J. Endocrinol. Invest. 14: 47-51,1991

Intranasal and intramuscular human calcitonin in female osteoporosis and in Paget's disease of bones: a pilot study A.E. Pontiroli*, E. Pajetta*, A. Calderara*, M. Alberetto*, G. Pozza*, V. Manganelli**, G. Resmini**, L. Tessari**, and V. Maresca***. *Clinica Medica and **Clinica Ortopedica, Istituto Scientifico San Raffaele, Universita di Milano and ***Ciba-Geigy, Dipartimento Medico, Origgio, Italy. ABSTRACT. It has been shown that human calcitonin (hCT) is absorbed through the nasal mucosa when administered together with promoters like sodium glycocholate (SGC) or dihydrofusinate. The aim of this study was to compare the clinical and metabolic effects of intranasal (in) and intramuscular (im) hCT in patients with osteoporosis or with Paget's disease of bones. Fifteen women with postmenopausal or with senile osteoporosis entered a randomized six months trial with in hCT (plus SGC) or with im hCT 100 U on alternate days. Six women in each group were treated for 2 months, and only four women in each group continued treatment

for an additional 4 months period. In hCT, but not im hCT, reduced subjective pain, while urinary cAMP increased to a similar extent in the 2 groups. Other metabolic indexes and bone mineral content (BMC) were unchanged, no new fractures took place, and side effects were fewer with in than with im hCT. To confirm the analgesic effect of in hCT, twelve patients with Paget's disease of bones were randomly treated for 20 days with in or im hCT 100 U/day: during the short period of treatment, pain was reduced by in, not by im hCT, and urinary cAMP excretion similarly increased in the two groups of patients.

INTRODUCTION

First study Patients with postmenopausal and senile osteoporosis. Fifteen consecutive women entered the trial as outpatients. Diagnosis of spinal osteoporosis was based on the X-ray evidence of vertebral fractures: twelve women had one vertebral fracture in the dorsal spine, and three women had one fracture in the dorsal spine and one in the lumbar spine. Bone mineral content (BMC), single photonic beam, was evaluated at 1/3rd and 1/1 Oth of the radial length (6) using a 2780 Digital Bone Densitometer (Norland, Fort Atkinson, Wisconsin, USA). Criteria for exclusion were kidney failure, and secondary osteoporosis. No woman had received previous treatment for osteoporosis. All women were encouraged to follow a normocalcic (800 mg) and normo phosphatic (1100 mg) standard 2,000 Kcal diet during the study, and were randomly allocated to treatment with im or in hCT. Seven women, aged 73.0±2.62 yr (62 to 82 yr) received each other day in hCT 100 U (plus 15 mg SGC) as a spray solution, and eight women, aged 69.3±2.82 yr (60 to 83 yr) received each other day im hCT 100 U. Six women in each group completed the expected 2 months trial, and four women in each group continued treatment for an additional 4 months period; three women dropped out because of poor compliance or because of side effects.

Salmon calcitonin (sCT) is effectively absorbed through the nasal mucosa as such, i.e. without the aid of promoters or surfactants (1); intranasal (in) sCT is effective in the management of osteoporosis and of Paget's disease of bones (2,3). We have previously shown that in normal subjects human calcitonin (hCT) raises plasma hCT levels only when administered together with a promoter, like sodium glycocholate (SGC) or dihydrofusinate (4,5). The aim of the present pilot study was to compare the efficacy of in and intramuscular (im) hCT in post-menopausal and senile osteoporosis, and in Paget's disease of bones. MATERIALS AND METHODS The whole study was approved by the Ethical Committee of Istituto San Raffaele and patients gave written informed consent.

Key-words: Osteoporosis, calcitonin (human), nasal administration, Paget's disease of bones. Correspondence: Antonio E. Pontiroli M.D. Istituto San Raffaele. via Olgettina 60. 20132 Milano. Italy Received April 26, 1990; accepted November 5.1990.

47

A.E. Pontiroli, E. Pajetta, A. Calderara, et al.

Before treatment, and after 7, 14,30,60, and 180 days, the following were evaluated: pain score (visual analogic scale, VAS, 7, 8) urinary hydroxyproline, phosphorus and calcium, serum alkaline phosphatase, creatinine, phosphorus, calcium, and plasma calcitonin (IRCT). The same phYSician always assessed the pain score. BMC was re-evaluated only in women completing the 6 months treatment. Drugs known or suspected to influence the above considered variables were not allowed.

20 days wash-out. All patients completed the trial. Serum calcium, phosphorus, plasma IRCT, urinary calcium, phosphorus and c-AMP were measured during the wash-out period (0, 20, 40, 60 days), during drug administration (70 and 80 days) and again at the end of the second wash-out period. Assessment of pain score (VAS) and of side effects was always performed by the same physician. Drugs Human calcitonin (Cibacalcin, Ciba Geigy, Basle, Switzerland) was administered im according to manufacturer's recommendations . For intranasal administration , 0.5 mg of commercially available hCT powder were mixed with 15 mg sodium glycocholate powder (Calbiochem, La Jolla, California) in a breakable plastic envelope inserted in a brown glass bottle containing the manufacturer's diluent (1.0 ml): immediately before use, the plastic envelope was broken, the bottle was shaken, the envelope was removed, and a manual spray valve was screwed on top of the bottle: the valve (kindly supplied by Koster, Milano, Italy) delivers 0.1 ml, so that each administration requires 8 to 10 puffs in the 2 nostrils in order to deliver the 1.0 ml volume. Subjects were instructed to take a deep breath af-

Second study Patients with Paget's disease of bones. Twelve consecutive patients with Paget's disease of bones (six men and six women, aged 55 to 81 yr, mean 65.0 ± 2.54 yr) entered the trial as outpatients; eight patients were newly diagnosed, and four had received their last treatment with ethidronic acid at least 3 months before. Criteria for inclusion were clinical, Xray and laboratory evidence of active Paget's disease. All patients were encouraged to follow a normocalcic and normophosphatic standard 2,000 kcal diet. They underwent a 60 days wash-out period during which only paracetamol was allowed; then they were randomized to either in or im hCT, 100 U/day for 20 days, followed by an additional

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48

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