Bone loss: Epidemiology of bone loss
© Current Science Ltd 2000
Received: 29 November 1999
Accepted: 17 July 2000
Published: 3 August 2000
Bone loss occurs when the cellular events of bone formation are quantitatively larger than bone formation. This manuscript discusses the measurement of bone loss, occurrence in the population, risk factors and consequences of bone loss. Recent developments in bone mass measurement and biomarkers have improved our ability to assess bone loss. This process is a normal concomitant of ageing. There are a number of other risk factors, including sex hormone deficiency, physical inactivity, calcium/vitamin D deficiency, inflammatory arthritis, corticosteroids, smoking and alcohol. The major consequence of bone loss in our ageing society is fracture.
Keywordsbone loss epidemiology
Bone is a highly metabolically active tissue; remodelling continues throughout life. The remodelling process is an active coupling of the processes of bone formation and resorption. An imbalance in this active coupling phenomenon, in which the cellular events of bone resorption are quantitatively larger than bone formation, leads to bone loss.
The epidemiology of osteoporosis is distinct from that of bone loss. Although excessive bone loss during ageing is likely to contribute to the incidence of osteoporosis, patients with fractures do not consistently have more rapid bone loss, greater bone resorption or a lower rate of bone formation. Any unifying hypothesis on the epidemiology of osteoporosis needs to consider the relative contributions of low peak bone density and bone loss to the deficit in bone density in adulthood.
Assessment of bone loss
Bone mass can be determined in the total skeleton or in local parts of the skeleton, such as the spine, hip and forearm. Current methods for evaluating skeletal status, assessing osteoporosis and bone loss and determining fracture risk rely mostly on the non-invasive assessment of bone mineral content and bone mineral density. The diagnostic procedure is complicated by the fact that different body sites contain different ratios of trabecular to cortical bone, which have different rates of loss. Furthermore, the measurement of bone mass at one site (such as the radius) might not accurately estimate the bone mass at another site (such as the spine or hip), although there is clearly correlation between sites.
A repeat bone mass measurement can be used to assess bone loss. It is important to understand the limitations of these methods. Most studies on involutional bone loss have used absorptiometric techniques such as single photon absorptiometry, dual photon absorptiometry and, more recently, dual X-ray absorptiometry and single X-ray absorptiometry. Most of these techniques adjust the estimate of bone mineral for the errors in accuracy, which arise from variability in fat mass between individuals. It is likely that such errors of accuracy contribute to errors in the estimation of bone mass. Moreover, variable fat content of the spine with age is likely to contribute to errors in the estimation of bone loss . At the spine the problem is compounded by the increasing prevalence of osteoarthritis and vascular calcification at the lumbar spine with age.
A further problem is that neither single nor dual X-ray absorptiometry measures true bone density (g/cm3). The areal bone density (g/cm or g/cm2) that they provide yields an overestimate of volumetric bone mineral density. This inaccuracy is negligible in the short term but is more important in longitudinal studies, particularly as the width of many bones can increase with age . A recent study by Grampp et al  advocated the use of quantitative computed tomography as the most accurate method of assessing bone loss.
Another approach to the estimation of the rate of loss has been the measurement of biochemical markers of bone turnover. Previous reports concerning the association of markers with bone loss have been inconsistent. Some cross-sectional studies have found that there is a weak inverse relationship between biochemical markers and bone density, and that marker levels are elevated during periods of accelerated bone loss, such as early menopause [4,5]. Several algorithms have been developed from longitudinal data to provide an estimate of bone loss and stratify people into categories on the basis of their rate of bone loss [6,7]. The large day-to-day variations in the concentration of biochemical markers, and heterogeneity in biochemical markers of bone turnover in patients with fractures, make the application of these techniques difficult even for longitudinal data. More work is required to stratify further the risk of bone loss, but at present the use of biochemical markers has limited value in predicting bone loss in individuals .
Occurrence of bone loss
Bone loss is a normal concomitant of ageing and occurs in both genders after peak bone mass has been attained . Starting from the middle of the third decade, women lose 35% of their cortical bone and 50% of their trabecular bone , whereas men lose approximately two thirds of this amount over their respective lifetimes .
