Epidemiology, etiology, and diagnosis of osteoporosis

  • Nancy E. Lane
    Correspondence
    Reprint requests: Nancy E. Lane, MD, Director and Professor, Aging Center, Medicine and Rheumatology, University of California at Davis Medical Center, 4625 2nd Ave, Suite 2005, Sacramento, CA 95817.
    Affiliations
    Aging Center, Medicine and Rheumatology, University of California at Davis Medical Center, Sacramento, CA
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      Osteoporosis, a major public health problem, is becoming increasingly prevalent with the aging of the world population. Osteoporosis is a skeletal disorder characterized by compromised bone strength, which predisposes the individual to an increased risk of fractures of the hip, spine, and other skeletal sites. The clinical consequences and economic burden of this disease call for measures to assess individuals who are at high risk to allow for appropriate intervention. Many risk factors are associated with osteoporotic fracture, including low peak bone mass, hormonal factors, the use of certain drugs (eg, glucocorticoids), cigarette smoking, low physical activity, low intake of calcium and vitamin D, race, small body size, and a personal or a family history of fracture. All of these factors should be taken into account when assessing the risk of fracture and determining whether further treatment is required. Because osteoporotic fracture risk is higher in older women than in older men, all postmenopausal women should be evaluated for signs of osteoporosis during routine physical examinations. Radiologic laboratory assessments of bone mineral density generally should be reserved for patients at highest risk, including all women over the age of 65, younger postmenopausal women with risk factors, and all postmenopausal women with a history of fractures. The evaluation of biochemical markers of bone turnover has been useful in clinical research. However, the predictive factor of these measurements is not defined clearly, and these findings should not be used as a replacement for bone density testing. Together, clinical assessment of osteoporotic risk factors and objective measures of bone mineral density can help to identify patients who will benefit from intervention and, thus, can potentially reduce the morbidity and mortality associated with osteoporosis-associated fractures in this population.

      Key words

      Epidemiology of osteoporosis

      Prevalence

      Elderly people are the fastest growing population in the world and, as people age, bone mass declines and the risk of fractures increases.
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      • Melton 3rd, L.J.
      Epidemiology and outcomes of osteoporotic fractures.
      Osteoporosis, defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture, is a major public health problem throughout the world.
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      • Poor G.
      • Reid I.
      • Ehrlich G.
      • Kanis J.
      • et al.
      Interim report and recommendations of the World Health Organization Task-Force for Osteoporosis.
      The social and economic burden of osteoporosis is increasing steadily because of the aging of the world population.
      • Cummings S.R.
      • Melton 3rd, L.J.
      Epidemiology and outcomes of osteoporotic fractures.
      Currently affecting more than 10 million people in the United States, osteoporosis is projected to impact approximately 14 million adults over the age of 50 by the year 2020.
      • National Osteoporosis Foundation
      America's bone health: the state of osteoporosis and low bone mass in our nation.
      Worldwide, approximately 200 million women have osteoporosis.

      International Osteoporosis Foundation. The facts about osteoporosis and its impact. International Osteoporosis Foundation Web site. Available at: http://www.osteofound.org/press_centre/fact_sheet.html. Accessed July 26, 2005.

      Although the likelihood of developing osteoporosis currently is greatest in North America and Europe, it will increase in developing countries as population longevity in these countries continues to increase.
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      • Poor G.
      • Reid I.
      • Ehrlich G.
      • Kanis J.
      • et al.
      Interim report and recommendations of the World Health Organization Task-Force for Osteoporosis.

      Clinical consequences

      The annual incidence of osteoporotic fractures exceeds 1.5 million in the United States.
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      Hip fractures, long considered more devastating than any other type of osteoporotic fracture, are projected to increase from an estimated 1.7 million in 1990 to 6.3 million by the year 2050.
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      Epidemiology and outcomes of osteoporotic fractures.
      Notably, 1 in 5 persons die during the first year after a hip fracture,
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      whereas nearly one third require nursing home placement after hospital discharge, and fewer than one third regain their prefracture level of physical function.
      NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy.
      Vertebral fractures also are associated with an increased incidence of morbidity, including back pain, height loss, deformity (kyphosis), disability, and mortality.
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      Impact of postural deformities and spinal mobility on quality of life in postmenopausal osteoporosis.
      Moreover, multiple thoracic fractures can result in restrictive lung disease, and altered abdominal anatomy caused by lumbar fractures can lead to constipation, abdominal pain, distention, reduced appetite, and premature satiety. The pain, physical limitations, and lifestyle and cosmetic changes caused by osteoporotic fractures can have serious psychologic effects, including depression, loss of self-esteem, anxiety, fear, anger, and strained interpersonal relationships.
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      The impact of incident vertebral and non-vertebral fractures on health related quality of life in postmenopausal women.
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      Epidemiology of osteoporotic fractures.

      Economic burden

      Osteoporotic fractures cost the US health care system approximately $17 billion annually, with an annual cost projected to approach $50 billion by the year 2040.
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      Management of osteoporosis.
      These direct medical costs represent a greater burden than the projected annual costs of stroke, breast cancer, diabetes, or chronic lung disease.
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      Management of osteoporosis.
      Worldwide, the economic burden of osteoporosis parallels that seen in the United States, with expenditures for osteoporotic fractures rising faster than the general rate of inflation in almost every country.
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      Epidemiology and outcomes of osteoporotic fractures.
      Also, the indirect cost of osteoporotic fractures, the costs associated with fracture-related morbidity and mortality, are substantial. Clearly, the clinical and economic consequences of osteoporosis call for a concerted effort to assess patients at risk to allow for prevention and early intervention when appropriate.

