lpriflavone's ability to reduce bone loss is the estrogenlike effect researchers find most ntriguing. Estrogens inhibit bone-degrading osteoclast activity, a process also called bone resorption. Several studies suggest that ipriflavone and its metabolites exert their osteoprotective effect(s) in a similar manner--by inhibiting bone resorption.

One short-term human study examined the effect of 600 mg/day of iprif lavone on accelerated bone loss caused by Paget's disease, a genetically linked bone disease characterized by skeletal deformity and bone pain. 11 Sixteen patients with active Paget's disease were given either 1,200 mg iprif lavone/day (four divided doses) for one month and then a month of 600 mg/day of iprif lavone (three divided doses), or the reverse, with a 15-day 'Washout" period in between. Both doses suppressed bone pain and biochemical markers of bone turnover. The 1,200-mg/600-mg daily dose regimen also more signif icantly reduced bone pain.

Another study investigated the effects of iprif lavone in men and women with hyperparathyroidism. 12 Parathyroid hormone (PTH) is one of the two principal calcium-regulating hormones in the body, but it also promotes bone breakdown. Nine patients were given 1,200 mg/day ipriflavone (three divided doses) for 21 days, and five of these patients took the same amount for an additional 21 days. All the patients exhibited similar reductions in blood and urinary markers of bone resorption.

 

Recent studies in female rats that had undergone surgical menopause (their ovaries were removed to mimic the estrogen-def icient staite of menopause-associated accelerated bone loss) demonstrated that ipriflavone inhibited bone resorption on a scale equal to that of estradiol injections. Iprif lavone did not, however, mitigate the uterine atrophy that generally accompanies estrogen deficiency. This finding supports the theory that ipriflavone mimics estrogen's effects primarily in bone tissue--not on female sex organs.

Results of an animal study done by Japanese researchers suggest that ipriflavone may inhibit bone breakdown by activating receptors on the surface of osteoclast cells. 14 This prompts calcium to enter the bone-degrading cells, effectively slowing them down. The receptors that accept ipriflavones may exist in human bone but have yet to be identified in human osteoclast cells.

Additional evidence suggests that ipriflavone activates bone-building cells called osteoblasts. When human osteoblasts are exposed to iprif lavone and its metabolites, various cellular processes are enhanced, including the manufacture of bone-matrix proteins and bone-mineral deposition (mineralization).

A two-year study investigated ipriflavone's spinal bone-building effects in 198 postmenopausal women with low vertebral bone density. 17 These women, who were not receiving osteoactive drugs, took either 200 mg of ipriflavone three times daily along with 1 g of calcium, or only calcium and a placebo. After six months of ipriflavone-calcium supplementation, spinal bone density increased 1.4 percent, remained at the same density for 12 months, and tapered off slightly in the second year of the study. Although a 1.4 percent increase sounds small, it is a clinically significant amount and predicts a lesser risk of fracture. (Similar effects have been found on bone density in the forearm of postmenopausal women. 18) Bone density in the control group decreased overall by 1.2 percent after two years.

 

Twenty women in the placebo group who had recently become menopausal (less than five years prior) experienced an even greater decrease in bone density-4.9 percent--after the second year. This is likely because the most rapid bone loss occurs within the first five years of menopause. Eighteen recently menopausal women who took the ipriflavone-calcium supplements, however, showed no change in bone density. Similar to other study results, biochemical markers of bone loss diminished among the women taking both ipriflavone and calcium. 19,20

 

One possible reason for these favorable results is that most women do not get enough calcium in their diets, and this study may have corrected an underlying deficiency. Data from the limited number of recently menopausal women, however, suggests that supplementing only with calcium does not have any appreciable effect on retarding rapid bone loss. Ideally, this study would have included a control group that received a double placebo--one for calcium and one for ipriflavone, with a fourth group receiving iprif lavone and a placebo for the calcium. This would have allowed researchers to tease out the true contributions of each supplement and get a better idea of ipriflavone's possible interactions with calcium. Recommended disage: 300mg - 2 times a day with meal

 

Treatment of bone loss in oophorectomized women with a combination of ipriflavone and conjugated equine estrogen.

Nozaki M, Hashimoto K, Inoue Y, et al. Int J Gynaecol Obstet 1998;62:69-75.

OBJECTIVE: We previously reported that 0.625 mg/day of conjugated equine estrogen (CEE) could not prevent acute bone loss in the first year after oophorectomy. The effect of additional administration of ipriflavone on bone mineral density (BMD) and biochemical indices of bone remodeling were studied to investigate whether concurrent use of CEE and ipriflavone prevent acute bone loss in the early stages following surgical menopause. METHODS: One-hundred and sixteen oophorectomized women were randomly divided into four groups according to treatment; group 1: placebo, n = 30; group 2: CEE (0.625 mg/day), n = 29; group 3: ipriflavone (600 mg/day), n = 30; group 4: CEE (0.625 mg/day) plus ipriflavone (600 mg/day), n = 27. Vertebral BMD was measured using dual energy X-ray absorptiometry (DEXA) and two biochemical indices of bone metabolism, urinary pyridinoline (Pyr) and serum intact human osteocalcin (hOC), were also measured before, 24 weeks, and 48 weeks after initiation of treatment. RESULTS: BMD was reduced 48 weeks after treatment by 6.1, 3.9 and 5.1% in groups 1-3, respectively, but by only 1.2% in group 4. Pyr decreased by 49.5, 32.0 and 41.5% in groups 2-4, respectively. hOC also decreased by 45.2 and 21.6% in groups 2 and 4, but increased by 40.5% in group 3, suggesting an inhibitory action of CEE and ipriflavone on the turnover of bone metabolism and stimulatory action of ipriflavone on bone formation. CONCLUSION: Concomitant use of ipriflavone with CEE from an early stage after oophorectomy inhibited bone loss and was considered to be effective in maintaining bone mass after oophorectomy.



