JOURNAL OF ADOLESCENT HEALTH 1992;13:306-310
Osteoporosis as the Presenting Sign of Leukemic Relapse in an Adolescent: Case Report and Literature Review REUBEN D, ROHN,
ERIC J. WERNER,
Osteoporosis in adolescence is rare and usually secondary to an underlying disease process whose diagnosis may be difficult to detect. Osteoporotic vertebral collapse is an uncommon presenting sign of acute lymphoblastic leukemia (ALL). We describe a 13-year-old boy with osteoporotic vertebral collapse secondary to relapse of ALL whose blood count and blood morphology were normal but whose 123 = (OHJ = vitamin D level was deficient. A combination of chemotlherapy, calcitriol ana calcitonin therapy was successful in reversing the process. His case is presented to describe the diagnostic and therapeutic issues involved. KEY WORDS
Osteoporosis Leukemia 1,25 = (OH), = vitamin D
Osteoporosis during adolescence is a rare event that is generally secondary to an underlying disease process. Leukemias, lymphomas, and certain solid tumors may be associated with osteoporosis. Osteoporotic vertebral collapse as the presenting feature of acute lymphoblastic leukemia (ALL) is uncommon and virtually always associated with clinical and laboratory abnormalities suggestive of that disease (l3). To our best knowledge, no cases of relapse of ALL have been described that have presented solely with osteoporosis and vertebral collapse. The mech-
Ftvm theDepartment of Pediatrics, Eastern Virginia MedicalSchool, Norfolk, Viwinia. &dress “&printrequests to: Ret&n D. Rohn, M.D., Director,Adoht Medicine and Endocrinology,Children’sHospital of the King’s ~lrghters, 800 West Otney Road. Norfolk, VA 23507. Manuscriptaccepted November22,199~
L. BYRD, M.D.
anisms underlying such an event are poorly understood. We describe osteoporosis and vertebral collapse in a 13-year-old boy, who had no other clinical or laboratory evidence of ALL, to discuss diagnostic and therapeutic issues, as well as to describe hitherto unreported associated metabolic changes.
Case Presentation Our patient initially presented at 6 2/12 years of age with malaise, fatigue, poor appetite, intermittent fever, and easy bruising. Physical examination detected mild lqatosplenomegaly, mild lymphadenopathy, and asymmetric testes with a testicular volume of 6 mL on the right and 4 mL on the left (normal for age is less than 3 mL each). His laboratory data were as follows: leukocytes 33,6OO/mm’ (70% lymphs, 25% polys, 1% monos, 2% eos, 2% blast cells), hemoglobin 8.4 g/dL, hematocrit 25.6%, platelet count 64,OOO/mm’.A bone marrow aspirate was hypercellular with 86% blasts present. Morphologic cytochemical, and cell surface marker analysis confirmed ALL. He was begun on the Childrens Cancer Study Group (CCSG) protocol for intermediate prognosis ALL. He was successfuully induced into remission, underwent cranial and testicular irradiation, and 2 years of maintenance chemotherapy. At 12 years of age, while still in clinical and hematologic remission, he underwent testicular biopsy which indicated bilateral testicular fibrosis. Human chorionic gonadotropin (HCG) testing (1500 U 3 times per week for 6 weeks) showed him to be hypogonadal (testosterone = 100 ng/dL; nl > 250 ng/dL). He was then begun on Depo-testosterone therapy, 50 mg monthly. At 13 years of age, back pain developed and over
o Society for Adolescent Medicine, 1992 Published by ElsevierWence Publishing Co., Inc., 655 Avenue of the-Americas,New York, NY 10010
OSTEOPOROSIS IN THE LEUKEMIC RELAPSE
Figunz 1. Radiogruph of the spine, demonstratiq osteoporosis and vertebral collapse in our patient. Lower thoracic and the lumbar vertebrae are numbered for clarity.
