From The April 1998 issue of Nutrition Science News
Nutrient Profile
Ipriflavone: The New Bone Builder
Osteoporosis can lead to vertebral fractures and deformities as well as height loss.

By Anthony L. Almada

During the mid-1980s a word association test would probably have proceeded like this: osteoporosis: bones; bones: calcium; calcium: milk or Tums™. Calcium was the micronutrient additive of choice, and female consumers were bombarded with advertisements for calcium-enriched orange juice, food bars and other beverages. At the same time, the National Dairy Council ushered in its "Everybody Needs Milk" campaign.

Despite the hype, calcium is not the only nutrient important to bones and to women at risk of osteoporosis. Scientific studies published during the 1980s suggested an operative role in bone biology for almost every available supplement on the market. In vitro studies from 1981 indicated that flavonoids, in particular, had the estrogen like effect of protecting bone. Estrogens, and perhaps even progesterone/progestins, inhibit bone-degrading cells called osteoclasts.^1-3

Then in 1988, Japan registered an osteoporosis drug called ipriflavone (Osten®), a synthetic isoflavone. Italy, Hungary and a number of other countries soon followed suit.

Estrogen Look-alike
Like other isoflavones, the chemical structure of ipriflavone resembles that of estrogen, likely explaining why it mimics the hormone in certain ways. Despite its ability to augment the activity of naturally occurring or administered estrogens, ipriflavone does not appear to have any classical "estrogenic" effects such as stimulating breast or uterine tissue growth.^4,5 Such effects may be dangerous for postmenopausal women who are genetically prone to female cancers. There are some exceptions, however. Certain ipriflavone metabolites appear to synergize the effects of estradiol, the most potent estrogen in human cells.⁶ Plus, the ipriflavone metabolite daidzein also is mildly estrogenic.^7,8

Ipriflavone's ability to reduce bone loss is the estrogen like effect researchers find most intriguing. 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.^9,10

One short-term human study examined the effect of 600 mg/day of ipriflavone 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 ipriflavone/day (four divided doses) for one month and then a month of 600 mg/day of ipriflavone (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 significantly reduced bone pain.

Another study investigated the effects of ipriflavone 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-deficient state of menopause-associated accelerated bone loss) demonstrated that ipriflavone inhibited bone resorption on a scale equal to that of estradiol injections.¹³ Ipriflavone 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.

Bone Builder
Additional evidence suggests that ipriflavone activates bone-building cells called osteoblasts. When human osteoblasts are exposed to ipriflavone and its metabolites, various cellular processes are enhanced, including the manufacture of bone-matrix proteins and bone-mineral deposition (mineralization).^15,16

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 ipriflavone 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.

Market Hurdles.
Although initial research indicates ipriflavone helps build and protect bone, it may never become as mainstream as calcium, for the following reasons:

•Ipriflavone's dubious classification as a "natural compound" invites regulatory agencies to investigate the compound and possibly forestall its sales because, to date, no studies have convincingly demonstrated that ipriflavone occurs in nature. One study suggests ipriflavone occurs in bee propolis, but the detection method used was questionable and indirect.²¹ In addition, all published biomedical literature refers to ipriflavone as a synthetic isoflavone--a drug.

•Ipriflavone may temporarily inhibit certain liver detox pathways, resulting in abnormally high blood concentrations of drugs such as theophylline (an asthma drug).²² People who participated in published ipriflavone trials were screened for such drugs and therefore had no side effects other than minor gastrointestinal complaints. The average postmenopausal female consumer, however, runs a greater risk of ipriflavone-drug interactions, given the number of prescription medications taken by women of this age.

•A three-times-per-day dosing regimen is difficult to adhere to, especially when the supplement's effects are not immediately obvious. A one-year study, however, showed a two-times/day dose of 300 mg had similar bone-loss-arresting effects in women with low spinal bone mass.²³ A longer study is needed to validate the comparable efficacy of this more tolerable dose schedule.

•Ipriflavone's long-term effects on bone density and its possible side effects have yet to be determined. Studies so far indicate that ipriflavone's effect on spinal and forearm bone loss persists only one year after supplementation. A three-year, multi-center European ipriflavone trial measuring bone mass/density, spinal/peripheral fracture incidence and side effects will be completed by year's end. The postmenopausal women in this trial have low spinal bone mass and are receiving 200 mg of ipriflavone three times per day plus 500 mg of calcium.

Despite these potential obstacles, ipriflavone may be the next popular bone-building supplement. It promises to be an affordable alternative for women who elect to take low-dose estrogens to prevent the rapid bone loss that often accompanies postmenopause.²⁴ Research indicates that ipriflavone may also help prevent high blood cholesterol associated with estrogen deficiency,²⁵ reduce bone pain and increase immunity.²⁶ It may even prove helpful to older men who also are at risk for osteoporosis. Before such claims can be substantiated, however, more clinical trials must be conducted.

Anthony L. Almada, a nutritional and exercise biochemist, is the leader of IMAGINutrition, a nutrition think tank in Aptos, Calif. He also was a co-founder of EAS in Golden, Colo.

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Article Info
Issue: Nutrition Science News 04/98
Department: Nutrient Profile
Author: Anthony L. Almada, M.Sc.