Don't Wait for a Fracture Identifying Osteoporosis

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Osteoporotic fracture occurs as a late consequence of osteoporosis and is preventable. Nevertheless, despite well-defined risk factors and the availability of precise, reliable modalities for assessing bone density, some physicians still seem reluctant to evaluate patients for this common condition. Measurement of bone density is a practical and predictive tool for determining fracture risk and can be performed routinely at menopause. Decreased bone density values indicate a need for preventive treatment.

Like the proverbial elephant, osteoporosis has been described in ways that vary according to the scientific orientation of the describer. It has been defined clinically as the presence of fracture; biomechanically as decreased bone strength; radiographically as osteopenia; histomorphometrically as reduced bone matrix per unit of bone volume; and epidemiologically as increased fracture risk.¹ However, fracture represents an end-stage consequence that should be considered a preventable outcome rather than a defining characteristic.

The feature common to all definitions of osteoporosis is reduced bone mass. An international consensus development conference has stated that osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.² For adult women, the World Health Organization (WHO) defines normal bone mass (i.e., bone mineral density [BMD]) as not more than 1 standard deviation (SD) below the mean of the young adult reference range, low BMD (osteopenia) as 1 to 2.5 SD below the mean, and osteoporosis as more than 2.5 SD below the mean.³

A progressive loss of bone density is associated with aging. The trabeculae become thinner, and some trabeculae may become disconnected.⁴ The result is a marked reduction in the amount of cancellous bone in addition to thinning of cortical bone.

Cancellous and cortical bone have different mechanical properties. Cortical bone is stiffer, withstanding greater stress (the load per unit area of bone) but less strain (the amount of deformation in terms of the percentage of change in bone diameter) before failure. The decrease in the total amount of bone tissue and dimensions with aging reduces bone strength and stiffness and increases brittleness all of which predispose to fractures that can lead to death.⁵

Among other types of fractures, osteoporosis specifically makes the individual susceptible to hip fracture. In the United States, approximately 1.5 million osteoporotic fractures occur each year, with a mortality of 10% to 50% following hip fracture depending on the age of the patient.⁶ In fact, the gradient of fracture risk with low BMD is somewhat greater than that reported for the risk of coronary artery disease with elevated serum cholesterol a much more common target for routine screening than osteoporosis.^2,7 However, despite the existence of well-known risk factors and reliable screening tools, many physicians fail to assess patients for this silent but treatable condition.⁸ Early clinical recognition of such a pathophysiologic process with a potentially fatal outcome enables the physician to intervene and halt or reverse its progress.

RISK FACTORS
The probability of the development of osteoporosis varies with the magnitude of peak bone mass achieved between the ages of 20 and 40 years and on the rate and duration of subsequent bone loss. After bone mass peaks during the fourth decade, age-associated losses are about 1% each year although annual losses of 3% to 5% may occur in women during the 5 years following menopause.² Lifetime losses may reach 30% to 40% of peak bone mass in women and 20% to 30% in men.

The magnitude of peak bone mass and the rate and duration of bone loss are influenced by many factors. Risk factors associated with low bone mass are considered etiologic. In addition to advanced age, the principal risk factors for osteoporosis are female sex, European or Asian ancestry, slender body build, and bilateral oophorectomy before natural menopause.^9,10 Advanced age, low body weight, reduced muscle strength, and estrogen deficiency are all associated with loss of appendicular bone mass in older women.¹¹

Although many factors influence osteoporosis risk, assessment of risk factor status alone (other than bone density) cannot reliably identify perimenopausal women with low bone mass, nor can it accurately predict the likelihood of fracture in part because these factors account for only about 33% of the variability in BMD.^2,12 Of the various contributing factors, only BMD can be measured as a predictor of future fracture risk. Measurement of BMD is a better predictive tool to evaluate patients for osteoporosis and subsequent osteoporotic fracture than is clinical assessment of predisposing risk factors. Thus, BMD measurement has been recommended as the best approach for assessing individual risk of osteoporosis, diagnosing suspected osteoporosis, and guiding treatment of established osteoporosis.^2,13

CLINICAL PERSPECTIVE
Certain clinical signs such as height loss, kyphosis, and minimal-trauma fractures suggest that osteoporosis is already present. The major clinical manifestation of osteoporosis (i.e., fracture) can be devastating. Fracture prevention is the ultimate clinical objective of early diagnosis, and early detection of low BMD identifies those at risk for osteoporosis. As there are no consistently effective, safe methods for fully restoring normal bone to the osteoporotic skeleton, prevention of osteoporosis must be the primary goal of intervention.^2,14,15

For women between the ages of 65 and 84 years, 85% of hip and spine fractures are attributable to osteoporosis.⁶ Most osteoporotic fractures occur in postmenopausal women, more than half of whom will sustain such a fracture.¹⁶ Most osteoporotic fractures are precipitated by a fall.² Many factors that reduce balance in the elderly (e.g., effects of aging, diseases, and medications) contribute to the risk of falls.

