Full Length ArticleMinodronic acid ameliorates vertebral bone strength by increasing bone mineral density in 9-month treatment of ovariectomized cynomolgus monkeys
Introduction
Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture [1]. Nitrogen-containing bisphosphonates (N-BPs) are widely used drugs for treatment of osteoporosis because of their strong inhibition of accelerated bone turnover, which results in an increase in bone mineral density (BMD) and consequent fracture prevention [2], [3], [4], [5], [6]. Minodronic acid is a N-BP that is a strong inhibitor of farnesyl diphosphate synthase, the target enzyme of N-BPs, due to the imidazopyridine ring in the minodronic acid side chain [7], [8]. The approved doses of oral minodronic acid for osteoporosis are 1 mg/day and 50 mg/28 days [9], [10], [11], [12], which are the lowest doses for orally available N-BPs worldwide. Minodronic acid reduced the relative risk for new vertebral fracture at 2 years by 58.9% in Japanese osteoporosis patients with 1 to 5 fragility fractures [6]. This risk reduction is comparable to that seen with other N-BPs and tends to be greater than that with selective estrogen receptor modulators (SERMs) [2], [3], [4], [5], [6], [13], [14]. The 58% reduction in vertebral fracture risk quoted here for minodronic acid is no greater than the 50–70% reduction in vertebral fracture risk previously recorded for all other N-BPs during Phase III and IV testing. It is generally accepted that vertebral fracture risk reduction with N-BPs tends to be greater than that seen with SERMs. Minodronic acid caused an increase in lumbar BMD of 10.4% at 3 years in a fracture prevention study [9], and this may contribute to the reduced risk for vertebral fracture. In addition, increase in lumbar BMD was reported by switching daily and weekly N-BP (mainly alendronate and risedronate) to minodronic acid at 50 mg/28 day [12].
Non-clinical studies offer the advantage of assessment of bone quality compared to clinical fracture trials through direct assessment of bone strength and BMD at the same skeletal site [15]. The long-term non-clinical efficacy of N-BPs has been shown in estrogen-depleted ovariectomized (OVX) models in large animals treated for over 16 months [16], [17], [18], [19], [20]. All studies except minodronic acid were conducted with iv or sc treatment because N-BPs have characterized drug-food interaction. The duration of these studies is equivalent to 4 years of treatment in humans, based on bone turnover (number of complete resorption and formation cycles/year) in each species, and covered a number of cycles, as requested in regulatory guidelines [21], [22]. Thus, the lengths of these non-clinical studies were longer than corresponding clinical studies of 1 to 2 years. Therefore, these studies explain long term effects, but mechanical strength in fracture prevention may differ at the early stage of treatment with N-BPs.
Bone mineral content (BMC) is a primary predictor for vertebral mechanical strength in preclinical studies using large animals over 16 months [16], [20]. In addition, bone trabecular structure such as trabecular thickness has been identified as a secondary predictor for mechanical strength in non-clinical studies of some N-BPs [23], [24]. A strong association between BMD and the risk of fracture is also well recognized clinically [25]. Jacquest et al. recently reported that an increase of total hip BMD, rather than BMD itself, was associated with vertebral and non-vertebral fracture prevention by zoledronic acid in a clinical fracture study [26]. However, the importance of the increase in BMD for bone strength is unclear because no previous non-clinical studies of N-BPs have examined the link between an increase of BMD and mechanical strength.
In this study, the effect of minodronic acid on vertebral BMD and bone mechanical strength were evaluated in OVX monkeys for 9 months, which corresponds to 2 years in the human bone remodeling cycle. Two doses of minodronic acid of 15 and 150 μg/kg/day were selected, with the higher dose exceeding the clinical dose (1 mg/day) and providing a safety margin of over 5-fold. Alendronate at 500 μg/kg/day was used as a reference drug of widely used N-BPs. Parameters of bone mechanical strength for animals treated with minodronic acid and alendronate were compared with OVX controls to examine how N-BPs improve bone mechanical strength. The influence of BMD and BMC, and the increase in BMD and BMC over 8 months, on bone mechanical strength was tested by regression analysis.
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Animals
This study was approved by the Internal Animal Care and Use Committee of INA Research Philippines, Inc. (Laguna, Philippines). Forty female cynomolgus monkeys aged 8.6 to 16.6 years old based on dental state and individual records were acquired from Siconbrec (Manila, Philippines) and A.T. Viri Primate Breeding Corp. (Manila, Philippines). Each animal had epiphyseal closure and adult skeletal status confirmed by X-ray. Animals were individually housed in stainless steel cages. The animal room
General health of animals
Minodronic acid and alendronate were well tolerated by all animals. Body weights of monkeys at baseline and week 37 were indicated in Table 1. Lack of ovarian function in OVX monkeys was confirmed by a decrease in serum estradiol to < 10 pg/mL and an absence of menstruation, while regular menstruation was observed in sham-operated monkeys.
Bone turnover markers
Levels of urinary DPD/Cr and NTX/Cr and serum osteocalcin and BAP in OVX controls were significantly higher than in sham animals at months 4 and 8 (Table 2).
Discussion
OVX resulted in significant increases in bone turnover markers, urinary DPD/Cr and NTX/Cr, and serum BAP and osteoclcin. These data indicate increased systemic bone turnover in OVX controls at months 4 and 8. High-dose minodronic acid and alendronate significantly reversed the increases in bone turnover markers. Inhibition of bone turnover markers was less apparent with low-dose minodronic acid. OVX caused a relative decrease in lumbar BMD compared to sham animals, to a similar extent to that
Disclosures
MT, HM and KK are employees of Ono Pharmaceutical Co., Ltd. Minodronic acid was launched by Ono Pharmaceutical Co., Ltd. and Astellas Pharma Inc. in Japan.
Acknowledgements
This study was supported by Ono Pharmaceutical Co., Ltd. and Astellas Pharma. Authors' roles: Study design, study conduct: MT and HM. Data analysis and interpretation: MT, HM and TM. Drafting manuscript: MT. Revising manuscript content and approving final version of manuscript: All. We thank Flordeliza P de Villa, Iori Itagaki, Takashi Hayashi and Norio Muto (INA Research Philippines, Inc.) for their expertise and technical support in animal care and assessments of BMD, histomorphometry, and
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