 5, part 1
a salmon c a l c i t o n i n - b i n d i n g globulin was acquired by 30% (6 of 19) of the children in response to r e p e a t e d a d m i n i s t r a t i o n of salmon calcitonon, a l t h o u g h there was no evidence o f h o r m o n e resistance. It has b e e n suggested that the severity o f the osteoporotic process in osteogenesis imperfecta m a y be related to increased m e t a b o l i c rates. -~; There is a n a t u r a l t e n d e n c y for osteogenesis imperfecta to improve with age. Y o u n g children generally exhibit more active osteoporosis t h a n older children, a n d osteoporosis generally abates in severity after puberty. It is not surprising that calcitonin t r e a t m e n t was most effective in the youngest patients studied. M a n y o f the s y m p t o m s experienced by older patients are d u e to bone a n d joint deformities a n d are not likely to be responsive to calcitonin treatment. Our present indications for t r e a t m e n t o f osteogenesis imperfecta with synthetic s a l m o n calcitonin are: (1) Children below 5 years of age, (2) patients i m m o b i l i z e d by limb pain with or without radiologic evidence o f stress fractures or degenerative arthritic changes, (3) patients immobilized by cast for t r e a t m e n t o f fractures or surgical procedures, a n d (4) patients at any age, who h a v e b e e n doing well a n d suddenly start to have fractures. The data from our study indicate a beneficial effect o f s a l m o n calcitonin in osteogenesis imperfecta a n d suggest the desirability of a properly controlled study o f treated and u n t r e a t e d patients. The optimal dose a n d d u r a t i o n of calcitonin treatment, and w h e t h e r calcitonin can be used prophylactically to p r e v e n t m a j o r skeletal m a l f o r m a t i o n s and growth retardation, remain to be determined. We thank Ms. Jacquelyne S. Bayer tbr her assistance in the preparation of the manuscript. REFERENCES
1. Lee WR: A quantitative microscopic study of bone formation in a normal child and two children suffering from osteogenesis imperfecta, in Richelle LJ and Dallemagne M J, editors: Proceedings of The Second Symposium on Calcified Tissues, Leige, 1964. Leige, 1965, Belgium, p 451. 2. Ramser JR, Villanueva, AR, Pirok D, and Frost HM: Tetracycline-based measurement of bone dynamics in 3 women with osteogenesis imperfecta, Clin Orthop 49:141, 1966. 3. Villanueva AR, and Frost HM: Bone formation in human osteogenesis imperfecta measured by tetracycline bone labeling, Acta Orthop Scand 41:531, 1970. 4. Castells S, Lu Chun, Baker RK, and Wallach S: Effects of synthetic salmon calcitonin in osteogenesis imperfecta, Curr Ther Res 16:1, 1974. 5. Friedman J, and Raisz LG: Thyrocalcitonin: inhibitor of bone resorption in tissue culture, Science 150:1465, 1965. 6. Wallach SA, Chausurer, A, and Mittlemen R: In vivo inhibition of bone resorption by thyrocalcitonin, Endocrinology 80:61, 1967.
Osteogenesis treated with calcitonin
7.
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10. 11.
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13. 14.
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16.
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18.
191
20.
21. 22. 23.
24.
25.
26,
27.
