Original Full Length ArticleEffect of combined teriparatide and monthly minodronic acid therapy on cancellous bone mass in ovariectomized rats: A bone histomorphometry study
Introduction
Bisphosphonates, denosumab, and teriparatide [parathyroid hormone (1–34): PTH (1–34)] are widely used in the treatment of postmenopausal osteoporosis. A meta-analysis of randomized controlled trials has clarified that alendronate, risedronate, zoledronic acid, and denosumab prevent vertebral, nonvertebral, and hip fractures [1] and that teriparatide [PTH (1–34)] prevents vertebral and nonvertebral fractures [1]. Although these drugs effectively reduce the incidence of fragility fractures, the risk reduction rates are not more than 70% [1]. So, the 1-year efficacy of combination therapy with teriparatide and potent anti-resorptive drugs has been studied in patients with postmenopausal osteoporosis [2], [3], [4]. The concurrent use of daily alendronate was reported to reduce the anabolic effect of PTH (1–84) on cancellous bone mineral density (BMD) and cortical volume at the hip [2]. Conversely, teriparatide [PTH (1–34)] and zoledronic acid (once a year) or denosumab (once 6 months) had an additive effect on the lumbar spine and hip BMD [3], [4], suggesting the efficacy of teriparatide in combination with intermittent anti-resorptive drugs for BMD. However, whether teriparatide has an additive effect with weekly or monthly bisphosphonates in patients with postmenopausal osteoporosis remains unclear.
Oral minodronic acid, which is a third-generation bisphosphonate, was developed in Japan. Randomized controlled trials have shown that daily minodronic acid reduced the incidence of vertebral fracture in patients with involutional osteoporosis [5], and that monthly (every 4 weeks) minodronic acid had a similar effect on surrogate markers for daily minodronic acid [6]. Because of its desirable pharmacological characteristics in terms of a low affinity for bone and the strong inhibition of farnesyl pyrophosphate synthase [7], [8], minodronic acid rapidly and strongly reduces bone turnover [9], and its effect is considered to be reversible after the discontinuation of treatment, similar to risedronate [10]. Because adherence to bisphosphonate therapy is superior for a monthly dosing regimen, compared with a daily or weekly dosing regimen [11], the monthly administration of minodronic acid is now widely prescribed.
Teriparatide has been hypothesized to have a potentially additive effect on bone mass when used in combination with monthly minodronic acid therapy in patients with postmenopausal osteoporosis. To address this research question, a preclinical study was performed using a rat model of postmenopausal osteoporosis. An ovariectomy (OVX) is known to deteriorate cancellous bone structure, leading to a decrease in cancellous bone mass in the tibial proximal metaphysis of rats [12]. The purpose of the present study was to determine whether teriparatide and the monthly administration of minodronic acid would have an additive effect on cancellous bone mass in OVX rats.
Section snippets
Animal model
Six-week-old female Sprague–Dawley rats (n = 50) were purchased from Charles River Japan (Kanagawa, Japan) and were housed in an animal room (temperature 24 °C, humidity 50%, and 12-h on/off light cycle) with free access to water. After 1 week for adaptation to their new environment, 7-week-old rats were randomized using the stratified weight method into five groups of 10 animals each, including a sham-operation + vehicle group (SHAM group), an OVX + vehicle group (OVX group), an OVX + minodronic acid
Influence of OVX
The initial body weight did not differ significantly among the five groups. OVX increased the final body weight, regardless of the drug therapy. OVX did not significantly influence the femoral weight, but it did decrease the femoral distal metaphysis BMD (Table 1).
Effect of minodronic acid
Minodronic acid did not significantly influence the femoral weight, but it did mitigate the OVX-induced decrease in femoral distal metaphysis BMD(Table 1).
Effect of teriparatide
Teriparatide increased the femoral weight and the femoral distal metaphysis BMD
Discussion
The present preclinical study was conducted to determine whether teriparatide and monthly minodronic acid would have an additive effect on the cancellous bone mass (BV/TV) in OVX rats. Minodronic acid prevented the OVX-induced decreases in BV/TV, while teriparatide increased the BV/TV beyond the values observed in the sham controls. The effects of teriparatide and monthly minodronic acid on the cancellous bone structure differed between the two drugs. A combination of teriparatide and
Conflict of interest
All authors state that they have no conflict of interest.
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