Introduction

Ipriflavone (7-isopropoxyisoflavone;Figure 1), a non-hormonal isoflavone derivative, is currently used in several countries for prevention and treatment of postmenopausal osteoporosis. This compound is devoid of estrogenic activity in humans, but increases the activity of estrogens. Ipriflavone has been shown to be effective in reducing bone turnover rate mainly through an inhibition of bone resorption, and has been effect to stimulate of bone formation. Inhibitory effect of ipriflavone on bone resorption has been demonstrated both directly by the activation of mature osteoclast and the formation of new osteoclasts by stimulating estrogen-induced calcitonin secretion by thyroids in vivo. There are some evidence that ipriflavone has direct effect on bone formation. Several clinical studies have demonstrated that bone mineral density (BMD) was increased or maintained in patients treated with ipriflavone. Recently, a large multicentral study, Ipriflavone Multicenter European Fracture Study (IMEFS), was designed in order to investigate the efficacy of ipriflavone on the prevention of vertebral and the effect on BMD in women with postmenopausal osteoporosis.[1]

Pharmacokinetics

Ipriflavone is metabolized mainly in the liver and excreted in the urine. Food appears to enhance its absorption. When given to healthy male volunteers, 80 percent of a 200 mg dose of IP was absorbed when taken after breakfast. Ipriflavone appears to be extensively metabolized. In dogs and rats, seven metabolites were identified in the plasma, labeled MI-MVII. In humans, however, only MI, MII (daidzein), MIII, and MV seem to predominate. The mean excretion half-life in healthy human volunteers was 9.8 hours for ipriflavone and ranged from 2.7-16.1 hours for its metabolites. Ipriflavone metabolism was not found to be significantly different in elderly osteoporotic or mild kidney failure patients than in younger, healthy subjects. Studies using labeled ipriflavone in rats found it concentrated primarily in the gastrointestinal tract, liver, kidneys, bones, and adrenal glands.

Mechanisms of Action

Ipriflavone appears to have several mechanisms of action, all of which enhance bone density, making ipriflavone seemingly superior to many of the other treatments available for osteoporosis prevention and treatment. While it has been popular to label osteoporosis drugs as primarily either anti-resorptive or bone forming, this does not take into account the fact these two processes are coupled. Because of this coupling, substances which have a beneficial effect on prevention of bone resorption by osteoclasts may also prevent osteoblastic activity when taken long-term. Treatments which are primarily anti-resorptive include estrogen, calcium, bisphosphonates, and calcitonin, while sodium fluoride, anabolic fragments of parathyroid hormone, and insulin-like growth factor demonstrate mainly bone forming activity. While Ipriflavone is considered to be primarily an anti-resorptive, it also possesses bone forming properties. Anti-resorptive mechanisms: An animal study found Ipriflavone inhibited parathyroid hormone-, vitamin D-, PGE2- and interleukin 1?-stimulated bone resorption. Bonnuci et al found parathyroid-stimulated osteoclastic activity and resulting hypercalcemia were inhibited in a dose-dependent manner by Ipriflavone supplementation in rats. 7 Ipriflavoneriflavone metabolites have also been found to inhibit bone resorption. An in vitro study on fetal rat long bones found all metabolites capable of inhibiting parathyroid-stimulated bone resorption. MIII was the strongest inhibitor, approximately three times more potent than MII; MI and MV were the least potent.

Bone-forming mechanisms: Ipriflavoneriflavone and metabolite II stimulated cell proliferation of an osteoblast-like cell line (UMR-106a – a cell line often used to determine the effect of various hormones and drugs on bone metabolism). Ipriflavone and metabolite I increased alkaline phosphatase activity, metabolite V enhanced collagen formation, and Ipriflavone alone inhibited parathyroid hormone activity. 14 Bone marrow osteoprogenitor cells and trabecular bone osteoblasts were isolated from human donors and incubated with Ipriflavone and its metabolites. These substances were found to regulate osteoblastic differentiation by enhancing the expression of important bonematrix proteins and facilitating mineralization.

Effect on Advanced Glycation End Products (AGE): AGE (proteins nonenzymatically reacted with sugar) have been implicated in a number of chronic degenerative conditions especially related to diabetes and aging. AGE have also been implicated in bone resorption around amyloid deposits in dialysis-related amyloidosis. Both ipriflavone and calcitonin were found, in vitro, to inhibit this AGE-associated bone resorption.This may have implications for age- and diabetes-related osteoporosis as well.

Lack of Estrogen Effect: One of the benefits of ipriflavone in the treatment of osteoporosis is its lack of estrogenic effect. Melis et al administered ipriflavone or placebo to a group of 15 postmenopausal women. Leutinizing hormone, follicle-stimulating hormone, prolactin, and estradiol were measured after a single oral dose of 600 or 1000 mg, and after 7, 14, and 21 days of treatment with 600 or 1000 mg doses. No differences in endocrine effect were noted between the ipriflavone and placebo groups.

Effect on Crystalline Structure: Certain osteoporosis medications, such as sodium fluoride, increase bone density but change the crystalline structure, making the bone actually more fragile. 24 A study using high doses of ipriflavone (200-400 mg/kg/day) in rats for 12 weeks found no change in the crystalline structure of the bone. The researchers concluded “the positive effect of ipriflavone on bone mineral density appears to be associated with an increased apatite crystal formation rather than an increase of crystal size.”25 A study on rat long bones found ipriflavone increased the resistance to fracture by 50 percent without changing mineral composition or bone crystallinity.

Safety of Ipriflavone

In general, ipriflavone appears to be quite safe and well tolerated. As of 1997, longterm safety of ipriflavone (for periods ranging from 6-96 months) had been assessed in 2,769 patients for a total of 3,132 patient years in 60 human studies in Hungary, Japan, and Italy. 1 The incidence of adverse reactions in the Ipriflavone-treated patients was 14.5 percent, while the incidence in the placebo groups was 16.1 percent. Side-effects were mainly gastrointestinal (GI). Since the placebo groups in most studies received calcium, it is not unreasonable to assume calcium may have as much to do with GI effects as ipriflavone. Other symptoms observed to a lesser extent included skin rashes, headache, depression, drowsiness, and tachycardia. Minor transient abnormalities in liver, kidney, and hematological parameters were documented in a small percent of subjects.

While ipriflavone was found to have potential for treatment of renal osteodystrophy and short-term use was without side-effects, pharmacokinetic studies have revealed elevated levels of ipriflavone and its metabolites in the serum of patients with moderate to severe renal failure. 55 Patients with mild renal disease seem to tolerate ipriflavone at doses similar to those of healthy subjects. Researchers recommend lower doses (200-400 mg/day) in patients with more advanced renal failure. Further study of its safety in this population is warranted.

Conclusion

The therapeutic benefits of ipriflavone in the prevention and treatment of osteoporosis have been well researched. Ipriflavone appears to restrain bone loss in postmenopausal women and in some cases, particularly in elderly populations, stimulates new bone growth and decreases fracture rates. It has also been found to enhance the effect of low-dose estrogen on bone preservation. Ipriflavone appears to be effective in prevention of acute bone loss after surgery or GnHR-As, and may protect from steroid-induced osteoporosis as well.

References

[1] Kitatani K, Morii H. Nihon Rinsho. 1998;56(6):1537-1543.

[2]Head KA. Ipriflavone: an important bone-building isoflavone. Altern Med Rev. 1999;4(1):10-22.