Invest in your bones

How diet, life styles and genetics affect bone development in young people 

Introduction

The world is facing an osteoporosis epidemic.

Every 30 seconds, someone in the European Community has a fracture as a result of osteoporosis. The number of hip fractures (actually a fracture of the head of the femur in the thigh) is expected to double in the next 20 years due to increasing population and increased life expectancy. According to Gro Harlem Brundtland, director general of the World Health Organization, the greatest increase in osteoporosis will take place in the developing world.

Obviously osteoporosis is widespread, and as the world’s population ages, more and more people will suffer from this debilitating, and sometimes fatal, disease. Therefore it is essential to develop a worldwide strategy for osteoporosis management and prevention. But the general public poorly understands whether osteoporosis can be prevented. One of the best preventive measures to avoid later-in-life osteoporotic fractures is to build up the strongest bones possible during childhood and adolescence. Healthy adults generally reach their peak bone mass by age 20. It is estimated that a 10% increase of peak bone mass reduces the risk of an osteoporotic fracture during adult life by 50%. 

Thus, an efficient way of preventing osteoporotic fractures occurring in the second half of life is to build up the strongest bones possible during the juvenile periods when rapid bone growth occurs, thereby achieving maximum bone mass by the end of the teen years. 

Is there a key age at which bone development takes place?

Bones are living tissue, and the skeleton grows continually from birth to the end of the teen years, reaching a maximum strength and size around the age of 20. Some ages are particularly important for accelerated growth of the skeleton.  

The first period of rapid bone growth occurs from birth to two years. A second period of rapid bone growth corresponds to the years of puberty, when sexual maturation takes place, roughly from age 11 to 14 in girls and 13 to 17 in boys. During puberty, the speed of building up bones in the spine and hip increases by approximately five times.

In girls, the bone tissue accumulated during the ages 11 to 13 approximately equals the amount of bone lost during the 30 years following menopause. However, preventive measures should not be concentrated only on these periods of accelerated bone growth. Indeed the skeleton appears to respond quite well to changes in the intake of calcium or in the degree of physical activity during the years preceding the period of sexual maturation.

During growth the gain in bone mineral mass is mainly due to an increase in bone size with very little change in bone density, i.e. in the amount of bone tissue within the bones. Just because a child is growing tall, this does not mean that his or her bone mass is growing at a sufficient rate. 

What role does gender play in bone growth? 

From birth to the onset of the sexual maturation, the bone mineral mass at any given age is the same in girls as in boys. During puberty bone mass increases more in boys than in girls.

This difference appears to mainly due to a more prolonged period of accelerated growth in males than in females, resulting in a larger increase in bone size and thickness of the cortical shell of the bones.

Note that form birth to the end of the growth period there is no gender difference in the density of the spongious bone which is found beneath the harder cortical shell. 

What proportion of bone mass comes from genetics, what proportion from life style? 

Many factors can influence bone mineral mass accumulation from life to the end of the teen years, and thus account for the marked difference of peak bone mass between individuals. At the end of puberty, in healthy individuals of the same sex, same age and having the same height, the difference in the amount of bone contained in the lumbar spine can vary by factor of two. For example, one sexually mature, 165cm tall girl might have 10 grams of bone mineral in one lumbar vertebrae while a physically similar girl of the same age might have 20 grams. Why does this surprisingly large variation exist? Certainly it is due to genetics as well as life style determinations, such as nutrition, physical activity and risk factors, but the relative importance of each variable is unclear. 

Comparison either between parents and children or between monozygotic and dizygotic twins suggest that genetics accounts for 60 to 80% of the variability in individual peak bone mass. The hereditary transmission of bone mass is very likely dependent upon several genes which have not been yet identified, but which are being intensively searched for in several research centers throughout the world. However, environmental factors such as nutrition and exercise and exercise may be underestimated when calculating the role of genetics. 

What is the influence of diet? 

Calcium

Calcium is essential for healthy  bone development, and increasing the calcium intake in children and adolescents increases bone growth. The benefit of increasing the calcium intake is greater in the shaft of the long bones in arms and legs than in the spine. The skeleton appears to be more responsive to calcium supplementation before the onset of puberty has started. Milk and other dairy products are the most abundant source of calcium. Are children getting enough calcium? Increasingly they are not, and in some countries there is widespread concern about the decrease in the consumption of dairy products. 

What is the reason for this decrease?

This trend may be related to the fact that many children do not have a proper breakfast, with its traditional variety of calcium-rich foods. The reasons are an increasingly fast-placed life and the independent life styles of different people in a family. Also, children increasingly drink soft drinks during meals and snacks instead f milk products. Another factor is that many children, particularly teenage girls, believe that diary products ar high in fat content and that eating too many dairy products will lead to obesity. Of course this is related to a perception, particularly among girls, that skinny is beautiful. Besides being of debatable aesthetics, an obsession with thinness can lead to eating disorders, such an anorexia, which can in turn damage a girl’s skeleton. Eating disorders often are associated with cessation of menstrual periods, with a corresponding decrease in estrogen levels. Since estrogen in girls is essential in growing bone tissue, a girl who suffers amenorrhea (an unnatural cessation of menstruation not due pregnancy) is likely to suffer reduced bone growth. For those who refuse or cannot consume dairy products there are available alternatives such as calcium-enriched foods which can be prescribed by dieticians or pediatricians. 

