Granulocytosis and Lymphocytopenia in the Blood as Indicators for Drug Adverse Reaction during Calcitonin

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1 Ata Media et Biologia Vol. 44, No.4, , 1996 Granuloytosis and Lymphoytopenia in the Blood as Indiators for Drug Adverse Reation during Calitonin Therapy in Patients with Osteoporosis after Gastretomy Inluding a Case Report Minoru FUKUDA Soihiro YAMAMURA Tadamasa HANYU and Toru AB0 lthe Sakamahi Hospital, Arakawa-mahi; 2The Department of Orthopedis and 3The Department of Immunology, Niigata University Shool of Mediine, Niigata, Japan Reeiued jul-v ; aej)!ed Sej)!ember Summary. Calitonin therapy for patients with osteoporosis after gastretomy is widely applied. Sine a drug adverse reation of this hormone is obsure, it is unknown how long the therapy an be ontinued or when it should be stopped. In this linial study, it was found that patients with suh osteoporosis (even after the initiation of alitonin therapy) had a low proportion of granuloytes and a high proportion of lymphoytes in the peripheral blood. This leukoyte pattern indiates the parasympatheti nerve dominane in the hosts. When they were treated with a single injetion of alitonin, the leukoyte pattern returned transiently to a normal pattern (i.e., an inrease of granuloytes), in parallel with inreases in pulse rate and blood pressure (Le., sympatheti nerve strain). Most of these hanges were reversible. One typial patient who reeived long-term alitonin administration and fell vitim to anorexia, insomnia, atarats, et. (all of whih are signs of sympatheti nerve strain) is then presented. During six years, of therapy, granuloytosis and lymphoytopenia were observed beginning four years after initiation. When the alitonin therapy was eased, all signs disappeared in parallel with normalization of the leukoyte pattern. These results suggest that an overdose of alitonin administration manifests itself as sympatheti nerve strain, and that the leukoyte pattern in the blood is a good indiator of suh reation. Key words-alitonin, granuloytosis, lymphoytopenia, osteoporosis, gastretomy. Correspondene: Minoru Fukuda, M.D., The Department of Immunology, Niigata University Shool of Mediine. Asahimahi 1. Niigata 951, Japan. INTRODUCTION Patients who undergo total gastretomy often suffer from osteoporosis due to alium malabsorption. I) To improve this situation, ombination therapy with alitonin and vitamin D 3 has been arried out in suh patients. 2 ) However, we notied that the ontinuation of suh therapy sometimes indues signs of alitonin overdose, suh as atarats, anorexia, insomnia, tahyardia, et. It is suspeted that these onditions are due to sympatheti nerve strain indued by alitonin. 3,4) Namely, metaboli ativities in the musle and other tissues are elevated by alitonin. As a result, the prodution of alium triprosphate, a metaboli substane \vhih is the major omponent of bone, is elevated in the body. This effet of alitonin aelerates bone formation but may also be related to a drug adverse reation (e.g., hyperalemia indues sympatheti nerve strain). In reent studies by us and other investigators, the administration of alitonin was found to have potent immunosuppressive ativity in humans and mie. 5-8 ) There are many reports on alitonin reeptors on lymphoytes 9,IO) and granuloytes. 11,12) In this study, attention was foused on the levels of lymphoytes and granuloytes in the peripheral blood during alitonin therapy in patients with osteoporosis after gastretomy. To our knowledge, this kind of study has remained uninvestigated until present. It was demonstrated that granuloytosis and lymphoytopenia were indued after the administration of alitonin in these patients. Usually, this effet was 209

