Pharmacotherapy for ossification of the spinal ligaments: Clinical trial of disodium (1-hydroxyethylidene) diphosphonate to inhibit progression of ossification of the posterior longitudinal ligament in the cervical spine after posterior decompression surgery

Abstract

Introduction With advances in surgical techniques for ossification of the posterior longitudinal ligament (OPLL), the surgical results of both anterior and posterior procedures have been improved. However, the regression of neurological symptoms due to progression of OPLL during the follow-up period has been reported, and preventing progression of OPLL after surgery is an issue to be solved urgently from the viewpoint of stable long-term surgical results. Fortunately, the incidence of neurological symptom appearance is relatively low, but the incidence of postoperative progression of OPLL during the follow-up period is reported to be high after both anterior and posterior decompression. After anterior procedures, the reported incidence varies from 31% to 36% [1,2]. After posterior procedures, including laminectomy [3] and laminoplasty [4-7], the incidence is reported to be high (40%-100%). Etidronate disodium-chemical name: disodium (1- hydroxyethylidene) diphosphonate, or EHDP-has the ability to adsorb onto hydroxyapatite and its noncrystalline precursors chemically and to inhibit aggregation, growth, and calcifi cation of these crystals [8]. It is therefore widely used to treat heterotopic ossification in clinical practice. Considering that OPLL is a form of heterotopic ossification, we hypothesized that EHDP has the therapeutic potential to inhibit the progress of OPLL because of its calcifi cation-inhibitory effect. The preventive effect of EHDP on postoperative ossification was evaluated by other investigators in 66 patients with OPLL of the cervical spine who underwent posterior decompression and were treated with a cyclic regimen of oral EHDP at 200-1000 mg daily for 3 months followed by treatment withdrawal for 3 months; this regimen was repeated for 2 years [9]. At study termination, signifi cant suppression of ossification was observed with EHDP 1000 mg/day compared with control treatment; moreover, at the 1-year follow-up there was no progression of ossification. These clinical fi ndings led us to conduct the present study: a randomized dose-ranging, double-blind, placebo-controlled, parallel-group, multicenter study (study 1). Simultaneous with study 1, a retrospective study (study 2) was conducted, as the target disease is rare and the size of the patient population in study 1 was considered to be small and likely to limit the power to detect signifi cant group differences. The effi cacy of EHDP in inhibiting progression of OPLL after posterior decompression was evaluated based on the combined data from studies 1 and 2. We also conducted a pilot study of EHDP to reconfi rm the results of the previous clinical trial. © Springer 2006.