Ipriflavone

Ipriflavone (chemical structure: 7-isopropoxyisoflavone) is an isoflavonoid synthesized from the soy isoflavone daidzein. It promises successful use in the prevention and treatment of osteoporosis and other metabolic bone diseases. Ipriflavone was discovered in the 1930s, but has only recently become the focus of international medical research. More than 150 clinical and animal studies on the safety and effectiveness of ipriflavone were carried out in Italy, Hungary and Japan. By 1997, 2769 patients had been treated over a total of 3132 patient-years.

Pharmacokinetics

Ipriflavone is mainly metabolized in the liver and excreted in the urine. Food intake appears to improve its absorption. When administered to a group of healthy male volunteers, 80% of a 200 mg dose of ipriflavone was found to be absorbed when taken immediately after breakfast. No significant differences in ipriflavone metabolism were found in elderly patients with osteoporosis or mild forms of renal insufficiency compared to young healthy volunteers. Studies on rats with labeled ipriflavone showed that storage occurs predominantly in the gastrointestinal tract, liver, kidneys, bones and adrenal glands.

Mechanisms of action

Antiresorptive mechanism: In an animal study, it was shown that ipriflavone acts as an inhibitor of parathyroid hormone-, vitamin D-, PGE2- and interleukin-1-beta-stimulated bone resorption. Bonnuci et al. found that in rats, parathyroid-stimulated osteoclast activity and the resulting hypercalcemia were inhibited in a dose-dependent manner by ipriflavone supplementation. Bone-forming mechanism: An in vitro study of the osteoblastic effects of ipriflavone and its metabolites resulted in extremely interesting findings. Ipriflavone and one of its metabolites stimulated cell proliferation of an osteoblast-like cell line (UMR-106a - a cell line often used to study the effects of various hormones and drugs on bone metabolism). Ipriflavone and one of its metabolites increased alkaline phosphatase activity, while another ipriflavone metabolite stimulated collagen formation. In addition, ipriflavone alone is able to inhibit parathyroid hormone activity. Absence of direct estrogenic effect: One of the advantages of ipriflavone in the treatment of osteoporosis is the absence of a direct estrogenic effect. Melis et al. administered ipriflavone or placebo to a group of 15 postmenopausal women. LH, FSH, prolactin and estradiol were measured after a single oral dose of 600 mg or 1000 mg and after 7, 14 and 21 days of treatment with 600 or 1000 mg. There were no differences in endocrine parameters between the ipriflavone and placebo groups. Vaginal cytology was unchanged after 21 days of treatment with ipriflavone or placebo compared to a significant increase in superficial vaginal cells in the estrogen-treated group. In vitro investigation of the interaction between ipriflavone and pre-osteoclastic cell lines revealed that this was not mediated by a direct interaction with estrogen receptors. Instead, specific binding sites for ipriflavone were identified in the cell nuclei of preosteoclasts. The existence of ipriflavone binding sites was confirmed by Miyauchi and coworkers. This group identified 2 classes of binding sites in chick osteoclasts and their precursors. Similar ipriflavone binding sites were identified in human leukemia cells, a cell line with similar characteristics to osteoclast precursors. Although ipriflavone has no direct estrogen effect, it appears to potentiate the estrogen effect. Calcitonin secretion is modulated by estrogen. While ipriflavone alone does not trigger an increase in calcitonin levels, it acts synergistically with estrogen, so that lower doses of estrogen are sufficient to normalize calcitonin secretion. Apparently, ipriflavone increases the sensitivity of the thyroid gland to estrogen-stimulated secretion.

Therapy studies

In the last 10 years, more than 60 clinical studies have been conducted on the use of ipriflavone in the prevention and treatment (reversal) of bone substance loss, most of them under double-blind and placebo-controlled conditions. An overview of these studies follows. Postmenopausal osteoporosis: Ipriflavone has been studied in numerous double-blind, placebo-controlled trials in Italy, Hungary and Japan. The same treatment protocol was used in most studies: 200 mg ipriflavone or placebo 3 times daily. In almost all studies, calcium (500 to 1000 mg) was also administered to both the ipriflavone and placebo groups. Several 2-year studies in postmenopausal women (mean age 50-65) concluded that bone mass was maintained or slightly improved in the ipriflavone groups, while the placebo groups showed significant bone loss. Furthermore, there is some evidence that ipriflavone may be particularly effective in the treatment of senile osteoporosis (osteoporosis in women or men over 65). This is the result of 2 studies in seven Italian centers. In these studies, a total of 112 subjects between the ages of 65 and 79 were observed over a period of two years. The subjects received either 600 mg ipriflavone + 1 g calcium or placebo + 1 g calcium daily. A 4-6% increase in bone density was recorded in the ipriflavone groups, while bone density decreased by 3% in the placebo groups. However, the most clinically relevant result in the larger of the two studies was the decrease in fracture rates in the ipriflavone group (2 out of 41 patients in the ipriflavone group compared to 11 out of 43 patients in the placebo group).

Ipriflavone for the treatment of osteoporosis in combination with other nutrients or medications

Ipriflavone improves the effect of other bone-protective substances including 1a-hydroxyvitamin D (a form used in Japan for osteoporosis therapy). Several studies investigated the effect of ipriflavone and estrogen in the treatment of osteoporosis. While low doses of conjugated estrogen (0.15-0.30 mg/day) are sufficient to suppress hot flashes and other neurovegetative symptoms of menopause, higher doses (0.625 mg/day or higher) must be used to achieve an osteoprotective effect. Several studies have shown that in combination with ipriflavone, lower doses of oestrogen are also sufficient for bone protection.