Vitamin D

Vitamin D is essential for bone growth and health at all ages, because vitamin D helps the body absorb ingested calcium and to deposit the calcium, with phosphate, into the skeleton. One natural source of vitamin D is exposure to sunshine.

When exposure to natural sunlight is insufficient (for example, when babies are kept indoors), it is essential to supplement infants with approximately 400 I.U.of vitamin D per day. A failure to ensure a normal supply of vitamin D, either by sunshine exposure or by oral supplementation, may jeopardize the building up of strong.

Proteins

In addition to calcium, protein plays a key role in bone mass acquisition. During growth, under-nutrition, including insufficient caloric intake and protein, can severely impair bone development. Low protein intake can be detrimental for skeletal integrity by lowering both the production and action of a growth factor, IGFI, which enhances bone formation. In addition this growth factor stimulates both the intestinal absorption of the bone mineral elements, calcium and phosphate, via an increase in the renal production of calcitriol, the hormonal form of vitamin D. Therefore, during growth and pubertal maturation, an impaired production and/or action of IGF-1 due to a low protein intake may result in reduced bone development. This is why we find a positive correlation between protein intake and bone mass gain in children.

What is the influence of sport and exercise?

Young bones respond more to exercise than do adult bones.

The most effective exercise is weight-bearing exercise-walking, gymnastics, aerobics, ball games, competitive sports, dancing and children and adolescents who exercise regularly show significant increase in bone mass.

Interestingly, the increased bone mass that results from intense physical activity, training for competitive sports, during childhood and adolescence is maintained in young adults even after training slows down or ceases completely. 

Too much exercise, particularly among girls, can harm bone growth, particularly when intensive physical activity is accompanied by loss of body weight and reduced sexual hormone production that leads to the cessation of menstruation. Obviously, most young people do not engage in intense physical activity at a high competitive level. So how much exercise is enough?

Moderate exercise programs in schools increase the bone mass gain of children. It is still not clear which moderate exercises are most effective for developing bone a different sites of the skeleton.

On the one hand it is certain that bone, like muscle, can become stronger in response to more or less moderate physical stress. On the other hand, the increasingly attraction of television, video games or surfing on the internet promotes a sedentary life style which does not favor the optimal development of bone mass and strength during childhood and adolescence. 

What is the impact of smoking, coffee, and soft drinks? 

Tobacco

Over the last ten years tobacco use among adolescents has increased substantially in several countries, particularly in female teenagers. Smoking may affect the attainment of peak bone mass, particularly when it is associated with other health risk behavior such as inadequate nutrition and low physical activity. However, the greatest concern is the fact that cigarette use during adolescence increases the risk of continued and heavy smoking during adulthood. In adult female smokers bone mineral mass is reduced and the risk of hip fractures is increased. The same increased risk also exists in men. Therefore, avoiding tobacco use during adolescence is an efficient way of reducing the risk of osteoporotic fractures as well as preventing other health problems in later life. 

Alcohol

There is little information on the influence of alcohol on peak bone mass attainment in young people. In adult men and women excessive alcohol consumption is associated with   a decrease in bone formation. Hence, it can be predicted that alcohol will also exert a negative effect on bone mass development during adolescence. 

Coffee

There is no evidence that caffeine consumed in a reasonable amount impairs bone mass acquisition during adolescence. 

Soft drinks

It has been suggested that low peak bone mass results from the excessive consumption of soft drinks because of the high phosphate content of carbonated cola beverages. There is no scientific evidence that supports this claim. However, soft drinks are not necessarily good for bone health, and any negative influence of soft drinks on the acquisition of peak bone mass is probably related to the associated low consumption of calcium-rich beverages, the so-called “milk-displacement effect”. 

Body weight and bone health

Excessive leanness in adolescence leads to a low peak bone mass. It is not clear whether obesity during childhood and adolescence either impairs or favors bone mass gain. 

What other research needs to be done? 

In order to establish scientifically based recommendations, additional research is needed on the impacts of nutrition and physically activity on peak bone mass and strength. Particularly it will be important to determine, by well designed studies carried out at various ages during childhood and adolescence with a follow up period till the end of skeletal development, the most efficient ways to increase peak bone mass and strength. 