      Etiology and pathogenesis of osteoporosis

      Bone strength reflects the integration of 2 main features: bone density and bone quality.
      • National Institutes of Health
      NIH consensus statement: osteoporosis prevention, diagnosis, and therapy.
      Many factors contribute to the risk of osteoporotic fractures, all of which should be taken into account in the assessment of fracture risk in patients (Figure).
      Figure thumbnail gr1
      FigurePathogenesis of osteoporotic fractures. Adapted from Riggs and Melton.
      Used with permission of Raven Press.

      Impact of bone density and bone quality on the risk of fracture

      The World Health Organization (WHO) has defined criteria for assessing bone status and determining the risk of fracture. These criteria are defined by the T-score, which is the number of standard deviations (SDs) by which a patient's test result exceeds (positive T-score) or falls below (negative T-score) the mean of the young adult group.
      • WHO Study Group
      Assessment of fracture risk and its application to screening for postmenopausal osteoporosis.
      Bone density—also called bone mineral density (BMD)—is expressed as a relationship to 2 norms: the T-score and the Z-score (the expected BMD for the individual's age and sex).
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      This criterion of bone density is used conventionally as a proxy for overall bone strength and is expressed as grams of mineral per square centimeter or grams per cubic centimeter.
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      Bone density: BMC, BMD, or corrected BMD?.
      Evidence that the risk of fracture increases as BMD declines has been demonstrated in multiple epidemiologic studies.
      • Marshall D.
      • Johnell O.
      • Wedel H.
      Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.
      • European Prospective Osteoporosis Study (EPOS) Group
      The relationship between bone density and incident vertebral fracture in men and women.
      • Miller P.D.
      • Siris E.S.
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      • Wehren L.E.
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      • et al.
      Prediction of fracture risk in postmenopausal white women with peripheral bone densitometry: evidence from the National Osteoporosis Risk Assessment.
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      • Ensrud K.
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      Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group.
      For example, in the European Prospective Osteoporosis Study with a cohort of 1924 women, the risk of incident vertebral fracture increased by a factor of 1.5 per 0.1 g/cm2 decrease in the spinal BMD value. Although BMD is the standard test for the diagnosis of osteoporosis before treatment, ongoing research indicates that BMD measurement alone may not be adequate for assessing fracture risk and treatment efficacy. A more useful concept may be bone quality, which reflects the integration of both BMD and bone strength. Bone strength is determined by structural and material properties that impact overall bone quality.
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      Osteoporosis imaging.
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      • Boonen S.
      The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management.
      The structural properties of bone include geometry (size and shape) and microarchitecture (eg, trabecular thickness and connectivity and cortical thickness/porosity). The material properties of bone include mineralization (mineral-to-matrix ratio and crystal size), collagen composition (type and cross-links), and damage accumulation (such as microfractures). These components of bone strength are affected by the bone turnover rate, in which old bone is resorbed and new bone is created.
      • Link T.M.
      • Majumdar S.
      Osteoporosis imaging.
      • Felsenberg D.
      • Boonen S.
      The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management.
      In older women, abnormalities in the bone remodeling process compromise these properties, increasing the propensity for fracture.
      • Seeman E.
      The structural and biomechanical basis of the gain and loss of bone strength in women and men.
      In addition, estrogen deficiency after menopause has been associated with an accelerated loss of bone and bone turnover, leading to a substantial increase in the risk for fracture.
      • Felsenberg D.
      • Boonen S.
      The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management.
      • Seeman E.
      The structural and biomechanical basis of the gain and loss of bone strength in women and men.
      Decreases in estrogen levels increase bone resorption by lengthening the life span of osteoclasts and decrease bone building by shortening the life span of osteoblasts.
      • Seeman E.
      The structural and biomechanical basis of the gain and loss of bone strength in women and men.
      Antiresorptive agents have been shown to reduce the risk of vertebral fracture without producing large gains in lumbar spine BMD, providing evidence that factors other than BMD play a role in bone strength.
      • Cummings S.R.
      • Karpf D.B.
      • Harris F.
      • Genant H.K.
      • Ensrud K.
      • Lacroix A.Z.
      • et al.
      Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs.
      In these patients, changes in bone turnover markers may also be evaluated to help assess bone strength and fracture risk reduction.

      Pathogenesis of osteoporosis

      Normal bone turnover involves a balance between the processes of bone resorption and bone formation in which osteoclasts remove (resorb) bone by acidification and proteolytic digestion and osteoblasts secrete osteoid (organic matrix of bone) into the resorption cavity.
      • Manolagas S.C.
      Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.
      In postmenopausal women, the rate of bone turnover increases dramatically and remains elevated for up to 40 years after cessation of ovarian function, leading to continuous, progressive bone loss.
      • Garnero P.
      • Sornay-Rendu E.
      • Chapuy M.-C.
      • Delmas P.D.
      Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.
      The basis for the increased bone turnover is thought to be due in part to a shortening of the lifespan of osteoblasts and a prolongation of the lifespan of osteoclasts.
      • Manolagas S.C.
      Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.

