Invited Symposium: Regulators of Skeletal Growth and Integrity in Health and Disease
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Introduction
Both genetics and environmental factors influence skeletal growth and thereby the so-called peak bone mass (PBM), a variable corresponding to the amount of bony tissue present at the end of skeletal maturation. PBM is an important determinant of osteoporotic fracture risk, since the mass of bony tissue present at any time during adult life is the difference between the amount accumulated at maturity and that lost with aging. Hence, it is of major interest to explore ways of increasing PBM. Epidemiological studies indicate that an increase by 10% of PBM in the female population would decrease the risk of fragility fracture by 50%. Such an increase would roughly correspond to the difference between male and female PBM as measured at the level of either radial or femoral diaphysis.
As a first step toward the objective of increasing PBM, it appears essential to understand how bone mass evolves during development and to identify the key factors that influence its accumulation rate. Before puberty, no substantial sex difference in bone mass of either the axial or appendicular skeleton has been reported. There is no evidence for a gender difference in bone mass at birth. Likewise, the volumetric bone mineral density appears to be also similar between female and male newborns. This absence of a substantial sex difference in bone mass is maintained until the onset of pubertal maturation. During puberty the gender difference in bone mass becomes expressed. This difference appears to be mainly due to a more prolonged bone maturation period in males than in females, with a larger increase in bone size and cortical thickness. Puberty affects much more the bone size than the volumetric mineral density (Gilsanz et al.,1994). There is no significant sex difference in the volumetric trabecular density at the end of pubertal maturation. During puberty, the accumulation rate in areal BMD at both the lumbar spine and femoral neck increases four to six fold over a 3- and 4-year period in females and males, respectively. The change in bone mass accumulation rate is less marked in long bone diaphysis. At the beginning of the third decade, there is a large variability in the normal values of areal BMD in axial and appendicular skeleton. This large variance, which is observed at sites particularly susceptible to osteoporotic fractures such as lumbar spine and femoral neck, is barely reduced after correction for statural height, and does not appear to substantially increase during adult life. The height-independent broad variance in bone mass which is already present before puberty appears to increase further during pubertal maturation at sites such as lumbar spine and femoral neck.
Bone Mass Accumulation
Many factors, more or less independent, are supposed to influence bone mass accumulation during growth. The list of these determinants classically includes: heredity, sex, dietary components (calcium, proteins), endocrine factors (sex steroids, calcitriol, insulin-like growth factor-I (IGF-I)), mechanical forces (physical activity, body weight), and exposure to risk factors.
Over the last 10 years numerous data have been published on the relationship between calcium intake and bone mass acquisition during childhood and adolescence. Among observational studies some but not all sustain the notion that increasing the calcium intake would promote a greater bone mass gain, and thereby a higher peak bone mass. Obviously, only prospective intervention studies allow us to determine to what extent calcium supplementation can influence bone mass growth and investigate, in case of a positive response, how such an intervention may interfere with the processes of bone formation and resorption. Only a few prospective randomized, double-blind, placebo-controlled intervention trials have examined the effects of calcium supplements in children and adolescents. Overall they indicate that calcium supplementation can increase bone mass gain, although the magnitude of the calcium effects appears to be highly variable. Indeed, the response to calcium supplementation appears to vary according to the skeletal sites examined, and the stage of pubertal maturation at the time of the intervention.
Other factors may influence the response to calcium supplementation. It is possible that the type of response observed at various skeletal sites may also depend upon the chemical composition of the calcium salt. As described below, our own recent prospective randomized, double-blind, placebo-controlled study in prepubertal girls indicates that the spontaneous calcium intake is an important determinant of the magnitude of the response. It also suggests that the calcium effect could be modulated by an interaction with the vitamin D receptor genotype.
Study Findings
Initial non-interventional studies carried out in children and adolescents allowed us to examine cross-sectionally and then longitudinally the relationship between skeletal growth and some putative determinants of peak bone mass, such as pubertal maturation, nutrition, physical exercise and genetics. The nutrient intakes were assessed by two five-day diaries in about 200 female and male subjects aged 9-19 years. The tight relationship found between the energy intakes and the number of weekly hours spent in physical activity provides an estimate of the good reliability of the diary method used in this study. As expected, the calcium intake was significantly larger in boys than in girls at any pubertal stage. In the whole cohort that included subjects of both sexes from Tanner stage P1 to P5, the gain in bone mass as assessed by dual energy X ray absorptiometry (DXA) in determining the areal bone mineral density (BMD) or content (BMC) at spinal and femoral levels, was not statistically significant after adjusting for sex, age and/or pubertal stage. The same negative result was obtained with the P2-P4 subgroup. However, a positive relationship between calcium intake and bone mass accrual was obtained in the prepubertal (P1) boys and girls. At the lumbar spine (L2-L4) level of P1 subjects the association was significant not only for the gain in BMC and BMD, but also for that of the bone area, suggesting a positive effect on bone size. Interestingly, the pattern of the relationship between calcium and the gain in standing height was similar to that of the L2-L4 BMC, BMD and area, i.e. significant in P1 but not in the whole cohort or in the P2-P4 subjects. Note that the protein intake was also associated with bone mass acquisition in prepubertal female and male subjects, even after adjustment for calcium intake.