Conclusion and recommendations 

The prevention of osteoporosis begins with optimal bone mass acquisition during growth. Factors which limit this acquisition result in a reduced peak bone mass, which in turns is an important determinant of the risk of osteoporotic fracture in later life. Several non-genetic factors, particularly nutrition, physical activity, and sun exposure can influence substantially the gain of bone mass during childhood and adolescence. Despite a certain number of uncertainties which need more research, there is enough evidence from studies on bone development in children and adolescents so that the following recommendations for bone growth in children and adolescents can be made: 

• Ensure an adequate calcium intake which meets the relevant dietary recommendations in the country or region concerned
• Avoid undernutrition and protein malnutrition
• Maintain an adequate supply of vitamin D through sufficient exposure to the sun or oral supplementation
• Increase the general level of physical activity
• Avoid smoking
• Educate adolescents about the risk of high alcohol consumption

Each country or region should develop its own strategy in order to translate these general recommendations into specific adapted to the local cultural and economic conditions. 

The Silent Epidemic

Osteoporosis is a disease in which the bone structure has been eroded so that the mass of bone is reduced and the architecture is disputed, predisposing to fragility or a susceptibility to fracture with minimal trauma, particularly, of the spine, hip, wrist, pelvis and upper arm. Osteoporosis and associated fractures are an important cause of mortality and morbidity 

In many affected people, bone loss, which occurs in women and men of all races, is gradual and without symptoms or warning signs until the disease is advanced. Osteoporosis is a global problem which is increasing in significance as the population of the world both grow and ages. For these reasons, osteoporosis is often referred to as the “silent epidemic”. 

Basic bone biology: bone loss and structural degradation of the skeleton 

The loss of bone occurs throughout life an becomes more severe after menopause in women when lack of estrogen, the female hormone, results in an increase in bone remodeling or renewal on the inner surface. We do not understand why bone remodeling occurs so intensely after estrogen withdrawal after menopause but when this is prevented from occurring fine structural arrangement of bone and its mass are maintained. 

After menopause, osteoclasts erode the honeycomb structure of trabecular bone. As a result the spine loses its flexibility, its ability to act as a shock absorber or spring moving in its elastic range. With the erosion of the trabecular network, loading, even daily walking, can result in the loss of flexibility in the vertebrae of the spine and may produce microfractures. In the long bones, which are weight-bearing pillars, the cortical shell is placed around the perimeter with a marrow cavity between to confer bending rigidity so necessary in ambulant persons. As we age the cortical shell becomes porous and liable to fracture as the mass of bone is compromised. The result these structures can no longer support the loads and may crack. 

The bone thinning process during ageing can be likened to a block of ice that disappears particularly rapidly in the last stages melting. Bones become more fragile, more quickly during ole age. One in every two women and one in every four men will sustain an osteoporotic fracture in their lifetime. Spine fractures result in increased risk of death, physical deformity, dependence and severe pain. One fracture occurs every seven minutes and the burden of fractures is increasing because more and more persons are living into old age. 

Fracture kill, cause pain, disability, loss of independence, loss of self-esteem and drain the health care budget 

Virtually all aspects of the problem of fractures and bone fragility are to be discussed at the Congress. The importance of vertebral fractures is underestimated. Vertebral fractures cost €329 million annually in direct costs alone; this is just 25% less than hip fractures which are much more frequently reported. Patients with vertebral fractures have a lower quality of life than patients with hip fractures. Many spine fractures result in severe pain that produces long-term disability, curvature of the spine, and respiratory problems because of the collapse of the vertebral column. 

Hip fractures have a profound impact on quality of life. Twenty percent of patients with hip fractures die within the first six months of fracture, and are likely to be unable to live at home, and require nursing homes or assistance from family members of health professionals and many require assistance in daily activities. It costs twice as much to treat a hip fracture patient (€6000 per patient) than it does to treat obstructive lung disease or myocardial infraction, and a hip fracture is three times more costly to treat than alcoholic liver disease. 

Doctors, patients, governments don’t know 

Despite the devastating impact on quality of life and costs to health care systems throughout the world, doctors, patients and governments do not recognize how serious osteoporosis is to put this lack of knowledge in context, it would be totally unacceptable if a doctor failed to treat high blood pressure and the patient and then had a stroke. Similarly, if a doctor failed to lower cholesterol in a patient who later suffered a myocardial infarction, this would be regarded as negligence. Yet doctors are not diagnosing patients at risk of osteoporosis, nor are they patients who have already fractured a bone, despite the fact that easy diagnostic techniques exists and any fracture is predictor of future fractures. 

The reasons doctors do not diagnose osteoporosis partly relate to the mistaken belief that brittle bones reflect a ‘natural’ ageing process and that nothing can be done.

We now have safe and effective ways of measuring bone density using densitometry, ultrasound and quantitative computed topography, techniques that identify women and men at greatest risk for fracture due to low bone density. The loss of bone during ageing can be prevented. The thinning of trabeculae, which form the naturally spongy honeycomb network of bone, can rebuild the decayed structure of bone. Drug therapy is cost effective yet doctors are not investigation or treating women or men with fractures.