5 weeks progressed until he was unable to walk. Initial lumbar spine films and bone scan were normal, but repeated x-ray films of the spine showed profound osteoporosis, with compression fractures at T12-L3 (see Figure 1). A whole-body bone scan and magnetic resonance imaging (MRI) of the spine detected no other abnormalities and no defects of the marrow. Computed tomography (CT) scan demonstrated decreased bony trabecular density throughout the spine, with sufficiently mineralized cortices. No focal findings could be detected. There was no suggestion of ALL in the laboratory studies (Table l), nor in the blood smear, in which no blast cells or red blood cell morphologic abnormalities were identified; however, significant met-
abolic changes were detected. Urinary calcium and hydroxyproline levels were elevated and the serum 1,25-dihydroxyvitamin D level was undetectable in two different samples. His initial creatinine clearance (Ccr) was moderately compromised. His serum osteocalcin level was also elevated (Table 1). A bone marrow biopsy was hypercellular and the bone marrow aspirate detected 69.6% blast cells. Cellular analysis confirmed early pre-B-cell ALL. Chemotherapy was reinstituted along with calcitonin (0.5 mg subcutaneously daily] and calcitriol (0.75 mcg daily). The leukemia went into remission within 4 weeks of resumption of chemotherapy and remained so on subsequent treatment. Within 3 months, his 1,25dihydroxyvitamin D level returned
JOURNAL OF ADOLESCENTHEALTH Vol. 13, No. 4
ROHN ET AL.
Table1. Comparisonof Initial Studies at Onset of Osteoporosis
and Vertebral Collapse With Results
Following Therapy Test
Calcium (serum) Phosphorus (serum) Alkaline phosphatase 25 (OH) vitamin D 1.25 (OH), vitamin D osteok&in PTH (N-Terminal) Calcium (urine) Phosphorus (unne) Hydroxyproline (urine) Cmatinine clearance
(8.5-10.8) (3.0-5.5) (60-320) (9-52) (15-M) (1.6-9.2) (8-24) (50-150) (40-1300) (7-43) (97-137) (4.5-14.5) (12-18)
10.6 5.4 184 35
24.6 10 142
9.3 4.8 221 42 -
8.9 3.9 159 59 10.2
MCV MCH Poly Lymph
mcm3 pglcell % %
49.8 9 729 1278 112 67 8.6 12.3 36.2 86 29.2 69 30
9.1 4.2 132 34 16 13 -
mg/dL mg/dL U/L ng/mL PglmL ng/mL pg/mL m@dy mg/dy mg/dy mL/min lO?mm’ gldL
Mono Platelets ESR LDH
1 366 18 141
‘Repeated twice. PTH, parathyroid hormone; WBC, white blood cell count; Hbg, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase.
to normal as did his osteocalcin level (Table 1). He was then able to walk with a brace. Within 9 months he was able to ambulate normally. At that point spinal films showed complete healing.