      Risk factors for osteoporosis and osteoporotic fractures

      Several interacting factors contribute to the risk of osteoporotic fracture, including clinical, medical, behavioral, nutritional, and genetic variables.
      • Cooper C.
      • Melton L.J.
      Epidemiology of osteoporosis.

      Clinical factors

      A major determinant of bone density in an older individual is her or his peak bone mass.
      • Cooper C.
      • Melton L.J.
      Epidemiology of osteoporosis.
      • Mora S.
      • Gilsanz V.
      Establishment of peak bone mass.
      Although the attainment of peak bone mass begins in utero and is typically complete by age 40, the main contributor to this process is the amount of bone that is gained during adolescence.
      • Cooper C.
      • Melton L.J.
      Epidemiology of osteoporosis.
      • Mora S.
      • Gilsanz V.
      Establishment of peak bone mass.
      Generally, it is thought that low peak bone mass is associated with an increased risk of osteoporotic fracture, although the role of peak bone mass as a factor in osteoporosis has not been thoroughly explored.
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      • Mora S.
      • Gilsanz V.
      Establishment of peak bone mass.
      In the first years after cessation of ovarian function at menopause, bone loss accelerates
      • Garnero P.
      • Sornay-Rendu E.
      • Chapuy M.-C.
      • Delmas P.D.
      Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.
      and bone mass continues to decline with age.
      • Hannan M.T.
      • Felson D.T.
      • Dawson-Hughes B.
      • Tucker K.L.
      • Cupples L.A.
      • Wilson P.W.
      • et al.
      Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study.
      Therefore, in addition to peak bone mass, aging itself is a risk factor for bone loss.
      • Cooper C.
      • Melton L.J.
      Epidemiology of osteoporosis.
      Postmenopausal women with a low body weight, low percentage of body fat, or low body mass index are at increased risk of low bone mass and rapid bone loss, both of which are independent contributing factors to postmenopausal osteoporosis.
      • Ravn P.
      • Cizza G.
      • Bjarnason N.H.
      • Thompson D.
      • Daley M.
      • Wasnich R.D.
      • et al.
      Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group.
      In women aged 65 years or older, both low serum total estradiol concentrations (<5 pg/mL) and high serum concentrations of sex hormone-binding globulin (≥1 μg/dL) have been shown to increase the risk of hip and vertebral fractures, without relation to BMD.
      • Cummings S.R.
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      • Stone K.
      • Ensrud K.
      • Jamal S.
      • et al.
      Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group.
      The strong association between a history of hyperthyroidism and the risk of hip fracture in elderly women, also independent of BMD, may be attributable to long-lasting impairment of bone strength, neuromuscular function, and/or muscle strength.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
      Several studies also have documented an association between prior fracture history at any site and the risk of future vertebral and hip fractures.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
      • Klotzbuecher C.M.
      • Ross P.D.
      • Landsman P.B.
      • Abbott 3rd, T.A.
      • Berger M.
      Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis.
      • Lindsay R.
      • Silverman S.L.
      • Cooper C.
      • Hanley D.A.
      • Barton I.
      • Broy S.B.
      • et al.
      Risk of new vertebral fracture in the year following a fracture.
      • Black D.M.
      • Arden N.K.
      • Palermo L.
      • Pearson J.
      • Cummings S.R.
      Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group.
      These observations suggest that existing defects in bone microarchitecture may influence the risk of fracture and that this risk may be independent of BMD. Moreover, it has been shown that in women who have an incident vertebral fracture develop, 1 in 5 have a new vertebral fracture develop in the subsequent year.
      • Lindsay R.
      • Silverman S.L.
      • Cooper C.
      • Hanley D.A.
      • Barton I.
      • Broy S.B.
      • et al.
      Risk of new vertebral fracture in the year following a fracture.
      Impaired vision (ie, poor depth perception and reduced ability to perceive contrast) independently increases the risk of hip fracture in elderly white women
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
      and contributes to the propensity to fall, which is another independent risk factor for fracture.
      • Albrand G.
      • Munoz F.
      • Sornay-Rendu E.
      • Duboeuf F.
      • Delmas P.D.
      Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: The OFELY Study.
      Poor hand grip strength, which can be caused by cognitive impairment, joint disorders, diabetic neuropathy, and/or pain, is a strong independent risk factor for fragility fractures in postmenopausal women.
      • Albrand G.
      • Munoz F.
      • Sornay-Rendu E.
      • Duboeuf F.
      • Delmas P.D.
      Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: The OFELY Study.

      Medical factors

      Secondary osteoporosis is associated with a number of medical disorders, including gastrointestinal diseases (eg, malabsorption syndromes and inflammatory bowel disease), hematologic disorders (eg, thalassemia and pernicious anemia), and hypogonadal states (eg, amenorrhea).
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      Moreover, exposure to certain medications may contribute to and/or exacerbate osteoporosis (Table I).
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      Glucocorticoids are the most commonly implicated class,
      • Saag K.G.
      Glucocorticoid-induced osteoporosis.
      affecting both the quantity and quality of bone.
      • Peel N.F.A.
      • Moore D.J.
      • Barrington N.A.
      • Bax D.E.
      • Eastell R.
      Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis.
      The magnitude of the increased risk of vertebral fracture in glucocorticoid-treated men and women is disproportionate to observed decreases in BMD, leading investigators to speculate that in addition to reducing bone mass, glucocorticoid treatment may lead to bone quality defects mediated by increases in bone turnover and trabecular perforation.
      • Peel N.F.A.
      • Moore D.J.
      • Barrington N.A.
      • Bax D.E.
      • Eastell R.
      Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis.
      • van Staa T.P.
      • Laan R.F.
      • Barton I.P.
      • Cohen S.
      • Reid D.M.
      • Cooper C.
      Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy.
      Postmenopausal women who already have low bone mass are likely to reach a fracture threshold with glucocorticoid treatment sooner than patients with initially higher BMD values.
      • Saag K.G.
      Glucocorticoid-induced osteoporosis.
      Table IMedical therapy that may be associated with reduced bone mass in adults
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.

