Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR-based genotyping of lactase gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis.Introduction: Lactase deficiency is a common autosomal recessive condition resulting in decreased intestinal lactose degradation. A Ϫ13910 T/C dimorphism (LCT) near the lactase phlorizin hydrolase gene, reported to be strongly associated with adult lactase nonpersistence, may have an impact on calcium supply, bone density, and osteoporotic fractures in the elderly. Materials and Methods: We determined LCT genotypes TT, TC, and CC in 258 postmenopausal women using a polymerase chain reaction-based assay. Genotypes were related to milk intolerance, nutritional calcium intake, intestinal calcium absorption, bone mineral density (BMD), and nonvertebral fractures. Results: Twenty-four percent of all women were found to have CC genotypes and genetic lactase deficiency. Age-adjusted BMD at the hip in CC genotypes and at the spine in CC and TC genotypes was reduced by Ϫ7% to Ϫ11% depending on the site measured (p ϭ 0.04). LCT (T/CϪ13910) polymorphisms alone accounted for 2-4% of BMD in a multiple regression model. Bone fracture incidence was significantly associated with CC genotypes (p ϭ 0.001). Milk calcium intake was significantly lower (Ϫ55%, p ϭ 0.004) and aversion to milk consumption was significantly higher (ϩ166%, p ϭ 0.01) in women with the CC genotype, but there were no differences in overall dietary calcium intake or in intestinal calcium absorption test values. Conclusion:The LCT (T/CϪ13910) polymorphism is associated with subjective milk intolerance, reduced milk calcium intake, and reduced BMD at the hip and the lumbar spine and may predispose to bone fractures. Genetic testing for lactase deficiency may complement indirect methods in the detection of individuals at risk for both lactose malabsorption and osteoporosis.
Pre-clinical data have shown that osteoprotegerin (OPG) inhibits osteoclast function and therefore plays an important role in bone remodelling. This study aimed to evaluate the clinical value of serum OPG. Do higher OPG serum levels reflect decreased bone resorption and perhaps higher bone mass in women? Serum OPG levels were measured in 177 healthy women (aged 17-85 years) and in 48 untreated patients (mean age 71 +/- 5) with established osteoporosis, and related to age, bone mass, markers of bone turnover and, in the case of patients with osteoporosis, to pre-existing vertebral fractures. In healthy women OPG levels showed a positive correlation with age (r = 0.25, p < 0.001) but not to bone mass or markers of bone turnover. In women with osteoporosis, however, there was a strong relationship between serum OPG and markers of bone turnover (serum c-terminal crosslinked telopeptides of thpe I collagen (sCTX): r = +0.82, p < 0.0001; osteocalcin (OC): r = +0.69, p < 0.0001), with patients who had higher levels of bone-turnover markers showing higher serum levels of OPG. After adjustment for bone mass and bone markers, patients with pre-existing vertebral fractures had significantly lower serum OPG levels than patients without fractures (57 +/- 8 vs. 97 +/- 10 pg/ml, [mean +/- SE], p < 0.01). The age-dependent increase of OPG as an antiresorptive factor may reflect an insufficient paracrine mechanism of bone cells to compensate for bone loss in older age. In patients with osteoporosis, however, OPG correlated strongly with markers of bone turnover; this may point toward a higher level of RANKL/OPG expression in these patients. Finally, low OPG serum levels seem to be associated with vertebral fractures. We hypothesise that low OPG levels in preset conditions of bone turnover may indicate a higher risk of fracture in patients with osteoporosis.
Both decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with HL to osteoporosis. Lactose-free calcium supplementation may help to maintain BMD in HL subjects.
The fact that individuals heterozygous for primary adult lactose intolerance (LCT -13910 ) show intermediate BMDs is indeed interesting, and on this point, we fully agree with Büning et al. In our results, we explicitly mentioned an "increasing, but not significant gene-dose effect" in nonvertebral fractures and low BMD for heterozygous subjects.(1)In fact, it has recently been shown that subjects heterozygous for the LCT -13910 polymorphism have reduced lactase activity (2) compared with homozygous lactose-tolerant subjects. However, the ratio of lactase/sucrase activity in this study was significantly higher in LCT -13910 heterozygous subjects than in homozygous lactose-intolerant individuals. This remaining activity is possibly sufficient for clinically unremarkable lactose maldigestion, but nonetheless, may exert effects on bone metabolism and osteoporosis risk over a longer period. The observation of decreased BMD in LCT -13910 heterozygous subjects, therefore, rather additionally supports than contradicts our conclusion that adult-type hypolactasia is associated with osteoporosis.The aversion to dairy nutrients and a consequently decreased calcium supply together with intestinal calcium malabsorption may well be the first and most important cause of an individually decreased calcium balance and risk for osteoporosis in lactose-intolerant subjects. However, we have increasing evidence that some of the effects of the LCT -13910 polymorphisms on bone size and stature might not be calcium dependent alone, because they persist after correction for calciotropic parameters (JBJ van Meurs and AG Uitterlinden, personal communication, 2004).(3) Thus, some of the regulatory aspects of the lactase phlorizin hydrolase (LPH) gene have to be assumed to be independent of a simple lactose intolerance effect per se.Furthermore, we have to consider several other environmental and genetic influences on calcium and lactose digestion that interfere with the LPH conditions, such as the vitamin D system. Our and other recent data show a strong influence of the vitamin D system on the severity and phenotypical consequence of lactose intolerance regarding bone, (3) which will be further analyzed.We have to state clearly that primary adult lactose intolerance is a condition that affects about one-half of the world's population. It has a severe impact on calcium supply and bone properties and should be kept in mind in every future human nutritional and pharmaceutical study in this field. The new possibility of an exact diagnostic tool for lactose intolerance using LCT -13910 genotyping will add further aspects to the discussion on consumption of dairy nutrients that is ongoing in the Journal, (4) because the intake of diary nutrients is directly influenced by the genetic disposition to lactose intolerance, at least in adults.Further investigations, including interventional studies, will be necessary to fully explain the role of lactase activity and lactose intolerance for osteoporosis.
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