Search PubMed⌕ Search

Biomedical subjects

Ego Seeman

Publications and source records attributed to Ego Seeman.

At least 19 recordsLinked to original sources
PubMed2004

A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women.

BACKGROUND: Although many studies have assessed the effects of estrogen and raloxifene hydrochloride on bone mineral density and serum lipid concentrations, there are few direct comparative data. METHODS: Randomized placebo-controlled trial for 3 years, intention-to-treat analysis. Six hundred nineteen postmenopausal women with prior hysterectomy (mean age, 53.0 years) were studied in 38 centers in Europe, North America, Australasia, and South Africa. They were randomized to 60 mg/d or 150 mg/d of raloxifene, 0.625 mg/d of conjugated equine estrogen (CEE), or placebo. Bone density of the lumbar spine and proximal femur, biochemical markers of bone turnover, and fasting serum lipid concentrations were assessed for 3 years. RESULTS: Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results. Conjugated equine estrogen produced significantly greater depression of serum osteocalcin, bone-specific alkaline phosphatase, and urine C-telopeptide, compared with raloxifene. Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P < or =.002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P < or =.01 compared with the other groups). Hernias occurred less frequently in those receiving 150 mg/d of raloxifene or CEE (P =.03 vs placebo). CONCLUSIONS: Raloxifene and CEE have beneficial effects on bone density and bone turnover, although effects of CEE are more marked. Raloxifene and CEE produce different patterns of lipid responses and have distinct adverse effect profiles.

Alkaline Phosphatase↗
PubMed2004

Osteoporosis and the global competition for health care resources.

Global aging superimposed on existing infectious diseases and trauma will aggravate competition for health care resources to diagnose and treat osteoporosis. Efforts to implement public health measures are needed, but the targeted approach to assessment and treatment of high-risk individuals must also be refined. Increases in the elderly population worldwide will cause a dramatic rise in osteoporotic fractures, but other age-related diseases will increase as well. Changes will be superimposed on existing public health problems (e.g., malaria, alcoholism), and these acute health care needs will take priority in some areas. Societies in most parts of the world may have to limit osteoporosis control to broad public health measures, and such efforts (e.g., calcium and vitamin D supplementation) should be supported. In these regions, clinical decision-making will generally be limited to treating patients with fractures (who presumably have already failed any public health measures in place), or in a few wealthy countries, to patients with low bone density identified by case-finding. Case-finding approaches will vary with the resources available, although unselective (mass) screening by bone densitometry is largely ineffective and unaffordable anywhere. The key to clinical decision-making on behalf of individuals will be an assessment of absolute fracture risk, and the tools needed to predict the risk of an osteoporotic fracture over the next 10 years are now being developed. These include bone density measures, but also incorporate other risk factors (e.g., fracture history, corticosteroid use), which may allow extension of fracture risk prediction to nonwhite populations and to men. Even with a universal risk prediction tool, cost-effective treatment thresholds will vary by country based on the level of fracture risk in the region and on the resources available for health care. To better compete for these resources, efforts should be made to lower the cost of osteoporosis interventions. Additionally, evidence is needed that these interventions are really effective in reducing fractures in the community.

Aging↗
PubMed2004

Loss of regularity in the curvature of the thoracolumbar spine: a measure of structural failure.

UNLABELLED: Departure from regularity (smoothness) in the curvature of the spine was quantified and correlated with the number of fractures, deficits in height, BMD, and identified women with vertebral fractures. INTRODUCTION: Differences in anterior and posterior vertebral heights (VHs) form the thoracolumbar curvature needed for stability in bipedal gait. Modest differences in VHs within and between adjacent vertebrae allow the spine curve to change its trajectory gently. Large differences in VHs, as occur following a fracture, produce abrupt changes in the direction of the curve, producing a departure from regularity (i.e., irregularity or loss of smoothness). MATERIALS AND METHODS: VHs and BMD were measured using DXA in 697 Lebanese women 20-87 years of age. Regularity of the spinal curvature was measured by comparing the ratio of the anterior to the posterior VHs of one vertebra to this ratio of adjacent vertebrae. If these ratios are similar, there is a smooth transition in the trajectory of the spinal curve. Departure from this regularity (smoothness) was measured at each pair of adjacent vertebrae in each individual and expressed as the spinal curvature irregularity index (SCII) for the entire thoracolumbar spine. RESULTS AND CONCLUSIONS: In premenopausal women, the mean SCII was 8.5% (range, 4-15%); that is, regularity was 91.5%. Only 0.8% of women had a SCII >17%. In postmenopausal women, the mean SCII was 10% (range, 4-36%) and was correlated with age (r = 0.25), height (r = -0.21), BMD (r = -0.13), and the number of deformities assessed by quantitative vertebral morphometry (QVM; r = 0.31-0.60; all p < 0.001). About 5% of women had an SCII >17%, and this group had 3- to 9-fold more deformities (as defined by QVM) than women with SCII <17%, reduced lumbar spine BMD (-1.01 SD), and 2- to 4-fold greater height deficits (-0.5 SD) than women with deformities (by QVM). The SCII is a robust method of identifying structural failure that is easy to compute and does not require controls.

