Intravenous intermittent neridronate in the treatment of postmenopausal osteoporosis

Abstract

Bisphosphonates have been used with success in the treatment of osteoporosis, but oral therapy often lacks compliance. Here we report the results of clinical trial with aminobisphosphonate neridronate administered intravenously (IV). The study included 78 postmenopausal women with spine bone mineral density (BMD) at least −2.5 SD below peak. Patients were randomized to receive for 2 years either 50 mg IV neridronate bimonthly and 500 mg calcium plus 400 U vitamin D supplements daily (n = 39) or calcium–vitamin D supplements alone (control group, n = 39). Treatment was continued over 2 years with an additional 1 year follow-up of calcium–vitamin D supplements alone. Neridronate was well tolerated with the appearance of typical clinical signs of an acute phase reaction in only 3 of the patients after the first infusion. In the control group no significant changes in BMD or bone markers were observed. In the neridronate group BMD rose progressively at the spine rose up to 7.4% ± 6.1% (SD) and at the femoral neck up to 5.8% ± 8.2% (SD) at the end of the second year. In the succeeding follow-up these gains were maintained at both skeletal sites. Serum bone alkaline phosphatase (bone ALP) and serum type I collagen C-telopeptide (s-CTX) significantly decreased within 2 months. The bone ALP values reached a −35% plateau after 6 months, while s-CTX attained the lowest mean value (−47%) only by the end of the treatment with neridronate. Both bone markers returned almost to baseline values 1 year after treatment discontinuation. Treatment of postmenopausal osteoporosis with 50 mg IV neridronate bimonthly results in clinically relevant increases in BMD, among the largest so far observed with any other bisphosphonate.

Introduction

Oral bisphosphonates have been used with success in the treatment of osteoporosis and two of these compounds, alendronate and risedronate, have been approved worldwide for the treatment and prevention of osteoporosis [1], [2], [3]. However, all bisphosphonates are poorly absorbed from gastrointestinal tract (<1%) and the absorption is lowered apparently to zero by the presence of any food in the stomach [4]. Therefore, oral biophosphonates should be taken in fasting conditions at least 30 min before any breakfast (including coffee). Oral amino-bisphosphonates are known to cause occasionally severe gastrointestinal side effects [5] and this can be at least in part prevented by taking the tablets with a large amount of water and by maintaining the upright position for half an hour. This dosing schedule is very inconvenient and it may be responsible of lack of compliance and thereby to poorer therapeutic outcomes. In addition, oral aminobisphosphonates are totally inaccessible to patients even transiently compelled to bed. These limitations have led to initial development of intermittent intravenous (IV) infusions of bisphosphonates. Such use appears to be justified by the pharmacodynamic characteristics of the compounds [4] and by the positive results obtained in a number of pilot or phase 2 clinical trials, particularly with ibandronate and zoledronate [6], [7]. Neridronate is an aminobisphosphonate structurally similar to alendronate and pamidronate: the compounds differ only in the number of methyl groups of the side chain—5 for neridronate, 3 for alendronate, and 2 for pamidronate [4]. It has been investigated for the treatment of Paget’s disease of bone [2], [8], [9], [10] and recently registered in Italy for the treatment of osteogenesis imperfecta [11]. Here, we report the results of a pilot controlled trial on the effect of this new aminobisphosphonate given bimonthly (IV) in the treatment of postmenopausal osteoporosis.