Discussion Osteoporosis with vertebral collapse as the presenting sign or symptom of ALL is uncommon (1,3-20, Table 2). Although radiologic abnormalities have been reported in over 70% of cases, the most typical findings are osteolytic and osteosclerotic changes, radiolucent metaphyseal bands, and periosteal new bone formation (2). Furthermore, these reports concentrate on x-rays in new patients with ALL (1-19). This case is unusual for both the clinical presentation and the metabolic features. To our knowledge, osteoporotic vertebral collapse has not been reported as the presenting finding of ALL relapse. Moreover, our patient had no evidence of recurrent disease on physical examination nor any abnormalities of his blood counts or peripheral blood smear morphology. The severe demineralization in previously reported cases of osteoporosis and ALL has been attributed to induction of parathyroid hormone (PTH)
by lymphoblasts (21), ectopic production of prostaglandin E, or pro&&ion of osteoclast-activating factor (22). The latter substances have been described with solid tumor cancers (with hypercalcemia and osteolytic lesions). Recently, it has been suggested that reduced bone density in the lumbar spine may occur secondary to cranial irradiation (23). The mechanism is not understood, but since our patient had received cranial irradiation as part of his initial therapy, it may have played a role in his disease process. Earlier studies of vitamin D metabolism in such cases detected no abnormalities (3). In our patient, the unique metabolic findings were low 1,25-dihydroxyvitamin D levels, and elevated urine calcium and hydroxyproline levels. The latter two levels indicate active bone breakdown. Immobilization may have contributed to the hypercalciuria since the patient was bedridden for almost 2 weeks prior to the hospitalization. The reason for the deficiency of the active metabolite of vitamin D is unclear. One possibility would be the secretion of a substance which interferes with l-cx-hydroxylation of 25-hydroxyvitamin D. Since interfering chemicals have been described in other leukemias and solid tumors (see above), a similar or related substance might be secreted in ALL. Leukemic infiltration in
OSTEOPOROSIS IN THE LEUKEMIC RELAPSE
Table 2. Review of Cases of Vertebral Collapse in Acute Lymphscytic Leukemia (ALL)
Baty JM, Vogt EC Dresner E Epstein BS Brurmer S et al. Lightwood R et al. Ebel D Thomas LB et al. Reinberg SA Eschenback C Simmons CR et al. Kosenow J, Niecierle J Newman AJ, Melhorn DK Dubovsky D, Jacobs P Benz G, et al. DeCastro LA et al. Nadkarni KS et al. Blatt J et al. Leheup B et al. Samunda GM et al.
1935 1950 1957 1958 1960 1961 1961 1962 1964 1968 1972 1973 1975 1976 1977 1984 1984 1985 1987
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 1 3 20
Patients vertebral collapse
Total ALL patients 46
5 N.S. 32 50 N.S. 85 62 N.S. 172 N.S. N.S. N.S. 108 N.S. N.S. 350 250 N.S.
N.S. = Not Specified
the kidney could interfere with 1-ol-hydroxylation but this has not been recognized to occur. Renal function in our patient was somewhat compromised as evidenced by the reduction in creatinine clearance; however, the decrease in Ccr was not great enough to indicate severe renal disease. Moreover, the normal serum phosphate and PTH levels also argue against clinically significant renal compromise. Only severe renal disease with elevated phosphate and increased PTH levels (secondary hyperparathyroidism) is associated with decreased 1,25dihydroxyvitamin D levels. Osteocalcin, a vitamin-K dependent bone protein serves as an index of bone formation and is a sensitive marker of bone growth in normal children (24). Our patient’s elevated level of osteocalcin indicated that efforts toward compensatory bone remodeling were underway. It could be argued that it was the previous cranial irradiation which was responsible for the osteoporosis. Gilsanz et al. (23) describe two children with long bone fractures and osteoporosis following cranial irradiation for ALL. In our patient, however, the coincidence of the vertebral collapse with the diagnosis of ALL relapse, plus the metabolic changes present at the time of diagnosis, together with the subsequent healing of the bony changes with treatment, argue against such a possibility. To treat this boy’s condition, we used a combi-
nation of calcitonin and calcitriol therapy along with standard ALL chemotherapy. Since calcitriol alone could enhance renal calciuria, possibly compromising renal function, calcitonin was administered to help counteract this effect. No loss of renal function occurred. His Ccr was normal within 1 month of treatment (Table 1). In conclusion, the possibility of ALL-either at initial onset or in relapse-must be seriously considered in any child who has severe back pain and the radiologic findings of osteoporotic vertebral collapse. Acquired 1,25_dihydroxyvitamin D deficiency may play a role in the etiology of the osteoporosis and vertebral collapse. The addition of calcitonin and calcitriol to the therapeutic regimen may be useful in selected cases of osteoporosis in ALL.