This situation is unacceptable and efforts are being made to increase the awareness that this disease is preventable and treatable. 

Men suffer from osteoporosis as well as women and estrogen deficiency is an important cause of bone thinning in men 

Fractures are a serious problem in men as well as women. One third of hip fractures occur in men. By the year 2025 the numbers of hip fractures in men will be equal to that seen in women now, and the burden on health care systems will be compounded by the increasing numbers of hip fractures in women. The numbers of hip fractures is increasing because more and more women and men are living into old age. In addition, it appears that the age-specific risk of hip fracture is increasing as well. In other words, more elderly men and women suffer hip fractures today than the same number a generation ago. The reason for this is uncertain. Perhaps young people today produce a weaker skeleton than their elders because of changes of diet, environment and life styles. Perhaps elderly people lose more bone as they age. 

Although spine and hip fractures are less common in men, men suffer greater disability, morbidity and mortality than women for reasons that are incompletely understood. One possible explanation: Men have more illnesses than women in general because men are more reluctant than women to seek medical care. The prevalence of spine fractures is similar in men and women about 15-25% after the age of 50. 

Tobacco use, excess alcohol and male hormone (testosterone) deficiency contribute to the risk of osteoporosis in men but new data suggests that estrogen deficiency is important in men as well as women, and may be more important than testosterone deficiency as a cause of bone loss. Should we treat men with estrogen? The answer to this is not known but new estrogen drugs with specific benefits for the skeleton without feminizing effects may be an option in men. Testosterone regulates bone size in males and may be important in making the bone wider in men. Smoking interferes with production of estrogen and increases the degradation of estrogens and produces bone fragility in men as well as women. 

Osteoporosis begins before birth and develops during growth as well as during ageing. 

Bone fragility in old age has its origin in youth, if not during intrauterine growth. We know that the basic plan of the skeleton is hidden in the genetic code and passed down from generation to generation. Abnormalities in structure or variation in size and density probably originate in the genes but are modifiable through environmental factors acting throughout life. Maternal lepton levels may affect bone mass in the fetus, while vitamin D deficiency, protein malnutrition, and sex hormone deficiency in growth influence peak several size and density. Exercise is probably most important during the early years of growth at which time the skeleton is extremely responsive to loading and will grow larger and denser as a result. It is possible that children’s current passive life styles, with hours spent in front of computers and TV, causes lower peak skeletal development, which then sets up the situation for bone fragility in old age.  

Similarly, adults face numerous life style factors that contribute to low bone density- lack of exercise, little calcium (because of the fear dairy products contain and fat), insufficient protein, tobacco use in younger adults, and avoidance of sunlight in a skin cancer-fearing world. As well, geography plays a role. 

Monitoring progress and the effects of treatment can be done with a simple blood test  

Just as we need ways of   identifying persons at risk for osteoporosis and fractures we need tools that are easy to use and that can monitor who may be at risk for fracture, who may taking treatment properly, and whether the patient is responding to treatment . New evidence suggests that measurement of circulating biochemical markers of remodeling predicts bone loss, fracture risk and response to drug therapy. A blood sample or urine sample in the doctor’s office can be used to help the doctor determine whether the patient is at risk for osteoporosis, whether the patient is complying with treatment and whether the patient is responding to treatment. These tests, not yet in common use, are important in monitoring treatment and may encourage patients to comply with treatment. 

The cure is not too far away

Perhaps the most exciting data to be presented at this meeting concerns a wealth of evidence supporting the efficacy and safety of new therapies for prevention of bone loss, and restoration of bone mass, structure and strength using bone building agents such as intermittent subcutaneous injection of parathyroid hormone and oral strontium ran elate. 

PTH is a hormone which in large doses bone thinning but in low intermittent doses is ‘anabolic’ or bone building. For reasons that are still not understood, low dose administration stimulates the bone forming cells to make new bone so that the bone mass increases. The drug rebuilds the skeleton by increasing cortical and trabecular thickness and perhaps even trabecular connectivity- the connectedness of the honeycomb structure needed for the spine bones, the vertebra, to act as sponges or springs to be shock absorbers. Strontium ran elate, a new orally active drug, has been reported to increase bone formation and reduces bone resorption. The effects on fractures will be reported at this meeting but the data remain confidential at this time.

The new antiresorptive drug ibandronate reduce spine and non-spine fractures. Residronate maintain trabecular architechture, reduce spine and non-spine fractures within 12 months, and halves intertrochanteric hip fracture risk in people over 80  years old (not just in 70 79 year old women as believed). Alendronate reduces spine fracture risk in women with osteopenia as well as osteoprorosis and increases bone density in women and men with primary and secondary osteoporosis. Raloxifene is likely to have benefits outside the skeleton such as reducing the risk of breast cancer and ischemic cardiac events and may protect the skeleton in men as well as women. Newer drugs such as minodronate , bisphosphonate, and bazedoxifene acetate a third generation selective estrogen receptor modulator, expand the therapeutic alternatives in the field.

