Feature Article
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Osteoporosis and Aging: Etiology and Current Diagnostic Strategies Osteoporosis is a major medical, economic, and social health problem in the United States. The prevalence of osteoporosis increases with age and is the cause of major morbidity and disability in the elderly population, which is mainly attributed to osteoporosis-related fractures. Over the past decade, new strategies of risk identification and more sensitive assessment measurements have been developed.
(Annals of Long-Term Care 1998;6[11]:352-357)
Using the World Health Organization (WHO) definition of osteoporosis,1 22% of all postmenopausal women can be classified as having osteoporosis.2 The prevalence of osteoporosis increases with age, reaching 38% in people over age 75 and 57% in those over age 80.3 Major morbidity and disability in the elderly are mainly attributed to osteoporosis-related fractures. More than 1.5 million Americans suffer fractures associated with osteoporosis each year, with resultant pain, deformity, and loss of independence.4
Hip fractures are responsible for the most osteoporosis-related health care demands, with more than half a million fractures per year. The short-term mortality from hip fracture is 10% to 20%.5 Among survivors, half will never walk again without assistance, and one quarter will require long-term nursing home placement.4 The risk of hip fractures is greater in institutionalized individuals than in noninstitutionalized individuals.6 For women with vertebral fractures, there is considerable morbidity, including chronic pain, deformity, loss of self-esteem, and depression.5 The health care expenditure attributable to osteoporotic fractures in 1995 was estimated at $13.8 billion, 28.2% of which ($3.9 billion) was spent for nursing home care.7
Over the past decade, there has been considerable progress in the diagnosis of osteoporosis. New strategies of risk identification have been developed, and more sensitive techniques of bone density assessment have become available. This article reviews the etiology of osteoporosis. The pathogenesis of age-related osteoporosis will be discussed, and the different diagnostic strategies will be explored.
What Is Osteoporosis?
Osteoporosis is a disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to increased bone fragility and fracture risk.1 The new WHO consensus definition reflects the importance of bone mass measurement in the diagnosis of osteoporosis and implies that the occurrence of fractures is not essential to the diagnosis.
The introduction of accurate noninvasive bone mass measurements afforded the opportunity to make an early diagnosis of osteoporosis. Bone mineral density (BMD) of patients with osteoporotic fractures was generally found to be lower than that of age-matched nonfractured controls.8 However, it soon became evident that substantial overlap exists in the distribution of BMD of patients with and without fractures.9
Recognizing this fact, WHO recently based the diagnosis of osteoporosis on the presence of a spinal bone density more than 2.5 standard deviations below the mean for young adults.1 Kanis et al2 proposed that BMD values of 1 to 2 standard deviations below the young adult mean be used to identify women and men who have osteopenia, and consequently are at increased relative risk of fracture, but for whom a diagnosis of osteoporosis would not be justified because it would mislabel far more individuals than would actually be expected ever to fracture. In the United States, the National Osteoporosis Foundation sets the diagnostic criterion at 2 standard deviations below the mean for young adults.
The Etiology of Osteoporosis
Osteoporosis can be classified as primary or secondary, depending on the absence or presence of an associated medical condition known to cause bone loss (Table I). Secondary causes of osteoporosis can be identified in 20% of women and 40% of men presenting with vertebral fractures and should always be sought.10
An important subset of this group is glucocorticoid-induced osteoporosis. Osteoporosis develops in 30% to 50% of patients receiving long-term glucocorticoid therapy.11 The pathogenesis of this syndrome is multifactorial and includes decreased gastrointestinal calcium absorption, increased urinary calcium excretion, secondary hypogonadism, and impairment of osteoblast function.12
If no secondary cause is identified, osteoporosis is termed primary. One form of primary osteoporosis occurs in children or young adults of both sexes and with normal gonadal function and is frequently termed idiopathic osteoporosis. The other two forms of primary osteoporosis are known as type I osteoporosis and type II osteoporosis.