8 11
Shai F, Baker RK, and Wallach S: The clinical and metabolic effects of porcine calcitonin on Paget's disease of bone, J Clin Invest 150:1927, 1971. Castells S, Inamdar S, Baker RK, and Wallach S: Effects of porcine calcitonin in osteogenesis imperfecta tarda, J PEDIATR 80:757, 1972. Goldfield EB, Braiker BM, Pendergast TT and Kolb FO: Synthetic salmon calcitonin treatment of Paget's disease and osteogenesis imperfecta, JAMA 221:1127, 1972. Caniggia A, and Genari C: Calcitonin treatment in EkmanLobstein disease, Calif Tissue Res 9:243, 1972. Rosenberg, E, Lang R, Boisseau U, Raja Nasathit S, and Avioli LV: Effect of long-term calcitonin therapy on the clinical course of osteogenesis imperfecta, J Clin Endocrinol Metab 44:346, 1977. Keutmann HT, Parsons HT0 and Potts YF Jr: Isolation and chemical properties of two calcitonins from salmon ultimobranchial glands, J Biol Chem 245:1491, 1970. Castells S: New approaches to treatment of osteogenesis imperfecta, Clin Orthop 93:239, 1973. Falvo KA, Root L and Bullough PG: Osteogenesis imperrecta: Clinical evaluation and management, J Bone Joint Surg 56A:783, 1974. Renuart, AW: Screening for inborn errors of metabolism associated with mental deficiency or neurologic disorders or both, N Engl J Med 274:384, 1966. Efron ML, Young D, Moser HW, and MacCready, RA: A single chromatographic screening test for the detection of disorders of amino acid metabolism, N Engl J Med 270:1378, 1964. Arnaud CD, Tsao HS, and Littledike T: Radioimmunoa,ssay of human parathyroid hormone in serum, J Clin Invest 50:21, 1971. Singer FR, Aldred 3P, Neer RM, Krane SM, Potts JT Jr, and Bloch KT: An evaluation of antibodies and clinical resistance to salmon calcitonin. J Clin Invest 51:2331, 1972. Colbert C, Spruit JJ, and Davila LR: Biophysical properties of bone: determining mineral concentration from the X-ray image, Trans NY Sci 30:271. 1967-68. Colbert C, and Garrett C: Photodensitometry of bone roentgenograms with an on-line computer, Clin Orthop 65:39, 1969. Smith R, Francis MJO, and Bange RJ: Osteogenesis imperfecta, Q J Med 44:36, 1975. Shoenfeld YA, Fried A, and Ehrenfeld NE: Osteogenesis imperfecta, Am J Dis Child 129:679, 1975. Langness U, and Behnke H: Collagen metaboties in plasma and urine in osteogenesis imperfecta, Metabolism 20:456, 1971. August GP, Shapiro T, and Hung W: Calcitonin therapy of children with osteogenesis imperfecta, J PEI)LArR 91:1001, 1977. Juan D, Liptak P, and Gray TK: Absorption of inorganic phosphate in human jejunum and its inhibition by salmon calcitonin. J Ctin Endocrinol Metab 43:513, 1976. Haddard JG, and Caldwell JG: Calcitonin resistance: Clinical and immunologic studies in subjects with Paget's disease of bone treated with porcine and salmon calcitonins, J Clin Invest 51:3133, 1972. Cropp GTA, and Myers DN: Physiological evidence of hypermetabolism in osteogenesis imperfecta, Pediatrics 49:375. 1972.
807
Therapy of osteogenesis imperfecta with synthetic salmon calcitonin We evaluated the long-term use of synthetic salmon calcitonin in the management of osteogenesis impelfecta tarda and congenita. Forty-eight children, ranging in ageJrom 6 months to 15years, and two young adults, received synthetic salmon ealcitonin 2 MRC units/kg three days a week and a daily oral calcium supplement of 230 to 345 rag. The annual fracture rate was decreased during calcitonin therapy as compared to the period preceding therapy. There was an increase in the ability of the patient to stand and move and in the subjective feeling of strength in the lower extremities during calcitonin therapy. There was also a significant improvement in radiographic bone density, as determined by the method of photodensitometry, in patients under 5 years of age. Long-term administration of synthetic salmon calcitonin mmJ be beneficial to young children with osteogenesis imperfecta.
S a l v a d o r Castells, M.D.,* B r o o k l y n , N . Y . , Charles Colbert, P h . D . , Yellow Springs, Ohio, C h h a y a C h a k r a b a r t i , M . D . , B r o o k l y n , N . Y . ,
R i c h a r d S. Baehtell, M . D . , Yellow Springs, Ohio,
E. G e o r g e Kassner, M . D . , and Seiichi Y a s u m u r a , Ph.D., B r o o k l y n , N. Y.
THE MOST DEVASTATING SEQUELAE ofosteogenesis imperfecta are due to generalized osteoporosis of the skeleton, which leads to frequent fractures and severe skeletal deformities. Tetracycline labeling techniques and radiocalcium turnover s t u d i e s ' ' have shown increased bone turnover with predominant bone resorption. Calcitonin, a peptide hormone secreted by the parafollicular cells of the thyroid gland, inhibits bone resorption in vitr@ and in vivo? In human beings, calcitonin seems to From the Departments of Pediatrics, Unit of Growth and Metabolism, Physiology, and Radiology, State University of New York, Downstate Medical Center," and the Radiological Researc h Laboratory, Greene Memorial Hospital. SupPorted by grants from the National Foundation-March of Dimes, the Osteogenesis Imperfecta Foundation, Grant RR-312, the General Clinical Research Centers Project of the Division of Research Resources, NIH, PHS Grants A M 16475, ES 000831, ES 01825, and the National Science Foundation, Grant D1-44068. *Reprint address: Director, Unit of Growth and Metabolism, 450 Ctarkson Ave., Brooklyn, NY 11203.