The ease, safety and efficacy of new regiments like once weekly alendronate and residronate, three monthly ibandronate, neridronate or pamidrinate, and once yearly zolencronate reduce the inconvenience, adverse events and improve compliance to current treatments. There are many other advances, including confirmatory work regarding antifracture efficacy of vitamin D and calcium, alendronate in women and men with primary and secondary osteoporosis, the combination of monofluorophosphate and raloxifene, and reanalyses  of the calcitonin PROOF study. 

Conclusion 

The epidemic proportions of osteoporotic fracture will continue as people live longer, particularly in densely populated Asian countries. Will osteoporosis become a major 21^st century epidemic? The osteoporosis epidemic parallels that seen in the 19^th century with ischemic heart disease, diabetes, tobacco use and other diseases. The concerted efforts of scientists and governments throughout the world are needed to reduce the burden of fractures that ruin the lives of millions of people and will drain health care resources

Osteoporosis

International                                                                                                  

PLENARY LECTURE ABSTRACTS 

PL1. WHY IS OSTEOPOROSIS COMPLICATED BY FRACTURES? 

Ego Seeman, Austin and Repatriation Medical Centre, University of Melbourne, Melbourne, Australia

The bone is lever needed for movement and speed, with properties that meet the contradictory needs of strength yet lightness, and stiffness yet flexibility by stiffening the rope-like triple helical fibres of type 1 collagen with mineral crystals. Stiffness produces glass-like brittleness; cracks occur with slight deformation. The collagen weave confers flexibility. If energy is imparted to bone by impact loading or muscle contraction and no movement occurs, flexibility allows the energy to be stored in reversible (elastic) deformation. When exceeded, bone can store more energy but at the price of microfracture and irreversible (plastic) deformation. If the imparted energy exceeds the elastic and plastic limits of deformation, fracture occurs. Bone material is fashioned into long bones with a medullary canal and cortical mass placed distant from the central long axis conferring greater resistance to bending. In the axial skeleton, the vertebral bodies have a thin cortical shell and a orbicular spongiosa or cancellous network of plates and sheets that absorb energy during compressive loading like a spring and then returning to their original height. These features are fully expressed at the completion of linear growth.

Bones break because advancing age is accompanied by degradation of the material and structural properties responsible for resistance to structural failure; Two cellular mechanisms available to construct and reconstruct the skeleton, bone modeling and remodeling, fail to maintain and structural properties, in a host increasingly predisposed to falls. Remodelling replaces old with new bone and repairs material fatigue and micro-fractures. During ageing less bone is formed than removed in the basic multicellular units( BMUs) producing a negative bone balance. Whether this is an ‘appropriate’ response to reduced loading, or an ‘abnormality’ produced by reduced osteoblast lifespan, increased osteociast lifespan, or abnormal osteocyte mechanical signaling, is uncertain, but the effect is the same-bone loss and structural damage. Trabecular thinning removes horizontal trabeculae, increases loading or the remaining vertical trabeculae causing failure in buckling and vertebral collapse in comprehension. Endocortical resorption thins long bone cortices  and increases cortical porosity predisposing to buckling. The increased remodeling due to hypogonadism and secondary hyperparathyroidism produces more BMUs , each with a more negative bone already diminished in mass and disrupted in architecture. Mineral distribution of the remaining bone becomes uneven; older, more mineralized interstitial bone distant from remodeling may become susceptible to micro-damage and less repairable. Bone modeling effectively changes bone size and shape in  response to loading during growth, but may be impaired during ageing .Periosteal apposition is an adaptive response to increased stains caused by relatively increased loads at this surface produced by endosteal bone loss and trabecular disruption. Periosteal apposition maintains apparent volumetric density, reduces compressive stress by distributing loads on a larger area, and increases bone’s bending strength. Periosteal apposition during ageing may be reduced due to abnormalities in periosteal osteoblast function, osteocyte signaling or deficiency. Women sustain fractures more often than men because of less periosteal apposition, greater disruption of trabecular architecture and thinner more porous cortices (due to higher remodeling intensity, and perhaps a more negative BMU imbalance), more micro-damage, and perhaps more osteopcytic apoptosis. Women and men who sustain fractures may differ from women and men who do not for similar reasons. Fractures in Caucasians and Asians may be more common than in African American for similar reasons.

There is progress. We have identified and quantified, in vitro, and in animal studies, the material properties of bone, the structural properties of the bone, the three major cell types participating in the construction, maintenance and reconstruction of these materials and structures, and many local and systematic regulators that determine the number, lifespan and activity of these cells. Advances are needed to (i)link these causally to bone fragility in vivo, (ii) develop non-invasive methods to identify individuals with these, and (iii) develop specific treatments to correct the morphological abnormality. Densitometry has met some of the needs but 50% of fractures occur in persons without ‘osteoporosis’ and many women with osteoporosis do not sustain a fracture. Whether in vivo measurements of the material and structure determinants of bone strength can improve the sensitivity and specificity of available risk assessments remains to be seen. 