Osteoporotic fractures most commonly involve the hip, spine, and wrist. Of these, hip fracture is associated with the greatest morbidity and mortality. Of white North American women 50 years of age, 17.5% will have a hip fracture during their remaining lifetime.¹⁷ These fractures will contribute substantially to the 2 million person-years of functional impairment and an estimated $45 billion in direct medical costs attributable to osteoporosis between 1994 and 2004.¹⁸

Hip fractures are associated with a 5% to 20% excess mortality (i.e., mortality above that expected for age and sex) occurring 6 to 12 months after the fracture.^19,20 Of women surviving a hip fracture, 50% will be unable to walk independently and will experience reduced social activity.²¹ Hip fractures require nursing home care for almost 33% of patients, and almost 10% of nursing home residents have experienced a hip fracture. Some level of long-term care is necessary for 15% to 25% of hip-fracture survivors, with an estimated average nursing home stay of 7.6 years.^22,23

The prevalence of spinal fractures among the elderly is extremely high possibly exceeding 75% for older women if vertebral wedging is included.²⁴ Vertebral fractures are often painless but may be accompanied by severe, acute back pain followed by less severe, chronic pain persisting for up to a year. Chronic pain and kyphotic deformity due to osteoporotic vertebral fractures result in substantial functional limitation and lifestyle modification. The worst consequence of osteoporosis may not be death, but rather the diminished quality of life for survivors of vertebral fracture.

DIAGNOSIS
The direct relationship between bone strength and bone density is well documented.²⁵ Bone mass (measured by any method and at any site) is inversely related to fracture risk. Thus, it is possible to predict the risk of fracture by assessing BMD. Because low BMD cannot be confirmed merely by the presence of etiologic risk factors for osteoporosis, numerous tests have been developed to measure BMD and detect osteopenia or osteoporosis including absorptiometric bone densitometry. However, no single technology answers all clinical needs.¹

Bone Densitometry
The absorption of ionizing radiation by bone varies directly with bone density. The greater the bone density, the greater the absorbed energy as measured by a radiation detector. Conversely, the lower the bone density, the less energy is absorbed. Although conventional skeletal radiography can identify the codfishing of vertebral bodies that characterizes osteoporosis, it is otherwise not sensitive enough to detect even substantial trabecular bone loss, and is therefore of very limited value in detecting early osteoporosis.²⁶

Several noninvasive tests are available to assess bone density. These include single-photon absorptiometry (SPA), dual-photon absorptiometry (DPA), single-energy x-ray absorptiometry (SXA), dual-energy x-ray absorptiometry (DXA), radiographic absorptiometry (RA), and peripheral quantitative computed tomography (QCT). In practice, SPA and DPA have been largely replaced with SXA and DXA, respectively. All of these techniques have sufficient accuracy for the detection of low BMD.¹³

With the exception of QCT, all of these tests express results as total bone mineral (g), bone mineral per unit length (g/cm), or bone mineral per unit area (g/cm2) rather than per unit volume and therefore do not measure true bone density. Nevertheless, bone mineral density is the accepted terminology for the results of these studies. Quantitative ultrasonography (QUS) is currently under evaluation as an alternative to radiographic techniques.27 QUS assesses BMD by broad-band ultrasound attenuation and velocity of the sound wave both of which correlate with densitometric values obtained by SPA.

The requirements for any BMD test are the ability to predict fractures, high accuracy, reliability, rapidity, and low radiation dose. Equally important are cost and availability. These requirements are largely met by SPA, SXA, and DXA, and less adequately by DPA and QCT.¹³ RA has been enhanced recently by computed image processing and may also prove useful for fracture risk stratification.

Biochemical Markers
Standard markers of bone turnover include fasting urine calcium and serum alkaline phosphatase. Urine calcium is an inexpensive assay used to detect hypercalciuria signifying bone resorption, but it is usually not useful in assessing osteoporosis.

Serum alkaline phosphatase is the most commonly used marker of bone formation. Because this enzyme is produced by the liver and kidneys, as well as by osteoblasts, it lacks the specificity and sensitivity needed to assess osteoporosis.²⁸ However, tests that distinguish the osteoblast-derived isoenzyme have been developed and are gaining wider use.

Other biochemical markers that estimate bone resorption or formation have been identified. At present, these assays appear most useful for monitoring the efficacy of treatment. After antiresorptive therapy is instituted, markers of bone resorption are reduced by 50% or more within 30 days.

