Periosteal bone formation--a neglected determinant of bone strength.
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Biomechanical Phenomena↗
Biomedical subjects
Ego Seeman
Publications and source records attributed to Ego Seeman.
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↗
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↗
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↗
Invited Review: Pathogenesis of osteoporosis.
Patients with fragility fractures may have abnormalities in bone structural and material properties such as larger or smaller bone size, fewer and thinner trabeculae, thinned and porous cortices, and tissue mineral content that is either too high or too low. Bone models and remodels throughout life; however, with advancing age, less bone is replaced than was resorbed within each remodeling site. Estrogen deficiency at menopause increases remodeling intensity: a greater proportion of bone is remodeled on its endosteal (inner) surface, and within each of the many sites even more bone is lost as more bone is resorbed while less is replaced, accelerating architectural decay. In men, there is no midlife increase in remodeling. Bone loss within each remodeling site proceeds by reduced bone formation, producing trabecular and cortical thinning. Hypogonadism in 20-30% of elderly men contributes to bone loss. In both sexes, calcium malabsorption and secondary hyperparathyroidism increase remodeling: more bone is removed from an ever-diminishing bone mass. As bone is removed from the endosteal envelope, concurrent bone formation on the periosteal (outer) bone surface during aging partly offsets bone loss and increases bone's cross-sectional area. Periosteal apposition is less in women than in men; therefore, women have more net bone loss because they gain less on the periosteal surface, not because they resorb more on the endosteal surface. More women than men experience fractures because their smaller skeleton incurs greater architectural damage and adapts less by periosteal apposition.
Adult↗
The structural and hormonal basis of sex differences in peak appendicular bone strength in rats.
To identify the structural and hormonal basis for the lower incidence of fractures in males than females, sex differences in femoral mid-shaft geometry and breaking strength were studied in growth hormone (GH)-replete and -deficient male and female rats. Sexual dimorphism appeared during growth. Cortical thickening occurred almost entirely by acquisition of bone on the outer (periosteal) surface in males and mainly on the inner (endocortical) surface in females. By 8 months of age, males had 22% greater bone width and 33% greater breaking strength than females. Gonadectomy (Gx) at 6 weeks reduced sex differences in bone width to 7% and strength to 21% by halving periosteal bone formation in males and doubling it in females. Gx had no net effect on the endocortical surface in males but abolished endocortical bone acquisition in females. GH deficiency halved periosteal bone formation and had no net effect on the endocortical surface in males, but abolished bone acquisition on both surfaces in females, leaving males with 17% greater bone width and 44% greater breaking strength than females. Sex hormone deficiency produces greater bone fragility in males than females by removing a stimulator of periosteal growth in males and removing an inhibitor of periosteal growth in females. GH deficiency produces less bone fragility in males than females because males retain androgen-dependent periosteal bone formation while bone acquisition on both surfaces is abolished in females. Thus, periosteal growth is independently and additively stimulated by androgens and GH in males, inhibited by estrogen, and stimulated by GH in females. The hormonal regulation of bone surfaces establishes the amount and spatial distribution of bone and so the sexual dimorphism in its strength.
Animals↗
Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging.
UNLABELLED: The structural basis for sex differences in femoral neck (FN) fragility was studied in 1196 subjects and 307 patients with hip fracture. The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN geometry and structure that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age. INTRODUCTION: Femoral neck (FN) fragility in old age is usually attributed to age-related bone loss, while the sex differences in hip fracture rate are attributed to less bone loss in men than in women. The purpose of this study was to define the structural and biomechanical basis underlying the increase in FN fragility in elderly men and women and the structural basis of sex differences in hip fracture incidence in old age. MATERIALS AND METHODS: We measured FN dimensions and areal bone mineral density in 1196 healthy subjects (801 females) 18-92 years of age and 307 patients (180 females) with hip fracture using DXA. We then used the DXA-derived FN areal bone mineral density (BMD) and measured periosteal diameter to estimate endocortical diameter, cortical thickness, section modulus (a measure of bending strength), and buckling ratio (indices for structural stability). RESULTS: Neither FN cortical thickness nor volumetric density differed in young adult women and men after height and weight adjustment. The sex differences in geometry were confined to the further displacement of the cortex from the FN neutral axis in young men, which produced 13.4% greater bending strength than in young women. Aging amplified this geometric difference; widening of the periosteal and endocortical diameters continued in both sexes but was greater in men, shifting the cortex even further from the neutral axis maintaining bending strength in men, not in women. In both sexes, less age-related periosteal than endocortical widening produced cortical thinning increasing the risk for structural failure by local buckling of the enlarged thin walled FN. Relative to age-matched controls, women and men with hip fractures had reduced cortical thickness, but FN periosteal diameter was increased in women and reduced in men, differences are likely to be originated in growth. CONCLUSIONS: The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN diameters, cortical thickness, and geometry that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age.
