[Fetal programming and the etiology of osteoporosis]. / Programowanie plodowe a etiologia osteoporozy.

Osteoporosis is a multifactorial skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in increased risk of fracture. Peak bone mass is an important predictor of later risk of osteoporosis. Epidemiological studies revealed that the risk of osteoporosis might be modified by exposure to environmental factors during intrauterine life and early postnatal period. This review summarizes the influence of fetal programming on the development of osteoporosis based on the epidemiological studies and potential mechanisms of epigenetic regulation of gene expression.

Programming of osteoporosis and impact on osteoporosis risk.

Osteoporosis is a skeletal disorder characterized by reduced bone quantity and quality and an increased susceptibility to fracture, and seems to be one of many chronic conditions that might be influenced by events early in life. Specifically, there is growing evidence of an interaction between the genome and the environment in the expression of the disease.

Epigenetic influences in the developmental origins of osteoporosis.

Osteoporosis is a major public health problem due to consequent fragility fractures; data from the UK suggest that up to 50% of women and 20% men aged 50 years will have an osteoporosis-related fracture in their remaining lifetime. Skeletal size and density increase from early embryogenesis through intrauterine, infant, childhood and adult life to reach a peak in the third to fourth decade. The peak bone mass achieved is a strong predictor of later osteoporosis risk. Epidemiological studies have demonstrated a positive relationship between early growth and later bone mass, both at peak and in later life, and also with reduced risk of hip fracture. Mother-offspring cohorts have allowed the elucidation of some of the specific factors in early life, such as maternal body build, lifestyle and 25(OH)-vitamin D status, which might be important. Most recently, the phenomenon of developmental plasticity, whereby a single genotype may give rise to different phenotypes depending on the prevailing environment, and the science of epigenetics have presented novel molecular mechanisms which may underlie previous observations. This review will give an overview of these latter developments in the context of the burden of osteoporosis and the wider data supporting the link between the early environment and bone health in later life.

Does birthweight predict bone mass in adulthood? A systematic review and meta-analysis.

SUMMARY: This systematic review and meta-analysis assessed the strength and magnitude of the association between birthweight and adult bone mass. Higher birthweight was associated with higher bone mineral content of the spine and hip in adult men and women at ages between 18 and 80 years across a range of settings. INTRODUCTION: The aim of this review was to assess the strength and magnitude of the association between early size and adult bone mass. METHODS: Systematic review and meta-analysis of studies that assessed the association between birthweight or weight at 1 year, and bone mineral content (BMC) or bone mineral density (BMD) in adulthood. RESULTS: Fourteen studies met inclusion criteria. Nine assessed the relationship between birthweight and lumbar spine BMC, most showing that higher birthweight was associated with greater adult BMC. Meta-analysis demonstrated that a 1 kg increase in birthweight was associated with a 1.49 g increase in lumbar spine BMC (95% CI 0.77-2.21). Birthweight was not associated with lumbar spine BMD in 11 studies. In six studies, considering the relationship between birthweight and hip BMC, most found that higher birthweight was associated with greater BMC. Meta-analysis demonstrated that a 1 kg increase in birthweight was associated with a 1.41 g increase in hip BMC (95% CI 0.91-1.91). Seven studies considered the relationship between birthweight and hip BMD and, in most, birthweight was not a significant predictor of hip BMD. Three studies assessing the relationship between weight at 1 year and adult bone mass all reported that higher weight at one was associated with greater BMC of the lumbar spine and hip. CONCLUSIONS: Higher birthweight is associated with greater BMC of the lumbar spine and hip in adulthood. The consistency of these associations, across a range of settings, provides compelling evidence for the intrauterine programming of skeletal development and tracking of skeletal size from infancy to adulthood.

Birth weight and adult bone mass: a systematic literature review.

SUMMARY: This systematic literature review comprised 16 studies. The association of birth weight with bone parameters was much more evident for bone mineral content (BMC) rather than bone mineral density (BMD). This is an important finding since a reduction in BMC is strongly associated with an increased risk of fractures. INTRODUCTION: The purpose of this study was to conduct a systematic literature review of studies that have investigated the association between birth weight (BW) and adult bone mass. METHODS: The search included English language articles, indexed in MEDLINE, using the key words: ("birth size" OR "birth weight" OR birthweight) AND (osteoporosis OR "bone mass" OR "bone density" OR "bone mineral density" OR "bone mineral content" OR "bone area"). A methodological quality appraisal of the reviewed studies was performed. RESULTS: Sixteen articles were reviewed. Eleven of 13 studies that measured BMC verified a positive effect of BW on this parameter, and nine even after adjustment for adult body size. Among the ten studies that found an unadjusted association between BW and BMD, two reported that the significance remained after adjustment for current body size. Interaction between prenatal and postnatal variables on the determination of adult bone mass was only tested by two studies. The results must be interpreted with caution due to the existence of few papers on the issue, as well as heterogeneous sample characteristics, investigated bone sites, and implemented analysis procedures. The aspects of methodological quality that frequently fail are as follows: representativeness of the planned and actually measured sample as well as proper adjustment for confounding. CONCLUSION: Based on the amount of accumulated evidence, it is probable that BW have a positive association with adult BMC rather than BMD, which is an important finding for clinical and public health policies since a reduction in BMC is strongly associated with an increased fracture risk.