Ipriflavone versus salmon calcitonin

In an open, controlled 12-month study of 40 postmenopausal women, ipriflavone was compared with salmon calcitonin. After 12 months of treatment, a significant improvement in bone density was observed in both groups: a 4.3% improvement in bone density in the ipriflavone group and a 1.9% increase in the calcitonin group.

Ipriflavone in the prevention of surgery- or drug-induced osteoporosis

Research groups investigated the therapeutic benefit of ipriflavone in reducing iatrogenic bone substance loss following treatment with GnRH-A. In a double-blind placebo-controlled study, 78 patients treated with GnRH agonists (3.75 mg leuprorelin every 30 days for 6 months) were randomized into 2 study groups receiving either ipriflavone (600 mg/day) or placebo. Both groups were given an additional 500 mg/day of calcium. In the placebo group, markers of bone remodeling (urinary hydroxyproline and osteocalcin) were significantly increased, while bone mineral density was also significantly decreased after 6 months. In contrast, there were no changes in bone density or bone remodeling markers in the ipriflavone-treated group. Animal studies also show that ipriflavone reduces bone loss during long-term corticosteroid therapy and immobilization.

Ipriflavone in the treatment of other diseases

Ipriflavone has also been used successfully for other conditions affecting the skeletal system. The spectrum includes ostitis deformans Paget, hyperparathyroidism, otosclerosis and renal osteodystrophy.

Demand in sport

7-isopropoxyisoflavone is an anabolic ipriflavone, i.e. it builds muscle and bone. Ipriflavone is a nutrient-dividing agent, i.e. it supplies nutrients to muscle and bone formation and passes them on so that they are not stored in fat. In animal studies, when ipriflavone was added to feed, there was a weight gain of seven to 20 percent with the same amount of feed. On closer examination, it was found that it was an increase in muscle mass and not fat. The fat content decreased in all animals. Studies have also shown that nitrogen storage and methionine uptake in the muscles increased. Both are indicators of anabolic activity. Ipriflavone also increases endurance. In one experiment, rats were given three grams of load per 100 grams of body weight. They then had to swim in cold water. Ipriflavone drastically increased the time during which they were able to swim. The control animals improved from 166 to 196 minutes over a period of 45 days, while the animals fed with ipriflavone increased from 162 to 255! Furthermore, ipriflavone lowers cholestrin levels and lowers bad LDL cholesterol while increasing good HDL cholesterol. Many athletes have reported that while taking ipriflavone, back pain and other complaints of the passive musculoskeletal system were alleviated or healed more quickly. My recommendation is to take a dosage of 800 - 1250mg daily, divided into several single doses.

Safety and side effects

Ipriflavone is probably safe and harmless for most people when used under medical supervision. Ipriflavone can cause side effects such as stomach pain, diarrhea and dizziness.

There are concerns that ipriflavone may cause a reduction in white blood cell counts in people who take it for more than 6 months. For this reason, white blood cell counts should be monitored, especially with long-term use of ipriflavone.

Precautions and warnings

Pregnancy and lactation: Not enough is known about the safety of ipriflavone during pregnancy and lactation. For this reason, pregnant and breastfeeding women should avoid ipriflavone to be on the safe side.

Weakened immune system: Ipriflavone can reduce the number of white blood cells, making it more difficult for the body to fight infections. This is particularly concerning for people who already have a weakened immune system due to AIDS, chemotherapy, taking medication to suppress immune function after organ donation or for other reasons. If you suffer from a weakened immune system, you should discuss taking ipriflavone with your doctor.

Low white blood cell count (lymphocytopenia): As ipriflavone can cause lymphocytopenia, there are concerns that it may exacerbate pre-existing lymphocytopenia.

Interactions

Care should be taken when combining ipriflavone with the following medications:

Drugs that are broken down by the liver (cytochrome P450 1A2 (CYP1A2) substrates, cytochrome P450 2C9 (CYP2C9) substrates).

Some drugs are broken down by the liver. Ipriflavone can reduce the rate at which the liver breaks down certain drugs. Taking ipriflavone in combination with drugs that are broken down by the liver can increase the effects and side effects of some drugs. For this reason, you should consult your doctor before taking ipriflavone if you are taking medicines that are broken down by the liver.

Medications that reduce the function of the immune system

Ipriflavone could reduce the function of the immune system. Taking ipriflavone in combination with drugs that reduce the function of the immune system could reduce the function of the immune system too much. For this reason, ipriflavone should not be used when taking medications that reduce the function of the immune system.

Theophylline

The body breaks down theophylline in order to excrete it. Ipriflavone may reduce the rate at which the body breaks down theophylline. Taking ipriflavone in combination with theophylline could increase the effects and side effects of theophylline.

References

1. Int J Gynaecol Obstet. 2002 Dec;79(3):195-207. use of alternative and complementary medicine in menopause. Kang HJ, Ansbacher R, Hammoud MM.
2. Calcif Tissue Int. 1997;61 Suppl 1:S3-4. ipriflavone: background. Gennari C.
3. United States Patent 4,163,746. 1979 Aug 7. metabolic 5-methyl-isoflavone-derivatives, process for the preparation thereof and compositions containing the same. Feuer L, Harkas L, Nogradi M, Vermes B, Gottsegen A, Wolfner A.