0021-972X/78/4703-0633$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society

Vol. 47, No. 3 Printed in U.S.A.

Calcium and Salmon Calcitonin in Treatment of Osteoporosis* JENIFER JOWSEY, B. LAWRENCE RIGGS, PATRICK J. KELLY, AND DAVID L. HOFFMAN Section of Orthopedic Research and the Division of Endocrinology/Metabolism and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901 ABSTRACT. Calcitonin has been considered of therapeutic value in osteoporosis because of its effects in tissue culture. In the whole animal, however, the predominant result seems to be hypocalcemia, which might be expected to have the opposite effect of stimulating parathyroid hormone secretion and therefore resorption of bone. Indeed, in a short term study of 3- and 4-month duration in osteoporotic women, this was found to be so. A combination of calcium and calcitonin was therefore considered a more promising therapeutic alternative for this disease. Calcium was given to 26 patients, alone or with

vitamin D, for a period of 15 months, and the effects on serum and urine calcium and phosphorus and on bone resorption and formation were evaluated. Calcium and vitamin D decreased serum parathyroid hormone levels, reduced bone resorption, and increased urinary calcium. The addition of calcitonin to the calcium and vitamin D did not seem to change these effects. Neither form of treatment resulted in change of bone mass. Calcium, with or without vitamin D supplements, may prevent the development of osteoporosis, but it seems unlikely that calcitonin has any additional desirable effect in the disease. (J Clin Endocrinol Metab 47: 633, 1978)

T

HE HYPOCALCEMIC action of calcitonin has been firmly established. In man, the decrease in serum calcium that almost always occurs after infusion of calcitonin y is accompanied by an increase in the renal excretion of calcium (1-3). The hypocalcemia can be produced in the absence of parathyroid glands and this suggests a direct action on the kidney (3). However, a decrease in serum calcium can also be elicited in nephrectomized animals (4) and in the absence of any immediate decrease in intestinal absorption of calcium (5). Because the decrease in serum calcium concentration is associated with a decline in serum phosphorus levels, it has been suggested that calcitonin has a direct effect on bone, namely one of decreasing resorption, which is independent of the parathyroid glands, renal function, and intestinal absorption. An effect of both porcine and salmon calcitonin on bone cAMP has been demonstrated Received October 27, 1977. Address requests for reprints to: Dr. J. Jowsey, % Section of Publications, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55901. * This work was supported in part by Research Grant AM-8658 from the NIH, USPHS.

in cultured calvaria in vitro (6). Other tissue culture studies have demonstrated a decrease in the release of previously incorporated 45Ca from fetal rat bones (7). Further evidence for an effect of the hormone has come from electron microscopic studies; these have shown an effect on bone cells which occurs as rapidly as 3 min after injection of the hormone (8). The use of calcitonin in the therapy of osteoporosis was an obvious sequel. A number of studies have been completed in which calcitonin has been administered to osteoporotic subjects. The conclusions differ, probably largely because of the difference in the type of patients, dose of calcitonin, and interpretation of the data. The majority of studies in which radiocalcium kinetics were used shows a consistent decrease in Vo-, a measurement of the removal of calcium from bone (9, 10). This was accompanied by a decrease in Vo+, the rate of calcium accretion into bone. However, other studies in animals, including direct observation of bone, have indicated that calcitonin does not prevent stimulated bone resorption. The studies included animal models of osteoporosis induced by oral phosphate, immobilization, and estrogen deficiency (11-15). The only consistent changes

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JOWSEY ET AL.

634

seemed to be bone and serum changes consistent with hyperparathyroidism. In man, direct measurement of circulating parathyroid hormone (PTH) in osteoporotic patients showed a significant increase of 16 microliter equivalent (/xleq)/dl in four of five patients after 1-4 months of treatment with porcine calcitonin (16). It was suggested that calcium be added to calcitonin therapy in the hope that the combination would show that calcium prevented the stimulation of PTH secretion. In one such study by Cohn et al. (17), patients treated for 3 months with porcine calcitonin plus calcium showed a decrease in urinary levels of hydroxyproline, a finding that suggested a decrease rather than an increase in bone resorption. In the present report, we describe an investigation of the combined effect of calcitonin and calcium and compare it with the effect of calcium alone, both for brief periods (3-4 months) and after prolonged treatment (15 months). We used salmon rather than the porcine calcitonin used by Cohn et al. (17). The major aim of the study was to determine whether combined calcium and calcitonin had any advantage over calcium alone in the therapy of osteoporosis. Materials and Methods We studied 26 patients (24 women and 2 men). Their ages ranged from 51-73 yr (mean, 62 yr); only three patients were more than 70 yr. The diagnosis of osteoporosis rested on the presence of one or more compression fractures of the vertebrae. Radiological reports stated that the majority of patients presented with one to three compression fractures of the lumbar and thoracic spine; six of the patients demonstrated multiple compression fractures of the lumbar and thoracic vertebrae. In addition, all patients were reported as having biconcavity of both compressed and normal vertebrae. A Singh index was also measured (18). No patients were taking any form of treatment, with the exception of a high milk intake. None had any disease other than osteoporosis, with the exception of two patients with mild hypertension and one patient who had had a subtotal gastrectomy 4 yr previously. The patients were admitted to a clinical study unit and a dietary history was taken; the estimated dietary calcium, phosphorus, and calorie intake was given during the study unit period in a diet that approximated the patient's habitual diet.

