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Keywords:

  • BONE RESORPTION;
  • BONE FORMATION;
  • VAN BUCHEM DISEASE;
  • PREDNISONE;
  • SCLEROSTIN

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

A 23-year-old man with the rare sclerosing bone disorder van Buchem disease presented with progressively worsening headaches that eventually became persistent and associated with papilledema. Increased intracranial pressure was diagnosed, and the patient had a ventriculoperitoneal drain inserted as well as simultaneously receiving treatment with prednisone. Before starting treatment, there was biochemical evidence for increased bone turnover and for steady increases in bone mineral density (BMD) at the spine and total hip despite the patient having reached his peak height of 197 cm at the age of 19 years. Treatment with prednisone for 2 years resulted in biochemical and histologic suppression of bone formation as well as of bone resorption and arrest of further bone accumulation. Our data suggest that glucocorticoids (GCs) may represent an attractive alternative to the high-risk surgical approaches used in the management of patients with progressive sclerosing bone disorders. Our findings also suggest that whereas sclerostin may not be required for the action of GCs on bone formation, it may well be important for the action of GCs on bone resorption. The exact mechanism by which sclerostin may be involved in the regulation of bone resorption is as yet to be explored. © 2010 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

Van Buchem disease is a rare bone sclerosing disorder described for the first time in 1955.1 It belongs to the group of craniotubular hyperostoses and is characterized by progressive generalized osteosclerosis, particularly of the mandible and the skull, owing to excessive bone formation.2 It is caused by a 52-kb deletion 35 kb downstream of the SOST gene, which encodes sclerostin, on chromosome 17q12-21.3, 4 This protein is produced in the skeleton exclusively by the osteocytes and inhibits bone formation by antagonizing the Wnt signaling pathway.5 Clinical manifestations of the disease are due to entrapment of cranial nerves often associated with facial palsy and loss of hearing and smell.2 Van Buchem disease is thought to have milder clinical manifestations than sclerosteosis, a craniotubular hyperostosis with similar phenotype owing to inactivating mutations of the SOST gene.6, 7 Management of the complications of both these sclerosing dysplasias is surgical, aiming at removal of the excess of bone, a technically difficult and sometimes dangerous procedure.8–10 No medical treatment is available for either sclerosing disease. Glucocorticoids (GCs) are known inhibitors of bone formation,11, 12 and we hypothesized that administration of these agents to patients with complications due to bone overgrowth may arrest its further progress.

We present here sequential observations of a patient with van Buchem disease with life-threatening increased intracranial pressure who was treated successfully with prednisone.

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

The patient first came under our care at the age of 10 years with an established diagnosis of van Buchem disease. The disease was diagnosed clinically and radiologically in infancy and later confirmed genetically by the finding of a 52-kb homozygous deletion 35 kb downstream the SOST gene on chromosome 17q12-q21 [the patient was briefly described (patient 15) by Staeling-Hampton and colleagues3]. The parents are consanguineous and were both confirmed to be heterozygotes for the disease. There were 3 phenotypically normal sisters in whom no genetic testing has been so far undertaken.

As described in this disorder, clinical manifestations started early in childhood. The patient had a facial palsy at the age of 3 years and developed progressive deafness requiring the use of a hearing aid by the age of 10 years, followed by bilateral bone-anchored hearing aids. He has otherwise been well with normal growth development along the 95th centile, reaching a final height of 197 cm by the age of 19 years. He completed his secondary education and is employed as office assistant manager. He married at the age of 20 years, and he is the father of 3 healthy children.

The patient demonstrated the typical clinical and radiologic features of van Buchem disease, with enlarged head and mandible and no syndactyly or other digit malformations. During the 15-year duration of follow-up, there were no other clinical signs or symptoms, and blood pressure was normal. Hematologic and biochemical parameters, including those of mineral metabolism, demonstrated no abnormalities over the years. Skeletal radiographs showed thickening of the calvarium, base of the skull, and long bones and sclerosis of the vertebrae (Fig. 1). Bone mineral density (BMD) values of the spine and hip were markedly increased at presentation (Z-score +6.2) and continued to increase in parallel with that of his healthy peers without, however, attaining a peak (highest Z-score being 7.7). Biochemical markers of bone turnover always were increased compared with normal values for age but followed a normal pattern of change with a further increase during the growth spurt and a progressive decline thereafter, although never reaching the normal range (Fig. 2).

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Figure 1. Radiographs of the skull showing thickening of the calvarium and the base of the skull and of the hand illustrating the absence of syndactyly or other malformations.