Adult↗
PubMed2004

7: Treatment of osteoporosis: why, whom, when and how to treat. The single most important consideration is the individual's absolute risk of fracture.

All women and men with a history of fragility fractures should be considered for treatment of osteoporosis to reduce their risk of future fracture. There is high-level evidence for the anti-fracture efficacy of treatment in women with osteoporosis, particularly if there is prevalent fracture; the evidence is less compelling for women with osteopenia, with or without a fracture, and for men. The rigorously investigated drugs reported to reduce vertebral fractures are the bisphosphonates alendronate and risedronate, the selective oestrogen-receptor modulator raloxifene, the anabolic agent parathyroid hormone and, most recently, strontium ranelate. Only the two bisphosphonates and hormone replacement therapy (HRT) have been reported to reduce hip fractures in community-dwelling women, and calcium plus vitamin D and hip protectors have been reported to reduce these fractures in elderly people in institutions. HRT is not recommended in women for fracture risk reduction alone. Evidence for the anti-fracture efficacy of calcitonin, fluoride, anabolic steroids and active vitamin D metabolites is insufficient to justify their use; lifestyle changes, while not shown to reduce fracture risk, may have a role in maintaining bone strength throughout life.

Age Factors↗
PubMed2004

Hormone therapy and risk of non-vertebral fracture: Geelong osteoporosis study.

In this population-based study, we evaluated the association between exposure to hormone therapy (HT), bone mineral density (BMD) and the prevalence of non-vertebral fractures. The study was set in a region located in southeastern Australia where complete fracture ascertainment was determined from radiological reports. Current HT use for at least 6 months was ascertained in women with non-vertebral fractures [median age 70.9 years; inter-quartile range (IQR) 66.5-75.9 years] and randomly selected controls (median age 70.8 years; IQR 65.2-75.0 years). Current HT use was documented in 20 of 262 cases and 49 of 364 controls. The odds ratio (OR) for non-vertebral fracture associated with HT use was 0.53 (95% CI 0.31-0.92). HT use was associated with 2.6-7.5% higher BMD at axial and appendicular sites. HT use is associated with a halving of risk for non-vertebral fractures and higher BMD.

Aged↗
PubMed2004

The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis.

BACKGROUND: Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. METHODS: To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. RESULTS: New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. CONCLUSIONS: Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.

Administration, Oral↗
PubMed2004

Seasonal periodicity of serum vitamin D and parathyroid hormone, bone resorption, and fractures: the Geelong Osteoporosis Study.