      National Osteoporosis Foundation. Medications that may cause bone loss—pack of 50. Available at: http://www.nof.org/catalog/order_form_stand_alone_080505. Accessed July 26, 2005.

      AluminumLithium
      Anticonvulsants (phenobarbital, phenytoin)Heparin (long-term use)
      Benzodiazepines (long-acting)Progesterone (parenteral, long-acting)
      Cytotoxic drugsSupraphysiologic thyroxine
      GlucocorticoidsTamoxifen (premenopausal use)
      Gonadotropin-releasing hormone agonistsTotal parenteral nutrition
      Immunosuppressants
      Adapted from National Osteoporosis Foundation.
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.

      Behavioral factors

      Several behavioral risk factors increase the odds of developing osteoporosis and atraumatic fractures. One is cigarette smoking, which is associated with accelerated bone loss and increased risk of hip fracture in the elderly, apparently caused at least in part by reduced intestinal calcium absorption efficiency.
      • Krall E.A.
      • Dawson-Hughes B.
      Smoking increases bone loss and decreases intestinal calcium absorption.
      • Law M.R.
      • Hackshaw A.K.
      A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect.
      A low level of physical activity has been positively correlated with the risk of fracture in certain studies.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
      • Albrand G.
      • Munoz F.
      • Sornay-Rendu E.
      • Duboeuf F.
      • Delmas P.D.
      Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: The OFELY Study.
      After adjustment for confounding variables (eg, self-rated health and neuromuscular function), this correlation did not always remain significant in clinical studies.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
      • Albrand G.
      • Munoz F.
      • Sornay-Rendu E.
      • Duboeuf F.
      • Delmas P.D.
      Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: The OFELY Study.
      Alcohol intake of 207 mL or more (≥7 fl oz) per week is a risk factor for bone loss.
      • Hannan M.T.
      • Felson D.T.
      • Dawson-Hughes B.
      • Tucker K.L.
      • Cupples L.A.
      • Wilson P.W.
      • et al.
      Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study.
      In addition, caffeine intake has been correlated positively with the risk of hip fracture and the rate of bone loss in elderly women with the tt variant of the vitamin D receptor.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.

      Nutritional factors

      Dietary calcium intake is correlated modestly with BMD, although this relationship is apparent mainly in lean men and women with low body mass index values (<27 kg/m2).
      • Nguyen T.V.
      • Center J.R.
      • Eisman J.A.
      Osteoporosis in elderly men and women: effects of dietary calcium, physical activity, and body mass index.
      Vitamin D deficiency is an established risk factor for fractures in the elderly, due to the higher bone turnover, reduced calcium absorption, and loss of bone mass resulting from secondary hyperparathyroidism.
      • Lips P.
      Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.
      A number of prescription medications also have been shown to interfere with calcium absorption, including diuretics, corticosteroids, anticonvulsants, immunosuppressive medications, nonsteroidal anti-inflammatory drugs, asthma medications with corticosteroids, and a number of antibiotics (Table I).
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.

      National Osteoporosis Foundation. Medications that may cause bone loss—pack of 50. Available at: http://www.nof.org/catalog/order_form_stand_alone_080505. Accessed July 26, 2005.