JCE&M • 1978 Vol 47 • No 3

The patients remained ambulatory during the study period and were encouraged to leave the unit for outside activities such as walks, shopping, and ^ movies, so that as little change as possible occurred in their usual lifestyles. The following tests were completed with the use of standard laboratory techniques: fasting morning serurh total and ionized calcium and serum phosphorus, magnesium, alkaline phosphatase, and creatinine. Serum immunoreactive PTH (iPTH) was -* measured by the use of an antiserum in an RIA that has its major determinants directed against the carboxyl-terminal region of the PTH molecule (19). iPTH measurements were made in fasting morning serum in all patients. Urine was collected " for 24 h for measurement of calcium, phosphorus, creatinine, and sodium, from which tubular reabsorption of phosphorus and creatinine clearance was calculated. Toxicity studies included hemoglobin concentration, leukocyte count, and differential neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts. A bone biopsy was taken from the anterior or median iliac crest with a bone trephine -* (8.0 mm diameter). The specimen was fixed in neutral formalin, dehydrated in alcohol, and embedded in methyl methacrylate; undemineralized sections were cut, microradiographs were prepared, and the sections were stained with the Paragon stain. Bone-forming and bone-resorbing surfaces were evaluated, and the thickness of unmin- y eralized osteoid was measured at a magnification of 100 times (20). Bone mass was measured by means of a videodensitometric analysis of the microradiographs of the bone biopsy specimens taken at the 15-month interval but not in those taken at shorter intervals (21). The bone mass measurements included both trabecular and cortical bone. Symptoms were recorded by the physician on \ the patients' return visits. The patients were dismissed from the unit and instructed to remain on their habitual diets. The numbers of patients and the treatment regimens are shown in Table 1. The dosage of drugs was as follows: calcium, 1 g daily (given as the carbonate); vitamin D, 50,000 U twice a week; salmon calcitonin (generously supplied by Armour Co.), 50 Medical Research Council (MRC) U im every morning in short term studies and 100 MRC U in long term studies. All patients took a multivitamin tablet (1 Hexavitamin/day) to prevent vitamin deficiency. The patients returned after 3 or 12 months and the tests were repeated. The essential data consisted of a comparison between values before and after the treatment periods. However, the extent of the changes was also

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CALCIUM AND CALCITONIN FOR OSTEOPOROSIS

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TABLE 1. Treatment regimens with calcium (Ca), Ca plus vitamin D (D), or Ca plus calcitonin (CT) Treatment Average age (yr) group

Regimen Biopsy

Treatment

Biopsy Treatment Bx Ca + CT (16), 3 months 62 Bx Ca + D" Ca + D (10), 3 months Bx Ca + D (10), 12 months 64 Ca + CT Bx Ca + CT (10), 3 months Bx Ca (10), 3 months Numbers in parentheses are the number of patients. " Patient in clinical study unit for tests and bone biopsy. b Patients included for comparison from previously published data (22). Ca

61

Bx"

Ca (16), 3 months

compared between the calcium and the calcium plus calcitonin groups. Comparisons were made between different groups of patients who had been on the same treatment for the same period of time and also between the same patients on different forms of treatment. Thus, results in 16 patients who had been on calcium for 3-4 months were compared with results in the same 16 after they had been on calcium plus calcitonin for 3-4 months, and results in patients treated with calcium and calcitonin for 12 months were compared with results in a different group who had been treated with calcium plus vitamin D for the same length of time. In the long term groups, the data at the end of the study were compared with those at the beginning of the treatment period and also with the data after 3 months of initial treatment with calcium. In addition, data at the end of the 3 months were compared with the initial data. All data were analyzed by means of Student's paired t test, and a two-tailed P value was calculated.

Biopsy

Treatment

Bx

Ca + CT (8), Bx 12 months

Bx Bx

TABLE 2. Laboratory values in untreated osteoporotic patients Osteoporotic patients Mean No. Age (yr) Serum Ca (mg/dl) Ca2+ (mg/dl) P (mg/dl) iPTH (julEq/dl) Urine Ca (mg/24 h) P (mg/24 h) TRP (%) Bone Resorption (%) Formation (%) Osteoid width

SD

Normal range 33-73

624

34

7.8

9.5

0.3 0.4 0.4

31.4

34 32 34 34

122.0 673.9 79.4

32 33 32

55.6 179.3 6.2

>80

8.1 2.0

34 34 21

4.2 1.2 1.6

1.7-6.4 0.4-6.7 10.5-19.3

4.11 3.9

13.5

15.2

8.9-10.1 3.35-5.05 2.5-4.5 Undetectable to 40