Type I osteoporosis occurs in a subset of postmenopausal women who are between 51 and 75 years of age and is characterized by an accelerated and disproportionate loss of trabecular bone. Fractures of vertebral bodies and distal forearm are common complications.13 Type II osteoporosis is found in a large proportion of women and men over the age of 70 and is associated with fractures of the femoral neck, proximal humerus, proximal tibia, and pelvis.14
Age-Related Osteoporosis
Two major types of age-related osteoporosis have been defined (Table II): type I, or postmenopausal, osteoporosis; and type II, or senile, osteoporosis.
Type I: Postmenopausal Osteoporosis
As stated above, type I osteoporosis affects mainly trabecular bone and results in fractures primarily in vertebral bodies and the distal forearm. It occurs more frequently in women than in men with a ratio of 6:1 and is related to the accelerated bone loss in women found in the first two decades after menopause.4
The precise mechanisms involved in the pathogenesis of bone loss due to estrogen deficiency are not completely understood. However, it is clear from published evidence that estrogen governs skeletal cytokine activity and that, with the depletion of this hormone, up-regulation of several key cytokines results in accelerated bone resorption.15 The cytokines most often implicated are interleukin (IL)-1, IL-6, IL-11, and tumor necrosis factor (TNF).16-19
Type II: Senile Osteoporosis
As already stated, type II osteoporosis affects both trabecular and cortical bone and is associated with fractures of the femoral neck, proximal humerus, proximal tibia, and pelvis.14 The primary pathogenesis appears to be due to age-related decline in renal 1,25 (OH)2 D production caused by a diminished renal response to parathyroid hormone (PTH), as well as a decrease in renal 1-alpha-hydroxylase enzyme activity.20 Several investigators were able to demonstrate a loss in 1-alpha-hydroxylase enzyme in cortical renal slices in older rats, even in the absence of appreciable renal disease.20
Additional factors implicated in causing type II osteoporosis include deficient cutaneous synthesis of vitamin D after sunlight exposure and decreased hepatic conversion of vitamin D to 25 (OH) D, which occurs more frequently in older adults.21 There is also evidence that, with age, intestinal mucosal cells become relatively resistant to the effect of 1,25 (OH)2 D, thus impairing intestinal calcium absorption.22 This low vitamin D state in turn results in decreased calcium absorption from the gut leading to hypocalcemia, which stimulates the release of PTH, causing calcium to be mobilized from the skeleton in order to restore serum levels.
The Diagnosis of Osteoporosis
Identifying patients at risk of developing osteoporosis is important in order to determine those who will benefit from the different therapeutic interventions. Methods to identify such patients include a thorough medical history to pinpoint possible risk factors, imaging bone densitometry, laboratory studies, and bone histomorphometry.23
Medical History
The main aim when obtaining a medical history in a patient with suspected osteoporosis is to identify risk factors for osteoporotic fractures (Table III). Risk factors include early natural or operatively induced menopause, prolonged periods of amenorrhea, poor nutrition, a history of limited exercise, a family history of possible osteoporosis, and a history of excessive alcohol intake or smoking.24
Cummings and Black,25 in a prospective study involving 9516 postmenopausal women, found that the risk of a fracture of the proximal part of the femur increased with every five years of aging. An increased risk was also associated with the following:
* Maternal history of hip fracture
* Tall height
* Lack of weight gain with aging
* Poor health
* Previously treated hyperthyroidism
* Use of anticonvulsants or long-acting benzodiazepines
* Lack of exercise
* Lack of unsupported standing for four hours a day
* Pulse rate of more than 80 beats per minute with the patient at rest
* History of any fracture after age 50
* Consumption of caffeine
* Poor visual depth perception
* Inability to rise from a chair without using the arms
* Low bone mass
Cummings and Black reported that if an individual had two of these risk factors, the risk of a hip fracture was one per 1000 patients per year. If the patient had five or more risk factors in addition to that of low bone mass, the risk of a hip fracture increased to 27 per 1000 patients per year.
