Osteoporosis:
Focusing On Ipriflavone and Other Key Nutrients




 

Ipriflavone

Flavonoids (also known as bioflavonoids) are ubiquitous in plants that undergo photosynthesis. Scientists first become interested in flavonoids in the early 1930s when it was discovered that many of these compounds exhibited vitamin-like activity. Flavonoids have since been demon-strated to have antioxidant, antimicrobial, antimutagenic and anticarcinogenic activities . Recently, focus has centered on the effects that flavonoids may have on bone metabolism. Certain flavonoids, specifically a class of flavonoids called isoflavones, can exert estrogen-like activity. This has caused researchers to investigate their utility in preventing postmenopausal bone loss. While the data regarding the ability of isoflavones to help prevent bone loss are equivocal, ipriflavone (IP), a specific isoflavone derivative has received a significant amount of research with very positive results.

Currently, the measurement of BMD is considered the gold standard in terms of assessing the degree of osteoporosis present. Unfortunately, BMD is a static measurement. Recently, a marker of bone turnover, the N-linked telopeptide assay (NTx) has become available as a clinical tool to dynamically assess the efficacy of anti-resorptive therapy. This assay measures type I collagen degradation products and has been correlated with changes in BMD. A reduction in the NTx value represents a beneficial out-come for the osteoporotic patient. While the effect of calcium and other anti-resorptive therapies have been investigated for their ability to produce changes in this assay ^21-22, reports demon-strating the effect of ipriflavone, or ipriflavone-containing products on this marker are lacking. Douglas Laboratories ® has recently completed a pilot trial investigating the effect of an ipriflavone-containing dietary supplement on urinary N-linked telopeptide levels in postmenopausal women ²³. A total of 8 women, at least 5 years post menopause were recruited to participate in the study. Women were free from any history of bone or kidney disorders and were not receiving hormone replacement therapy. The women received either a supplement containing 300 mg ipriflavone, 150 mg calcium, and 50 IU vitamin D taken twice daily with meals, or an identical looking placebo for 3 months. The participants received NTx measurements before and after the study. After 3 months, there was an average 29% decrease in NTx values for those subjects consuming the supplement, while an increase in NTx values was observed for those taking the placebo.

The effectiveness of IP at slowing changes in postmenopausal bone density has been well established via measurements of changes in bone mineral density (BMD). Although BMD is a use-ful indicator of fracture risk, BMD provides only a static picture of bone metabolism. Urinary markers offer the clinician a dynamic and easily measured indication of response to treatment. Our preliminary data provide additional evidence to support the use of IP or IP-containing supplements for the preven-tion of bone loss in postmenopausal women.

Calcium and vitamin D ₃

Osteoporotic fractures can be reduced if peak bone mass and age-related bone loss can be minimized. Once women reach menopause, bone loss occurs rapidly (3%/year) over the first 5 years post menopause and then continues at approximately 1%/year during the following years ²⁴. Calcium and vitamin D₃ work in concert, with D₃ mediating the intestinal absorption of calcium as well as having direct effects on calcium metabolism in the kidney and bone. Studies investigating the ability of supple-mental calcium and vitamin D₃ to slow bone loss have yielded equivocal results, with some studies demonstrating a positive effect ^25-28 and others showing no effect ^29-30. These conflicting results may be due to differences in study design, the type of calcium used, the sites of bone loss investigated (spine vs. hip), as well as varying menopausal status and dietary calcium intake in the subjects being investigated. A number of recent studies, however, have reported a positive effect of supplemental calcium alone, or in combination with vitamin D₃ on bone loss. Dawson-Hughes et al. ²⁵ assessed the effect of calcium supplementation on bone density in postmenopausal women. Supplementation with 500 mg/d calcium citrate malate in women with a dietary calcium intake <400 mg/d resulted in significantly less loss of bone density over a two year period compared with placebo. The ability of calcium to diminish the loss of bone was site specific and was less evident in women consuming >400 mg/d from their diet. Dawson-Hughes et al. ³¹ also reported that supplementation with 400 IU/d vitamin D₃ prevented wintertime bone loss in healthy postmenopausal women. Investigations of the combined supplementation of calcium and vitamin D₃ have also yielded positive results. Aloia et al. ³² found that bone loss was diminished in postmenopausal women receiving 1700 mg/d calcium and 400 IU/d vitamin D₃ over a 3 year period. The positive effect of vitamin D₃ on the efficacy of calcium is not unexpected, as these nutrients function together. Finally, Chapuy et al. ³³ recently reported that the combined supplementation of 1200 mg/d calcium and 800 IU/d D3 in nursing home residents significantly reduced fracture rates during a 3 year trial. None of the trials mentioned above reported any noteworthy side effects as a result of supplementation.

Vitamin K

Vitamin K has been known for many years to be involved in the synthesis of a number of proteins (vitamin K dependent proteins) by acting as a co-factor for their carboxylation ^34. Vitamin K's most well understood function is as a co-factor for proteins involved in blood coagulation; however, vitamin K dependent proteins have also been identified in bone ³⁵. One of these proteins, osteocalcin, is involved in regulating bone mineralization ³⁶, and may require more vitamin K than the proteins involved in blood coagulation in order to function properly ³⁷. This has lead to the concept that current intake of vitamin K may be less than adequate and supplemental vitamin K may be beneficial for optimal bone health.

