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The benefits of treatment with intravenous pamidronate in osteogenesis imperfecta (OI) have recently been reported.1–3 These include reduced bone resorption, increased bone density, and improved clinical outcomes as judged by apparently lower fracture rates. We would like to report a single case of OI treated by the orally administered bisphosphonate, clodronate, with good effect.
A boy, whose mother was affected with clinically diagnosed type 1 osteogenesis imperfecta, was referred to our unit aged 13½12 with a recent onset of severe back pain that had required hospital admission. He appeared of normal stature with blue sclerae and was able to walk independently. He had sustained four previous limb fractures; lateral radiographs of the thoracic and lumbar spine confirmed three vertebral wedge fractures. He was 158.9 cm tall (10th centile) and weighed 49 kg (25th centile). Lumbar spine bone mineral density scanning by dual x ray absorpiometry (DXA, Hologic QDR-1000, Hologic, Bedford, MA) revealed a BMD of 0.398 g/cm2 (Z score −5.22, comparing his value to the average young man). Fasting urinary hydroxyproline/creatinine ratio, an index of bone resorption, was 96.6.
With informed parental consent for “off label” usage, he was commenced on oral sodium clodronate (Bonefos, Leiras Oy, Turku, Finland) at a dose of 400 mg daily. Dietary intake of calcium and vitamin D was above the estimated average requirement and supplementation was not given. Subsequent BMD scanning after one year of therapy showed an improvement of bone density by 7.8% to 0.468 g/cm2 with a consequent increase in the BMD Z score to −5.09.
Treatment with clodronate was continued for five years, during which time he did not sustain any new low trauma fractures. By the end of treatment, his BMD was 0.552 and his Z score had improved from −5.22 at first referral to −4.59. The fasting urinary hydroxyproline:creatinine ratio was decreased by 86% compared to baseline (13.6 v 96.6). Clodronate was discontinued for eight months; during this time his BMD remained stable but the Z score showed a small decline. His height at that stage lay on the 50th centile (176 cm) and his weight on the 10th (58 kg). The BMD remained considerably below the normal value and clodronate was recommenced at a dose of 800 mg daily.
Eight years after initial referral, his bone mineral density had increased by 60.6% to 0.613 g/cm2 (Z score −4.16). To compensate for the expected increase in bone size, the bone mineral adjusted density (BMAD) was computed (BMDL1–L4/square root of areaL1–L4) and showed an improvement of 24.6% in BMAD over the duration of therapy. Clodronate was discontinued when the patient was aged 22. He had reached a height of 177.4 cm and a weight of 60.8 kg, and the spine BMD Z score was −3.92. He had suffered no atraumatic fractures since commencing oral clodronate.
The rationale in using bisphosphonates for osteogenesis imperfecta is the inhibition of osteoclastic bone resorption leading to increased bone density and a potentially lower risk of fracture. This young man exhibited a good response to therapy with oral clodronate, suffering no adverse reactions. The increase in height of 18 cm over eight years, moving him from the 10th to 50th centile, suggests that his growth was not impaired by therapy.4 Many studies have shown that clodronate does not impair mineralisation. We are unable to determine the contribution of remodelling of vertebral fractures to his height gain.
A limitation of this report is that pubertal status was not documented at presentation. However, the increases in lumbar spine density are in excess of the expected average rates in growing children (3–6% per year and 14–16% during puberty).1 The increase was also observed following adjustment for bone growth by BMAD and Z scores relating the measured BMD to age matched controls. The Z score (−5.22 to −3.92) improvement during therapy was not dissimilar to that reported with pamidronate1 in younger children.
We agree that there is increasing evidence of a role for bisphosphonate therapy as part of the multidisciplinary management of osteogenesis imperfecta. Oral clodronate in our patient appeared to elicit a similar response to that of cyclical intravenous pamidronate, suggesting that orally administered bisphosphonates may be of value in the management of this disease.
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