Type 1 (postmenopausal) osteoporosis generally occurs before the age of 65. It affects 5-25% of women in early menopause [10,12]. Eastell et al  found that the ratio of trabecular to cortical bone of the vertebral body was 75:25, whereas other investigators found the ratio in the femoral neck to be 30:70 . As trabecular bone loss is accelerated relative to cortical bone loss after menopause, regions with substantial amounts of trabecular bone might become fragile sooner.
Type 2 osteoporosis occurs in both men and women and involves the loss of both trabecular and cortical bone. The prevalence of this type of bone loss is universal after peak bone mass has been attained.
Studies have shown that from age 30-40, bone loss (both trabecular and cortical) begins [10,11] and that menopause is followed by an immediate decrease in bone mass and density within a year at both peripheral and central sites. The increased rate of bone loss reaches equilibrium approximately 10 years after menopause and then merges into a continuous age-related loss of predominantly cortical bone .
There is no firm evidence that bone loss is a bimodal process (in other words that there are fast losers and slow losers). Some studies have stratified their analysis of fracture risk into those who are fast, normal and slow bone losers. The results of this analysis indicate that those with a faster rate of bone loss have a higher future risk of fracture .
Risk factors for bone loss
In contrast with the total variance in bone density, which is undoubtedly predominantly genetic , studies on the genetic determinants of bone loss have yielded conflicting results [18,19,20]. From these data the view has emerged that environmental factors such as exercise might exert a large influence on bone loss at skeletal sites such as the hip and wrist, whereas genetic factors might be important in determining spinal bone loss. Gene-environment interactions undoubtedly contribute at all sites of bone loss.
Of the many factors that influence bone loss, sex hormone deficiency is by far the most important. Data from several studies have shown that rapid bone loss in women after the menopause can be effectively prevented by hormone replacement therapy . As well as sex hormones, abnormalities of the calciotropic hormones are associated with bone loss .
Distinct from the accelerated phase of postmenopausal bone loss is a continuous and more gradual process of age-related bone loss that starts before the menopause in women and continues throughout life in both sexes . This type of loss was previously considered to be a relatively slow and constant process, but longitudinal prospective research has provided evidence for a phase of accelerated bone loss in old age, affecting mainly the hip [23,24]. It is difficult to differentiate the relative contributions of age and oestrogen deficiency in most patients .
There have been few longitudinal studies investigating the effect of physical activity on bone loss. Some studies have shown beneficial effects of exercise on bone mass in post-menopausal women. A recent longitudinal study provided evidence that a physically active lifestyle in the later decades of life can retard proximal femur loss . This suggested an interaction between physical activity, weight, weight change and age-related bone loss. Underlying the idea that physical activity increases muscle strength and hence bone mass, several studies have examined the mechanical influence on bone loss .
Calcium intake has a significant effect on bone loss in women although the magnitude of effect seems to be dependent on age and site . There is evidence that calcium supplementation slows the rate of bone loss in postmenopausal women , especially in those with a low dietary intake of calcium . Moreover, the supplementation of calcium and vitamin D has been shown to reduce the risk of hip fracture in institutionalized elderly patients, who might be deficient in these nutrients .
The osteoporosis associated with inflammatory diseases such as rheumatoid arthritis and neoplastic diseases such as myeloma is due in large part to increased bone loss. This has been extensively documented in rheumatoid arthritis, where there is evidence of systemic and periarticular bone loss at an early phase in the disease . Corticosteroids also cause osteoporosis by inducing accelerated bone loss .
Smoking predisposes to osteoporosis by inducing an earlier menopause and by causing an increased metabolic breakdown of oestrogen, both of which tend to accelerate bone loss .
High intakes of alcohol are known to have deleterious effects on bone mass, owing to the inhibitory effect of the alcohol on osteoblastic activity and the fact that the individuals who consume large amounts of alcohol are also prone to protein and/or calcium malnutrition, reduced mobility and hypogonadism.
