Jean-Philippe Bonjour

Gain in bone mineral mass in prepubertal girls 3–5 years after discontinuation of calcium supplementation: a follow-up study

BACKGROUNDnCalcium supplementation during childhood and adolescence increases bone-mass accrual. Whether or not this benefit persists after discontinuation of supplementation is not known. We previously showed a favourable effect of milk-extracted calcium phosphate incorporated in various foods on accumulation of bone mineral mass in 8-year-old girls. We now report the results of a follow-up study undertaken more than 3 years after the end of calcium supplementation.nnnMETHODSnAnthropometric and bone variables were measured in 116 of the 144 girls whose data had been studied at the end of the supplementation period. The mean time elapsed between the end of the intervention period and this follow-up measurement was 3.5 years. Areal bone mineral density was measured by dual-energy X-ray absorptiometry at the same six skeletal sites as those studied during the intervention phase.nnnFINDINGSnWe were able to remeasure 62 and 54 girls of the calcium-supplemented and placebo groups, respectively. The increase from baseline in the overall mean bone mineral density of the six skeletal sites was still highly significant (calcium-supplemented group 179 mg/cm(2) [SE 8] vs placebo group 151 mg/cm(2) [7], p=0.012). A significant difference in favour of the supplemented group was also seen with respect to mean bone mineral content (p=0.031) and mean bone area (p=0.04). Difference in pubertal maturation did not seem to account for the recorded differences.nnnINTERPRETATIONnOur results suggest that this form of milk-extracted calcium phosphate taken during the prepubertal period can modify the trajectory of bone mass growth and cause a long-standing increase in bone mass accrual, which lasts beyond the end of supplementation.

Protein Intake and Osteoporosis

The amount of bone present at a given age is determined by the mass acquired during growth (the so-called peak bone mass) and by the subsequent rate of bone loss. The attainment of peak bone mass appears to be highly affected by the state of protein supply and intake during childhood and adolescence. Indeed, in childhood and adolescence, the need for protein is increased to meet the demand required by body growth. For instance, in animal studies, rats treated with growth hormone spontaneously select a high protein diet (1). Thus, during growth, the adaptation to lower protein intake should be much more difficult than later on in life. Protein undernutrition results in a reduction of height, weight, and overall body protein (2). The recommended daily allowance for protein varies between 2.0 in children to 1.0 in adolescents, and 0.75 g/kg per day in adults (3). On the other hand, a sufficient protein intake is also mandatory for the maintenance of bone homeostasis in the elderly. Indeed, malnutrition can be considered as a risk factor for hip fracture because it can be expected to accelerate age-dependent bone loss, to increase the propensity to fall by impairing movement coordination, to affect protective mechanisms, such as reaction time and muscle strength, and thus to reduce the energy required to fracture an osteoporotic proximal femur.

CHAPTER 20 – Physiology of Calcium and Phosphate Homeostases

Calcium and phosphate play prominent roles in the regulation of cell function. Calcium and phosphate homeostasis are controlled by bidirectional calcium and phosphate fluxes, occurring at the levels of intestine, bone, and kidney. The latter organ plays a central role in regulating the extracellular concentration of either ion. Sensitive and efficient regulatory mechanisms, involving extracellular calcium sensing, are triggered by changes in calcium demand or supply. Similarly, the renal handling of phosphate can adjust its capacity to meet the need for phosphate of the organism. Not only calciotropic peptides or steroid hormones are capable of modifying the different calcium and phosphate fluxes to various extents, but also a variety of local factors are implicated in the regulation of calcium and phosphate homostasis, to protect the organism against a deficiency or an overload. Finally, by directly influencing renal tubular calcium and phosphate transports, or by releasing calcium from intracellular stores, calcium itself plays the role of an effector on homostatic mechanisms.

