Case Report

A Case of Bone Pain Caused by Erythropoietin

Takashi Yamada,* Yoshito Terai, Yoshiki Yamashita, NobuyukJ Kim, and Minoru Ueki

Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan

A 62-year-old female patient was hospitalized prior to undergoing an operation for endometrial cancer. She received erythropoietin in doses of 6,000 I U every other day in preparation for predeposit autologous blood donation. About 4 hours after the injection, the patient felt a back pain in the pelvic region. This is the first report of bone pain caused by erythropoietin.

IntJ Clin Oncol 1996;1:61-62

Key words: predeposit autologous blood transfusion; bone pain; erythropoietin

INTRODUCTION

Predeposit autologous blood transfusion has been intro- duced into gynecologic clinical practice with the idea of mitigating the adverse reactions of homologous blood transfusions during operations for malignant tumors. 1 Erythropoietin (EPO) has been used to increase the amount ofpredeposi t autologous blood available if transfusion is required. We recently observed a patient who experienced bone pain that appeared to have been caused by EPO.

CASE REPORT

T he patient was a 62-year-old gravida IV, para IV female. In December 1991, she underwen t a left mastectomy, lymphadenectomy, and cobalt irradiation for breast cancer. She was placed on oral tegafur and uracil (UFT: | Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) after surgery and continued on this regimen until March 1995. She had menarche at age 15 and meno- pause at age 53. She was hospitalized on May 19, 1995 to undergo surgery for stage Ib endometrial cancer. In preparation for the May 20th and 26th predeposit au- tologous blood donations (400 m L each), the patient received epoetin beta (EPO; Epogin injection: | Chugai Pharmaceutical Co., Ltd., Tokyo, Japan), 6000 IU, and iron chondroitin sulfate (Fe; Blutal: | Dainippon Phar- maceutical Co., Ltd., Osaka, Japan) 80 mgintravenously (IV), every other day, starting May 21, for a total of five administrations of each to promote hemopoiesis. Ap-

Received Jan. 17, 1996; revised Mar. 12, 1996; accepted for publication in revised form Apr. 10, 1996. *Correspondence and reprint requests to: Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki, Osaka 569, Japan.

proximately, 4 hours after the first erythropoietin injec- tion the patient complained of a tingling back pain in the pelvic region. Th e pain was intense while in the standing or sitting position, and improved in a recumbent posi- tion. The pain persisted for approximately 2 hours and began to fade thereafter. It was absent the next morning. The same condition returned after each intravenous injection of the drug, but no analgesic was required. Other adverse reactions, such as elevations in blood pressure were not noted.

On May 30, an abdominal-modified-radical hyster- ectomy, bilateral salpingoophorectomy, and bilateral pelvic lymphadenectomy were performed. Intraoperative blood loss was more than 300 mL, and 800 m L of the predeposit autologous blood was returned to the patient immediately after surgery. The patient's peripheral blood count values are shown in Table 1. The other laboratory data before and after treatment showed no abnormality. No other adverse reactions to the blood transfusion, such as allergic reaction, infection, bleeding tendency, or embolism were noted. Iron was administered in a dose of 80 mg IV after surgery, but no bone pain occurred.

Table 1. Blood Cell Count Values.

Pre-t Pre Post Post

Day 1 Day 1 Day 4

WBC (x 103//~L) 7.24 7.85 10.92 5.42 RBC (x 106/pL) 4.11 3.46 3.78 4.36 Hb (g/d L) 12.4 10.6 11.2 12.7 Ht (%) 37.9 32.6 35.6 40.9 PLT (x 104/#L) 23.4 22.7 20.3 23.9 Reti (%0) - 50.6 44.8 25.7

Pre-t, pretreatment with erythropoietin; Pre, preoperative; Post, postoperative; WBC, white blood cell; RBC, red blood cell; Hb, hemoglobin; Ht, hematocrit; Reti, reticulocyte.

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Erythropoietin and Bone Pain

DISCUSSION

EPO is a glycoprotein 2'3 produced and secreted mainly in the kidney. 4,5 I t acts on the erythroblast precursor cells to p romote differentiation to erythrocytes. 6 In recent years, h u m a n erythropoietin gene cloning 7,8 was successful. This made possible the large scale produc- tion of EPO by genetic engineering. EPO is widely used prior to blood collection for predeposit autologous blood transfusions, to treat anemias associated with chronic renal failure (CRF) , and azidothymidine (AZT) associ- ated anemias.

Adverse reactions to E P O primarily include; a rise in blood pressure, 9,1~ headache, clouding of conscious- ness, and convulsions. In addition, dermal symptoms, liver function impairment , gastrointestinal upsets, and sensory organ symptoms have also been reported with EPO. Bone pain has not been reported. The bone pain occurred in our pat ient with the intravenous administra- t ion of 6000 I U of EPO and Fe 80 mg; but the pat ient remained asymptomat ic after postoperative intravenous administrat ion of Fe 80 mg. This suggests that E P O may be responsible for the bone pain symptom.

Bone pain has been reported with granulocyte colony stimulating factor (G-CSF). 11-14 Mild to moderate bone "medul lary" pain was dose-dependent and character- ized as a transient pulsating pain localized primarily in the lower back, posterior iliac crest, and sternum. 14 This medullary pain was associated with intravenous infu- sion, with onset at approximately 10-15 minutes after the initiation of a half-hour infusion of G-C S F , usually on day 1 and days 4-6 of treatment. 14 The bone pain caused by G - C S F was treated with acetaminophen 13 or indomethacin. 14 This bone pain may be caused by G- CSF bone mar row stimulation, but its mechanism is not known in detail. T h e etiology of the bone pain with EPO administration is currently unknown.

It is generally desirable to reduce the dosage or discontinue the drug when adverse drug reactions have occurred. In our case, however, since the pain was transient, the injection of E P O was cont inued as origi- nally planned without using any analgesia. At present, EPO studies are underway to evaluate its efficacy in (1) anemia found in p remature infants, (2) cancer-associ- ated anemias, (3) intractable anemias, and (4) anemias secondary to chronic inflammation. Due to the potential occurrence of this new bone pain adverse reaction, caution should be exercised in the use of EPO, as the indications for use are further expanded.

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