Higher weight is associated with lower rates of bone loss ; conversely, older women with a smaller body size are at increased risk of hip fracture . This increased risk is seen predominantly in those with involuntary weight loss .
Other risk factors for bone loss include gastrointestinal disorders causing malabsorption, the use of drugs such as anticonvulsants, chronic renal disease and amenorrhoea .
Outcome of bone loss: clinical implications
The major consequence of bone loss in our ageing society is fracture. The relative contributions of peak bone mass and bone loss to the development of low bone mass later in life with its attendant fractures requires clarification. Until these factors can be measured and their contributions to fracture development calculated it will be difficult to determine the exact role of bone loss in fracture development, because other factors associated with bone loss such as the development of microarchitectural abnormalities and microdamage could also be contributing.
Bone density decreases with advancing age as a result of bone loss . Prospective epidemiological studies indicate that bone mineral density is the single best predictor of fractures [38,39]. A 1 SD decrease in bone mass can account for a 50-100% increase in the risk of all non-spine fractures, and a 1 SD difference in bone mass in the femoral neck is associated with a relative risk of 2.6 for subsequent hip fracture.
Bone turnover is difficult to interpret on an individual level. Heterogeneity in histomorphometric parameters of bone turnover, and biochemical markers of bone turnover , are found in patients with fractures. Eriksen et al  showed that patients with vertebral fractures had increased bone resorption and decreased bone formation at the cellular level but not at the tissue level. Meunier et al  found that approximately 50% of patients with vertebral fractures had no evidence of abnormalities in bone resorption or formation, approximately 30% had higher bone resorption surfaces, and approximately 20% had evidence of decreased formation.
Approximately 40 in 100 women will experience one or more fractures after the age of 50 years. At 50 years for women the lifetime risk is 17.5% for hip fracture, 16% for vertebral fracture and 16% for Colles' fracture; for men, the respective lifetime risks are 6%, 5% and 2.5% . The consequences of these fractures, which can include reduced life expectancy, prolonged medical care and loss of independence, have a profound socioeconomic impact in an ageing population . The different fracture risk in men is a result of a number of contributing factors, including less bone loss with ageing .
Management of bone loss
The two approaches that can be adopted in bone loss modification are, firstly, to identify those at greatest risk and, secondly, to move the distribution of bone loss for the whole population. From the viewpoint of the individual patient, bone loss is only one of the factors associated with ageing that contributes to fracture risk; management therefore needs to be individualized. Initially addressing their modifiable risk factors remains the gold standard of current medical practice. Following this pharmacological intervention might be required for those individuals identified as being 'at risk'.
No discussion of epidemiology would be complete without considering the pharmaco-epidemiology of bone loss. In recent years a plethora of antiresorptive agents have become available. Rather than identify their individual strengths on the modification of bone loss, we would encourage readers to consider the various consensus statements available .
- Pacifici R, Susman N, Carr PL, Birge SJ, Avioli LV: Single and dual energy tomographic analysis of spinal trabecular bone: a comparative study of normal and osteoporotic women. J Clin Endocrinol Metabol . 1987, 64: 209-214.View Article
- Parfitt AM: Age related structural changes in trabecular and cortical bone: cellular mechanisms and biomechanical consequences. Calcif Tissue Int. 1984, 36: 122-128.
- Grampp S, Genant HK, Mathur A, Lang P, Jergas M, Takada M, Gluer CC, Lu Y, Chavez M: Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination, and diagnostic classification. J Bone Min Res. 1997, 12: 697-711.View Article
- Uebelhardt D, Schleemer A, Johansen JS, Gineyts E, Christiansen C, Delmas PD: Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium crosslinks. J Clin Endocrinol Metab . 1991, 72: 367-373.View Article
- Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD: Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Min Res. 1996, 3: 337-349.