Imaging Studies and the Measurement of Bone Mineral Density
Measurement of BMD is probably the most useful means for stratifying people by level of fracture risk.26 Low bone mass increases the risk of osteoporotic fractures, and this risk is independent of the risk associated with increasing age.27 There is a 1.5- to 3-fold increase in the fracture rate for each standard deviation of decrease in BMD.28
Although the risk of a fracture increases continuously as BMD declines, it is useful, from a practical standpoint, to define cutoff values for the purpose of intervention. Defining osteoporosis as a BMD of 2.5 standard deviations less than the average value for young adults identifies approximately 30% of postmenopausal women who are at highest risk for a fracture and who need corresponding counseling and treatment. Defining an additional cutoff value as 1 standard deviation less than the average value for young adults creates another group that includes approximately 15% of postmenopausal women in whom the prevention of bone loss would be most useful as well.2
Bone mass can be determined with a number of noninvasive methods. Routine radiographs are relatively insensitive in detecting significant bone loss; 30% of bone mass must be lost before the radiograph appears abnormal.29 Lateral radiographs of the thoracolumbar vertebrae can show loss of horizontal trabeculation, prominent end plates, and anterior wedging, and radiographs of the upper femur can reveal loss of the trabecular pattern that normally traverses the greater trochanter. Even with the use of this insensitive measure, close to 30% of elderly women and 20% of elderly men will be diagnosed as having osteoporosis.29
Over the past decade, considerable progress has been made in the development of more accurate methods for assessing bone density noninvasively. Currently, a variety of techniques are available. These techniques include single-energy x-ray absorptiometry, dual-energy x-ray absorptiometry (DXA), quantitative computed tomography, and quantitative ultrasound.
Single-energy x-ray absorptiometry can be used to measure BMD at the distal radius and calcaneus.30,31 Although the value of BMD measurements at these sites was initially controversial, the results from recent studies using the rectilinear scanning devices now available document the value of measuring BMD at these sites in predicting osteoporotic fractures.32-35 Single-energy x-ray absorptiometry has proven to be a valuable method in the diagnosis of osteoporosis, providing reasonable precision and low radiation exposure.31 This technique may be of value in evaluating nursing home residents for osteoporosis.
Use of single-energy measurements is not possible, however, at sites with variable soft tissue thickness and composition (ie, the axial skeleton, hip, or whole body). For this reason, DXA was introduced to correct for unknown path length in the body.31 DXA has a high rate of precision and subjects the patient to an extremely low dose of radiation. It is currently the most frequently used method of evaluating bone density in clinical practice.36
Skeletal sites that consist predominantly of trabecular bone have been considered the preferred sites for measurement, because trabecular bone is thought to respond faster to metabolic stimuli than cortical bone. In addition, the incidence of fractures is greater at sites that are largely trabecular--such as vertebral bodies, femoral neck, distal radius, and calcaneus--compared to sites that consist mostly of cortical bone.37 Cummings et al,28 in a prospective study involving 8134 women (65 years or older), assessed BMD measurements by DXA of the femoral neck, spine, distal radius, and calcaneus as a predictor of hip fracture risk.
The risk of spine fractures, on the other hand, suggests measurement of BMD in both the spine and the hip for better assessment of fracture risk.38 Williams-Russo et al,39 in a longitudinal clinical trial, found that DXA measurements were highly reproducible when assessing the lumbar spine, but not the femoral neck.
Although the number and availability of DXA scanners have grown rapidly over the last few years, the use of standard DXA scanners is not often practical for nursing home residents mainly because of problems of transportation. In that regard, the recently introduced peripheral DXA (p-DXA) scanners that measure BMD at the forearm40 may be more practical in the nursing home. P-DXA technique measures BMD at the appendicular skeleton and has been shown to effectively diagnose osteoporosis.40-42 Furthermore, peripheral bone density has been shown to reliably predict future fracture risk, especially in older individuals.43
Quantitative computed tomography scanning can be used to examine vertebral bodies or distal radius.36 Among radiographic methods, this is the most sensitive to changes in bone mass. However, it is less precise, more costly, and results in a higher exposure to radiation than DXA.36 The use of quantitative computed tomography is currently limited to research purposes.