Intrauterine programming of bone. Part 2: alteration of skeletal structure.

UNLABELLED: Osteoporosis is believed to be partly programmed in utero. Rat dams were given a low protein diet during pregnancy, and offspring were studied at different ages. Old aged rats showed site-specific strength differences. In utero nutrition has consequences in later life. INTRODUCTION: Epidemiological studies suggest skeletal growth is programmed during intrauterine and early postnatal life. We hypothesize that age-related decrease in bone mass has, in part, a fetal origin and investigated this using a rat model of maternal protein insufficiency. METHODS: Dams received either 18% w/w (control) or w/w 9% (low protein) diet during pregnancy, and the offspring were studied at selected time points (4, 8, 12, 16, 20, 47, 75 weeks). RESULTS: Using micro-CT, we found that at 75 weeks of age female offspring from mothers fed a restricted protein diet during pregnancy had femoral heads with thinner, less dense trabeculae, femoral necks with closer packed trabeculae, vertebrae with thicker, denser trabeculae and midshaft tibiae with denser cortical bone. Mechanical testing showed the femoral heads and midshaft tibiae to be structurally weaker, whereas the femoral necks and vertebrae were structurally stronger. CONCLUSIONS: Offspring from mothers fed a restricted protein diet during pregnancy displayed significant differences in bone structure and density at various sites. These differences result in altered bone characteristics indicative of significantly altered bone turnover. These results further support the need to understand the key role of the nutritional environment in early development on programming of skeletal development and consequences in later life.

Review: developmental origins of osteoporotic fracture.

Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-related bone loss and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterised in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content (BMC), but not volumetric bone density, than girls. Furthermore, there is a dissociation between the peak velocities for height gain and bone mineral accrual in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors such as cigarette smoking. In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birth weight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of pituitary-dependent endocrine systems such as the HPA and GH/IGF-1 axes. Maternal smoking, diet (particularly vitamin D deficiency), and physical activity also appear to modulate bone mineral acquisition during intrauterine life; furthermore, both low birth size and poor childhood growth are directly linked to the later risk of hip fracture. The optimisation of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.

Epidemiology of osteoporotic fracture: looking to the future.

This paper reviews the recent literature on candidate genes, anthropometric and environmental factors, and the evolving area of intrauterine fetal programming with regard to the development of osteoporosis.

Association of birth weight with osteoporosis and osteoarthritis in adult twins.

OBJECTIVES: Twin studies present a unique opportunity to examine the association of birth weight with adult life phenotypes in a design that naturally accounts for maternal factors and a range of early environmental factors, which might potentially bias the association. In this study, we explored the association of birth weight with osteoporosis (OP) and osteoarthritis (OA), in a large national cohort of female twins. METHODS: Intra-pair differences between the reported birth weight of the twins (n=4008) were examined for an association with: (i) intra-pair differences in bone mineral density (BMD) and bone mineral content (BMC) at the lumbar spine, hip and forearm using linear regression; and (ii) osteoarthritis status in pairs discordant for radiographic disease at the hand, hip and knee using matched logistic regression. The confounding influences of height and weight were taken into account. RESULTS: The mean age of the twins was 47.5+/-12.3 yr. Intra-pair differences in birth weight were significantly associated with BMD at the spine (P=0.047), total hip (P=0.016) and femoral neck (P<0.001), but not at the forearm (P=0.245). These were entirely explained by the birth weight association with height and weight. The associations of intra-pair differences in birth weight and BMC were highly significant (P<0.001) at all sites, but were partly explained by adjustment for adult height and weight. We found no clear association between intra-pair birth weight differences and OA in twins discordant for any of the radiographic OA phenotypes at any site. CONCLUSIONS: Bone mass and especially BMC are highly associated with birth weight. These associations are accounted for mainly by environmental factors that are independent of maternal factors such as gestational age, maternal smoking and nutrition, and are largely mediated by skeletal size and particularly adult height. Birth weight does not appear to be a major influence on the later development of radiographic OA in women.