      Genetic factors

      Race is a key determinant of BMD and the risk of fracture. Incidence rates obtained from studies among different racial and ethnic groups demonstrate that although women have higher fracture rates compared with men overall, these differences vary by race and age. For example, in white and Asian subjects, women had higher rates for all age groups older than 50 years. For Hispanic subjects aged 50 to 59 years, men had a higher rate than women, but this gender relationship reversed after age 60. Black men had higher rates than black women until age 70, after which the women had higher rates. For both genders and all race and ethnic groups, the rates increased sharply with age.
      • Villa M.L.
      • Nelson L.
      Race, ethnicity, and osteoporosis.
      Studies conducted in the United States that directly compared non-Hispanic white, Asian, Hispanic, and black subjects have shown that Asian subjects, a population that usually has low bone mass, did not have an increased rate of hip fractures compared with non-Hispanic black and Hispanic subjects.
      • Villa M.L.
      • Nelson L.
      Race, ethnicity, and osteoporosis.
      The highest mean BMD values and lowest hip fracture rates have been reported for black women.
      • National Institutes of Health
      NIH consensus statement: osteoporosis prevention, diagnosis, and therapy.
      • Fang J.
      • Freeman R.
      • Jeganathan R.
      • Alderman M.H.
      Variations in hip fracture hospitalization rates among different race/ethnicity groups in New York City.
      These results demonstrate that race and ethnicity, as well as age and gender, influence the incidence of hip fractures. Nonetheless, in a retrospective review, black patients experienced a longer period of hospitalization after hip fracture and were more likely to be nonambulatory at discharge than white patients.
      • Furstenberg A.L.
      • Mezey M.D.
      Differences in outcome between black and white elderly hip fracture patients.
      Moreover, using Health Care Financing Administration data from 1980 to 1982, black women had a higher mortality rate during hospitalization for hip fracture than white women.
      • Kellie S.E.
      • Brody J.A.
      Sex-specific and race-specific hip fracture rates.
      Body size is another factor affecting the risk of fracture. One study in older, non-Hispanic white women showed that older women with smaller body builds are at increased risk of hip fracture because of lower hip BMD values.
      • Ensrud K.E.
      • Lipschutz R.C.
      • Cauley J.A.
      • Seeley D.
      • Nevitt M.C.
      • Scott J.
      • et al.
      Body size and hip fracture risk in older women: a prospective study. Study of Osteoporotic Fractures Research Group.
      Although all measurements of body size (including total body weight, percentage weight change since age 25, lean mass, fat mass, body fat percentage, hip girth, body mass index, and modified body mass index) were associated with hip fracture risk, measurement of total body weight by itself was found to be sufficient for ascertaining hip fracture risk and was not improved by measurements of the other attributes of body size and composition.
      • Ensrud K.E.
      • Lipschutz R.C.
      • Cauley J.A.
      • Seeley D.
      • Nevitt M.C.
      • Scott J.
      • et al.
      Body size and hip fracture risk in older women: a prospective study. Study of Osteoporotic Fractures Research Group.
      Women with a maternal history of hip fracture are approximately twice as likely to experience hip fractures as women without such a family history.
      • Cummings S.R.
      • Nevitt M.C.
      • Browner W.S.
      • Stone K.
      • Fox K.M.
      • Ensrud K.E.
      • et al.
      Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
      • Albrand G.
      • Munoz F.
      • Sornay-Rendu E.
      • Duboeuf F.
      • Delmas P.D.
      Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: The OFELY Study.

      Predicting fracture risk in postmenopausal women: The FRACTURE Index

      Recently, investigators from the Study of Osteoporotic Fracture Research Group developed the FRACTURE Index, an algorithm to predict the risk of hip, vertebral, and nonvertebral fractures using easily assessed risk factors.
      • Black D.M.
      • Steinbuch M.
      • Palermo L.
      • Dargent-Molina P.
      • Lindsay R.
      • Hoseyni M.S.
      • et al.
      An assessment tool for predicting fracture risk in postmenopausal women.
      The FRACTURE Index was designed to be used as a tool not only for physicians but for patients. As a self-administered questionnaire, women assess their risk for fracture and use the results to facilitate a discussion with their physicians.
      • Black D.M.
      • Steinbuch M.
      • Palermo L.
      • Dargent-Molina P.
      • Lindsay R.
      • Hoseyni M.S.
      • et al.
      An assessment tool for predicting fracture risk in postmenopausal women.
      As shown in Table II, this instrument takes into account the major established risk factors, which include age, personal history of fracture, maternal history of hip fracture, weight, smoking status, and mobility.
      • Black D.M.
      • Steinbuch M.
      • Palermo L.
      • Dargent-Molina P.
      • Lindsay R.
      • Hoseyni M.S.
      • et al.
      An assessment tool for predicting fracture risk in postmenopausal women.
      The maximum possible score is 11 without BMD information and 15 with BMD information, and the investigators recommend that postmenopausal women with a total score 4 or greater without BMD assessment or 6 or greater with BMD assessment should undergo further evaluation by their physician.
      • Black D.M.
      • Steinbuch M.
      • Palermo L.
      • Dargent-Molina P.
      • Lindsay R.
      • Hoseyni M.S.
      • et al.
      An assessment tool for predicting fracture risk in postmenopausal women.
      Further evaluation may include a thorough physical examination, medical history, and radiographs to ensure no prior fractures. In addition, a comprehensive chemistry profile, tests for thyroid function, serum or urinary calcium level, vitamin D level, and bone turnover markers may help determine or rule out any secondary causes of osteoporosis or underlying metabolic diseases that may affect bone health. However, it should be noted that this scoring system was designed for risk assessment in older, postmenopausal white women and may not be applicable to other population groups.
      • Black D.M.
      • Steinbuch M.
      • Palermo L.
      • Dargent-Molina P.
      • Lindsay R.
      • Hoseyni M.S.
      • et al.
      An assessment tool for predicting fracture risk in postmenopausal women.
      Table IIThe FRACTURE Index questions and scoring
      QuestionsPoint value
      1. What is your current age?
       <65 y0
       65-69 y1
       70-74 y2
       75-79 y3
       80-84 y4
       ≥85 y5
      2. Have you broken any bones after age 50?
       Yes1
       No/don't know0
      3. Has your mother had a hip fracture after age 50?
       Yes1
       No/don't know0
      4. Do you weight 125 lb or less?
       Yes1
       No0
      5. Are you currently a smoker?
       Yes1
       No0
      6. Do you usually need to use your arms to assist yourself in standing up from a chair?
       Yes2
       No/don't know0
       If you have had a current BMD assessment, then answer the next question.
      7. What was your total hip T-score?
       ≥ −1.00
       Between −1.0 and −2.02
       Between −2.0 and −2.53
       < −2.54
      Adapted from Black et al.
      • Black D.M.
      • Steinbuch M.
      • Palermo L.
      • Dargent-Molina P.
      • Lindsay R.
      • Hoseyni M.S.
      • et al.
      An assessment tool for predicting fracture risk in postmenopausal women.