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Figure 2. Sequential measurement of serum alkaline phosphate activity (AP) in units/L, urinary hydroxyproline/creatinine ratio (OHP/Cr) in µmol/mmol, and height (cm) in a patient with van Buchem disease over a 10-year period. Interrupted lines indicate the upper limit of normal range.

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At the age 23 years, the patient complained of progressive headaches that eventually became persistent and were associated with dizziness and signs of increased intracranial pressure in the form of papilledema. The diagnosis was confirmed radiologically, and a ventricular-peritoneal drain was implanted, and the patient was concomitantly started on prednisone 30 mg/day that was reduced to 10 mg/day within 1 month. In the following 2 years he received different doses of prednisone, as depicted in Fig. 3, but no calcium or vitamin D supplements. These interventions were followed by rapid improvement of his symptoms, and the improvement was sustained during the follow-up period. There were no appreciable changes in metabolic parameters with treatment (highest values of serum cholesterol and glucose were 5.6 and 6.1 mmol/L, respectively, and of urinary calcium excretion 7.8 mmol/24 hours).

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Figure 3. Biochemical markers of bone formation and resorption before and during treatment with prednisone. P1NP = diamonds and solid line; β-CTX = closed circles and interrupted line.

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Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

The biochemical markers of bone turnover procollagen type I N propeptide (P1NP) and C-terminal telopeptide of type I collagen (β-CTX) were measured in serum at regular intervals using the E-170 system (Roche BV, Woerden, Holland). BMD was measured by dual-energy X-ray absorptiometry (DXA; Hologic QDR 4500, Waltham, MA, USA). An iliac crest biopsy was obtained after in vivo labeling with two courses of tetracycline separated by 12 days. Bone histomorphometry was performed on undecalcified histologic bone sections by Dr Pascale Chavassieux (INSERM Unit 831, University of Lyon, Faculty of Medicine R Laennec, Lyon, France). Immunohistochemical staining for sclerostin was performed in our laboratory using a previously described technique.13

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

Biochemical markers of bone turnover

The changes in serum P1NP and β-CTX before and during prednisone treatment are depicted in Fig. 3. Before treatment, values of both markers of bone turnover were elevated and decreased to within the normal reference adult range within 4 weeks of starting treatment with prednisone. The effect of prednisone on bone turnover depended on the dose administered, and attempts to reduce the dose below 5 mg/day were associated with increases in serum markers of bone turnover. It was notable that during treatment, there was a close relationship between serum β-CTX and P1NP values, with the two markers demonstrating parallel changes during adjustments of the dose of prednisone, suggesting a tight coupling of bone resorption and bone formation. There was a highly significant correlation between the two markers throughout the 2-year period of follow up (R2 = 0.765).

BMD

The changes in BMD measured at the spine and hip for the 6 years preceding the start of prednisone treatment and for 2 years thereafter are shown in Table 1. Despite high baseline values, BMD continued to increase steadily during adulthood by about 4% every 2 years, demonstrating no further increase after 2 years of treatment with prednisone.

Table 1. Bone Mineral Density Measurements and Height of a Patient With van Buchem Disease Before and After 2 Years of Prednisone Treatment (Date: Month/Year)
DateHeightLS BMDChange (%)TH BMDChange (%)
  1. Note: Height in cm, LS BMD = lumbar spine BMD in g/cm2, TH BMD = total hip BMD in g/cm2.

2-2001193.91.6341.410
4-2003197.01.7879.41.74123.5
1-2005197.01.8553.81.8204.5
2-2007197.01.9344.31.8883.7
5-2007Start prednisone    
6-2009197.01.921–0.71.8950.4

Bone histology

On an iliac crest biopsy taken 2 years after the start of prednisone treatment, there was sclerosis and no evidence of active bone remodeling. Cancellous bone volume was clearly increased, and bone trabeculae were thick and well connected. The extent of eroded surfaces was very low (0.4%; normal 3.1% ± 1.1%), and Howship's lacunae were devoid of osteoclasts. In addition, no osteoid seams were seen, and there was no tetracycline uptake on examination under fluorescent light. As expected and described previously,14 osteocytes did not stain for sclerostin.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

This case illustrates the beneficial effect of prednisone treatment on bone metabolism in a patient with van Buchem disease and life-threatening increased intracranial pressure. Treatment resulted in a histologically documented dramatic decrease in bone formation. Following therapy, there was also no further increase in BMD at the spine and hip. Although clinical manifestations of increased intracranial pressure improved significantly, this cannot be attributed solely to treatment with prednisone because the patient had a ventriculoperitoneal drain implanted simultaneously at the time of starting prednisone.

