High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann’s syndrome)

doi:10.1016/S0022-3476(97)70068-4

The Journal of Pediatrics

Volume 131, Issue 4, October 1997, Pages 592-597

https://doi.org/10.1016/S0022-3476(97)70068-4 Get rights and content

Abstract

Objective: Clinical observation of bone pain, unusual fractures in two patients, and diffuse osteopenia/osteoporosis led us to assess bone mineral content and density in 30 patients with severe congenital neutropenia who were treated with recombinant-methionyl-human granulocyte colony-stimulating factor (r-metHuG-CSF).

Study design: We reviewed roentgenograms in 29 of these 30 patients to evaluate bone loss before and during treatment. In addition, in 17 of the 30 patients, bone mineral status could be assessed by both quantitative computed tomography (Q-CT; n = 16) and dual energy x-ray absorptiometry (DXA; n = 1). In one patient, Q-CT was not possible because of severe vertebral fractures.

Results: Of the 30 patients investigated, 15 had evidence of osteopenia/osteoporosis observed on spine radiographs ( n = 5), on Q-CT/DXA ( n = 1/ n = 1), or on radiographs and Q-CT ( n = 8). In 13 of the 30 patients, only a lateral radiograph of the lumbar spine was available, 5 of 13 showing either increased kyphosis and wedging of the vertebrae or compression fractures of the vertebral bodies, indicating severe established osteoporosis. In eight patients, the findings of the spinal radiographs were normal. In nine patients, spinal radiographs were taken before r-metHuG-CSF treatment. Osteoporotic vertebral deformation ( n = 3) or reduced bone mass ( n = 3) was seen in six of these nine patients. The levels of serum biochemical markers of bone metabolism were all within normal ranges except for mild elevation of the serum alkaline phosphatase level. The degree of spinal bone mineral loss did not correlate with dose and duration of r-metHuG-CSF treatment or with the age or sex of the patients.

Conclusions: These data indicate a high incidence of bone mineral loss in children with severe congenital neutropenia. The underlying pathogenesis of bone demineralization is not clear. It is more likely that the bone loss was caused by the pathophysiologic features of the underlying disease, but it is possible that r-metHuG-CSF accelerates bone mineral loss. (J Pediatr 1997;131:592-7)

Section snippets

Patients

In the International Registry for SCN (SCNIR), we followed up 424 patients with severe chronic neutropenia (220 congenital, 65 cyclic, 121 idiopathic, and 18 other types of neutropenia). ⁵ Because Q-CT measurements were performed only at the Medical School Hannover, the incidence of osteopenia/osteoporosis in patients from other centers is not known. In 30 randomly selected patients with SCN (14 male and 16 female), enrolled in our r-metHuG-CSF studies, the BMC was investigated after informed

Results

Of the 30 patients investigated, 15 had evidence of osteopenia/osteoporosis observed on spine radiographs (n = 5), on Q-CT/dual energy X-ray absorptiometry (n = 2), or on radiographs and Q-CT (n = 8) (Table II). In five of these 15 patients (nos. 109, 112, 101, 105, and 103), osteoporosis became a clinical problem. Two of them experienced pathologic fractures (one had a metacarpal fracture and one had a fracture of the tibia caused by minor trauma). Two other patients complained of mild to

Discussion

Clinical symptoms of osteopenia/osteoporosis and detection of substantial bone mineral loss in spinal radiographs in our initial patients with SCN led us to evaluate bone mineralization in all subsequent patients with SCN who received r-metHuG-CSF treatment. Fifteen of 30 patients investigated had either reduced BMC values as determined by Q-CT alone (n = 2) or with accompanying evidence from plain radiographs of osteopenia/osteoporosis (n = 13). Histomorpho-metric quantification of bone loss

References (27)

SA Atkinson et al.
Mineral homeostasis and bone mass in children treated for acute lymphoblastic leukemia
J Pediatr
(1989)
HS Barden et al.
Bone status of children receiving anticonvulsant therapy
Metab Bone Dis Relat Res
(1982)
K Kruse et al.
Monomeric serum calcitonin and bone turnover during anticonvulsant treatment and in congenital hypothyroidism
J Pediatr
(1987)
RM Shore et al.
Bone mineral status in growth hormone deficiency
J Pediatr
(1980)
J Jowsey et al.
Juvenile osteoporosis: bone findings in seven patients
J Pediatr
(1972)
MY Lee et al.
Bone modulation in sustained hematopoietic stimulation in mice
Blood
(1991)
K Mempel et al.
Increased serum levels of granulocyte colony-stimulating factor in patients with severe congenital neutropenia
Blood
(1991)
MA Bonilla et al.
Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias
Br J Haematol
(1994)
K Welte et al.
Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia
Blood
(1990)
CD Dale et al.
A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (Filgrastim) for treatment of severe chronic neutropenia
Blood
(1993)

WP Hammond et al.

Treatment of cyclic neutropenia with granulocyte colony-stimulating factor

N Engl J Med

(1989)

K Welte et al.

Pathophysiolgy and treatment of severe chronic neutropenia

Ann Hematol

(1996)

CE Cann et al.

Precise measurement of vertebral mineral content using computed tomography

J Comput Assist Tomogr

(1980)

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^☆: Reprint requests: Karl Welte, MD, Pädiatrische Hämatologie und Onkologie, Kinderklinik der Medizinischen Hochschule Hannover, D-30625 Hannover, Germany.

^☆☆: 9/21/80857

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High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann’s syndrome)☆,☆☆

Abstract

Section snippets

Patients

Results

Discussion

J Pediatr

Metab Bone Dis Relat Res

J Pediatr

J Pediatr

J Pediatr

Blood

Blood

Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias

Br J Haematol

Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia

Blood

A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (Filgrastim) for treatment of severe chronic neutropenia

Blood

Treatment of cyclic neutropenia with granulocyte colony-stimulating factor

N Engl J Med

Pathophysiolgy and treatment of severe chronic neutropenia

Ann Hematol

Precise measurement of vertebral mineral content using computed tomography

J Comput Assist Tomogr