- Christiansen C, Riis BJ, Rodbro P: Prediction of rapid bone loss in postmenopausal women. Lancet. 1987, i: 1105-1108.View Article
- Falch JA, Sandvik L, van Beresteijn ECH: Development and evaluation of an index to predict early postmenopausal loss. Bone . 1992, 13: 337-341.PubMedView Article
- Bauer DC, Sklarin PM, Stone KL, Black DM, Nevitt MC, Ensrud KE, Arnaud CD, Genant HK, Garnero P, Delmas PD, Lawaetz H, Cummings SR: Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J Bone Min Res . 1999, 14: 1404-1410.View Article
- Riggs BL, Wahner HW, Melton LJ, Richelson LS, Judd HL, Offord KP: Rates of bone loss in the appendicular and axial skeletons of women: evidence of substantial vertebral bone loss before menopause. J Clin Invest. 1986, 77: 1487-1491.PubMedPubMed CentralView Article
- Riggs BL, Wahner HW, Seeman E, Offord KP, Dunn WL, Mazess RB, Johnson KA, Melton LJ: Changes in bone mineral density of the proximal femur and spine with ageing: differences between the postmenopausal and senile osteoporosis syndromes. J Clin Invest. 1982, 70: 716-723.PubMedPubMed CentralView Article
- Riggs BL, Wahner HW, Dunn WL, Mazess RB, Offord KP, Melton LJ: Differential changes in bone mineral density of the appendicular and axial skeleton with ageing. J Clin Invest. 1981, 67: 328-335.PubMedPubMed CentralView Article
- Lindsay R: Prevention of osteoporosis. Clin Orthop . 1987, 222: 44-59.PubMed
- Eastell R, Wahner HW, O'Fallon WM, Amadio PC, Melton LJ, Riggs BL: Unequal decrease in bone density of lumbar spine and ultra-distal radius in Colles' and vertebral fracture syndromes. J Clin Invest . 1989, 83: 168-174.PubMedPubMed CentralView Article
- Liu G, Chou T, Seeman E: Age-related changes in the proportions of cortical and trabecular bone of the vertebral body and proximal femur. In Proceedings of the Annual Meeting of the Australian/New Zealand Bone Mineral Society.Bone Min Res. 1992, 67:
- Riggs BL, Melton LJ: Involutional osteoporosis. N Engl J Med. 1986, 314: 1676-1686.PubMedView Article
- Riis BJ: The role of bone loss. Am J Med. 1995, 98: 29S-32S.PubMedView Article
- Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S: Genetic determinants of bone mass in adults: a twin study. J Clin Invest. 1987, 80: 706-710.PubMedPubMed CentralView Article
- Slemenda CW, Christian JC, Reed T, Reister TK, Williams CJ, John-ston CC: Long term bone loss in men: Effects of genetic and environmental factors. Ann Intern Med. 1992, 117: 286-291.PubMedView Article
- Kelly PJ, Hopper JL, Macaskill GT, Pocock NA, Sambrook PN, Eisman JA: Genetic factors in bone turnover. J Clin Endocrinol Metab . 1991, 72: 808-813.PubMedView Article
- Kelly PJ, Nguyen T, Hopper J, Pocock N, Sambrook P, Eisman J: Changes in axial bone density with age: a twin study. J Bone Min Res. 1993, 8: 11-17.View Article
- Riggs BL, Melton LJ: The prevention and treatment of osteoporosis. N Engl J Med. 1993, 328: 460-464.View Article
- Stone K, Bauer DC, Black DM, Sklarin P, Ensrud KE, Cummings SR: Hormonal predictors of bone loss in elderly women: a prospective study. J Bone Min Res. 1998, 13: 1167-1174.View Article
- Jones G, Nguyen T, Sambrook P, Kelly PJ, Eisman JA: Progressive loss of bone in the femoral neck in elderly people: longitudinal findings from the Dubbo osteoporosis epidemiology study. Br Med J. 1994, 309: 691-695.View Article
- Ensrud KE, Palermo L, Black DM, Cauley J, Jergas M, Orwoll ES, Nevitt MC, Fox KM, Cummings SR: Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures. J Bone Min Res. 1995, 10: 1778-1787.View Article
- Riggs BL, Khosla S, Melton LJ: A unitary model for involutional osteoporosis: Estrogen deficiency causes both Type 1 and Type 2 osteoporosis in postmenopausal women and contributes to bone loss in ageing men. J Bone Min Res. 1998, 13: 763-773.View Article