A number of observations have related vitamin K to bone. Postmenopausal bone loss is associated with poor vitamin K intake, and patients with hip fractures have been reported to have very low circulating concentrations of vitamin K ^38-39. Additionally, circulating concentrations of undercarboxylated osteocalcin have been reported to be inversely correlated with bone density in the hip ⁴⁰. It has also been observed that supplementation of post-menopausal women with 1 mg vitamin K for 2 weeks increases serum markers of bone formation and may reduce urinary losses of calcium ⁴¹. However, data with respect to the effect of supplemental vitamin K on bone mass or fracture are limited. One Japanese study, ⁴² has shown a significant reduction in postmenopausal bone loss in women receiving supplemental vitamin K. Similar studies from Western countries assessing the effect of supplemental vitamin K are being awaited.

The role that manganese, copper, zinc and vitamin C play in the metabolism of bone has been extensively investigated. Nonetheless, compared with calcium and vitamin D 3 their exact biochemistry with respect to bone metabolism is not as well understood. Copper and vitamin C are both required for the proper formation of collagen. Additionally, vitamin C plays a role in the formation of glycosaminoglycans. Manganese is involved in the synthesis of mucopolysacchrides that are essential for the formation of the bone matrix, and zinc deficiency causes a reduction in collagen synthesis and osteoblasts (cells involved in the formation of new bone) activity. Cross-sectional and animal data report the diets deficient in manganese and copper are associated with a lower bone mineral density. Saltman and Strause ⁴³ supplemented post-menopausal women with either 1) 1000mg/d calcium citrate, 2) trace minerals (5mg/d copper, 2.5 mg/d manganese, and 15 mg/d zinc), 3) a combination of calcium and trace minerals, or 4) a placebo for 2 y. Women receiving the trace minerals plus calcium lost significantly less bone mineral density compared with placebo. Neither the minerals nor the calcium alone showed a significant difference compared with placebo. These data suggest an important interaction between calcium and trace minerals in the prevention of bone loss in postmenopausal women.

Given that sixty percent of all the magnesium in the body is located in bone, it is reasonable to conclude that magnesium is also closely related to bone structure and function. Magnesium status has been shown to influence various parameters that affect bone metabolism. Magnesium deficiency has been associated with the inhibition of parathyroid hormone release and increased resistance to parathyroid hormone. Additionally, magnesium deficiency is associated with a decreased concen-tration of serum vitamin D₃ and results in tissue resistance to the action of vitamin D₃ . Prospective studies examining the effect of supplemental magnesium on bone density are very limited. Rude and Olerich supplemented 5 patients with gluten sensitive enteropathy (who often have malabsorption problems) with 504 -576 mg/d magnesium. Supplementation for 2 years resulted in an increase in bone mineral density and an increase in serum parathyroid hormone. No other data on magnesium supplementation and bone parameters are available.

Silicon

Silicon is a trace mineral that has been implicated in the formation and maintenance of healthy bone. Its exact function remains unclear; however, animal data have accumulated indicating its essentiality. Rats and chicks placed on diets containing only 1ppm silicon showed incomplete and deformed skeletal development 44. The defect appears to be in the formation of glycosaminoglycans and collagen, both of which are needed for the formation of the bone matrix ⁴⁵. Silicon has been found attached to collagen and increases during the early mineralization process of bone ⁴⁶. It appears that silicon helps to provide a stable organic matrix to allow for the proper formation of bone to occur.

Boron

Boron is another trace element that is involved in bone metabolism and mineralization, although like silicon, its exact function is unclear. Similar to other trace minerals, boron¹s action on bone may be mediated through its ability to affect other parameters associated with bone, including calcium, magnesium, parathyroid hormone, calcitonin, osteocalcin ⁴⁷. The results of supplementing animals and humans with boron have yielded conflicting results based on the amount supplemented and the model studied. Consumption by rats of water containing 300 mg boron/L resulted in a decrease in the calcium content and size of certain bones. Daily consumption of 4 and 8 mg boron/kg body weight in pigs (equivalent to approximately 550 mg/d in humans) resulted in decreased bone mineral content and decreased bone mass. Chapin et al ⁴⁸ supplemented rats with varying concentrations of boron (1.4 mg - 63 mg/kg body weight) and reported an increase in vertebral strength at all doses of boron supplementation. Investigations of boron supplementation in humans were started with a report by Nielson ⁴⁹ who placed postmenopausal women on a low boron diet followed by a diet supplemented with 3 mg/d boron. Supplementation significantly reduced the loss of urinary calcium and magnesium as well as increased serum levels of estrogen (involved in preventing bone demineralization). Peace et al. ⁵⁰ attempted to repeat these results in a similar study involving postmenopausal women, but was unable to confirm the earlier results. Meacham et al. ⁵¹ investigated the effects of boron supplementation (3 mg/d) in pre-menopausal women over 10 months, and found that boron supplementation increased serum magnesium levels. Science is continuing to uncover new ways to help slow the continual loss of bone in postmenopausal women. Together with a healthful diet and proper vitamin and mineral supplementation, IP is now recognized to be an effective addition to the arsenal of tools available to the practitioner in the fight against osteoporosis.

Written by Andrew Halpner, Ph.D.
Dr. Halpner received his Ph.D. in Nutrition from Tufts University School of Nutrition Science and Policy. His extensive research and interests focus around antioxidant nutrients, including their interactions and ability to prevent and treat age-related degenerative diseases. Dr. Halpner is Director of Product Development and Technical Services for Douglas Laboratories ®

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