0022-3476/79/110807+05500.50/0 9 1979 The C. V. Mosby Co.
be effective in treating disease with an abnormally high rate of bone resorption. 7 We have reported that the administration of porcine calcitonin to two patients with osteogenesis imperfecta tarda caused a retention of calcium and a decrease in hydroxyproline excretion in one, ~ suggesting that calcitonin might be beneficial to children with osteogenesis imperfecta. Similar favorable responses to the administration of calcitonin in osteogenesis imperfecta have been reported? -~' Abbreviations used OI: ostengenesis imperfecta MRC: Metabolic Research Council BM: bone mineral mass BA: bone image area MC: mineral concentration rPMC: rate of MC change in patient rNMC: rate of MC change in normal subject In animal studies, '~ salmon calcitonin has been shown to be more potent and longer lasting than porcine calcitonin in its effects on serum calcium levels, suggesting that salmon calcitonin may provide a more convenient and more effective form for long-term therapy of osteo-
VoL 95, No. 5, part 1, pp, 807-811
808
Castells et aL
The Journal of Pediatrics November 1979
Table I. Clinical data
Osteogenesis imperfecta type
Period of treatment (mo)
Patient (n)'
Mean age (yr)
M
" F
9 6 4 6
2.9 7.8 13.2 12.5
4 4 3 3
5 2 1 3
20.6 18.8 16:0 18.5
2.9 2.8 2.8 1.7
12 9 4
1.8 7.4 7.8
7 5 2
5 4 2
19.4 20.8 15.3
4 . 0 - 0.9 3.7 _~ 0.7 2.0 = 1.0
Tarda I < 5 yr 5-10 yr > 10 yr Tarda II Congenita < 5 yr 5=10 yr > 10 yr
Sex
Annual fracture fate Before -:- 0.5 ~- 1.0 ~ 1.1 -~ 0.5
On 0.8 0.4 0.4 0.2
z 0.3 ~- 0.3 ~ 0.3 -+ 0.1
1.1 z 0.5 0.5 --- 0.2 0.3 z 03
qP < 0.002)
(P<0.03) (P < 0.01) (P
Improvement of paiients on therapy Activity (n)
[ Leg strength I (n)
9 5 3 6
9 6 3 5
3 2 3
9 5 4
Individual 16atient data are available upon request. genesis imperfecta, la Short-term administration of synthetic salmon calcitonin to children with osteogenesis tmperfecta seems capable of reducing the increased bone resorption of osteogenesis imperfecta2 This study was undertaken to evaluate long-term therapy with synthetic salmon calcitonin in a large number of patients With osteogenesis imperfecta. MATERIALS
AND METHODS
We treated 48 children, ages 6 months to 15 years, and two young adults (20 and 22 years of age) with osteogenesis imperfecta, with synthetic salmon calcitonin for up to 48 months (Table I). In each patient the clinical diagnosis was substantiated by radiographic findings, a history of multiple fractures, a n d / o r the presence of blue sclera. The patients were classified as having osteogenesis lmperfecta congenita or tarda (types l and 2) according to the clinical classification of Falvo et al. x" N o n e of the patients had received any other specific therapy for osteogenesis imperfecta for at least six months before entry i n t o the study. On admission into the study, each patient was hospitalized for 7 to 10 days. Several baseline evaluations were made: (1) annual fracture (ate (the average n u m b e r of fractures during the two years preceding calcitonin therapy); (2) functional activity level (the ability of the pauent to stand and move); (3) subjective feeling of strength in the lower extremities in patients old enough to provide this information. Complete blood count, urinalysis, and laboratory studies with the SMA-12 Technicon AutoAttal'~zer (serum sodium, potassium, chloride, bicarbonate.~,calcium, alkaline phosphamse, glutamic oxaloacetic transammase, total protein, albumin, bilirubin, glucose, and blood urea nitrogem, were normal initially and remained normal during synttaetic salmon calcitonin therapy. Standard
