Journal of Osteoporosis or its isoﬂavones promote insulin-like growth factor-I (IGF- I) production [31]. In a recent review, Atmaca [49] stated that soy isoﬂavones act on both osteoblasts and osteoclasts through genomic and nongenomic pathways. Using a rat model of osteopenia, Arjmandi et al. [31] found that soy protein increased the gene expression of IGF-I as indicated by higher femoral mRNA levels. In that study, incorporation of soy protein with normal isoﬂavone content (2.3 mg/g pro- tein) had a greater eﬀect on femoral IGF-I mRNA than the isoﬂavone-depleted soy protein-based diet (approximately 0.1 mg/g protein). This ﬁnding indicates that isoﬂavones may have a role in enhancing the synthesis of IGF-I and more importantly at the bone level. Similarly, Arjmandi et al. [46] showed that soy protein supplementation also signiﬁcantly increased serum IGF-I levels in humans. It is well recognized that IGF-I enhances osteoblastic activity in humans and IGF-I concentrations have been reported to correlate positively with bone mass in pre- [50], peri- [51], and post- [52] menopausal women. Nonetheless, these indirect observations should be conﬁrmed using in vitro and in vivo models including long-term human studies in which more deﬁnitive techniques such as bone histology and bone histomorphometry are assessed. Ma et al. [53] carried out a meta-analysis of 10 random- ized controlled trials on the inﬂuence of soy isoﬂavone intake on spine bone mineral density (SBMD) in 608 menopausal women and found that isoﬂavones contributed signiﬁcantly to the increase of SBMD, especially in post-menopausal women. They concluded that Intervention duration for 6 months may be enough for isoﬂavones to produce favorable eﬀects on spinal bone and that the intake of isoﬂavone at the level of > 90 mg/day may be better for protecting against spinal bone loss. 5. Ipriﬂavone: The Synthetic Isoﬂavone and Management of Osteoporosis Ipriﬂavone (IP) is an isoﬂavone, synthesized from the soy isoﬂavone, daidzein. Only a few studies have been conducted with IP to determine its eﬃcacy in inhibiting the decrease in BMD and only six intervention studies have been so far carried out in humans on the eﬀects of IP on bone mass and turnover [54–59]. Other papers related to ipriﬂavone include a review of randomised controlled trials (RCTs) [60] and a review on the mechanisms of action of iproﬂavone on bone metabolism [61]. There has been so far only one large multicentre RCT on the eﬀects of ipriﬂavone on BMD and turnover in postmenopausal women [62]. Several in vitro studies suggest that ipriﬂavone (typically 200 mg orally 3 times per day) may inhibit bone resorption and increase bone formation, a mechanism by which ipri- ﬂavone could prevent bone loss in postmenopausal women [61]. Four of the human intervention studies provided assessed the eﬀects of ipriﬂavone on BMD and biochemical markers of bone turnover in patient populations with acute leukemia [57], with stroke-induced hemiplegia [58], or with pharmacologically-induced hypogonadism caused by the administration a gonadotropin hormone-releasing hormone 5 agonist [54, 59]. It should be mentioned that evidence on the beneﬁts of ipriﬂavone from these studies does not establish that these patient populations are representative of the general population with regard to bone status, or that results obtained in studies on such patients relating to the treatment of rapid bone loss can be extrapolated to the maintenance of bone mineral density in the general population of adults. Three of the papers showing the beneﬁts of ipriﬂavone report the results of four randomised controlled trials investigating the eﬀects of ipriﬂavone consumption on BMD and/or bone turnover which have been conducted in post- menopausal women with either osteopenia or osteoporosis. One of the papers [60] reviewed two Italian multicentre studies performed in elderly women with established osteo- porosis. Elderly women with diagnosis of osteoporosis and prevalent vertebral fractures were enrolled in seven centres. A total of 149 subjects entered the two studies, and 111 com- pleted the 2-year intervention period. In both studies, the women were randomly allocated to receive either ipriﬂavone 600 mg/day or placebo for two years according to a double- blind, placebo-controlled, parallel design. In the ﬁrst study, 14 women in the ipriﬂavone group and 13 in the placebo completed the 2-year treatment. Radial BMD signiﬁcantly increased at years one (by 4%) and two (by 5%) of the intervention in the ipriﬂavone group compared with placebo. The urinary hydroxyproline/creatinine ratio decreased sig- niﬁcantly in the ipriﬂavone group compared to placebo. In the second study, 41 women in the ipriﬂavone group and 43 in the placebo group completed the 2-year treatment. Radial BMD signiﬁcantly increased at years one and two of the intervention in the ipriﬂavone group compared with placebo. The urinary hydroxyproline/creatinine ratio decreased signiﬁcantly in the ipriﬂavone group compared to placebo. The methodological weaknesses of these studies include small sample size, no intention-to-treat analysis, and high rate of drop outs in the ﬁrst study, which all limit the conclusions that can be drawn in relation to the beneﬁts of ipriﬂavone in preventing the decrease in BMD. Gennari [55] randomised 56 postmenopausal women with low vertebral BMD and postmenopausal age less than ﬁve years to receive either ipriﬂavone (200 mg three times daily) or placebo for two years. All subjects received also 1,000 mg/d of calcium. A statistically signiﬁcant lower decrease in vertebral BMD was observed in the ipriﬂavone group compared with placebo at one and two years (−0.4% and −4.9% in the iproﬂavone and placebo groups at two years, resp.). At the end of the study, urine hydroxypro- line/creatinine excretion, a marker of bone resorption, was signiﬁcantly higher in the placebo group than in the ipriﬂavone group. In the study by Ohta et al. [56], 60 women with postmenopausal osteopenia or osteoporosis were randomly assigned to receive either 600 mg/d ipriﬂavone or 0.8 g/d calcium lactate for one year. The rate of the decrease in L2-4 BMD was signiﬁcantly greater in the calcium lactate group than in the ipriﬂavone group. Median urinary deoxypyridinoline concentrations signiﬁcantly decreased in the ipriﬂavone group after one year compared to baseline,