      Diagnosis of osteoporosis

      Assessment of existing bone mass, determining the fracture risk based on this clinical assessment, and making decisions regarding the appropriate therapeutic intervention are the ultimate goals when evaluating patients for osteoporosis.
      • National Institutes of Health
      NIH consensus statement: osteoporosis prevention, diagnosis, and therapy.
      The WHO established diagnostic criteria for osteoporosis on the basis of BMD T-scores.
      • WHO Study Group
      Assessment of fracture risk and its application to screening for postmenopausal osteoporosis.
      The T-score describes the patient's BMD in terms of the number of SDs by which it differs from the mean peak value in young, healthy persons of the same sex.
      • Brunader R.
      • Shelton D.K.
      Radiologic bone assessment in the evaluation of osteoporosis.
      The WHO uses a threshold of 2.5 SDs below the mean of young adult women as the criterion for a diagnosis of osteoporosis.
      • WHO Study Group
      Assessment of fracture risk and its application to screening for postmenopausal osteoporosis.
      The criterion for a diagnosis of osteopenia (low bone mass) is more than 1.0 SD but less than 2.5 SDs below the reference mean.
      • WHO Study Group
      Assessment of fracture risk and its application to screening for postmenopausal osteoporosis.
      However, T-scores were developed for the estimation of the prevalence of osteoporosis across populations not for the assessment of osteoporosis in specific patients.
      • Faulkner K.G.
      • von Stetten E.
      • Miller P.
      Discordance in patient classification using T-scores.
      Moreover, although T-scores originally were based on the BMD of the hip measured by dual-energy x-ray absorptiometry (DXA), the scores are now applied to BMD at other skeletal sites and/or measured by different methods.
      • National Institutes of Health
      NIH consensus statement: osteoporosis prevention, diagnosis, and therapy.
      Currently, the National Osteoporosis Foundation and the International Society for Clinical Densitometry consider central DXA of the hip and/or spine as the preferred measurement for a diagnosis of osteoporosis.
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      • Leib E.S.
      • Lewiecki E.M.
      • Binkley N.
      • Hamdy R.C.
      Official positions of the International Society for Clinical Densitometry.

      Candidates for assessment

      The National Osteoporosis Foundation, US Preventative Services Task Force, and the American Association of Clinical Endocrinologists recommend that BMD testing be performed to guide treatment decisions, based on the patient's risk profile.
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      • US Preventive Services Task Force
      Screening for osteoporosis in postmenopausal women: recommendations and rationale.
      • AACE (American Association of Clinical Endocrinologists) Guidelines
      American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003.
      Specifically, BMD testing is indicated for all women aged 65 years or older irrespective of other risk factors, for younger postmenopausal women with 1 or more risk factors, and for postmenopausal women who have had fractures (to confirm the diagnosis and to determine disease severity).
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      • US Preventive Services Task Force
      Screening for osteoporosis in postmenopausal women: recommendations and rationale.
      • AACE (American Association of Clinical Endocrinologists) Guidelines
      American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003.

      Methods of assessment

      Patient history and physical examination

      Many metabolic bone diseases, such as hyperparathyroidism and osteomalacia, also are associated with low BMD measurements; therefore a complete and thorough history taking and physical examination are essential to establishing a correct diagnosis of osteoporosis.
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      A complete history should be obtained, with specific attention given to the previously discussed risk factors, including medical, family, and medication histories.
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      Although patients with decreased BMD values usually have no specific abnormal physical findings, a thorough physical examination may detect kyphosis, a protruding abdomen, and height loss, which signify prevalent vertebral compression fractures; back tenderness, which is usually present only after an acute fracture; reduced gait speed or grip strength, which often are reduced in patients who have had or are about to have a hip fracture; and poor visual acuity, which is a risk factor for falling.
      • Lindsay R.
      • Cosman F.
      Osteoporosis.
      Certain other physical findings, such as nodular thyroid, hepatic enlargement, jaundice, or cushingoid features, may reveal secondary causes of osteoporosis (eg, hyperparathyroidism, liver disease, or Cushing's syndrome).
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.

      University of Washington Online Continuing Medical Education. Osteoporosis and bone physiology. Diagnosis of osteoporosis 2003. Available at: http://uwcme.org/courses/bonephys/diagnosis.html. Accessed November 11, 2003.

      A low Z-score (based on the number of SDs below the BMD of an age-matched population of the same sex) also may be indicative of secondary osteoporosis.

      Radiologic and laboratory assessments

      Assessments of BMD

      BMD is the standard tool used to diagnose osteoporosis. Several methods of imaging have been developed to measure BMD, including DXA and quantitative computed tomography (QCT). The WHO guidelines for the diagnosis of osteoporosis are based on DXA measurements of the hip or spine.
      • WHO Study Group
      Assessment of fracture risk and its application to screening for postmenopausal osteoporosis.