References 1. Elatt J, Martini SL, Penchansky L. Characteristics of acute
lymphoblastic leukemia in children with osteopenia and vertebral compression fractures. J Pediatr 1984;105:208-2. 2. Wilson JKV. The bone lesions of childhood leukemia. Radiology 1959;72:672-81. 3. Leheup B, Membre H, Gerard H, et al. Lymphoblastic leukemiawith osteopenia and vertebral com);re&ion fractures. J Pediatr 1985;106:858. 4. BatyJM, Vogt EC. Bone changes of leukemia in children. Am J Roentgen01 1935;34:3104. 5. Dresner E. Bone and jdnt lesions in acute leukemia d11dtheir response to folic acid antagonists. Quart J Med 1950;19:33952. 6. Epstein BS. Vertebral changes in childhood leukemia. Radiology 1957;;68:65-9. 7. Brunner S, Gudbjerg CE, Iversen T. Skeletal lesions in leukemia in children. Acta Radio1 1958;49:419-24. 8. Lightwood R, Barrie H, Butler N. Observations on one hundred cases of leukemia in childhood. Br Med J l%O;l: 747-52. 9. Ebel D. Osteoporose und Fischwirebelbildung im Wachstumsalter. Zbl Neurochir 1961;21:24-33. 10. Thomas LB, Forkner CE, Frei E, et al. Skeletal lesions of acute leukemia. Cancer 1%1;14:608-21. 11. Reinberg SA. Clinico-roentgenologicaicalobservations over a peculiar manifestation of leukemia in childhood-Brevispondyly. Pediatrija 1962;41:115-23. 12. Eschenbach C. ijber eine seltene Form der Wirbelstiulenbeteiligung an akuten Leukosen im Kindesalter 1964;113:68-70. 13. Simmons CR, Harle TS, Singleton EB. The osseous manifestations of leukemia in children. Radio1 Clin North Am1968;
14. Newman AJ, Melhom DK. Vertebral. compression in childhood leukemia. Am J Dis Child 1973;125:863-5. 15. Kosenow J, Niederle J. Wirbeltiulenvertinderungen im Riintgenbild bie malignen Geschwulsterkrankungen des Kindasalters. Mschr Kinderheilk 1972;120:1-8. 16. Dubovsky D, Jacobs P. Vertebral rarefaction in acute lymphobiastic leukemia. S Afr Med J 1975;49:241-2.
ROHN ET AL.
17. Benz G, grandeis E, Willich E. Radiological aspects of leukaernla in childhood-An analysis of 89 children. Pediat Radiol 1976;4:201-13. 18. DeCastro LA, Kuhn JP, Freeman AI, et al. Complete remodeline of the vertebrae in a child successfully treated for acute lymphocytic leukemia (ALL). Cancer 1977~40:398401. 19. Nadkami KS, Advani SH, Dinshaw KA, et al. Vertebral involvement in childhood acute lymphoblastic leukemia. Indian J Pediat 1984;51:103-7. 20. Samuda GM, Cheng MY, Yeung CY. Back pain and vertebral compression: An uncommon presentation of childhood acute lymphoblastlc leukemia. J Ped Orthoped 1987;7:175-8.
JOURNAL OF ADOLESCENT HEALTH Vol. 13, No. 4
21. Ramsay NKC, grown DM, Nesbit ME, et al. Autonomous production of parathyroid hormone by lymphoblastic leukemic cells in culture. J Pedlatr 979;94:623-6. 22. Raisz LG, Luben RA, Mundy GR, et al. Effective osteoclast activating factor from human leukocytes on bone metabolism. J Clin Invest 1975;56:408-13. 23. Gilsanz V, Carlson ME, Row TF, et al. Osteoporosis after cranial irradiation for acute lymphoblastic leukemia. J Pediatr 1990;117:23&44. 24. Johansen JS, Giwercman A, Hartwell D, et al. Serum Bone Gla-protein as a marker of bone growth in children and adolescents: Correlation with age, -height, serum insulin-like growth factor-l, and serum testosterone. 1 Clin Endocrinol Metab 1988;67:273-8.