OSTEOPOROSIS
The well-established skeletal benefits of estrogen therapy (48) combined with the estrogen-like effects of isoflavones (4) provided a sound basis for initial speculation that soy foods promote bone health. However, isoflavones and estrogen often exert very different effects, and their impact on bone mineral density (BMD) appears to be one case in which this is true, notwithstanding prospective epidemiologic data showing that soy food consumption is protective against fracture.
With regard to the latter point, a study from Shanghai in 24,403 postmenopausal women found that higher soy protein intake (>10 g/d) was associated with an approximate one-third reduction in fracture risk (49). After adjustment for age, major osteoporosis risk factors, socioeconomic status, and other dietary factors, the RRs (95% CI) for fracture were 1.00, 0.72 (0.62, 0.83), 0.69 (0.59, 0.80), 0.64 (0.55, 0.76), and 0.63 (0.53, 0.76) across quintiles of soy protein intake (P-trend < 0.001). During the 4.5-y follow-up period, there were 1170 fractures of all types, although hip (3.3%) and spinal (14.9%) factures accounted for <20% of the total. In agreement are the results of a Singaporean study that included 63,257 Chinese participants between the ages of 45 and 72 y that found that soy intake was unrelated to hip fracture risk in men, whereas in postmenopausal women (n = 35,241) soy protein intake was associated with an approximate 25% reduction in risk (50). Compared with women in the lowest quartile of intakes for tofu equivalents (<49.4 g/d), soy protein (<2.7 g/d), and isoflavones (<5.8 mg · 1000 kcal−1 · d−1), those in the second–fourth quartiles exhibited a 21–36% reduction in risk (all P < 0.036). Among the women in this cohort, there were a total of 692 hip fractures during the 7.1-y follow-up period.
One caveat about both of these observational studies is that most of the observed decrease in risk occurred when comparing women in the second soy protein intake quintile or quartile with those in the first. The low intake in this second-intake group raises questions about the biological plausibility of the findings.
In any event, a third prospective study that included 337 postmenopausal white Seventh-day Adventist women also provides support for a bone-protective effect of soy foods. After a 2-y follow-up period, in comparison to not drinking soy milk, consuming soy milk at least once per day was associated with a 56% (OR: 0.44; 95% CI: 0.20, 0.98; P-trend = 0.04) decreased risk of osteoporosis based on calcaneal broadband ultrasound attenuation. In this study, soy milk consumption was almost as protective as estrogen use. However, because dairy intake was protective to a similar degree, the results suggest that the benefits of soy milk may have been attributable to its high calcium content, rather than its isoflavone content.
Despite containing oxalate and phytate, 2 compounds that inhibit calcium absorption, the absorption of this mineral from fortified soy milk is quite good (51). The high bioavailability of calcium from soy milk is supported by the results of a 1-y intervention study in nearly 200 adolescent Chinese girls from Hong Kong aged 14–16 y, which found that supplementation with calcium-fortified soy milk (375 mL/d, 600 mg calcium) improved hip BMD relative to the control group who consumed their usual diet without supplementation (52). In contrast, no benefits were observed in an 18-mo intervention study in postmenopausal Chinese women, but in this case, the soy milk provided only 250 mg calcium/d (53). Also, no information about the bioavailability of the fortificant was provided.
The first clinical trial evaluating the effects of isoflavones on BMD in postmenopausal women was published in 1998 (54). Since then, the more than 25 clinical trials that have been conducted have produced mixed results as evidenced by the conclusions of 3 recently published meta-analyses (55–57). However, most trials were small in size and short in duration. Ideally, conclusions about skeletal benefits should be based on large, long-term studies. Three such studies in postmenopausal women, 2 in the United States (58, 59) and one in Taiwan (60), involving isoflavone supplements have been conducted. They were 2 or 3 y in duration and included between 200 and 400 women. Isoflavone intakes ranged from 80 to 300 mg/d. None of the trials found isoflavones to favorably affect hip or lumbar spine BMD. In addition to these 3 studies, a 2-y study by Vupadhyayula et al (61) in 203 postmenopausal women also failed to find that isoflavone-rich soy protein favorably affected lumbar spine, femoral neck, or total femur. A 2-y study in postmenopausal women (n = 403) also found that isoflavone supplementation was without effect, but because the intervention product was a supplement derived from soy germ, which, as noted has a different isoflavone profile than soy foods, the findings may not be relevant to soy foods (62).
There are several possible explanations for the differing results from the 2 Asian epidemiologic studies noted above and the clinical trials. It may be that the benefits of soy in the epidemiologic studies reflect lifelong intake, which contrasts with the 2- to 3-y intervention period in the clinical trials. It is also possible that components in soybeans other than isoflavones promote bone health, although there is no evidence in support of this possibility.