Scientific Opinion on the substantiation of health claims related to
ipriflavone and maintenance of bone mineral density (ID 1872) pursuant to
Article 13(1) of Regulation (EC) No 1924/2006[sup]1[/sup]
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)2
European Food Safety Authority (EFSA), Parma, Italy
Słowa kluczowe:
Ipriflavone
bone
bone mineral density
health claims
post-menopausal women
2. Znaczenie oświadczenia dla zdrowia człowieka
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Utrzymanie prawidłowej gęstości mineralnej kości u kobiet po menopauzie
The claimed effect is “bone health”. The Panel assumes that the target population is post-menopausal women.
Bone health relates to bone mass, bone mineral density (BMD) and bone structure, which all contribute to bone strength. Whereas bone structure and bone strength are not usually measured in vivo, BMD is a good indicator of bone health in the general population.
After menopause, an increased rate of bone loss and bone remodelling, and a decrease in BMD, are observed. These changes have been associated with an increased risk of bone fractures. Bone metabolism can be measured by assessing biochemical markers of bone turnover. BMD, a relevant factor for the assessment of bone health, can also be measured by established methods.
The Panel considers that maintenance of bone mineral density is beneficial to the health of post- menopausal women.
3. Naukowe uzasadnienia wpływu na zdrowie człowieka - Utrzymanie prawidłowej gęstości mineralnej kości u kobiet po menopauzie
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Utrzymanie prawidłowej gęstości mineralnej kości u kobiet po menopauzie
Six references reporting results of intervention studies in humans on the effects of ipriflavone on bone mass and turnover (Gambacciani et al., 1994; Gennari et al., 1998; Ohta, 1999; Pagano et al., 1999; Sato et al., 1999; Somekawa et al., 2001), one review of randomised controlled trials (RCTs) (Agnusdei and Bufalino, 1997) and one review on the mechanisms of action of iproflavone on bone metabolism (Reginster, 1993) have been provided for the substantiation of the claimed effect. The Panel also considers that an additional reference reporting the results of a large multicentre RCT on the effects of ipriflavone on BMD and turnover in post-menopausal women is also relevant to the evaluation of the claim (Alexandersen et al., 2001).
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 ipriflavone could prevent bone loss in postmenopausal women (Reginster, 1993).
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 (Pagano et al., 1999), with stroke-induced hemiplegia (Sato et al., 1999), or with pharmacologically-induced hypogonadism caused by the administration a gonadotropin hormone-releasing hormone agonist (Gambacciani et al., 1994; Somekawa et al., 2001). The Panel notes that the evidence provided 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 references provided 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, which may be considered as representative of the target population for the claim.
One of the references (Agnusdei and Bufalino, 1997) was a review of two Italian multicentre studies performed in elderly women with established osteoporosis. 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 completed 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 significantly 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 Panel notes that the methodological weaknesses of these studies (i.e. small sample size, no intention-to-treat analysis, and high rate of drop outs in the first study) limit the conclusions that can be drawn in relation to the claimed effect.
Gennari et al. (1998) randomised 56 post-menopausal 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, respectively). At the end of the study, urine hydroxyproline/creatinine excretion, a marker of bone resorption, was significantly higher in the placebo group than in the ipriflavone group.
In the study by Ohta (1999), for which only the abstract was available, 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, whereas no changes were observed in the control group. No statistical comparison between ipriflavone and control groups was reported for this marker of bone resorption.
Finally, in a large prospective, randomised, double-blind, placebo-controlled trial including 474 postmenopausal Caucasian women aged 45 to 75 years with osteopenia or osteoporosis (Alexandersen et al., 2001), subjects were randomly assigned to receive either ipriflavone (200 mg 3 times per day, n = 234) or placebo (n = 240) for three years in addition to 500 mg/d of calcium. Based on an intention- to-treat analysis, the annual percent change from baseline in BMD at the lumbar spine or at any of the other sites measured did not differ significantly between the ipriflavone and the placebo groups after 36 months of treatment. The response of biochemical markers of bone turnover did not differ between groups. The number of women with new vertebral fractures was not different between the intervention and control groups after three years of follow-up.
In weighing the evidence the Panel took into account that, although four small intervention studies suggest a role of ipriflavone in attenuating the loss of BMD at the lumbar spine in post-menopausal women by decreasing bone resorption, the largest RCT with the highest number of subjects and the longest follow-up indicates that ipriflavone does not prevent bone loss or affect biochemical markers of bone turnover in post-menopausal women.
The Panel concludes that a cause and effect relationship has not been established between the consumption of ipriflavone and maintenance of bone mineral density in post-menopausal women.