- Nguyen TV, Sambrook PN, Eisman JA: Bone loss, physical activity, and weight change in elderly women: the Dubbo osteoporosis epidemiology study. J Bone Min Res. 1998, 13: 1458-1467.View Article
- Frost HM: On our age-related bone loss: insights from a new paradigm. J Bone Min Res. 1997, 12: 1539-1546.View Article
- Citron JT, Ettinger B, Genant HK: Spinal bone mineral loss in estrogen-replete, calcium-replete premenopausal women. Osteoporosis Int. 1995, 5: 228-233.View Article
- Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ: Effect of calcium supplementation on bone loss in postmenopausal women. N Engl J Med. 1993, 328: 460-464.PubMedView Article
- Dawson Hughes B, Dallal GE, Krall EA, Sadowski L, Sahyoun N, Tan-nenbaum S: A controlled trial of the effect of calcium supplements on bone density in postmenopausal women. N Engl J Med. 1990, 323: 878-883.PubMedView Article
- Chapuy MC, Arlot ME, Dubeof F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ: Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med. 1992, 327: 1637-1642.PubMedView Article
- Gough AK, Lilley J, Eyre S, Holder PL, Emery P: Generalised bone loss in patients with early rheumatoid arthritis. Lancet. 1995, 344: 23-27.View Article
- Sambrook PN, Jones G: Corticosteroid osteoporosis. Br J Rheumatol. 1995, 34: 8-12.PubMedView Article
- Baron JA: Smoking and estrogen related disease. Am J Epidemiol. 1984, 119: 9-22.PubMed
- Ensrud KE, Lipschutz RC, Cauley JA, Seeley D, Nevitt MC, Scott J, Orwoll ES, Genant HK, Cummings SR: Body size and hip fracture risk in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Am J Med. 1997, 103: 274-280.PubMedView Article
- Ensrud KE, Cauley J, Lipschutz R, Cummings SR: Weight change and fractures in older women. Study of Osteoporotic Fractures Research Group. Arch Int Med. 1997, 157: 857-863.View Article
- Miller KK, Klibanski A: Amenorrheic bone loss. J Clin Endocrin Metab. 1999, 84: 1775-1783.
- Ooms ME, Vlasman P, Lips P, Nauta J, Bouter LM, Valkenburg HA: The incidence of hip fractures in independent and institutionalised people. Osteoporosis Int. 1994, 4: 6-10.View Article
- Melton LJ, Lane AW, Cooper C, Eastell R, O'Fallon WH, Riggs BL: Prevalence and incidence of vertebral deformities. Osteoporosis Int. 1993, 3: 113-119.View Article
- Eastell R, Robins SP, Colwell T, Assiri AMA, Riggs BL, Russell RGG: Evaluation of bone turnover in type 1 osteoporosis using biochemical markers specific for bone formation and bone resorption. Osteoporosis Int. 1993, 3: 255-260.View Article
- Eriksen EF, Hodgson SF, Eastell R, Cedel SL, O'Fallon WM, Riggs BL: Cancellous bone remodelling in type 1(postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption and bone loss at tissue and cellular levels. J Bone Min Res. 1990, 5: 311-319.View Article
- Meunier PJ, Sellami S, Briancon D, Edouard C: Histological heterogeneity of apparently idiopathic osteoporosis. In: Osteoporosis - Recent Advances in Pathogenesis and Treatment. Edited by Deluca HF, Frost HM, Jee WSS, Johnston CC, Parfitt AM. Baltimore: University Park Press;. 1990, 293-301.
- Lips P: Epidemiology and predictors of fractures associated with osteoporosis. Am J Med. 1997, 103: 3S-11S.PubMedView Article
- Cooper C: The crippling consequences of fractures and their impact on quality of life. Am J Med. 1997, 103: 12S-19S.PubMedView Article
- Gennari C, Nuti R: Bone loss in men. Calcified Tiss Int . 1996, 58: 1-3.View Article
- Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D: Guidelines for the diagnosis and management of osteoporosis. Osteoporosis Int. 1997, 7: 390-406.View Article