Journal of Hepatology 2000; 33: 812-817 Copyright C European Association
for the Study of the Liver 2000 Printed in Denmark All rights reserved
Munksgaard Copenhagen Journal of Hepatology
ISSN 0168-8278
Decreased bone mineral density after therapy with alpha interferon in
combination with ribavirin for chronic hepatitis C

Jose A. Solis-Herruzo 1 , Gregorio Castellano 1 , Inmaculada Ferna
ndez 1 , Raquel Mun~ oz 1 and Federico Hawkins 2

Departments of 1 Gastroenterology and 2 Endocrinology, Department of
Medicine, Hospital Universitario ''12 de Octubre'', Universidad
Complutense, Madrid, Spain

Background/Aims: Several thousand patients with
chronic hepatitis C have been treated with interferon
plus ribavirin. After observing a male patient who
developed severe bone loss during this treatment, we
studied skeletal status and bone mineral metabolism
in patients on therapy with interferon plus ribavirin.
Methods: Bone mineral density and biochemical bone
markers were studied in 32 male patients (31-58 years
old) treated for 12 months with either interferon alone
(group 1; n?13) or interferon plus ribavirin (group 2;
n?19).

Results: Bone mineral density was significantly lower
in group 2 (0.877o0.07 g/cm 2 ) than in group 1
(1.108o0.08 g/cm 2 , p0.001). Likewise, T- and Z-
score values were also decreased in group 2 (T:
?1.95o0.6. Z: ?1.76o0.51) compared with group 1
(T: 0.19o0.6; p0.001. Z: 0.26o0.6; p0.001).
Serum and urine biochemical bone markers were normal
in both groups. However, urinary calcium excretion
was decreased in patients on combined
therapy.

Conclusion:
Treatment of chronic hepatitis C with interferon
plus ribavirin may induce bone loss. This secondary
effect should be investigated during the follow-up
of these patients, since they may require therapies
aimed at prevention or amelioration of these defects.
Key words: Bone loss; Osteopenia; Ribavirin.

Ribavirin (1b-D-ribofuranosyl-1H-1,2,4 triazole-3-
carboxamide) is a water-soluble, synthetic guanosine
analogue that exerts a broad spectrum of activity
against several DNA and RNA viruses, including
viruses of the flaviviridae family (1,2). Randomized,
placebo-controlled studies have shown that therapy of
chronic hepatitis C with ribavirin for 24 to 48 weeks
resulted in a reduction in serum alanine aminotransferase
(ALT) levels (3-6). However, patients remained viremic
and ALT levels returned to pretreatment levels when
therapy was stopped (4). Combination therapy of ribavirin
with alpha interferon (IFN) has been demonstrated
to be more effective than IFN alone in inducing
virologic and histologic improvement (7-9). Ribavirin
is generally well tolerated. Its major adverse effects
are hemolysis and nonspecific symptoms of fatigue,
depression, insomnia, vertigo, anorexia, nausea,
nasal congestion and pruritus (10,11). Although, there
is little information about the effect of the combination
of ribavirin plus IFN on bone mineral density (BMD)
and bone turnover in patients with chronic hepatitis C,
back pain and bone fracture have been reported
in some patients (11).

In this paper we report the case of a male patient
treated with ribavirin plus IFN for 12 months, who
developed severe osteoporosis in the absence of any
other cause of osteoporosis. A survey among male
patients treated for 12 months with IFN alone or in
combination with ribavirin showed that osteopenia or
osteoporosis was a common finding among patients
treated with the combination of both antiviral agents,
but not in patients treated with IFN alone.

Case Report
A 55-year-old male physician with chronic hepatitis C
was referred to our hospital to be included in a trial of
combination therapy with IFN and ribavirin. In 1984,
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