2 210 M. FUKUDA et a1.: reversible. However, the long-term use of alitonin indued a drug adverse reation. The signs of overdose did not seem to be apparent up to 30% of a lymphoyte-to-total-ieukoyte ratio, but beame obvious at less than 20% (our unpublished observation). We believe this leukoyte pattern is an important indiator for drug adverse reation during alitonin therapy. The underlying mehanism in this phenomenon may be that granuloytes arry a high level of adrenergi reeptors on the ell surfae. 13,14) Namely, the effet of alitonin on the sympatheti nervous system might be the ause of granuloytosis in the peripheral blood of patients. MATERIALS AND METHODS Patients Twenty-four patients (male 11 and female 13) with osteoporosis after total gastretomy who had subsequently reeived ombination therapy of salmonalitonin (Yamanouhi Seiyaku, Tokyo, Japan) and vitamin D 3 for more than 3 years were seleted. In general, a sigle intramusular injetion of 10 IU alitonin in 0.5 ml water was given one a week (or twie a month for outpatients), and vitamin D 3 0 Jig of tablet) was given every day. The ages ranged from 57 to 84 years old (mean age 72.1). Twelve patients (male 11, female 1, mean age=68.7) with gastretomy who did not have osteoporosis for 5 years after surgery were also examined as a ontrol. A typial ase (female, 78 years old) who fell vitim to a drug adverse reation is also reported. \Vhen bone mineral density was greater than 2.5 SD below the mean value of peak bone marrow mass in young normal women, patients were estimated to have osteoporosis. Parameters examined The total number of leukoytes and the perentages of granuloytes and lymphoytes were examined in all subjets. To determine the levels of autonomi nervous system ativity, pulse rate and systoli blood pressure were measured before and after 0 h later) eah injetion of alitonin during the therapy. The serum level of alium and the bone mineral ontent (BMC) were also measured in patients, espeially at the time when therapy was started and thereafter. Statistial analysis Differenes in data was analyzed by a paired i-test. RESULTS Inrease in the proportion of granuloytes and derease in the proportion of lymphoytes in the blood after treatment with alitonin Patients with osteoporosis after gastretomy who reeived alitonin therapy were examined before and after (4 h later) the injetion of alitonin 00 IU) (Fig. 1). It was demonstrated that the absolute number of granuloytes (p < 0.01) as well as that of total while blood ells (WBC) inreased subsequent to alitonin injetion. The proportion of granuloytes was elevated (53~62%), but that of lymphoytes ( %) dereased signifiantly due to the treatment (p <0.01). The ontrol group, whih onsisted of patients without osteoporosis after gastretomy, showed a pattern omparable to those after the injetion of alitonin. This leukoyte pattern in ontrol patients was almost the same as that of healthy subjets (data not shown). In other words, those patients with osteoporosis tended to have a dereased level of granuloytes. To determine the effet of alitonin on the autonomi nervous system, the pulse rate and systoli blood pressure in 5 of 24 patients (seleted from those ; ':: :: ~ 3000 u L---L_--l_~_...L---'-_.l.----I.._----J'----' Before After Contra1 Fig. 1. Prominent inrease in the absolute number and proportion of granuloytes indued by alitonin in patients with osteoporosis and granuloytopenia. A single administration of alitonin (10IU in 0.5 ml water) was given to 24 patients with osteoporosis. The number and proportion of granuloytes and lymphoytes were enumerated before and after (4 h later) the administration. The ontrol group onsisted of 12 patients without osteoporosis after gastretomy. The variation indiated by bars represents one SD from the mean value in the number of granuloytes.

3 Granuloytosis and Calitonin Therapy E :::- 75 f <'J E Before After Before After Pulse rate Blood pressure Fig. 2. Administration of alitonin indued transiently sympatheti nerve strain. Five patients with osteoporosis \vere examined as to their pulse rate and systoli blood pressure before and after (1 h later) eah injetion of alitonin (10 IU in 0.5 ml water). A signifiant elevation of pulse rate (p<0.05) and systoli blood pressure (p < 0.01) was onsistently observed. in Fig. 1) were measured (Fig. 2). A signifiant inrease in the pulse rate (p < 0.05) and systoli blood pressure (p < 0.01) was seen in all tested subjets (l h after injetion). A follow-up study of one typial ase showing a drug adverse reation In general, omplaints during alitonin therapy in patients who underwent gastretomy are ommon. Suh a typial ase is represented, in parallel with the leukoyte pattern as shown by laboratory tests (Fig. 3). This female patient was 78 years old and had undergone gastretomy at the age of 69 years. One year after surgery, she experiened Lumbago, estimated to be osteoporosis, and then began a ombination therapy of alitonin and vitamin D 3 whih ontinued until reently. Possibly beause of the ombination therapy of alitonin and vitamin D 3, the level of granuloytes began to inrease (> 70%) and the level of lymphoytes began to derease «20%). From 1992 to 1993, she fell vitim to atarats and suffered from anorexia and insomnia. During this period, the serum Ca level beame gradually elevated, but the bone mineral ontent (BMC) was not. More importantly, in parallel with the onset of granuloytosis and lym- phoytopenia, the bone mineral ontent profoundly dereased. The level of lymphoytes then dereased by up to 10% in Sine it was suspeted that all of these signs had arisen from sympatheti nerve strain indued by alitonin, its administration was eased in All signs inluding even atarats subsequently disappeared and the level of lymphoytes returned to nearly 30%. DISCUSSION In the present study, we demonstrated that a single injetion of alitonin immediately hanged the leukoyte pattern in the blood, showing an inrease in the proportion of granuloytes and a derease in the proportion of lymphoytes. More preisely, these hanges were mainly indued by an inrease in the absolute number of granuloytes (note the inrease in the total number of leukoytes). This variation ontinued for several hrs after the injetion (data not shown). In other words, the levels of granuloytes and lymphoytes retutrned to the baselines thereafter. This situation was also onfirmed from the fat that the level of granuloytes was very low in patients shown in Fig. 1, irrespetive of alitonin therapy. However, patients who reeived alitonin therapy