Before prednisone treatment, the patient had an increased rate of bone turnover, as assessed biochemically, associated with a continuous increase in BMD of the spine and hip. The biochemical markers of bone formation, P1NP and osteocalcin, have been reported previously to be elevated in 6 patients with van Buchem disease compared with their levels in disease carriers, being above the upper limit of the normal range in 3 of them.15 Urinary cross-linked N-telopeptide of type I collagen (NTX) levels were higher in 4 patients with the disease compared with carriers. Bone density measured in the phalanges by radiographic absorptiometry was elevated in all these patients.15 There are, however, no longitudinal data reported to date in patients with van Buchem disease. In our patient, at least up to the age of 23 years, both biochemical markers of resorption and formation were increased. The clinical progression of the disease, which was due to bone overgrowth, as also evidenced by the steady increase in BMD, prompted us to use GCs in an attempt to arrest the process of bone accumulation.

The beneficial use of GCs has been reported previously in a patient with craniotubular hyperostosis owing to an unidentified genetic defect.16 In this patient, prednisone given for three courses of 10 weeks each reduced serum osteocalcin but had no effect on urinary deoxypyridinoline (DPD) and there were no reported changes in BMD. In a few patients with progressive diaphyseal dysplasia, a craniotubular hyperostotic disorder distinct from van Buchem disease, which is due to mutations of the gene encoding transforming growth factor β (TGF-β), prednisone treatment during childhood and adolescence led to clinical17, 18 and in one case radiologic improvement.19

GCs have a deleterious effect on the skeleton, increasing bone fragility by systemic and local actions.11 Their main action on bone metabolism is to decrease bone formation by inhibiting the proliferation and differentiation of osteoblasts and increasing their rate of apoptosis.12, 20 CCs also have been reported to increase bone resorption, particularly during the early phase of treatment, by stimulating osteoclastic activity and survival through an effect on the RANKL/OPG signaling pathway.21–23 Consistent with these findings, studies in animals24 and in humans25–33 have shown that administration of GCs significantly reduce biochemical markers of bone formation but have no effect or even increase those of bone resorption. Remarkably, administration of prednisone to our patient decreased not only bone formation but also bone resorption within 4 weeks of starting of treatment. Serum P1NP and β-CTX decreased and increased concurrently during alterations of prednisone dose, suggesting a tight coupling of bone resorption and formation during treatment. This was further supported by the strong correlation between the two biochemical markers of bone turnover before and during prednisone treatment.

The reason for this unique response of bone resorption to prednisone is not apparently clear but may well be related to the genetic defect of our patient with van Buchem disease. Recent studies have indicated that at least some of the negative effects of GCs on osteoblast function are due to inhibition of the canonical Wnt signaling pathway through stimulation of the Wnt antagonists Dkk1, Sfr1, and sclerostin and activation of GSK3β.34–36 In addition, it has been reported that in osteoblasts, Wnt signaling decreases bone resorption by downregulating the expression of RANKL and upregulating that of OPG,37–40 an action that can be reversed by GCs.21–23 It thus may be that sclerostin is not required for the action of GCs on bone formation, as suggested by the clear reduction of bone formation in our patient in the absence of sclerostin. In contrast, sclerostin may well be important for the action of GCs on bone resorption. We propose that in the absence of sclerostin, GCs may lose their ability to stimulate RANKL and decrease OPG by a mechanism that is as yet to be explored. In support of this hypothesis are the data in above-mentioned patient with craniotubular hyperostosis treated with prednisone.16 This patient was phenotypically very similar to ours and had increased bone turnover before treatment, although genetic analysis excluded abnormalities in the SOST gene. In this patient, prednisone treatment was associated with a significant decrease in serum osteocalcin but with no parallel change in urinary DPD excretion, a response compatible with that reported in other human studies. It may be, therefore, that sclerostin, besides its critical role in the regulation of bone formation, is also involved in the regulation of bone resorption, as also has been reported for Dkk1, another inhibitor of the Wnt signaling pathway.41 Alternatively, it may be that in the absence of sclerostin, bone resorption may be driven by bone formation through an as yet unknown action of GCs downstream the Wnt signaling pathway.

The long-term follow-up of this patient with life-threatening complications as a result of excess bone formation illustrates the beneficial effect of prednisone treatment on bone metabolism and suggests that using GCs may represent an attractive medical alternative to the currently used, technically difficult, and complication-associated surgical treatments of such patients. The results suggest further that sclerostin may be involved in the regulation of bone resorption by a mechanism that needs to be explored further.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

All the authors state that they have no conflicts of interest.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References

Special thanks to Dr Pascale Chavassieux for performing the histomorphometric analysis of the bone biopsy. This work was funded by EU FP7 (TALOS:Health-F2-2008-201099).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Methods
  6. Results
  7. Discussion
  8. Disclosures
  9. Acknowledgements
  10. References