Markers of bone resorption include urinary hydroxyproline, hydroxylysine, pyridinoline, deoxypyridinoline, N-telopeptides of cross-linked type I collagen, and plasma tartrate-resistant acid phosphatase (TRAP). Hydroxyproline and hydroxylysine are amino acids unique to collagen, and their urinary excretion reflects resorption of bone matrix.^28,29 Pyridinoline and deoxypyridinoline are cross-linking structures unique to collagen and elastin. Their concentrations in urine reflect collagen breakdown by osteoclasts.³⁰

A rapid and reliable enzyme-linked immunosorbent assay for cross-linked N-telopeptides of type I collagen is now available and may be valuable for assessing early menopausal bone resorption and monitoring antiresorptive therapy.²⁹ The serum marker TRAP may reflect osteoclast activity in osteoporosis.³⁰

Markers of bone formation include serum bone-specific alkaline phosphatase, procollagen (precollagen) I extension peptides, and osteocalcin. Bone-specific alkaline phosphatase may be a useful marker for monitoring osteoporosis because it is distinct from isoenzymes of hepatic and renal origin.²⁸ Procollagen I extension peptide is a byproduct of the metabolism of type I collagen and may be a systemic marker of bone collagen the predominant component of bone matrix.^28,30 Osteocalcin (also called bone Gla-protein) is synthesized by osteoblasts during bone formation. Serum osteocalcin may be helpful in assessing the rate of bone formation.

DENSITOMETRY:
WHO AND WHEN?
Bone mineral measurements at various skeletal sites can predict the risk of moderate-trauma osteoporotic fractures for at least 8 to 10 years into the patient s future.³¹ The immediate objective of evaluation by BMD measurement is to stratify patients into groups of varying risk for such fractures. Women with the lowest BMD (bottom quintile) have four times the risk of subsequent fracture compared with women in the top quintile when BMD is measured at any of four different sites (proximal radius, distal radius, os calcis, or lumbar spine).³²

The ultimate clinical objective is to prevent osteoporotic fractures in the women at greatest risk. To justify assessment for low BMD, there should be a specific treatment available that can effectively reduce fracture incidence e.g., estrogen replacement, alendronate, or raloxifene.¹ Although the lifetime probability of any fracture is very high, a significant minority of women possibly 25% of all women never sustain fractures. These women will not benefit from the unnecessary use of pharmacologic agents and may suffer adverse events. Menopause is probably the best time to evaluate women for their risk of osteoporosis and begin treating those found to be at increased risk.

Perimenopausal assessment would lead to treatment of a larger number of women over a longer period of time than would assessment at age 65 or after.¹⁵ However, the cost-effectiveness of early postmenopausal assessment and preventive therapy has been questioned, and some experts recommend preferential assessment of the elderly.^14,15

The cost of testing 50 million adults annually with DXA has been estimated at $3.75 billion, compared with an annual expense of $7 billion to $10 billion for treating fracture patients.³⁰ However, these costs can be substantially reduced with the use of appendicular bone density measurements, thus improving cost-effectiveness. Clearly, a treatment that can reduce fracture occurrence by 50% within 3 years will be highly cost-effective if it is targeted at high-risk women and if the cost of testing is equal to the cost of 1 month of drug therapy. One study showed that assessing asymptomatic, perimenopausal white women to detect low BMD in the hip and prescribing therapy for the women at the greatest risk of fracture is a reasonable, cost-effective use of health care resources.³³

Another obstacle to testing has been the absence of standardized interpretation of bone density and fracture risk. That obstacle has also been overcome with an approach recommended by an international consensus panel of osteoporosis experts.³⁴ This approach (Figure) is based on estimation of an individual's remaining lifetime fracture probability.³⁵

Table 1 lists the potential clinical applications of BMD measurements. All postmenopausal women should be assessed for BMD to determine fracture risk and establish a baseline for subsequent rate of bone loss and response to osteoporosis therapy. The National Osteoporosis Foundation has recommended BMD measurement for patients with estrogen deficiency, radiographic evidence of osteopenia or vertebral abnormalities, conditions requiring long-term corticosteroid therapy, and primary asymptomatic hyperparathyroidism.³⁶

Measurement of BMD may be particularly useful for women considering long-term estrogen replacement. Women are more likely to initiate preventive measures for osteoporosis if they are aware that they have low BMD.³⁷

CONCLUSION
Fracture is a preventable outcome of osteoporosis. Early clinical recognition of osteoporosis permits interventions that can reduce fracture incidence. Assessment of clinical risk factors other than BMD cannot accurately predict the likelihood of fracture in a given individual. Measurement of BMD is a reliable predictive tool and has been recommended to assess women for their risk of osteoporosis, diagnose suspected osteoporosis, and guide osteoporosis treatment. The ultimate clinical goal of these measurements is to prevent osteoporotic fractures in those at greatest risk. Menopause is the most useful time to assess women for their risk of osteoporotic fracture and target those found to be at increased risk for treatment.

References:

Richard D. Wasnich, MD, is Director of the Hawaii Osteoporosis Center in Honolulu. His web site is located at http://www.medsurf.com/

Originally published in The Female Patient -- October, 1998

© Copyright, 1998 Quadrant Publishing, All Rights Reserved

Reprints are not allowed without the expressed written consent of Quadrant Publishing.