Elsevier

The Lancet

Volume 359, Issue 9320, 25 May 2002, Pages 1841-1850
The Lancet

Series
Pathogenesis of bone fragility in women and men

https://doi.org/10.1016/S0140-6736(02)08706-8Get rights and content

Summary

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 hyperparathyroldism 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.

Section snippets

Bone mineral density (BMD) and osteoporosis

The mineralised skeleton is defined externally by its outer (periosteal) surface and by the endocortical, trabecular, and intracortical components of its inner (endosteal) surface (figure 1).1 Cellular activity on these surfaces produces net bone formation or resorption during growth and ageing, modifying the size, shape, architecture, mass, and strength of the skeleton. Periosteal bone formation defines the cross sectional area of the bone, whereas endocortical bone formation or resorption

Structural abnormalities

Women and men who sustain fragility fractures do so because they have reduced BMD. The deficits are generalised, but tend to be most severe at the site of fracture—eg, people with fractures of the spine have greater deficits at the spine than at the hip.7, 8, 9, 10

Individuals with spinal fractures have reduced vertebral BMD for two reasons. Vertebral size is smaller in cross sectional area and height, and there is less bone in the smaller bone—ie, the cortices are thin and porous, especially on

Origin of site-specific abnormalities

The site-specific structural abnormalities seen in individuals with fractures have their origins in growth as well as in ageing.7, 26, 27 The deficit in BMD in the daughters of women with fractures of the spine, relative to their age-matched peers, is about half that of their mothers, which is consistent with the view that the deficit sustained by their mothers, relative to their age-matched peers, was present when they were premenopausal. Women who begin the menopause with a low peak BMD are

Structural basis of irreversible bone loss

After longitudinal growth has stopped and peak bone size and peak BMD have been reached, bone remodelling continues on the endosteal surfaces. Osteoclasts resorb a volume of bone, leaving a focal resorptive cavity on the trabecular and endocortical surfaces or a cutting cone within the cortex (figure 6).49 After a delay, osteoblasts fill the cavity with a volume of new bone that undergoes rapid primary then slower secondary mineralisation. Provided that the volumes of bone removed and replaced

Heterogeneous basis of bone fragility

More women sustain fractures than men because they start with a smaller skeleton at peak and trabecular bone loss proceeds by more architectural disruption; women have a skeleton that adapts less well to ageing by periosteal apposition—ie, periosteal bone formation increases the cross sectional area of the bone less, so that the load per unit area on the bone decreases—and bone loss is offset less in women. Consequently, a higher proportion of elderly women than elderly men have bone size and

Conclusion

Osteoporosis or low BMD has no single cause. In thinking about the pathogenesis of structural failure, bone fragility is probably a better term to use than osteoporosis. The epidemiology, pathogenesis, prevention, and treatment of bone fragility better conveys the breadth, depth, and heterogeneous nature of the biomechanical problem of structural failure. To group individuals into one seemingly homogeneous group because they have a BMD below –2·5 SD, one or more spinal fractures, or a hip

Search strategy

The work is based on review of available international publications, printed in English, collected during the past 20 years, and documented in Advances of Osteoporosis and Progress in Osteoporosis; a journal I edit and in which all the published work in osteoporosis is summarised in abstract form. The main published work is based on the major bone journals (J Bone Miner Res, Bone, Osteoporos Int, Calcif Tissue Intern, J Clin Densitometry) and journals such as Lancet, N Engl J Med, Am J Med,

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