Vitamin D Receptor Gene Polymorphisms and Bone Mineral Homeostasis

Osteoporosis is a systemic skeletal disease characterized by a reduced bone mineral mass and a deterioration of bone tissue microarchitecture, with a consequent increased bone fragility and a higher risk of fracture (1). The latter also depends on factors unrelated to bone mineral mass itself. In the search for “osteoporosis genes,” it is important to keep in mind that bone mineral mass is a complex notion that maybe variably appreciated by different techniques. Actually, various parts of the skeleton are characterized by different proportions of spongious and compact bone, and thereby by different turnover rates. Whole body bone mineral mass can be measured. For this purpose, a variety of techniques based on the attenuation by bony tissue of either a photon radiation (dual X-ray absorptiometry [DXA], single photon absorptiometry [SPA] or ultrasonic energy) have been used. X-ray attenuation-based methods provide information on bone mineral content (BMC, in grams of hydroxyapatite equivalent) and areal bone mineral density (aBMD, in grams of hydroxyapatite equivalent per unit of bone scanned area). The latter integrates the notion of bone mineral mass and an adjustment for outer bone dimensions as determined in a plan perpendicular to the radiation beam direction (2). Besides, volumetric bone mineral density (grams per cubic square of bone tissue) can be assessed by quantitative computerized tomography (QCT), or indirectly estimated from results obtained with the DXA technology. Consequently, although it is presently unknown whether the same set of genes influences both cortical and spongious bone, the association of a single gene locus, which can by essence determine only one bone mineral mass constituent, with any of the measures of “bone mass” defined previously, will be burdened by a degree of imprecision proportional to the number and magnitude of genetic effects on the other constituents of bone mineral mass.

Nutrition and Insulin Growth Factor-I in Relation to Bone Health and Disease

At the skeletal level, IGF-I exerts a positive effect on bone mineral mass by a direct action on osteogenic cells. n n nAt the kidney level, IGF-I enhances both the renal reabsorption of inorganic phosphate (Pi) and the production of calcitriol, the hormonal form of vitamin D that stimulates the intestinal absorption of calcium and Pi, the two main bone mineral elements. n n nProtein undernutrition reduces IGF-I production, decreases skeletal acquisition during growth, and accelerates bone loss during adulthood. n n nThe stimulation of bone formation in response to IGF-I is impaired in presence of an inadequately low intake of proteins. n n nProtein undernutrition, probably by influencing negatively IGF-I production and action, contributes to the pathogenesis of osteoporotic fractures in elderly.

Undernutrition and osteoporosis

Undernutrition, particularly protein undernutrition, contributes to the occurrence of osteoporotic fracture, by lowering bone mass and altering muscle strength. Furthermore, the rate of medical complications after fracture can also be increased by nutritional deficiency. The IGF-I system appears to be directly involved in the pathogenetic mechanisms leading to osteoporotic hip fracture in the elderly and to its complications. In the presence of adequate calcium and vitamin D supplies, protein supplements increasing the intakes from low to normal, raise IGF-I levels, improve the clinical outcome after hip fracture, and attenuate the decrease in proximal femur bone mineral density in the year following the fracture. This nutritional approach is associated with a significant reduction of the stay in rehabilitation hospital. This underlines the importance of nutritional supports in preventing and healing osteoporotic fractures.

Genetics—Dietary Calcium Interaction and Bone Mass

Postmenopausal and age-related bone losses have long been recognized as major determinants of the risk for osteoporotic fractures. More recently, the importance of optimizing peak bone mass, which is achieved by the end of puberty (1, 2), to prevent the detrimental effects of later bone loss has been emphasized (3). A number of issues, however, are unclear in this regard, such as knowing to what extent the attainment of peak bone mass can be modified by external factors. Indeed, peak bone mass appears to be under strong genetic determination (4). Similarly, it is still not firmly established when during the course of skeletal growth these genetic factors are intervening or how much of the apparent heritability for bone mass is truly attributable to genetic effects. On the other hand, prospective studies showing significant alterations of the spontaneous bone mass growth through dietary or life-style interventions are rather limited. Besides, there are no available data concerning the potential influence of genetics—environment interactions on bone mass accrual during growth.