screening tests for inborn errors of metabolism (horizontal paper chromatography for amino acids. Clinitest for reducing substances. Phenistix for keto acids, nitroprusside test for sulfur-containing amino acids, cetyltrimethyla m m o n i u m bromide test for mucopolysaccharidesl were normal.i~. 16 Serum concentrations of parathyroid horm o n e were determined by immunoassay* before and during calcitonifa therapy. 17 Antibodies to synthetic salmon calcitonin were assayed at intervals during the course of the treatment, according to a method previously describedY Fourteen patients were followed in our clinic. No attempt was made to influence various factors that might affect the fracture rate, such as level of activity, exposure to accidents, use of physical therapy, or degree of parental supervision. The remaining 36 patients received basic medical care (which often included orthopedic treatment and physical therapy) in their own communities and were only seen in our clinic at monthly intervals to regulate their calcitonin therapy and to perform the necessary investigations. ,~:, Synthetic salmon calcitonin (AL0977) was supplied by A r m o u r Pharmaceutical Company. Prior to administration of the drug, intradermal testing was done with 0.5 ml of salmon calcitonin solution ~equivalent to 0.5 M R C units) and with veliicle control, using separate sites on the ventral surface of the forearm. N o patient had cutaneous hypersenslovity. The patients were hospitalized for baseline studies and initiation of treatment. The treatment regimen consisted of subcutaneous rejection of satmon calcitonin (2 M R C units/kg) three days a week and a daily oral calcium supplement (10 to l 5 ml o f Neocalglu*The annserum used for serum parathyroid hormone determlnanons was Ch-12. kindly provided and partially ct~aracterized by reaction with several defined molecular fragments of human PTH by Dr. C.D. Arnaud.
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cagon solution, equivalent to 230 to 345 mg of calcium). One or both parents were taught to administer subcutaneous injections. Before initiation of treatment each patient or parents signed a statement of informed consent. This investigation was approved by the institution's human research committee. Radiographic bone density was determined bY the method of radiographic photodensitometry (absorptiometry) of Colbert et al? 9' 20 This method automatically compares the minimal value of the patient's middle phalanges with that of age and sex-matched peer norms. A computer controlled microdensitometer* scans 1 mm "slices" of the image of each phalanx on a conventional nonscreen radiograph of the 9 and wrist. For the baseline study and each subsequent determination, a pair of radiograph s (exposed at 50 to 60 KVP) is obtained with an aluminum alloy reference wedge included in the field to permit correction for day-to-day variation in radiographic exposure and energy spectrum. The ratio of bone mineral mass to bone image area is the mineral concentration, expressed in computer units. We compared MC of calcitonin-treated patients with that of 308 normal subjects of both sexes (age range one to 20 years). In a normal population, values of MC at any age are symmetrically distributed about the mean (SD T 15%): We graphed serial values of MC for treated patients and normal subjects at various ages and measured the slope of the regression liner to determine the average annual rate of change in MC for treated patients and normal subjects of comparable age; ~R. the difference in these rates (npMC-RNMC) was used as a simple measure of efficacy of calcitonin treatment. &R > 0 indicates effective treatment. and AR _< 0 indicating treatment failure, although &R in untreated patients with OI is not known. RESULTS General. Most of the patients tolerated the therapeutic regimen of thrice weekly injections with minimal inconvenience. After the first injection, 25% Of the patients experienced flushing in the hands and feet. and 20% had nausea. These symptoms usually resolved after the second or third injection. In three patien m. nausea and vomiting persisted for several months and it was necessary to discontinue therapy. Two patients hacl urticarial reactions that required discontinuation of therapy. Many patients experienced subjective improvement as early as the second week of therapy; these panents also
*Mark III Microdensitometer connected on line to a Digital Equipment Company LINC-8 computer 9 +Determined by the method of least squares regression.