Effect of ipriflavone--a synthetic derivative of natural isoflavones--on bone mass loss in the early years after menopause.

Gennari C, Agnusdei D, Crepaldi G, et al.Menopause 1998;5:9-15.

OBJECTIVE: We studied whether oral administration of ipriflavone, a synthetic derivative of naturally occurring isoflavones, could prevent bone loss occurring shortly after menopause. DESIGN: Fifty-six women with low vertebral bone density and with postmenopausal age less than five years were randomly allocated to receive either ipriflavone, 200 mg three times daily, or placebo. All subjects also received 1,000 mg elemental calcium daily. RESULTS: Vertebral bone density declined after two years in women taking only calcium (4.9 +/- 1.1%, SEM, p = 0.001), but it did not change in those receiving ipriflavone (-0.4 +/- 1.1%, n.s.). A significant (p = 0.010) between-treatment difference was evidenced at both year 1 and year 2. At the end of the study, urine hydroxyproline/creatinine excretion was higher in the control group than in the ipriflavone group, as compared to no difference at baseline. Five patients taking ipriflavone and five taking placebo experienced gastrointestinal discomfort or other adverse reactions, but only one and four subjects, respectively, had to discontinue the study. CONCLUSIONS: Ipriflavone prevents the rapid bone loss following early menopause. This effect is associated with a reduction of bone turnover rate.



Effects of combined low dose of the isoflavone derivative ipriflavone and estrogen replacement on bone mineral density and metabolism in postmenopausal women.

Gambacciani M, Ciaponi M, Cappagli B, et al. Maturitas 1997;28:75-81.

OBJECTIVES: To assess the pattern of biochemical markers of bone metabolism and vertebral bone mineral density in early postmenopausal women treated with combined ipriflavone and low dose conjugated estrogens. METHODS: Bone biochemical markers and vertebral bone density were evaluated in a longitudinal, comparative, 2 year study conducted in postmenopausal women treated with sole calcium supplementation (500 mg/day), or with either ipriflavone (IP) at the standard dose (600 mg/day) plus the same calcium dose, low dose conjugated estrogens (CE) (0.3 mg/day) plus calcium, or low dose IP (400 mg/day) plus low dose CE (0.3 mg/day) plus calcium. The results were analyzed by repeated measures analysis of variance, as appropriate. RESULTS: No modifications of both urinary excretion of hydroxyproline and plasma osteocalcin levels were observed in calcium and in CE-treated women, while vertebral bone density significantly decreased (P < 0.0001) in both groups. In IP or IP + CE-treated women, plasma osteocalcin did not show any modification, while urinary hydroxyproline showed a significant (P < 0.05) decrease, that paralleled a significant (P < 0.05) increase in vertebral bone density. CONCLUSION: Postmenopausal IP administration, at the standard dose of 600 mg/day, can prevent the increase in bone turnover and the decrease in bone density that follow ovarian failure. The same effect can be obtained with the combined administration of low dose (400 mg/day) IP with low dose (0.3 mg/day) CE.

 

The latest ammunition in the arsenal against bone loss is a substance called Ipriflavone. It is a synthetic "isoflavone" or estrogen-like substance that mimics some of the positive effects of estrogen, including the ability to reduce bone loss. It works by increasing the body's uptake of calcium, inhibiting osteoclast cells (osteoclast cells resorb old bone so that new bone will take its place) and stimulating osteoblast cells (the ones that make new bone).

Ipriflavone was first registered as a drug in Japan in 1988 under the name of Osten. It was soon registered in several other countries as well. As this substance does not occur naturally in nature (except possibly in bee propolis), it should technically be classified as a drug. The FDA has not as yet chosen to inhibit its over-the-counter sale to the public.

The average increase in bone density using Ipriflavone in addition to Calcium is between 1.4% and 2% after 6 months and 5.8% after 12 months. Ipriflavone is also known to reduce the pain of osteaoporosis-by an average of 45% at 6 months and 62% at 12 months.

The suggested dose (in line with the studies) is either 200 mg. taken three times per day or 300 mg. taken two times per day. Although there is no toxic dose of this substance, Ipriflavone should not be taken by persons using theophylline (an asthma drug). In fact, if you are taking any prescription drugs, it is a good idea to ask your doctor if you can take Ipriflavone.



1. Almada, Anthony L., Ipriflavone: The New Bone Builder, Nutrition Science News, Apr. 1998 - Vol.3, No4.(pg.198, 200).

2. Bonucci, E., et al, Cytological and ultrastructural investigation on osteoblast and preosteoclast cells grown in vitro in the presence of ipriflavone: Preliminary results. Bone and Mineral. 19 (Suppl.) (1992) Elsevier Science Publishers B.V.

3. Notoya, Kohei, et al, Inhibitory Effect of Ipriflavone on Pit Formation in Mouse Unfractionated Bone Cells, Calcified Tissue International, 1992 Springer-Verlag, New York

4. Petilli, M., et al, Interactions Between Ipriflavone and the Estrogen Receptot, Calcified Bone International, 1995, Springer-Verlag, New York.

5. Kakai, Yoshio, et al, Effect of Ipriflavone and Estrogen on the Differentiation and Proliferation of Osteoclast Cells, Calcified Tissue International, 1992 Springer-Verlag, New York.

6. Valente, M., et al, Effects of 1-Year Treatment with Ipriflavone on Bone in Postmenopausal Women with Low Bone Mass, Calcified Tissue International, 1994 Springer-Verlag, New York.

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