Nodulosis, arthropathy and osteolysis (NAO) syndrome is a rare autosomal recessive multicenteric osteolysis.1,2 Few therapeutic studies have proved the efficacy of pamidronate in children with genetic osteoporotic syndrome such as osteogensis imperfecta.3,4
Therefore, we conducted an uncontrolled prospective study to assess the effect of cyclic intravenous pamidronate treatment on the clinical course of NAO syndrome in children and its effect on bone mineral density.
Seven children with NAO syndrome aged 5–14 years were treated with intravenous pamidronate between June 2003 and July 2004. The treatment was given after informed consent was obtained from the parents.
Pamidronate was diluted in 250 ml of isotonic saline and infused over a 4 h period on each of three consecutive days every 3 months for 1 year. The dose was 2 mg/kg/infusion. The patients were maintained on 800 IU/day vitamin D, and at least 800 mg/day of elemental calcium supplement. The patients had clinical and functional assessments using the Childhood Health Assessment Questionaire and the Visual Analogue Scale.5
All patients had normal serum levels of calcium, magnesium, phosphorus, alkaline phosphatase, parathyroid hormone, 25‐hydroxyvitamin D and 1,25‐dihydroxyvitamin D, serum osteocalcin, urine spot for cross‐linked N‐telopeptide type I collagen (NTX), calcium, phosphorus and creatinine. x Rays of hands and feet, and bone mineral density (BMD) of the lumbar spine and the whole body, were assessed before and at the end of the treatment course. z Scores and the number of standard deviations (SD) for BMD above or below the mean for age‐matched controls were derived on the basis of the manufacturer's data. The possible side effects were monitored.
The treatment was well tolerated by all patients. They reported a decrease in limb and joint pain and improvement in functional ability. However, it was not significant (p <0.094; table 1). All patients had significant and progressive reduction in urinary NTX with treatment (p <0.01), and low BMD in the lumbar spine ranging from 0.1 to 0.59 (mean (SD) 0.4 (0.18)) with z scores ranging from −2 to −5.5 (mean (SD) −3.25 (1.35)). At the end of treatment, the mean (SD) BMD increased significantly to 0.63 (0.04) (p <0.03) and z scores to −1.08 (1.2) (p <0.03). Increased mineralisation was observed on conventional x ray in one patient.
Table 1 Changes observed in patients with nodulosis, arthropathy and osteolysis during pamidronate treatment.
| Before | After | p Value | |
|---|---|---|---|
| Urinary NTX | 550.57 (367) | 252 (204) | 0.01 |
| Alkaline phosphatase | 255.7 (163.1) | 134.9 (36.6) | 0.094 |
| z Score lumbar BMD | −3.25 (1.35) | −1.08 (1.23) | 0.03 |
| z Score whole body BMD | −1.72 (1.57) | −1.18 (1.08) | 0.08 |
| VAS | 1.3 (0.27) | 0.77 (0.62) | 0.06 |
| CHAQ | 1.73 (1.0) | 1.29 (0.76) | 0.094 |
BMD, bone mineral density; CHAQ, Childhood Health Assessment Questionnaire; NTX, cross‐linked N‐telopeptide type I collagen;
VAS, Visual Analogue Scale.
Values are mean (SD).
Idiopathic osteolysis is a rare skeletal disorder, with progressive bone destruction.6,7,8 Recently, the mutational inactivation of matrix metalloproteinase‐2 has been identified in patients with NAO syndrome, which represents the first hereditery deficiency of a metalloproteinase described in man.2 Several studies have reported beneficial effects of bisphosphonate treatment in children with different genetic osteoporotic syndromes.4,9,10 We treated seven patients with NAO using cyclic intravenous pamidronate, which resulted in progressive reduction in urinary excretion of NTX, resulting from an improvement in the bone resorption. However, there was no significant change in alkaline phosphatase or osteocalcin levels. The z score of the lumbar spine improved significantly over the treatment period, suggesting an improvement in BMD, which may reflect an improvement in the balance between bone formation and resorption. We believe that these patients require an intensive and prolonged course of treatment, and a close follow‐up that will help delineate the beneficial effect of the treatment.
Footnotes
Competing interests: None declared.
References
- 1.Al‐Mayouf S, Majeed M, Hugosson C, Bahabri S. New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome. Am J Med Genet 2000935–10. [DOI] [PubMed] [Google Scholar]
- 2.Martignetti J, Aqeel A, Sewairi W, Boumch C, Kambouris M, Al‐Mayouf S M.et al Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 200128261–265. [DOI] [PubMed] [Google Scholar]
- 3.Glorieux F, Bishop N, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998339947–952. [DOI] [PubMed] [Google Scholar]
- 4.Lala R, Matarazzo P, Bertelloni S, Buzi F, Rigon F, de Sanctis C. Pamidronate treatment of bone fibrous dysplasia in nine children with McCune‐Albright syndrome. Acta Paediatr 200089188–193. [DOI] [PubMed] [Google Scholar]
- 5.Madi S, Al‐Mayouf S M, Gainger C, Bahabri S. The arabic version of childhood health assessment questionnaire modified for arabic children. Saudi Med J 20042583–87. [PubMed] [Google Scholar]
- 6.Pai G, Macpherson R. Idiopathic multicentric osteolysis: report of two new cases and review of the literature. Am J Med Genet 198829929–936. [DOI] [PubMed] [Google Scholar]
- 7.Petit P, Fryns J. Distal osteolysis, short stature, mental retardation and characteristics of facial appearance: delineation of an autosomal recessive subtype of essential osteolysis. Am J Med Genet 198625537–541. [DOI] [PubMed] [Google Scholar]
- 8.Eisenstein D, Poznanski A, Pachman L. Torg osteolysis syndrome. Am J Med Genet 199880207–212. [PubMed] [Google Scholar]
- 9.Bianchi M, Cimaz R, Bardare M, Zulian F, Leopre L, Boncompagni A.et al Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children: a prospective multicenter study. Arthritis Rheum 2000431960–1966. [DOI] [PubMed] [Google Scholar]
- 10.Lepore L, Pennesi M, Barbi E, Pozzi R. Treatment and prevention of osteoporosis in juvenile chronic arthritis with disodium clodronate. Clin Exp Rheumatol 19919(Suppl 6)33–35. [PubMed] [Google Scholar]