      DXA

      DXA is considered the gold standard of methods used to diagnose osteoporosis.
      • Lochmüller E.M.
      • Müller R.
      • Kuhn V.
      • Lill C.A.
      • Eckstein F.
      Can novel clinical densitometric techniques replace or improve DXA in predicting bone strength in osteoporosis at the hip and other skeletal sites?.
      This test is capable of measuring bone mineral content at any site in the body but usually is used at central sites (the lumbar spine and the proximal femur) and peripheral sites, including the distal forearm.
      • Brunader R.
      • Shelton D.K.
      Radiologic bone assessment in the evaluation of osteoporosis.
      • AACE (American Association of Clinical Endocrinologists) Guidelines
      American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003.
      This is accomplished by passing 2 beams of different energies through the bone at the site being measured.
      • Link T.M.
      • Majumdar S.
      Osteoporosis imaging.
      A major advantage of DXA is that it exposes the patient to radiation levels approximately 90% less than a standard chest radiograph.
      • National Osteoporosis Foundation
      Physician's guide to prevention and treatment of osteoporosis.
      The unit of measurement for bone density with the use of DXA is areal density (g/cm2); however, BMD is reported as a T-score on the basis of this measurement.
      Peripheral DXA techniques analyze BMD at the distal radius and the calcaneus with high precision and low radiation exposure.
      • Link T.M.
      • Majumdar S.
      Osteoporosis imaging.
      Because these measurements are less useful in predicting the risk of fractures of the spine and proximal femur than spinal and hip DXA, a low BMD value obtained by peripheral techniques is not sufficient for a diagnosis or for making treatment decisions, but it does warrant further assessment.
      • Link T.M.
      • Majumdar S.
      Osteoporosis imaging.
      In addition, peripheral sites are less likely than central sites to show an increase in BMD in response to treatment.

      QCT

      QCT also can be used to measure BMD of the lumbar spine or peripheral sites.
      • Brunader R.
      • Shelton D.K.
      Radiologic bone assessment in the evaluation of osteoporosis.
      Although BMD can be measured by QCT on any computed tomographic system, the equipment has to be calibrated by using a calibration phantom that contains elements with standardized densities of calcium hydroxyapatite.
      • Link T.M.
      • Majumdar S.
      Osteoporosis imaging.
      The accuracy of QCT of the spine in predicting spinal fracture is comparable to that of DXA but has the advantage of measuring true volumetric, or 3-dimensional, BMD, in contrast to the areal BMD obtained from DXA.
      • Miller P.D.
      Management of osteoporosis.
      QCT can distinguish between cortical and trabecular bone and thus is more sensitive to changes in BMD caused by the higher bone turnover rate of trabecular bone.
      • Brunader R.
      • Shelton D.K.
      Radiologic bone assessment in the evaluation of osteoporosis.
      It is also precise enough to detect skeletal changes over time, and it can be used to follow the disease state or to monitor results of osteoporosis therapy.
      • Brunader R.
      • Shelton D.K.
      Radiologic bone assessment in the evaluation of osteoporosis.
      Although these imaging techniques are useful for determining BMD when diagnosing osteoporosis, the role of BMD measurement in assessing treatment efficacy, particularly fracture risk reduction, remains unclear.
      • Cummings S.R.
      • Karpf D.B.
      • Harris F.
      • Genant H.K.
      • Ensrud K.
      • LaCroix A.Z.
      • et al.
      Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs.
      • Sarkar S.
      • Mitlak B.H.
      • Wong M.
      • Stock J.L.
      • Black D.M.
      • Harper K.D.
      Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy.
      • Watts N.B.
      • Cooper C.
      • Lindsay R.
      • Eastell R.
      • Manhart M.D.
      • Barton I.P.
      • et al.
      Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate.
      As seen in separate analyses for alendronate, raloxifene, and risedronate, increases in lumbar spine BMD with each therapy explain only a small portion (<20%) of the vertebral fracture risk reduction observed with these agents. Therefore, increases in BMD seen with treatment are not very predictive of the magnitude of vertebral fracture risk reduction.

