Nephrol Dial Transplant (2003) 18: III94-III96
© 2003 European Renal Association-European Dialysis and Transplant Association
Original Article
Role of osteoclastic dysfunction in the development of renal bone disease
Junichiro James Kazama1,2,,
Fumitake Gejyo1,
Takeshi Kurosawa3 and
Masafumi Fukagawa4
1 Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences,
2 Division of Intensive Care Medicine, Niigata University Medical Hospital,
3 Sumiyoshi Clinic Hospital and
4 Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Japan
 |
Abstract
|
|---|
A 47-year-old-man was referred for treatment for end-stage renal
failure. He had been diagnosed with type II adult onset
osteopetrosis before the deterioration of his renal function.
He presented with anaemia, severe hypocalcaemia, secondary hyperparathyroidism
and azotaemia. An iliac bone biopsy revealed increased bone
volume, disturbed osteoid calcification, active osteoclastic
bone resorption and fibrous transformation in the bone marrow
space. Incomplete osteoclastic dysfunction strongly suggested
hypocalcaemia and secondary hyperparathyroidism, and the osteoclastic
bone resorption also indicated secondary hyperparathyroidism,
even though bone resorption was potentially suppressed. The
present case shows that evidence of the involvement of osteoclastic
dysfunction in the development of renal bone disease can be
found in bone histology.
Keywords: adult onset type II osteopetrosis; end-stage renal failure; iliac bone biopsy; secondary hyperparathyroidism
|
Introduction
|
|---|
Autosomal dominant osteopetrosis is a rare disease characterized
by adult-onset general osteosclerosis caused by incomplete osteoclastic
dysfunction [
1]. We now know that this disease is heterogeneous,
and the genes responsible for the abnormality were discovered
recently [
2,
3]. Unlike the infantile type [
4], the prognosis
for adult-onset osteopetrosis is generally good. Solitary cases
of adult-onset osteopetrosis cannot be distinguished by clinical
appearance from those with the dominant autosomal hereditary
form.
|
Case report
|
|---|
A 47-year-old-man was referred for the treatment of end-stage
renal failure. His family history was unremarkable. He had been
diagnosed as having osteosclerosis before his renal function
deteriorated. Although the cause of renal failure was unknown,
his clinical profile suggested chronic glomerulonephritis.
The patient did not complain of bone pain at the time of admission. His height was 172 cm, and no skeletal deformities were found during his physical examination. Laboratory tests showed severe anaemia (haemoglobin 7.2 g/dl; haematocrit 20.3%), abnormal mineral metabolism (albumin 3.8 g/dl; Ca 4.4 mg/dl; inorganic phosphate, 7.7 mg/dl; alkaline phosphatase 539 IU/l; intact parathyroid hormone 830 pg/ml; intact osteocalcin 175.7 ng/ml) and advanced azotaemia (blood urea nitrogen 93.9 mg/dl; creatinine 9.2 mg/dl). His serum 1,25D3 concentration was 15.4 pg/ml. X-ray images demonstrated osteosclerosis in the cranial base and the spinal and pelvic bones, which is compatible with Andersen's type II osteosclerosis (Figure 1
). Dual-photon X-ray absorptiometry revealed that the bone mineral densities in his lumbar spine, femoral neck and distal radius were much greater than 2 SD of those of age- and sex-matched Japanese standards.
Haemodialysis maintenance therapy followed by administration
of erythropoietin did not improve his anaemia, but the hypocalcaemia
was ameliorated by the haemodialysis therapy and oral calcitriol.
Iliac bone biopsy was performed to assess bone metabolism (Figure 2). Extremely increased bone volume, which is a characteristic of osteosclerosis, was noted, as well as disturbed osteoid calcification, active osteoclastic bone resorption and fibrous transformation in the bone marrow space (Table 1, Figure 2).
View larger version (157K):
[in this window]
[in a new window]
|
Fig. 2. Biopsy of the iliac bone. Note the increased bone volume, disturbed osteoid calcification (*), active osteoclastic bone resorption (arrows) and fibrous transformation in the bone marrow space.
|
|
|
Discussion
|
|---|
Adult-onset autosomal dominant osteopetrosis is classified into
two distinct radiographic types, and the present case showed
the typical findings for Andersen's type II osteopetrosis [
5].
Adult-onset type II osteopetrosis, sometimes referred to as
Albers–Schonberg disease, is the most common form of osteopetrosis
and is caused by mutations in the ClCN7 chloride channel [
3].
To our knowledge, this is the first published report of Andersen's
type II osteopetrosis complicated with end-stage renal failure.
The biopsy specimen of the iliac bone provided a lot of information about the present case. Extreme hypocalcaemia, presumably caused by the osteoclastic dysfunction, had disturbed his bone mineralization, and would have promoted the development of secondary hyperparathyroidism despite the mildly decreased serum 1,25D3 concentration. Anaemia refractory to exogenous erythropoietin may have resulted from the decreased bone marrow space. An interesting finding was the active osteoclastic bone resorption, which seemed to contradict the finding of osteopetrosis. As autosomal dominant osteopetrosis is caused by incomplete osteoclastic dysfunction, extremely strong promotion of osteoclastogenesis and/or osteoclast activation would overcome the potential handicap of osteoclastic bone resorption.
This case demonstrates that secondary hyperparathyroidism can promote active bone resorption; however, there is a risk of recurrence and progression of osteopetrosis after the initiation of haemodialysis and active vitamin D therapy.
The increased skeletal resistance to PTH is a well-recognized abnormality in uraemic renal bone disease, and osteoclastic dysfunction seems to be the key mechanism [6]. The present case suggests the involvement of osteoclastic dysfunction in the development of renal bone disease by demonstrating that potentially disturbed osteoclastic function caused secondary hyperparathyroidism, which in turn promoted active osteoclastic bone resorption.
|
Notes
|
|---|
Correspondence and offprint requests to: J. James Kazama MD,
PhD, Division of Intensive Care Medicine, Niigata University
Medical Hospital, 1-754 Asahimachi-Dori, Niigata, Niigata 951-8510
Japan. Email:
jjkaz{at}med.niigata-u.ac.jp 
|
References
|
|---|
- Bollerslev J, Andersen PE Jr. Radiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis. Bone 1988; 9:7–13[Medline]
- Van Hul E, Gram J, Bollerslev J et al. Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12–13. J Bone Miner Res 2002; 17:1111–1117[CrossRef][Medline]
- Cleiren E, Benichou O, Van Hul E et al. Albers–Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 2001; 10:2861–2867[Abstract/Free Full Text]
- Wilson CJ, Vellodi A. Autosomal recessive osteopetrosis: diagnosis, management and outcome. Arch Dis Child 2000; 83:449–452[Free Full Text]
- Andersen PE Jr, Bollerslev J. Heterogeneity of autosomal dominant osteopetrosis. Radiology 1987; 164:223–225[Abstract/Free Full Text]
- Fukagawa M, Kazama JJ, Shigematsu T. Skeletal resistance to PTH as a basic abnormality underlying uremic bone diseases. Am J Kidney Dis 2001; 38 [Suppl 1]:S152–S155[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
Top
Abstract
Introduction