Nutrition and bone: is there more to it than just calcium and vitamin D?

Bone mass, structure and turnover are the major determinants of our risk of osteoporosis‐related fractures and it is pertinent therefore to examine the influences on these. While it is clear that genetic factors play the dominant role,1 environmental influences have an effect, and their importance lies in the opportunity that exists to alter these with positive benefits on fracture risk. Primary among these environmental influences is what we eat. Many readers will assume that calcium and vitamin D are the major dietary influences on bone metabolism and fracture risk and while these may be important, they are certainly not the only potential dietary influences. It is feasible therefore that supplementation of other macro‐ or micronutrients may have value in influencing fracture risk, perhaps especially in those with specific genetic traits, a practical use of gene‐nutrient interaction. Of even more practical significance would be the opportunity to relate specific food groups to our risk of future fracture, giving a real opportunity for targeted nutritional advice. Since calcium is the most important mineral constituent of the skeleton, it is no surprise that its role in regulation of bone mass by supplementation has been the centre of much controversy.2–4 However, a systematic review in 1990 concluded that there was a positive influence of calcium supplementation on bone at all ages,5 a conclusion acknowledged in the 1998 Nutrition and Bone Health Report from the Department of Health.6 While calcium intake seems to have important influences on skeletal growth in children,7 adolescents,8 and even in the perimenopausal years when used in high doses,9 it is its potential role in the prevention of fracture in the elderly that has received most attention in recent years. Here the evidence for its efficacy is conflicting, primarily because supplementation has frequently included both calcium and vitamin D. In a four‐year study from New Zealand in 1995, Reid and colleagues10 showed that supplementation with 1000 mg/day without additional vitamin D significantly reduced symptomatic fractures, although the subject numbers were small. Dawson‐Hughes et al.11 showed in 1997 that only 700 mg/day of calcium reduced non‐vertebral fractures by just over 50% in men and women, albeit when given with 500 IU of vitamin D, although again the number of subjects studied was small. However, it is in the prevention of hip fractures that most interest in calcium has arisen. In 1992, Chapuy et al. demonstrated that 1200 mg supplemental calcium, combined with 800 IU vitamin D and given to the elderly residents of French nursing homes, reduced hip fractures by 30% after 18 months,12 an effect which was largely maintained at 3 years.13 Clearly these data suggest the possibility of an effect of either calcium or vitamin D, leading to continued controversy as to the role of dietary calcium, its supplementation and the recommended daily intake even in the 21st century.14–16 The major dietary sources of calcium intake in a British household are milk and milk products, cereals and bread, the latter due to fortification of flour. Moving on to other minerals, potassium is worthy of attention due to its role as a buffer for endogenous acid production. Potassium bicarbonate ingestion reduces urinary calcium excretion and improves calcium balance in healthy young adults17 and can both reduce bone resorption and increase formation in postmenopausal women.18 Work from our own group highlights the potential relationship between potassium intake and peak bone mass19 and bone turnover rates,20 and others have shown similar links in the elderly.21 The evidence for a role for sodium is not conclusive,22 although an increase in dietary sodium intake leads to an increase in urinary sodium and a consequent increase in urinary calcium loss. Phosphorus contributes about half the weight of bone mineral, and yet evidence linking its intake to bone health is inconsistent. Dietary calcium:phosphate ratio may have importance, with bone health dependent on a high ratio. If this is the case, the habitual consumption of carbonated drinks with their low calcium : phosphate ratio may have detrimental effects which have yet to be fully elucidated. However recent work has shown no association between dietary phosphorous and calcium absorption assessed repeatedly over a 20+ year period,23 albeit in nuns, whose consumption of carbonated drinks may be low. Although certain other trace elements such as zinc,24 copper, 24,25 manganese24 and magnesium26 are essential co‐factors in bone metabolism, their influence on bone health is uncertain, although our own work suggests a possible role for zinc and magnesium.19 Vitamin D has a clear role in the absorption of calcium from the gut and after metabolism to its active metabolite 1,25(OH)2D3, in the regulation of bone turnover. It arises both from the diet by metabolism of ergocalciferol (vitamin D2) and also by metabolism from its precursors in the skin (7‐dehydrocholesterol) in response to ultraviolet light. Conversion of naturally sourced vitamin D to the metabolically active 25(OH)D3 and 1,25(OH)2D3 takes place in the liver and kidney, respectively. The conversion mechanisms become less effective in the elderly, leading to secondary hyperparathyroidism, bone loss and consequent risk of osteoporosis.24 Recently it has become clear that the wavelength of UV light is critical in the production of 25(OH)D, and that in the northerly latitudes of the UK these wavelengths are only achieved between the beginning of April and the middle of October.6 Supplementation of 25(OH)D improves calcium absorption, lowers PTH levels and reduces wintertime bone loss in postmenopausal women.27 Prevention of hip and other limb fractures with vitamin D supplementation has met with conflicting results. In a 4‐year study by Heikinheimo et al.,28 substantial reductions in fractures were observed in elderly Finns given a single injection of vitamin D (150,000–300,000 IU), similar to the Chapuy study described above, with 800 IU per day.12,13 However, no differences were seen in elderly free‐living Dutch patients supplemented with 400 IU of vitamin D but without additional calcium.29 The vitamin‐K‐dependent proteins, osteocalcin and bone GLA‐protein, are important constituents of bone.22 A low dietary intake of vitamin K is associated with an increase in the proportion of under‐carboxylated osteocalcin,30 which in itself is a risk factor for hip fracture31 and may be reversible by vitamin K supplementation.32 Recent evidence has suggested that low intakes of vitamin K are associated with hip fracture in both women33 and men.34 The relationship between protein intake and bone health remains controversial. While increasing protein intake is associated with increasing losses of urinary calcium,35 and higher fracture risk,36 a more recent report showed a negative association protein intake and hip fracture risk.37 Although there is good evidence to show that genetic factors play an important role in determining peak bone mass, it is less clear whether genetic factors are important in predicting rates of bone loss,1,38 where environmental factors may have more of an influence. Allelic variants of the vitamin D receptor have been associated with bone loss in several studies, and this association has been found by some investigators to be dependent on dietary calcium intake.39–41 Our own studies on 726 peri‐ and early postmenopausal women have found that calcium helps reduce bone loss at the hip only for women with the bb genotype of the VDR BsmI polymorphism and not for BB homozygotes or Bb heterozygotes.42 There is evidence to suggest that polymorphisms of the oestrogen receptor alpha may also be associated with bone loss.43–46 The beneficial effect of modest intakes of alcohol for reducing bone loss47 has been observed in our cohort, with preliminary evidence suggesting that this effect only occurs in those women carrying the p allele of the ER PvuII polymorphism (unpublished). The potential for gene nutrient interactions being used to inform specific advice and therapy tailored to the individual is immense. Rather than focus on individual nutrients, an alternative way of investigating the effect of diet on disease is to study food patterns and food groups. Recently it has been suggested that a diet rich in fruit and vegetables may be associated with higher bone mass,19–21 although other food groups have not been examined. Dietary patterns could exert their influence through the nutrients contained in the foods (i.e. vitamins, minerals) or through other components in the foods such as acid load, antioxidants or even phytoestrogens. There is clearly a need for appropriate supplement studies to be initiated with fruit and vegetables, as has been done with milk in adolescent girls, with positive effects on bone mass.48 Whether future studies will enable targeting of specific food based on the presence of genetic risk factors remains speculative at present.