UNLABELLED: In this population-based study, seasonal periodicity was seen with reduced serum vitamin D, increased serum PTH, and increased bone resorption in winter. This was associated with an increased proportion of falls resulting in fracture and an increased risk of wrist and hip fractures. INTRODUCTION: In a population of women who reside in a temperate climate and do not generally receive dietary vitamin D supplementation, we investigated whether seasonal vitamin D insufficiency is associated with increased risk of fracture. MATERIALS AND METHODS: An observational, cross-sectional, population-based study set in southeastern Australia (latitude 38-39 degrees S). Participants were drawn from a well-defined community of 27,203 women >/=55 years old: 287 randomly selected from electoral rolls, 1635 with incident fractures, and 1358 presenting to a university hospital with falls. The main outcome measures were annual periodicities of ultraviolet radiation, serum 25-hydroxyvitamin D [25(OH)D], serum parathyroid hormone (PTH), serum C-telopeptide (CTx), BMD, falls, and fractures. RESULTS: Cyclic variations in serum 25(OH)D lagged 1 month behind ultraviolet radiation, peaking in summer and dipping in winter (p < 0.001). Periodicity of serum PTH was the inverse of serum 25(OH)D, with a phase shift delay of 1 month (p = 0.004). Peak serum CTx lagged peak serum PTH by 1-2 months. In late winter, a greater proportion of falls resulted in fracture (p < 0.001). Seasonal periodicity in 439 hip and 307 wrist fractures also followed a simple harmonic model (p = 0.078 and 0.002, respectively), peaking 1.5-3 months after the trough in 25(OH)D. CONCLUSIONS: A fall in 25(OH)D in winter is accompanied by increases in (1) PTH levels, (2) bone resorption, (3) the proportion of falls resulting in fracture, and (4) the frequency of hip and wrist fracture. Whether vitamin D supplementation in winter can reduce the population burden of fractures requires further investigation.

Accidental Falls↗
PubMed2004

Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy.

The structural basis for the reduction in vertebral and nonvertebral fracture risk in patients using anti-resorptive therapy is not well understood. As reduced bone mineral density (BMD) increases the risk for fracture and anti-resorptive agents increase BMD, it was commonly held that the increase in BMD explained the fracture risk reduction until several meta-analyses either failed to detect a significant association between vertebral fracture risk reduction and the incremental increase in BMD or reported that only a small proportion of the vertebral fracture risk reduction was explained by changes in BMD. Recently, it was reported that the risk of nonvertebral fractures decreased when an increase in BMD accompanied anti-resorptive treatment [J. Clin. Endrocrinol. Metab. 87 (2002) 1586]. However, a reanalysis of the data, using the same statistical methods after correcting for discrepancies in the reported BMD and person-year data, suggested that the magnitude of reductions in nonvertebral fracture risk was not associated with the magnitude of increases in BMD at the end of the first year or at completion of the studies. We infer that only a small proportion of risk reduction in vertebral and nonvertebral fractures observed with anti-resorptive drug therapy is explained by the increase in BMD. Further studies are needed to define the structural basis of the fracture risk reduction.

Bone Density↗
PubMed2004

The varying distribution of intra- and inter-vertebral height ratios determines the prevalence of vertebral fractures.

Credible inferences regarding the burden of vertebral fractures (VFs) cannot be made without a globally accepted quantitative definition of 'fracture'. Currently, differences in anterior, middle, or posterior vertebral heights (VHs) within a vertebra, or between adjacent vertebrae, are used to define 'fracture'. However, VH differences are essential for the construction of thoracolumbar curves, evolutionary adaptations that provide stability in bipedal stance and gait. As there is no reference standard to distinguish anatomical variation from fracture, approaches to defining a VF use a reference range of VH ratios derived in premenopausal women or derived by trimming, a method that iteratively removes the tails of a distribution of VH ratios to produce a normal distribution. From this, reference ranges of VH ratio means and standard deviations (SDs) are obtained and a nominal deviation of 15% or more, or 3 SD or more is regarded as a 'fracture'. We measured VHs by quantitative vertebral morphometry (QVM) and bone mineral density (BMD) by dual energy X-ray absorptiometry in 697 Lebanese women (age 20-89 years) to compare the prevalence of VF ascertained by published methods and a new method that uses the premenopausal range (without trimming) and requires two VH abnormalities. VF prevalence using published methods reached 60% to 70% in pre- and post-menopausal women, and in women with normal or high BMD because VH ratios were not normally distributed and cut-offs used to define VF fracture fell within the observed distribution of the data. The new method resulted in a VF prevalence of 3.3% in younger and 14% in older women, 7% (high), 10% (middle), and 20% (low) BMD tertiles consistent with the notion that the method detected VF due to bone fragility. We suggest that using a fixed trimming method to define reference range and cut-offs or applying fixed cut-offs to identify VFs in populations, where these ratios are not normally distributed, may result in the capture of anatomical variation, not structural failure. Thus, group differences in the VF prevalence may reflect differences in methodology, not bone fragility. Improved criteria to define VF are needed before credible inferences can be made regarding the burden of VFs in women and men, and between sexes, races, countries, decades, and placebo arms of clinical trials.