4 212 M. FUKUDA et al.: ~ ~ 4000.:::> ~ "" I---WBCI ;::: 2500 <ll u ~ 60 :; 50 :g : Wh i t e blood e I I Granuloytes and Lymphoytes '=0 en en a :;::; :: ~ E6 38 <ll u BMC 8 a 36 -o-ca u o u BUC and Ca onen t rat ion Fig. 3. Time-kineti study of various parameters during alitonin therapy in one typial patient who fel1 vitim to signs of over-ativation of the sympatheti nerve system. She had undergone total gastretomy at the age of 69 years and was 78 years old in One year after surgery, she began a ombination therapy of alitonin and vitamin D:J' This therapy was eased at the end of The absissa indiates the year. BMC, bone mineral ontent. for long periods of time showed an irreversible effet. Namely, they showed granuloytosis and lymphoytopenia (relatively) during the therapy, with many ompliations due to sympatheti nerve strain. We found that all patients showing < 20% lymphoytes in the blood (n= 5) had the above-mentioned ompliations (in our ongoing study). \Ve \vish to emphasize that the lymphoyte level, less than 20%, may be an indiator antiipating the onset of ompliations beforehand. Why does alitonin indue granuloytosis and lymphoytopenia in the blood? It is hypothesized that sympatheti nerve strain is the main ause. There have been several reports that alitonin indues the ativation of the sympatheti nervous system. 3,4) It is also known that sympatheti nerve stimuli indue the release of alitonin ) Therefore, all effets indued by alitonin seem to be related to sympatheti nerve strain: 1) it inreases the basi metabolism in the body and results in inreases of the serum Ca level and of bone formation in onjuntion with Ca absorption from the intestine aided by vitamin D3; 2) it also indues side effets suh as sympatheti nerve strain if used for a long time; and 3) it inreases the levels of granuloytes whih arry adrenergi reeptors on the surfae. 1 :J,14) Although some lymphoytes suh as NK ells and extrathymi T ells express a onsiderable level of adrenergi reeptors, T and B ells express a lower level of adrenergi reeptors (S. Suzuki et a1., manusript in preparation). On the other hand, T and B ells arry rather holinergi reeptors and derease in number under onditions of sympatheti nerve strain. It is also related to the fat that the turnover of granuloytes from the bone marrow to the periphery is quite rapid (i.e., the lifespan of granuloytes is only 2 to 3 days). In this regard, the effet of alitonin first appears on the level of granuloytes. Until the present, the effets of alitonin on the body, espeially on the leukoyte system, have not been totally eluidated. Sine all funtions indued by alitonin are intimately related to the ativation of the sympatheti nervous system,3,4) we should pay attention to suh signs. We also notied an unexpeted derease in bone mineral ontent during the therapy. If we want to be aware of all suh signs as early as possible, the levels of granuloytes and lymphoytes in the peripheral blood of patients might be important indiators. Sine the diret indiators of sympatheti nerve strain (e.g., pulse rate, blood pressure, and serum levels of ateholamines) tend to be easily hanged by physial onditions at measurement, the leukoyte pattern is both more stable and onsistent in indiating the ativity of the autonomi nervous system. Aknowledgments. This work was supported by a grantin-aid from Niigata University. vve wish to thank Mrs. Kyona Kimura for preparation of the manusript.

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