809
Osteogenesis treated with calcitonin
Table II. Density difference in patients with osteogenesis imperfecta treated with calcitonin Patiem classification
No. o f patients
Mean
AR for entire treatment period* )8 -1.09 All patient s OI type 19 0.51 Congenital 19 1.67 Tarda Sex 21 -0.79 Male 17 -1.46 Female Age range (yr) 17 + 1.26 0.5-5 12 -3.00 5-10 10120 9 --2.99 AR during first year of treatmentt 38 + 1.44 All patients Age range (yr) 17 +6.14 0.5-5 12 --2.25 5-10 9 --2.50 i0-20
SD
SE
3.83
0.62
3.64 4.03
0.84 0.92
3.68 4.10
0.80 0.99
2.97 2.69 4.37
0 72 0.78 1.46
7.48
1.21
6.99 6.22 4.79
!.70 1.80 1.60
*AR = a P M C aNMC, where AR is the difference in annual rate of change in treated patien!s (~PMC) a n d aged-matched normal subjects (RNMC). t T o determine AR for first year of treatment, the slope of the plot of the patients first three densitometric studies (before and following after six and 1Zmonths of treatment ) was used for RPMC.
had objective evidence of increased mobility and increased strength in the extremities, which in general was sustained throughout the course of treatment. Most of the patients were able to increase their physical activity (Table I). Both adult patients reported that their chronic back pain decreased during the three-month treatment period. Some patients complained of aching bone pain during treatment, and radiographic evidence of stress fractures (usua!ly in the tibia or femur) was occasionally observed. I n some patients, persistent pain in the lower extremities appeared to be related to degenerative changes of the hips and knees. There was a decrease in the fracture rate per year during synthetic salmon calcitonin (3.2 fractures per year before therapy, 0.6 fractures per year during therapy)9 The decrease in the fracture rate was similar in the congenita and tarda types of osteogenesis imperfecta. In the 25 patients with OI tarda, the fracture rate before therapy was 2.7 and after, 0.5; in the 25 patients with the congenital type, the fracture rate before calcitonin was 3.6. and after therapy, 0.8. Although the average annual fracture rate during the three years prior to treatment was slightly higher in patient s with OI congenita than in patients with Ol tarda, the decrease in annual fracture rate was similar in both
810
Castells et al,
groups. We had anticipated that increased activity in patients whose mobility and strength had improved might lead to an increased fracture rate; this was not seen. Serum parathyroid hormon e levels were within normal range in all patients before therapy and there was no increase of serum parathyroid hormone levels during administration of synthetic salmon calcitonin. Serum antibodies to synthetic salmon calcitonin rose slightly in 30% of the patients. One patient who had received porcine calcitonin one year earlier had serum antibodies to salmon calcitonin on the baseline assay (Patient 1). DenSitometrie studies. The total number of radiographs suitable for radiographic absorptiometry were 214 (0 to 11 per patient); 12 patients with fewer than three usable radiographs were excluded from analysis. Statistical analysis of radiographic bone density was performed for 38 patiems (21 males, 17 females) of whom 19 had OI congenita, and 19 had OI tarda (Table II). The mean duration of treatment was 17 months (range 6 to 48 months) in these patients. AR was determined for the entire treatment group and for various subgroups. The statistical evaluation is summarized in Table II. For the entire treatment group (38 patients) AR was 1.09. indicating that treated patients did not gain bone mineral as rapidly as age-matched normals. AR varied with type of OI ~--0151 in the congenita form. 1.67 in the tarda form~ and sex ~-0.79 in males. -1.46 in femalesl, but these differences were not significant al the 5% level. We divided the patients into three age groups and determined AR for each: 0.5-5 years (+1.26), 5-10 years I 3.00), 10-20 yea1:s ~-2.99). Using a one-way analysis of variance. AR was significantly greater in the 0.5 to 5-year age group than in the others, and the 0.5 to 5-year age group was the only one in which the rate of bone mineral deposition exceeded the norm. The tendency for MC to "catch up" with the norm was maximal during the first year of treatment: AR during the first year of treatment Idetermined by measuring ~'PMC for the first year 0nly) was + 6.14. significantly greater than k R for the entire treatment period ( + i.26) IP < 0.01). During the first year of treatment, the tendency for MC to "catch up" with that of age matched controls was highly significant (P < 0.0025). DISCUSSION It appears from the present study that thrice weekly subcutaneous injections of synthetic saloaon calcitonin with daily oral supplementation of calcium was well tolerated. Nausea and vomiting were frequently found at the start of calcitonin administration, but these symptoms generally subsided during the first week of treatment. Flushing of the skin of the hands and feet (observed in