Absorptiometry, Photon↗
PubMed2004

Efficacy of risedronate on clinical vertebral fractures within six months.

OBJECTIVE: Postmenopausal osteoporotic women with pre-existing or new incident vertebral fractures are at high risk for future fracture, so prompt treatment is warranted. Risedronate has been shown to reduce the incidence of radiographically-defined vertebral fractures by approximately two-thirds within 1 year. RESEARCH DESIGN: This study examined the effects of risedronate treatment on the time course of the reduction in the risk of clinical vertebral fractures (i.e., symptomatic fractures), on the risk of moderate-to-severe radiographic vertebral fractures, and on height. RESULTS: In 2442 postmenopausal women with prevalent vertebral fractures from the Vertebral Efficacy with Risedronate Therapy (VERT) studies who received either risedronate 5 mg or placebo, daily risedronate reduced the risk of clinical vertebral fractures within 6 months (RR = 0.08, 95% CI 0.01-0.63), and by 69% at 1 year (RR = 0.31, 95% CI 0.12, 0.78). At 1 year, risedronate also reduced the risk of moderate-to-severe radiographically-defined vertebral fractures by 71% (RR = 0.29 95% CI 0.16, 0.54). Height loss was attenuated with treatment, most notably in patients who experienced new vertebral fractures, with a median difference of 0.73 cm compared with subjects receiving placebo (p = 0.005). CONCLUSION: Risedronate reduces the risk of clinical vertebral fractures in postmenopausal women with osteoporosis within 6 months of commencing treatment.

Body Height↗
PubMed2004

Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study.

UNLABELLED: This population-based study documented beta-blocker use in 59/569 cases with incident fracture and 112/775 controls. OR for fracture associated with beta-blocker use was 0.68 (95%CI, 0.49-0.96). Beta-blockers were associated with higher BMD at the total hip (2.5%) and UD forearm (3.6%) after adjusting for age, anthropometry, and thiazide use. Beta-blocker use is associated with reduced fracture risk and higher BMD. INTRODUCTION: Animal data suggests that bone formation is under beta-adrenergic control and that beta-blockers stimulate bone formation and/or inhibit bone resorption. MATERIALS AND METHODS: We evaluated the association between beta-blocker use, bone mineral density (BMD), and fracture risk in a population-based study in Geelong, a southeastern Australian city with a single teaching hospital and two radiological centers providing complete fracture ascertainment for the region. Beta-blocker use was documented for 569 women with radiologically confirmed incident fractures and 775 controls without incident fracture. Medication use and lifestyle factors were documented by questionnaire. RESULTS: Odds ratio for fracture associated with beta-blocker use was 0.68 (95% CI, 0.49-0.96) for any fracture. Adjusting for age, weight, medications, and lifestyle factors had little effect on the odds ratio. Beta-blocker use was associated with a higher BMD at the total hip (2.5%, p = 0.03) and ultradistal forearm (3.6%, p = 0.04) after adjustment for age, anthropometry, and thiazide use. CONCLUSION: Beta-blockers are associated with a reduction in fracture risk and higher BMD.

Adrenergic beta-Antagonists↗
PubMed2003

Femoral neck fragility in women has its structural and biomechanical basis established by periosteal modeling during growth and endocortical remodeling during aging.

To gain insight into the growth- and age-related origins of bone fragility at the proximal femur, we analyzed structural and biomechanical data of the femoral neck from a study of postmenopausal women with hip fractures and their 47 premenopausal daughters. Results were expressed as standard deviations (SD) or Z-scores (mean +/- SEM) adjusted for age and weight, derived using a normal reference population of 262 premenopausal women and 370 postmenopausal women. Women with hip fractures had increased femoral neck (FN) periosteal and endocortical diameters (1.01 +/- 0.26 SD and 1.18 +/- 0.25 SD, respectively). Cortical thickness was reduced by 0.96 +/- 0.1 SD and volumetric bone mineral density (vBMD) was reduced by 1.2 +/- 0.1 SD). The section modulus was normal while the buckling ratio was increased by 1.59 +/- 0.17 SD). Their daughters had increased FN diameter by about one half that of their mothers (0.48 +/- 0.16 SD), while endocortical diameter was increased by only one third (0.44 +/- 0.13 SD). Cortical thickness and vBMD were not reduced, the section modulus was increased (0.48 +/- 0.13 SD) while the buckling ratio was normal. We infer that the larger femoral neck size in women with hip fractures is growth-related; the wider endocortical cavity and thinner cortex is the result of excessive age-related endocortical bone resorption producing a thin cortex in a larger bone predisposing to structural failure by local buckling. The structural basis of bone fragility has some features originating during growth and others during aging.

