Synthetic human calcitonin in postmenopausal osteoporosis: A placebo-controlled, double-blind study

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Calcif Tissue Int (1991) 49:17-19

Calcified Tissue International 9 1991 Springer-Verlag New York Inc.

Synthetic Human Calcitonin in Postmenopausal Osteoporosis: A Placebo-Controlled, Double-Blind Study Sverker Ljunghall, 1 Per G/irdsell, 2 0 l o f Johnell, 2 Karin Larsson, 1 Erik Lindh, 1 Karl Obrant, 2 and Ingemar Sernbo 2 1Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden; and 2Department of Orthopedic Surgery, Malm~i, Sweden

Summary. A placebo-controlled, double-blind study was carried out over 4 months to evaluate two doses of synthetic human calcitonin (0.25 and 0.125 mg) given s.c. three times per week. Enrolled were 60 women, aged 56-82 years, who had experienced a vertebral fracture due to low-energy trauma within the preceding year. During active treatment there was within the first month a dose-dependent decrease of the indices of bone resorption (fasting urinary calcium and hydroxyproline excretions), whereas only the higher dose and a treatment period of 4 months produced a reduction of bone formation (serum osteocalcin). The bone mineral content (BMC) of the nondominant forearm was unchanged. T r e a t m e n t with calcitonin also had significant, dosedependent, analgetic effects. The amelioration of pain was, in multivariate analyses, related to a reduction in parameters felt to be markers for bone resorption. In the placebo group there was a significant reduction of the BMC of the forearm but no changes of any of the biochemical markers for bone turnover and no improvement of pain. In conclusion, treatment with two low doses of calcitonin induced changes of the b i o c h e m i c a l markers of bone t u r n o v e r in a dosedependent manner. The analgetic properties of calcitonin were also of salient clinical importance. The knowledge derived from this study could be adapted to the dosage schedule in long-term trials in osteoporosis.

Key words: Calcitonin - Osteoporosis - Biochemical markers - Analgesia.

Age-related bone loss and osteoporosis are the results of focal imbalance between bone resorption and formation in the course of bone remodelling. Calcitonin inhibits bone resorption both in vitro and in vivo [1]. Since coupling will attenuate also bone formation, secondary to the reduction of bone resorption, it is not evident that continuous long-term treatment with calcitonin will prove beneficial for the skeleton. Indeed, skeletal mass does not seem to be affected by large variations of endogenous plasma calcitonin in adults [2]. It is therefore necessary to derive optimal treatment strategies with regard to dosage and duration of therapy. A central nervous system effect of calcitonin with analgesia has also been described [3] and this possible therapeutic effect should also be further explored. We have performed a controlled study with synthetic human calcitonin in postmenopausal women with vertebral fractures. The rationale was to evaluate the minimal effective dose and the optimal dosage schedule based primarily on the assessment of biochemical markers for bone turnover.

Materials and Methods The study entailed 60 postmenopausal women between 56 and 82 years of age with a mean age of 69 years. All of them had a vertebral fracture caused by a low energy trauma within the preceding 12 months. Except for bone fragility the individuals were healthy and without severe disease. None of them suffered from secondary osteoporosis and none of them had previous or concomitant use of medications of potential importance for bone turnover. All patients had a bone density below the mean for normal premenopausal women, measured at the distal radius. Each of them gave informed consent to participate in the trial which was approved by the Ethical Committee of the Faculty of Medicine. The patients received, during 4 months, either placebo or synthetic human calcitonin (in one of two doses--O. 125 mg or 0.25 rag) by self-administered subcutaneous injection three times per week delivered in the same volume, regardless of dose, using a twinchamber disposable syringe. The study was double-blind and the 60 patients were randomly allocated, in equal numbers, to each of the three groups. In order to ensure balance between treatments the randomization was made in blocks of three patients each. Before the start of the trial and after 1 and 4 months measurements were made of biochemical markers for bone turnover. An assessment of pain was performed by use of a visual analog scale (VAS). The scale was 100 mm long and the patient was asked, on each visit, to indicate on the scale her present feeling of pain. During treatment the previous ratings were not available for the patient until the entire trial was completed. Adverse effects, local and systemic tolerability were investigated monthly. Serum and urinary electrolyte concentrations were measured as part of the clinical routine. Urinary hydroxyproline was determined using a photometric method (Medicinsk Laboratorium, Copenhagen), urinary cyclic AMP and intact serum parathyroid hormone (PTH) by radioimmunoassays. The bone mineral content (BMC) of the nondominant forearm was measured at both the distal (6 cm) and ultradistal (1 cm) sites by single photon absorptiometry (SPA). These measurements, which have a precision of around 1% in our laboratory and a long-term reproducibility below 2%, were carried out prior to the study and when it was terminated. Student's paired t test was used for evaluations of differences within each group and the unpaired t test was applied to test differences between groups. The calculations were made on the absolute values but for the sake of clarity the changes are presented in percent of the pretreatment values. The method of least squares was applied for correlation coefficients and the chi-square test when comparing proportions between groups. In the multiple regression analysis, techniques with a fixed given number of independent variables and a forward stepwise technique were used. P values < 0.05 were considered as significant.

Results Before the study there were no significant differences between the three groups (placebo, lower and higher dose of


S. Ljunghall et al.: Synthetic Calcitonin in Postmenopausal Osteoporosis

Table 1. Baseline values (mean +_ SEM) for the biochemical markers of bone turnover and bone mineral content in the three groups, each containing 20 patients. Reference values within parentheses) High dose Urinary calcium/creatinine (mmol/mmol)(0.10--0.50) Urinary hydroxyproline/creatinine (~mol/mmol)(5-30) Serum osteocalcin (txg/1)(3-13) Serum alkaline phosphatases (ixkat/1)(
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