The Journal of Pediatrics November 1979
25% of the patients) was probably a manifestation of vasodiiation and increased peripheral c!rculatiom Early increase in mobility and muscle strength in the extremities, frequently noted during the second week, was probably due to improved peripheral circulation, but may have reflected decreased osseous and articular pain due to the direct effect of calcitonin on bone. The marked improvement in radiographic bone density in patients under 5 years of age correlated Well with our clinical impression that young patients with osteogenesis imPerfecta respond better to salmon calcitonin than do older ones. However, the mean rate of increase observed during the first year of treatment was not sustained during the full cour, se of therapy. To evaluate the efficiency of calcitonin to promote bone density changes in older children, it would have been more appropriate to compare bone densltometry values of our treated patients to a control group of children with osteogenesis imperfecta rather than to compare it with a normal population. A control group of patients with osteogenesis imperfecta was not available. This lack of densitometric norms for untreated patients with OI did not enable us to determine whether calcitonin slowed down the rate of bone mineral loss in patients over 5 years of age. No consistent abnormalities of biochemical values in osteogenesis imperfecta can be followed to evaluate the response to the administration of calcitonin. Plasma alkaline phosphatase has been reported to be either normal -'1 or high, TM and urinary excretion of hydroxyproline has also been reporte d to be normal ~2or high. 23 In the present study there were no significant changes in these two measurements during therapy. Hypocalcemia or hypophosphatem!a was never observed in these patients. The lack of sustained hypocalcemia might explain why parathyroid activity remained normal during calcito.nin treatment. August et al -'~ h~We reported hypomagnesemia in two children treated with salmon calcitonin. Although there is evidence to suggest that calcitonin induces a net secretion of water, sodium, potassiumi chloride, calcium, and phospha*e into the jejunum, -~ the hypomagnesemia described in two children reported by August et ar -'~ might have been related to inadequate dietary intake of magnesium and in{erm'ittent, infections. In our study, there were no detectable symptoms of hypomagnesemia, but plasma levels of magnesium were not c!osely monitored. Salmon calcitonin differs by amino acid substitution along the polypeptide chain from human calcitonin; treatment with the former is recognized by the body as a foreign protein and stimulates formation of antibodies.,~.._,6 The data presented in this study indicate that
Volume 95 Number 5, part 1
a salmon c a l c i t o n i n - b i n d i n g globulin was acquired by 30% (6 of 19) of the children in response to r e p e a t e d a d m i n i s t r a t i o n of salmon calcitonon, a l t h o u g h there was no evidence o f h o r m o n e resistance. It has b e e n suggested that the severity o f the osteoporotic process in osteogenesis imperfecta m a y be related to increased m e t a b o l i c rates. -~; There is a n a t u r a l t e n d e n c y for osteogenesis imperfecta to improve with age. Y o u n g children generally exhibit more active osteoporosis t h a n older children, a n d osteoporosis generally abates in severity after puberty. It is not surprising that calcitonin t r e a t m e n t was most effective in the youngest patients studied. M a n y o f the s y m p t o m s experienced by older patients are d u e to bone a n d joint deformities a n d are not likely to be responsive to calcitonin treatment. Our present indications for t r e a t m e n t o f osteogenesis imperfecta with synthetic s a l m o n calcitonin are: (1) Children below 5 years of age, (2) patients i m m o b i l i z e d by limb pain with or without radiologic evidence o f stress fractures or degenerative arthritic changes, (3) patients immobilized by cast for t r e a t m e n t o f fractures or surgical procedures, a n d (4) patients at any age, who h a v e b e e n doing well a n d suddenly start to have fractures. The data from our study indicate a beneficial effect o f s a l m o n calcitonin in osteogenesis imperfecta a n d suggest the desirability of a properly controlled study o f treated and u n t r e a t e d patients. The optimal dose a n d d u r a t i o n of calcitonin treatment, and w h e t h e r calcitonin can be used prophylactically to p r e v e n t m a j o r skeletal m a l f o r m a t i o n s and growth retardation, remain to be determined. We thank Ms. Jacquelyne S. Bayer tbr her assistance in the preparation of the manuscript. REFERENCES
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Osteogenesis treated with calcitonin
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