Overall, these observational studies suggested that calcium supplementation before puberty could be particularly effective for stimulating bone mass gain. And furthermore, that in prepubertal children the calcium effect on bone mass could be mediated, at least in part, by an increase in bone size and longitudinal growth. A 3 year interventional study in identical twins by Johnston et al. (1992) indicated that calcium supplementation was effective in children who remained prepubertal. However, the twins who went through puberty or were postpubertal displayed no benefit. In another co-twin study carried out in adolescents with a mean age of 14 years of which 74% had already achieved menarche, a small but significant effect of calcium supplementation was observed after 6, but not after 18 months (Nowson et al., 1997).
Recently, we examined the effects of calcium supplements on bone mass accrual at various sites of the skeleton in prepubertal girls. With the objective of increasing calcium intake at the population level, a set of calcium-enriched foods were used rather than a single pharmaceutical calcium supplement. In our double-blind, placebo-controlled study (Bonjour et al., 1997), 149 healthy prepubertal girls aged 7.9±0.1 yrs (mean±SEM, range 7-9 yrs) were randomly allocated to receive, on a daily basis, one set of two food products containing or not (placebo) 850 mg of milk extracted calcium, for one year. The food products contained the same amount of energy and proteins. Bone mineral content (BMC), areal bone mineral density (BMD) and bone size were determined by dual-energy X-ray absorptiometry after one and two years.
The two groups were similar at baseline in terms of age, statural height, body weight, BMD/BMC at all sites, and of spontaneous calcium intake. Among the girls who completed the 12-month intervention study (active-treatment cohort, n=108), BMD gains at radial (metaphysis and diaphysis) and femoral sites (neck, trochanter and diaphysis), but not at the lumbar spine level, were 7 to 12 mg/cm2/yr significantly greater in the calcium-supplemented group (n=55) than in the placebo group (n=53). The difference in BMD gains between the calcium-supplemented and placebo groups was greater in girls with a spontaneous calcium intake below the median of 880 mg/day (mean BMD gain of the 6 sites: 30plusmn;3 vs 19±3 mg/cm2/yr, p=0.01, and 28±2 vs 23±2, p < 0.1 in spontaneously low and high calcium consumers, respectively). The increase in mean BMD of the 6 sites in the low calcium consumers was accompanied by significantly (p< .05) greater gains in both mean BMC and bone area. Examination of the changes in scanned bone area and in standing height suggests that calcium supplementation, as provided in our study, could affect bone modeling. Indeed, in the group of spontaneously low calcium consumers, calcium-enriched foods enhanced the gain of both mean scanned bone area and statural height to the level achieved by the spontaneously high calcium consumers. Morphometric analysis of the changes observed in the lumbar spine and in femoral diaphysis suggests that calcium could enhance both the longitudinal and the cross-sectional growth of the bones. Part of the difference in bone mass and bone size was still present one year after the end of the intervention study. Thus, this study suggests that milk calcium supplementation may affect not only the remodeling but also the modeling of the skeleton. This possiblity is in agreement with a recent report indicating that milk supplementation in adolescent girls is associated with an increase in both BMD and bone area (Cadogan et al., 1997)
In these prepubertal girls, we also observed a statistically significant association between the polymorphisms of the vitamin D receptor (VDR) gene and the baseline values of both spinal and femoral BMD (Ferrari et al.,1998). Note that we did not find this association in a cohort of premenopausal women, a large majority of them were the mothers of these prepubertal girls. Interestingly, in the girls who had the VDR genotype "BB", the calcium supplementation appeared to increase the bone mass gain up to the level of those having the "bb" VDR genotype. Such a differential response suggests an interaction between VDR genotype, calcium metabolism, and bone mineral mass accrual. These results could in fact explain the discrepant results regarding the association between VDR genotype and bone mass in adult subjects, since environmental factors such as dietary calcium could abolish the genetic difference in the potential to achieve peak bone mass. Whether VDR genotype would influence bone mass accrual in response to calcium supplementation by affecting more the modeling than the remodeling process remains to be determined.
Conclusions
In conclusion, our results suggest that the intake of milk calcium enriched food by girls having a spontaneously low consumption of dairy products could be considered as an approach to increase peak bone mass. The skeleton appears to be particularly responsive to calcium supplementation before pubertal maturation. This might hold true for other environmental determinants of PBM, since a recent report from Bass et al. (1998) also suggests that the prepubertal years are likely to be an opportune time for exercice to increase bone mass gain.
References
- Bass et al. (1998) J. Bone Miner. Res.13:500-507.
- Bonjour et al. (1997) J. Clin. Invest. 99:1287-1294.
- Cadogan et al. (1997) Br. Med. J. 315:1255-60.
- Ferrari et al. (1998) J. Bone Miner. Res.13: 363-370.
- Gilsanz et al. (1994) Radiology 190: 673-677
- Johnston et al.(1992) N. Engl. J. Med. 327:82-87.
- Nowson et al.(1997) Osteoporosis Int. 7:219-225.
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