PL2. CONTRIBUTION OF BONE BIOLOGY TO THE DEVELOPMENT OF NEW THERAPIES IN OSTEOPOROSIS 

Roland Baron, Yale University School of Medicine, New Haven, CT, USA and Aventis Pharmaceuticals, Romainville, France 

Many of the most important recent advances in the biology of bone cells and in the understanding of their role in the regulation of bone remodeling have lead to innovative approaches to the treatment of osteoporosis and other skeletal disorders, giving us an opportunity to get a glimpse at what the drugs of the future maybe for skeletal diseases.

These drug discovery approaches can be classified in three categories: 1) Pathophysiological approaches, attempting to correct the mechanisms that lead to altered bone remodeling, 2) Anti-resorptives, and 3) Anabolics. The pathophysiology of osteoporosis being centrally related to sex hormones (estrogen in women and possibility androgens in elderly men), three major findings in this field have been the discovery of a second receptor for estradiol (ER beta, in addition to the known ER alpha), the reports that some of the actions of the ERs may affect bone cell apoptosis through non-genomic mechanisms and finally the validation of the concept of selective modulators of the estrogen receptor(s), affecting differentially the various target organs of estradiol (SERMs), raising the possibility to selectively target bone and to develop similar compounds for the androgen receptor. In the field of antiresorptives and beyond the currently available compounds (bisphosphonates, calcitonin) several majo0r findings in bone biology have lead to programs are: the vitronection receptor (osteoclast adhesion), cathepsin k, an extracellular enzyme involved in the degradation of collagen, c-Src, an intracellular tyrosine kinase, the vacuolar proton pump, involved in acidification, and most importantly the patyway of RANK Ligand and its receptor RANK in osteioclast differentiation. In addition, the mevalonate pathway has been demonstrated to be the target for bisphosphonate action, leading to a new drug discovery approach. But the therapies of the future will certainly also involve a new class of compounds, bone anabolics. In this very active area of research, both in academia and in industry, several breakthroughs have recently been made. First and foremost, the anabolic potential of PTH when given intermittently has now been firmly established in human studies, validating the concept that anabolism is possible in osteoporosis treatment. An alternative to the use of PTH being ther regulation of the endogenous synthesis and secretion of this hormone, one approach is targeting the calcium receptors in the parathyroid gland, antagonising the blinding of Ca and therby increasing PTH levels (calcilytics). Other major finding s in this area are the identification of Cbfa-1, a transcription   factor necessary fro osteoblast differentiation of LRP5, a receptor involved in bone mass regulation in humans. Finally, most companies are currently engaged in genetic, genomic and gene expression profiling studies to identify novel genes involved in bone formation. Thus therapies for osteoporosis and new and more efficient drugs should be forthcoming in the next decade. 

PL3. QUALITY OF LIFE IN WOMEN WITH OSTEOPOROSIS

Elizabeth Barett-Connor and Susan Brenneman, UCSD, La Jolla Ca, 92093-0607; Merck & Co., Inc, West Point , PA 19486-0004, USA 

Osteoporotic fractures can cause site-specific decline in physical capabilities, poor body image, poor perceived health, depression, and fear of falling. Vertebral fractures with or without pain can impair physical activity, pulmonary function, and self-image. Functional capacity and independence are most dramatically changed after hip fracture, which results in loss of independence or death in more than half of affected women.

The preponderance of quality of life studies have been conducted in elderly women where co morbidity confounds the consequences of fracture. Unpublished data from the NORA study of 95,489 community-dwelling postmenopausal women, mean age 64, will be used to evaluate quality of life in younger women who have little co-morbidity. Approximately one in 10 of these NORA women reported a prior fracture of the hip, spine, rib, or distal forearm that had occurred after age 45. Quality of life, assessed by the SF-12 Health Surveys (Medical Outcomes Trusts & the Health Assessment Lab) will be compared in women with and without osteoporosis (as defined by the WHO diagnostic criteria of T-score<-2.5) and with and without a fracture history, stratified by age (<65:65+). Scores will be compared before and after adjusting for confounders. None of the NORA women had been told they had osteoporosis, so quality of life will not have been influenced by knowledge of the diagnosis. 

PL4. TRANSGENIC MODELS TO UNDERSTAND OSTEOPOROSIS

Gerard Karsently , Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA

Mouse genetics, defined here as a group of techniques aimed at altering gene expression and/or function in vivo, has invaded every field of biology, including bone biology. In doing so it has revolutionized thinking in each field it has entered. There are several reasons that fully justify such prominence.