Adult↗
PubMed2003

Body segment lengths and arm span in healthy men and women and patients with vertebral fractures.

We studied 112 healthy men and 261 healthy women aged 18-92 years, and 34 men and 73 postmenopausal women with vertebral fractures aged 45-90 years to determine (i) whether patients with vertebral fractures have shorter stature before fracture, and (ii) whether the difference between arm span and standing or sitting height can be used to identify patients with fractures. Arm span was measured by using a calibrated extended ruler. Standing height, sitting height and leg length were measured by using a Holtain stadiometer. The results were expressed in absolute term and standard deviation (SD) or Z-scores (mean+/-SEM). Advancing age was associated with decreased sitting height (r=-0.37 to -0.41, both P<0.01) and a trend towards decreased arm span (r=-0.12 to -0.17, P=0.06 and 0.07) in healthy men and women; leg length was independent of age in both sexes (r=-0.09 to -0.12, NS). In patients with vertebral fractures, sitting height was reduced in women (Z=-0.83+/-0.14 SD, P<0.01) and men (Z=-1.37+/-0.21 SD, P<0.01) but only the women had reduced leg length (Z=-0.46+/-0.15 SD, P<0.01) and arm span (Z=-0.76+/-0.15 SD, P<0.01). Univariate and multivariate analyses suggest that the predictive ability of the difference between arm span and standing or sitting height to identify patients with vertebral fractures is limited. We concluded that women, not men, with vertebral fractures may come from a population with short stature. The difference between arm span and standing or sitting height cannot be used to predict vertebral fracture risk.

Adolescent↗
PubMed2003

Bone quality.

Explore the source record for details and available documents.

Aging↗
PubMed2003

Epidemiology of hip and wrist fractures in Cameroon, Africa.

Osteoporosis and fragility fractures are believed to be uncommon in Africa. To reevaluate this notion, we documented all patients aged 35 years and older admitted to the two main urban hospitals in Cameroon following a diagnosis of fracture during 2 years. Among 513 patients sustaining fractures (192 women, 321 men), 13.5% of all fractures in women occurred at the hip (n=26), 4.7% at the forearm (n=9), and 81.8% (n=157) at other sites (mainly tibia and femoral shaft). In men, the corresponding figures were 9% (n=29), 1.9% (n=6), and 89.1% (n=286). Of the hip and wrist fractures occurring in women, 80.0% were low energy trauma fractures due to falls, 8.6% were high-energy trauma fractures (road accidents), and 11.4% were undefined. In men, the corresponding figures were 42.9%, 34.3%, and 22.9%. Using the 1997 estimates of the population, the annual incidence rates of low-energy trauma fractures (per 100,000 persons over 35 years and above) were 4.1 in women, 2.2 in men for hip fractures, 1.2 in women, and 0.2 in men for wrist fractures. The pattern of most of the hip and wrist fractures in women is consistent with underlying bone fragility. The low incidence of fragility fractures is confirmed and is likely to be, in part, the result of reduced longevity as only 1.1% of women and 0.7% of men survive beyond 65 years of age.

Adult↗
PubMed2003

Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis.