Adolescent↗
Pathogenesis of bone fragility in women and men.
There is no one cause of bone fragility; genetic and environmental factors play a part in development of smaller bones, fewer or thinner trabeculae, and thin cortices, all of which result in low peak bone density. Material and structural strength is maintained in early adulthood by remodelling; the focal replacement of old with new bone. However, as age advances less new bone is formed than resorbed in each site remodelled, producing bone loss and structural damage. In women, menopause-related oestrogen deficiency increases remodelling, and at each remodelled site more bone is resorbed and less is formed, accelerating bone loss and causing trabecular thinning and disconnection, cortical thinning and porosity. There is no equivalent midlife event in men, though reduced bone formation and subsequent trabecular and cortical thinning do result in bone loss. Hypogonadism contributes to bone loss in 20-30% of elderly men, and in both sexes hyperparathyroidism secondary to calcium malabsorption increases remodelling, worsening the cortical thinning and porosity and predisposing to hip fractures. Concurrent bone formation on the outer (periosteal) cortical bone surface during ageing partly compensates for bone loss and is greater in men than in women, so internal bone loss is better offset in men. More women than men sustain fractures because their smaller skeleton incurs greater architectural damage and adapts less effectively by periosteal bone formation. The structural basis of bone fragility is determined before birth, takes root during growth, and gains full expression during ageing in both sexes.
Adolescent↗
Preventing osteoporosis: outcomes of the Australian Fracture Prevention Summit.
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Aged↗
Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis.
Both raloxifene (RLX) and alendronate (ALN) can treat and prevent new vertebral fractures, increase bone mineral density (BMD), and decrease biochemical markers of bone turnover in postmenopausal women with osteoporosis. This phase 3, randomized, double-blind 1-yr study assessed the effects of combined RLX and ALN in 331 postmenopausal women with osteoporosis (femoral neck BMD T-score, less than -2). Women (aged < or = 75 yr; > or = 2 yr since their last menstrual period) received placebo, RLX 60 mg/d, ALN 10 mg/d, or RLX 60 mg/d and ALN 10 mg/d combined. At baseline, 6 and 12 months, BMD was measured by dual x-ray absorptiometry. The bone turnover markers serum osteocalcin, bone-specific alkaline phosphatase, and urinary N- and C-telopeptide corrected for creatinine were measured. The effects of RLX and ALN were considered to be independent and additive if the interaction effect was not statistically significant (P > 0.10) in a two-way ANOVA model. All changes in BMD and bone markers at 12 months were different between placebo and each of the active treatment groups, and between the RLX and RLX+ALN groups (P < 0.05). On average, lumbar spine BMD increased by 2.1, 4.3, and 5.3% from baseline with RLX, ALN, and RLX+ALN, respectively. The increase in femoral neck BMD in the RLX+ALN group (3.7%) was greater than the 2.7 and 1.7% increases in the ALN (P = 0.02) and RLX (P < 0.001) groups, respectively. The changes from baseline to 12 months in bone markers ranged from 7.1 to -16.0% with placebo, -23.8 to -46.5% with RLX, -42.3 to -74.2% with ALN, and -54.1 to -81.0% in the RLX+ALN group. RLX and ALN increased lumbar spine and femoral neck BMD, and decreased osteocalcin and C-telopeptide corrected for creatinine in an additive and independent manner, because the interaction effects were not significant. Although the ALN group had changes in BMD and bone markers that were approximately twice the magnitude as in the RLX group, it is not known how well these changes correlate to the clinical outcome of fracture. RLX+ALN reduced bone turnover more than either drug alone, resulting in greater BMD increment, but whether this difference reflects better fracture risk reduction was not assessed in this study.
Aged↗
An exercise in geometry.
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Biomechanical Phenomena↗