The first reason to explain the popularity of mouse genetics comes from the versatility of the technology. Indeed, it is now possible to delete a gene, decrease or increase its expression, or express it ectopically. The fact that these different manipulations can be done in vivo, during development or after birth, an in the cell type of choice, allows, two equally important questions regarding any gene product to be addressed: what it normally does and what it can do. This latter aspect may be of greater interest from a therapeutic perspective. Moreover, the ability to delete several contiguous genes or an entire cell population expands considerably the scope of the information that can be obtained and analyzed. The second reason stems form the issues that are at stake in bone biology. Little is known about the mechanisms controlling skeleton during development. Mouse genetics has shown that it is, along with chick embryology, the most powerful and elegant approach to address these  questions. However, what is specific to bone and only very few other mechanisms controlling the function of its osteoclasts. That such questions of physiology and pathophysiology can be addressed successfully by mouse genetics has become increasingly evident over time. Although there are physiologic difference between mice and humans, the similarities for every organ for outnumber these differences. This has now been amply demonstrated for most organ physiology including bone. A final reason explaining the importance of mouse genetics as a tool comes from its track record. The functions of most cloned genes have now been studied in mice. In a few instances these studies have generated such clear-cut and unexpected results that they have substantially altered the way we think. Recent developments that illustrate the fundamental changes is conception that mouse genetics has brought to bone biology include the discovery of osteoprotegerin (OPG) and its ligand (RANK, receptor activator of NF-kB ligand/ODF, osteoclast differentiation factor), the phenotype of vitamin D receptor (VDR)-deficient mice, the dual functions of Cbfa1 during development and postnatally, the independence of bone resorption from bone formation during bone remodeling, and the regulation of osteoblast by the hypothalamus. 

PL5. GENETICS OF COMPLEX DISEASES: THE BAD AND THE GOOD GENES

Stuart H Ralston, Bone Research Group, Department of Medicine and therapeutics, University of Aberdeen, UK

Osteoporosis is a common disease with a strong genetic component. Twin and family studies have been shown that genetic factors play an important role in regulating bone mineral density, ultrasound properties of bone, skeletal geometry, and bone turnover and well as contributing to the pathogenesis of osteoporotic fracture itself. Bone mineral density and other osteoporosis-related phenotypes are usually determined by the effects of several genes, but occasionally, osteoporosis or unusually high bone mass may occur as the result of mutations in a single gene. Examples are the osteoporosis-pseuduglioma syndrome, known to be due to inactivating mutations in the LRP-5 gene and a high bone mass syndrome, caused by activating mutations in LRP-5, in keeping with the hypothesis that polygenic influences determine BMD in the general population, linkage studies in man have so far defined several loci on chromosomes that show definite or probable linkage to bone mineral density. So far, the causative genes that influence BMD in these loci remain to be defined. Linkage studies in experimental animals have also identified several loci, which regulate BMD and bone structure, and a future challenge will be to investigate the relevance of these in humans. Most work in the field of osteoporosis genetics has focused on candidate gene studies in populations,  and case-control studies. Amongst the most widely studied candidate genes are the vitamin D receptor (VDR), the Collagen type 1 alpha 1 gene (COLIA)1 and the oestrogen receptor gene (ER). Polymorphisms of VDR have been associated with bone mass in several studies and there is evidence to suggest that these effects may be modified by dietary calcium and vitamin D intake. An Sp 1 blinding site polymorphism has also been identified in the COLIA1 gene, which predicts osteoporotic fractures independently of bone mass, and there is functional evidence to suggest that this polymorphism of the collagen gene regulation and bone quality. Polymorphisms of the ER gene have been associated with BMD in several studies, although the effects of ER on fracture have been less widely investigated. An important defect in most candidate gene studies in small sample size and this has led to conflicting results in different populations. Some researches are exploring the use of meta-analysis as a means of overcoming this problem and trying to gain to relevant endpoints such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important since they offer the prospect of delivering new markers for assessment of fracture risk and the identification of novel molecular targets for the design of new treatments that might be used to prevent osteoporosis. 