The net amount of bone lost during aging is determined by the difference between the amount of bone removed from the endocortical, trabecular and intracortical components of its endosteal (inner) envelope and formed beneath its periosteal (outer) envelope. Endosteal bone loss is determined by the remodeling rate (number of basic multicellular units, BMUs) and the negative balance (the difference between the volumes of bone resorbed and formed in each BMU). Bone loss already occurs in young adult women and men and is probably due to a decline in the volume of bone formed in each BMU. The rate of loss is slow because the remodeling rate is low in young adulthood. Bone loss accelerates in women at menopause because remodeling intensity increases and BMU balance becomes more negative as estrogen deficiency reduces osteoblast lifespan and increases osteoclast lifespan. The high remodeling rate also reduces the mineral content of bone tissue. The negative BMU balance results in trabecular thinning, disappearance and loss of connectivity, cortical thinning and increased intracortical porosity. These changes compromise the material and structural properties of bone while concurrent age-related subperiosteal bone formation increases the cross-sectional area (CSA) of bone partly offsetting endosteal bone loss and the loss of structural and material strength. Thus, treatments aimed at reducing the progression of bone fragility, and reversing it, should reduce activation frequency and so reduce the number of remodeling sites, reduce osteoclastic resorption in the BMU, and so reduce the volume of bone resorbed on each of the three components of the endosteal surface thereby reducing the progression of trabecular thinning, loss of connectivity, cortical thinning and porosity. If treatment also increases periosteal bone formation, the CSA of the whole bone and its cortical area will increase. If treatment also increases endosteal bone formation in the BMU, bone balance will be less negative, especially if resorption depth is reduced. This may produce thickening of trabeculae provided activation frequency is not too low. If treatment can increase de novo bone formation at quiescent endosteal surfaces, this will increase cortical and trabecular thickness, and reduce intracortical porosity. In this way, drugs directed at both the resorptive and formative aspects of remodeling, and bone modeling may (i) increase compressive and bending strength of cortical bone by increasing the diameter of the whole bone, its CSA and the distance the cortical mass is placed from the neutral long bone axis; (ii) maintain or increase peak compressive stress and peak strain in trabecular bone, preventing microcracks and buckling; and (iii) increase the material density of bone tissue, an effect that probably should not be permitted to reach a level which reduces resistance to microdamage accumulation and progression (toughness).

Aging↗
PubMed2003

The structural and biomechanical basis of the gain and loss of bone strength in women and men.

Structural failure (fracture) is a problem in biomechanics. Its solution resides, in part, in identifying the material and structural properties of bone that determine its mechanical resistance to structural failure. Bones must be stiff so that they do not bend when loaded, otherwise movement against gravity would not be possible. However, bones must also be flexible, otherwise their ability to absorb energy by elastic and plastic deformation will decrease and the energy imparted will be dissipated only by microdamage or complete fracture. Thus, failure may occur if bones deform too much (exceeding their peak strain) or too little (exceeding their peak stress). Phylogeny and ontogeny make bone "just right" for the functions it is predicted to perform, but the genetic material was not warned about the increased longevity the female enjoys after ovarian failure. Age-related and menopause-related abnormalities in bone remodeling produce loss of the material and structural properties that no longer keep bone "just right". High remodeling reduces the mineral content of bone tissue resulting in loss of stiffness (resistance to shortening in compression and lengthening in tension when loaded). Sex hormone deficiency increases the volume of bone resorbed and reduces the volume of bone formed in each BMU. Solutions to the biomechanic problem will emerge provided that the material and structural properties of bone that determine its strength are measured and studied. Drugs are available to reduce remodeling rate so that there is more time for completion of secondary mineralization to restore bone stiffness. If remodeling is suppressed too much the production of microdamage may increase as homogeneous and highly mineralized bone is less resistant to microdamage progression while reduced remodeling targeted to microdamage may result in microdamage accumulation. Drugs are available to reduce osteoclastic bone resorption and increase osteoblastic bone formation, which together will restore bone balance in the BMU and so prevent further loss of bone mass, prevent thinning and loss of trabeculae, thinning of cortices, and progression of porosity. These approaches prevent the progression of fragility but will not restore bone architecture. Even if a positive BMU balance is achieved, drugs that reduce remodeling are unlikely to reverse the structure damage. Slow remodeling means there are too few remodeling foci depositing their small net positive bone volume to progressively thicken cortices or trabeculae. Agents that are anabolic, that increase bone formation on the periosteal and endosteal surfaces are needed to restore the structure of bone. Other articles in this volume address this challenge. We do not understand the proportional contributions made by differences in bone size, cortical thickness, trabecular number, thickness, connectivity, tissue mineral content, microdamage burden, osteocyte density, porosity, to differences in spine and hip fracture rates within a sex, between sexes, between races, or between treatment, and control arms in clinical trials. The challenge for the future is to measure these specific materials and structural determinants of bone strength. Whether a combination of these material and structural properties will more accurately identify women likely to sustain fractures, or improve approaches to drug therapy is unknown. The quest to eliminate fragility fractures is a distant horizon seen through a glass darkly at this time.

Animals↗