      Biochemical markers of bone turnover

      Biochemical markers of bone turnover have been used widely in clinical research and represent the products of bone formation and resorption that are released into the circulation (Table III).
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      Quantitative changes in markers reflect the dynamic process of bone metabolism. For example, in postmenopausal women, bone formation and resorption markers are significantly higher than those of premenopausal women, reflecting the high bone turnover rate and associated bone loss that occurs with estrogen deficiency.
      • Garnero P.
      • Sornay-Rendu E.
      • Chapuy M.-C.
      • Delmas P.D.
      Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      In contrast, antiresorptive agents, which decrease osteoclastic activity, are associated with a decrease in bone-turnover markers and an increase in bone density in postmenopausal women.
      • Cooper C.
      • Melton L.J.
      Epidemiology of osteoporosis.
      • Eastell R.
      • Barton I.
      • Hannon R.A.
      • Chines A.
      • Garnero P.
      • Delmas P.D.
      Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate.
      • Sorensen O.H.
      • Crawford G.M.
      • Mulder H.
      • Hosking D.J.
      • Gennari C.
      • Mellstrom D.
      • et al.
      Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience.
      • Harris S.T.
      • Eriksen E.F.
      • Davidson M.
      • Ettinger M.P.
      • Moffett Jr., J.A.
      • Baylink D.J.
      • et al.
      Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women.
      • Watts N.B.
      • Nolan J.C.
      • Brennan J.J.
      • Yang H.-M.
      Esterified estrogen therapy in postmenopausal women: relationships of bone marker changes and plasma estradiol to BMD changes—a two-year study.
      • Follin S.L.
      • Hansen L.B.
      Current approaches to the prevention and treatment of postmenopausal osteoporosis.
      Table IIICurrently available bone turnover markers
      Bone-formation markers
       SerumBone-specific alkaline phosphatase
      Osteocalcin
      Carboxyterminal propeptide of type I collagen
      Aminoterminal propeptide of type I collagen
      Bone-resorption markers
       SerumCross-linked C-telopeptide of type I collagen
      Tartrate-resistant acid phosphatase
      N-telopeptide of collagen cross-links
      C-telopeptide of collagen cross-links
       UrineHydroxyproline
      Pyridinolines
      Deoxypyridinolines
      N-telopeptide of collagen cross-links
      C-telopeptide of collagen cross-links
      Adapted from Khosla and Kleerekoper.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      Markers of bone-formation are released from osteoblasts and typically are measured in serum.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      • Delmas P.D.
      • Eastell R.
      • Garnero P.
      • Seibel M.J.
      • Stepan J.
      The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation.
      Largely because of their tissue specificity and assay sensitivity, the most useful markers are bone-specific alkaline phosphatase (BSAP) and osteocalcin.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      • Fassbender W.J.
      • Steinhauer B.
      • Stracke H.
      • Schumm-Draeger P.M.
      • Usadel K.H.
      Validation of a new automated immunoassay for measurement of intact osteocalcin.
      • Gomez Jr., B.
      • Ardakani S.
      • Ju J.
      • Jenkins D.
      • Cerelli M.J.
      • Daniloff G.Y.
      • et al.
      Monoclonal antibody assay for measuring bone-specific alkaline phosphatase activity in serum.
      • Seibel M.J.
      Biochemical markers of bone remodeling.
      Although type I collagen is the major product synthesized and secreted by osteoblasts, it also is produced by other tissues and current assays lack selectivity for bone derived type I collagen.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      In addition, current assays for quantitating BSAP and osteocalcin are more effective at differentiating between normal and disease states compared with those for type I collagen.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      Bone-resorption markers are secreted during osteoclastic activity and include the collagen breakdown products pyridinoline, deoxypyridinoline, and cross-linked C- and N-telopeptides. Multiple assays are now available that can measure these products relatively quickly and inexpensively.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      Tartrate-resistant acid phosphatase, which is a lysosomal enzyme present in cells, until recently was limited as a bone-resorption marker because early assays lacked specificity for the osteoclast-derived enzyme (TRACP) and because of its instability in assay samples.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      • Halleen J.M.
      • Alatalo S.L.
      • Janckila A.J.
      • Woitge H.W.
      • Seibel M.J.
      • Väänänen H.K.
      Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption.
      Newer assays are now available that are selective for TRACP 5b, the osteoclast-specific isoform that is considered to be a promising marker for predicting vertebral fractures.
      • Halleen J.M.
      • Alatalo S.L.
      • Janckila A.J.
      • Woitge H.W.
      • Seibel M.J.
      • Väänänen H.K.
      Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption.
      • Gerdhem P.
      • Ivaska K.K.
      • Alatalo S.L.
      • Halleen J.M.
      • Hellman J.
      • Isaksson A.
      • et al.
      Biochemical markers of bone metabolism and prediction of fracture in elderly women.
      • Janckila A.J.
      • Takahashi K.
      • Sun S.Z.
      • Yam L.T.
      Tartrate-resistant acid phosphatase isoform 5b as serum marker for osteoclastic activity.
      Indeed, in large prospective studies, biochemical markers of bone resorption have been associated with increased vertebral and nonvertebral fractures independently of BMD. However, their use in predicting fracture risk in specific patients has not been defined clearly. The value of these markers in the assessment of fracture risk therefore is likely to be in combination with other important risk factors, including BMD.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.
      • Delmas P.D.
      • Eastell R.
      • Garnero P.
      • Seibel M.J.
      • Stepan J.
      The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation.
      Other potential uses of turnover markers include the ability to monitor drug efficacy, to predict increases in bone mass, and to assist in the selection of patients for treatment. Bone-turnover markers have little or no use in the diagnosis of osteoporosis, in the prediction of bone mass, and in the ability to monitor compliance.
      • Khosla S.
      • Kleerekoper M.
      Biochemical markers of bone turnover.

      Conclusion

      The clinical consequences and economic burden of osteoporosis indicate a need for intervention in women at high risk. Many risk factors are associated with osteoporosis and fracture, including low-peak bone mass achieved during growth, hormonal factors, the use of certain drugs, cigarette smoking, low physical activity, low intake of calcium and vitamin D, race, small body size, and a personal or family history of fracture. All these factors should be taken into account when assessing the risk of fracture to determine which patients require further assessment and/or treatment. Although all postmenopausal women should be evaluated by a thorough physical examination and history taking, radiologic laboratory assessments of BMD should be reserved for those patients at highest risk. These include all women over the age of 65, younger postmenopausal women with risk factors, and postmenopausal women with a history of fractures. Although biochemical markers of bone turnover have demonstrated utility in clinical research and trials, use of such testing in specific patients is not defined clearly and is not a replacement for BMD testing. Together, the judicious use of risk factor assessment and objective measures of bone strength can help to identify patients who would benefit from intervention, thus potentially reducing the social and economic burden of osteoporosis.

      Acknowledgment

      Dr Lane would like to thank Julia Schroeder for assistance in the preparation of this manuscript.

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