PL6. BONE FRAGILITY IN CHILDREN: OPPORTUNITY OF THERAPY

Francis H. Glorieux, Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada 

With senescence, bone will loss mass and resistance often resulting in fractures, decreased mobility and chronic pain. Such a picture may, at times, develop in a neonate or a growing child. It will then severely compromise growth and development, and restricts ambulation, further aggravating bone loss. The paradigm for such a severe osteoporosis in children is represented by Osteogenesis Imperfecta (OI) or brittle bone disease. It is a syndrome with a wide spectrum of clinical expression (from lethal to minor forms), in most cases associated with mutations in the genes encoding type 1 collagen, the major component of bone matrix. There is no evident correlation between mutations and severity of phenotype, and collagen mutations are not found in about 25% of the severe cases. Thus other factors (genes) are at plays that have yet to be identified. In OI, osteoblasts produce an abnormal matrix that does not respond to mechanical loads. In reaction, the osteoblast population is increased, and osteoclast activity is raised leading to the characteristic high turnover rate. Until recently, treatment had focused on fracture management, surgical corrections of deformities, and supportive rehabilitation programs. All medical therapies, other than those aiming at symptomatic pain relief have been ineffective in altering the course of the disease. They include fluoride, magnesium oxide, calcitonin and anabolic steroids. Compromised bone acquisition in young OI patients is further compounded by secondary bone loss induced by immobilization. In adults, bisphosphonates decrease turnover and reduce bone loss. Such a therapy (intermittent intravenous pamidronate) has been recently extended to children with severe OI, with remarkable results. Bone mineral density and physical activity greatly increased, fracture rate decreased and chronic pain disappeared, resulting in improved quality of life. No adverse effects on growth, bone modeling or fracture repair have been observed. At the tissue level, the impact of the treatment is most evident in cortical bone which thickens considerably, with lesser gain in cancellous bone. The cortical effect results from decreased endocortical resorption in the face of maintained periosteal apposition. The rate of the latter being age dependent, the younger the patient, the more striking the effect. Pamidronate can be safely administered two-week old babies with definite gain in terms of pain control, mobility and fracture incidence. Whether similar results can be obtained with daily/weekly oral alendronate administration is currently under evaluation. Overall reduction of bone turnover may have, on the long term, a significant impact on bone remodeling. This may be lead to alteration in bone tissue quality that will require careful evaluation.Other potential therapeutic avenues include the use of anabolic agents like growth hormone, bone marrow transplantation leading to engraftment of mesenchymal cells giving rise to competent osteoblasts, and various approaches of somatic cell therapy (in animal models). At this point none of these attempts have matched the results obtained with bisphosphonate therapy. The encouraging results obtained in OI make it reasonable now to consider extending the indication to other osteoporotic conditions in children, such as long-term use of steroids, prolonged immobilization, endocrine disorders, etc. In all these instances, the use of bisphosphonates, although not a cure, will likely improve the patients’ clinical condition to an extent unforeseen only a few years ago. 

PL7. DECISION MAKING PROCESS IN THE MANAGEMENT FO OSTEOPOROSIS: CAN THE SAME TOOLS BE USED

L. Joseph Melton III, Mayo Clinic, Rochester, MN USA 

Huge increases in the elderly population worldwide will cause a dramatic rise in osteoporotic fractures, with hip fractures alone increasing from 1.7 to 6.4 million annually between 1990 and 2050. However, similar increases will be seen for other age-related diseases (e.g. cancer cases increasing from 10.1to 23.8 million), and these will be superimposed on other major public health problems (e.g. malaria, alcoholism). Thus, osteoporosis prophylaxis will have to compete for medical resources, and other urgent health care needs will have priority in some regions. Other societies will focus control efforts on broad public health measures. Public health interventions are culture-sensitive and vary with the target population but do not involve individual risk assessment. Clinical decision-making will be limited to treating patients with fractures (who fail public measures) or, in some wealthy countries, patients with low bone mass identified by targeted case-finding. The approach to casefingding will vary with the resources available, although unselective (mass) screening by densitometry is largely unaffordable anywhere. Key to clinical decision-making for individual patients will be an assessment of near-term (5-10 years ) absolute fracture risk, and prediction tools are now being developed. These incorporate bone density, which predicts fractures equally in white women and men, (e.g. risk of falling). Inclusion of these other factors may allow extension of fracture risk prediction to nonwhite populations, but this must be validated. Even with a universal risk prediction tool, cost-effective treatment thresholds will vary by country  based on population fracture risk and available resources, and this will also affect clinical decision-making. Because of the competition for resources, accelerated efforts are needed to improve the effectiveness and lower the cost of osteoporosis interventions, as well as provide hard evidence that they result in the improved health outcomes promised.                       

PL8. NEW PERSPECTIVES IN OSTEOPOROSIS TREATMENT

Gregory R. Mundy, CTRC Institute for Drug Development, University of Texas Health Science Center San Antonio, USA 

Osteoporosis treatment in the next decade will likely be dominated by the search for anabolic agents. The forerunner will be parathyroid hormone, which has shown that substantial increases in bone mass and improvements in fracture rates are possible. However, an ideal agent will be one that is safe and possible. However, an ideal agent will be one that is safe and efficacious, but also orally available. Agents such as strontium ranealate will be thoroughly evaluated for their potential, but the likely candidates will come from agents identified by their capacity to affect specific molecular targets controlling bone formation, key transcription factors such as CBFA-1 will provide such targets, and important enzymes in the mevalonate pathway that regulate BMP 2 transcription will also be likely sources.

There is also a place for new resorption inhibitors, since the current drugs, albeit effective, are not deal pharmaceutical agents. A major limitation to drug discovery and development in our field is the cost of bringing a drug to market, and this will continue to provide a barrier until we provide faster and more efficient ways to satisfy regulatory requirements necessary for drug approval.