Quantitative ultrasound of the calcaneus has recently been proposed as a screening technique for osteoporosis.44 The attractiveness of this technique lies in its low cost, portability, ease of use, and freedom from ionizing radiation.31 There is evidence that quantitative ultrasound of the calcaneus may detect individuals at increased risk of fractures.45 However, correlation between quantitative ultrasound measurements of BMD at the calcaneus and DXA measurements of BMD at the spine and the proximal femur are not reliably high enough to predict BMD at lumbar spine or proximal femur from ultrasound results.46,47
Laboratory Studies
Laboratory studies are used mainly to exclude other diseases that can cause osteopenia, such as multiple myeloma, endocrinopathies, and osteomalacia. The initial workup of osteopenia (Table IV) should include determination of serum and urinary calcium (to check for the presence of calcium leak); serum levels of phosphorus, magnesium, alkaline phosphatase, vitamin D, and PTH; and thyroid function. These levels should be normal in uncomplicated osteoporosis, although some elderly patients with senile osteoporosis may have elevated PTH levels, presumably related to primary decreases in 1,25 (OH)2 D levels.15 Many clinicians will also include complete blood count with differential, erythrocyte sedimentation rate determination, and protein immunoelectrophoresis in the initial workup to screen for bone marrow abnormalities. Such abnormalities are seen in approximately 2% of patients who have osteopenia, and half of these abnormalities are multiple myeloma.48 Diagnoses of corticosteroid-induced osteoporosis, Cushing's disease, and diabetes mellitus are sought if they are suspected clinically.
Once endocrinopathies have been excluded, as many as 10% of older individuals who live in northern communities in the United States and who have osteopenia will be found to have varying levels of osteomalacia.23 Osteomalacia can be suspected in more than 50% of these individuals on the basis of blood tests that show low-normal serum calcium levels, low phosphate and 25 (OH) D levels, and high alkaline phosphatase and PTH levels. More subtle forms of osteomalacia are more difficult to diagnose and may necessitate bone biopsy.48
In recent years, it has become possible to identify high rates of bone turnover by measuring biochemical products of resorption and formation. Bone-specific alkaline phosphatase and osteocalcin are two sensitive serum markers for bone formation. Osteocalcin has been demonstrated to be an independent determinant of BMD of the hip in elderly women, and its level is a sensitive predictor of the subsequent risk of hip fracture.
Markers of bone degradation (like urinary hydroxyproline), on the other hand, are nonspecific. Recently, however, two markers of bone degradation that are highly specific to bone have become available. These are deoxypyridinoline and N-telopeptides.49,50 These markers not only indicate patients with active bone turnover likely to increase bone loss but also have been shown to predict fracture risk.51,52
Although previous assays required 24-hour urine collections, current enzyme-linked immunosorbent assays can be performed with a second-void morning spot urine. These tests may be of value in nursing home residents in whom DXA is particularly difficult to obtain because of transportation problems. Residents with a high level of urinary deoxypyridinoline or N-telopeptide have active bone turnover and have increased fracture risk. Such residents may benefit from therapeutic interventions.
Bone Histomorphometry
Bone histomorphometry assesses the quality of bone, which is independent of bone mass. Although laboratory and imaging studies may give insight into the status of bone mass as well as the rapidity of bone turnover, they provide no information with regard to the qualitative status of bone. A biopsy of tetracycline-labeled, undecalcified, iliac crest bone is the best method of differentiating high-turnover versus low-turnover osteoporosis, osteomalacia, secondary hyperparathyroidism, and complicated combinations of these conditions.23
Conclusion
Osteoporosis and related fractures are a cause of considerable morbidity and disability in older individuals. Although much is known about age-related bone loss, much is yet to be explained. It is important to identify persons at risk of developing osteoporosis in order to determine those who may benefit from therapeutic interventions. Clinical risk factors should be assessed, and bone density measurements should be undertaken when possible. Measurement of urinary biochemical markers of bone resorption may help identify patients with high turnover and at high risk of fracture who may benefit from treatment.
About the Author
Dr. Kamel is in the Division of Geriatric Medicine, Department of Medicine, Nassau County Medical Center, East Meadow, New York. Address for correspondence: Hosam K. Kamel, MD, Department of Medicine, Nassau County Medical Center, 2201 Hempstead Turnpike, East Meadow, New York 11554.
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52. Cummings SR, Black DM, Ensrud KE, et al. Urine markers of bone resorption predict hip bone loss and fractures in older women: The study of osteoporotic fractures. J Bone Miner Res 1996;11:S128. Annals of Long-Term Care - ISSN: 1524-7929 - Volume 6 - Issue 10 - October 1998 |