Osteoporos Int (2011) 22:271–279 DOI 10.1007/s00198-010-1221-6
ORIGINAL ARTICLE
Early treatment with zoledronic acid prevents bone loss at the hip following acute spinal cord injury J. S. Bubbear & A. Gall & F. R. I. Middleton & M. Ferguson-Pell & R. Swaminathan & R. W. Keen
Received: 24 June 2009 / Accepted: 19 January 2010 / Published online: 1 April 2010 # International Osteoporosis Foundation and National Osteoporosis Foundation 2010
Abstract Summary Osteoporosis after spinal cord injury is common. Reductions in bone density are rapid and fracture rates are higher after injury. Early treatment with 4 mg zoledronic acid significantly reduced bone loss at the hip compared to untreated individuals in the first year. Treatment appeared safe and well tolerated. Introduction Bone mineral density (BMD) is lost rapidly following spinal cord injury (SCI), predominantly in the lower limbs. Bone turnover markers suggest an early increase in resorption. Methods A randomised, open-label study of 14 patients with acute SCI randomised to receive 4 mg IV zoledronic acid or standard treatment. BMD was measured by dual-X-
J. S. Bubbear (*) : R. W. Keen Metabolic Unit, Royal National Orthopaedic Hospital, Brockley Hill, Stanmore HA7 4LP, UK e-mail:
[email protected] A. Gall : F. R. I. Middleton Spinal Cord Injuries Centre, Royal National Orthopaedic Hospital, Stanmore, Middlesex, UK M. Ferguson-Pell Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada R. Swaminathan Department of Chemical Pathology, St Thomas’s Hospital, London, UK R. W. Keen Institute of Orthopaedic and Musculoskeletal Science, University College Hospital, London, UK
ray absorptiometry at the lumbar spine and hip (femoral neck, total and trochanter) at baseline, 3, 6 and 12 months. Bone turnover markers (serum C-terminal telopeptide and Procollagen I N-terminal peptide and urinary N-terminal telopeptide/Cr ratio) were also measured. Results After 12 months, there was a significant difference in BMD between the groups at the total hip (12.4%, p=0.005), trochanter (13.4%, p=0.028) and lumbar spine (2.7%, p=0.033). However, the difference between groups at the femoral neck was not significant (4.8%, p=0.741). In the treated group, bone resorption was reduced and remained reduced up to 12 months. Other than flu-like symptoms immediately after the infusion, no adverse events were observed. Conclusion IV zoledronic acid is an effective and welltolerated treatment to prevent bone mineral density loss at the total hip and trochanter for up to 12 months following SCI. Keywords Bisphosphonate . Osteoporosis . Spinal cord injury . Zoledronic acid
Introduction Bone loss after spinal cord injury (SCI) occurs rapidly with reductions in bone mineral density (BMD) of 30–40% at the femoral neck and 50–60% at the proximal tibia [1]. The consequence of this bone loss is an increased risk of fragility fractures most commonly of the distal femur and proximal tibia [2, 3]. Serum and urinary bone turnover markers have been measured in acute SCI. An increase in bone resorption has been measured by increased levels of hydroxyproline as early as 1 month after injury and remains high for at least
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6 months [4]. The bone resorption markers deoxypyridinolone and N-terminal telopeptide (NTX) have also been shown to rise as early as 1 week post-injury and peak around 10–16 weeks with levels up to ten times normal levels [5]. Values had not returned to baseline by 6 months, indicating ongoing bone resorption. Similar increases in serum and urinary C-terminal telopeptide (CTX) have been seen at 3 months [6]. Bone formation, measured by osteocalcin, has been demonstrated as normal at 1 month and gradually increased over 6 months [4]. Total alkaline phosphatase has also been seen to rise in the first 16 weeks. These data therefore indicate an increase in bone resorption very early after SCI, and this is not coupled with an increase in bone formation. Bisphosphonates are potent inhibitors of bone resorption. Studies using bisphosphonates after SCI have shown a reduction in histomorphometric measures of bone resorption on bone biopsies after treatment with tiludronate [7] and some improvement in BMD with the use of alendronate [8]. Use of cyclical etidronate [9] and IV pamidronate [10] showed some bone preservation in those who were treated and regained walking, but not in other groups. A randomised controlled trial of oral alendronate in 31 patients with acute SCI has shown hip BMD to be preserved up to 12 months after injury in treated patients [19]. Zoledronic acid is a potent bisphosphonate [11]. A single dose has been shown to suppress bone resorption for up to 12 months in a phase 2 trial in postmenopausal women [12], to significantly reduce rates of osteoporotic fracture in women with postmenopausal osteoporosis [13] and normalised alkaline phosphatase in patients treated for Paget’s disease for up to 24 months. [14]. In the early, acute stage of SCI, patients are nursed supine and therefore administration of oral bisphosphonates immediately after injury is not possible. The administration of an intravenous drug that can be given annually is therefore advantageous over a weekly oral drug such as alendronate. We therefore postulated that administration of intravenous zoledronic acid early after SCI may prevent the bone loss seen in the acute phase of SCI.
Materials and methods Recruitment All patients admitted to the Spinal Cord Injuries Centre at the Royal National Orthopaedic Hospital, Stanmore, UK, aged 18 or over with neurological SCI, between September 2003 and February 2005, were invited to participate in this prospective open-label randomised study. Participants and
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investigators were not blinded to treatment allocation. Subjects had to have a SCI with neurological deficit within 3 months of inclusion in the study. Subjects were randomised by block randomisation to either receive 4 mg IV zoledronic acid (Zometa, Novartis Pharmaceuticals; active treatment group) or standard nursing and medical care. Subjects did not receive supplementary calcium and vitamin D due to concerns about increased risk of renal tract calculi following SCI. Subjects were excluded if pregnant or breastfeeding, previous history of allergic reaction to bisphosphonates, previous history of iritis or uveitis, significant renal impairment or evidence of vitamin D deficiency (serum 25-hydroxyvitamin D
