The Prevention and Treatment of Osteoporosis
Patricia Graham
Robert A. Adler
Francis J. Bonner
Gopi Kasturi
Bone health is important to overall health and quality of life. Bones provide a frame that permits mobility, and protects internal organs from injury, while being a storehouse for minerals vital to the self-sustaining functions of daily life. Although osteoporosis is the most common bone disease, because there are no warning signs before fracture, it continues to be underrecognized. It is often not treated, even after osteoporosis-related fractures have occurred. Disfigurement, chronic pain, depression, disability and increased mortality can result (1). Relatively few people are diagnosed in time for effective therapy to be administered to prevent a first or a second fracture. In the United States in 2007, the national average for osteoporosis screening after hip fracture was 20% (2). This research reflects similar worldwide data (3). In a recent Canadian study, of 2,075 women age 45 or older with fracture, 81% were from a standing height (designated fragility fracture); however, 6 to 8 months after fracture only 21% of patients had had osteoporosis screening or treatment (4).
Compared to performance measures for other diseases, in-hospital osteoporosis management of hip fracture patients in American hospitals has lagged considerably. For instance, after myocardial infarction, doctors prescribe a recommended β-blocker 93% of the time prior to hospital discharge; similarly, there is 81% compliance with lipid assessment post-stroke (2). Low bone mineral density (BMD) can be considered a precipitating factor for fractures, just as uncontrolled hypertension can lead to stroke. Although advances in many areas of osteoporosis research, patient care, and health care coordination have occurred in the last 10 to 15 years, we have far to go.
As osteoporotic fractures often result from a combination of reduced quantity and quality of bone, relative neuromuscular instability, and environmental hazards, physiatrists have the expertise and opportunity to apply the multidisciplinary rehabilitation model to successfully address medical, functional and communication factors that have contributed to the development of this serious public health issue. Shinchuk et al. found that 69.8% of community dwellers (median age: 60.2) admitted to a subacute rehabilitation facility after acute hospital stay had decreased BMD (5). Because many fractures, particularly those of the hip, pelvis, and lower extremity, require in-patient rehabilitation services, physiatrists are thus in a strategic position to implement a successful osteoporosis screening cascade.
DEFINITION
Fractures occur when applied loads are in excess of the capacity of the bone, which is dependent on the degree of bone mineralization and bone architecture. Osteoporosis is a disease characterized by low bone mass and deterioration of the microarchitecture of bone tissue, particularly trabecular bone; this leads to increased bone fragility and fracture risk (Fig. 39-1). Although bone mass is reduced in osteoporosis, the remaining bone demonstrates the normal composition of both organic (40%) and mineral components (60%).
The current procedure of greatest clinical utility for measuring bone density is the dual-energy x-ray absorptiometry or DXA. In 1994, the World Health Organization (WHO) established the term normal bone density to designate bone density within one standard deviation (SD) of the mean for normal young adults, and low bone density, or osteopenia, as the designation for those with bone density 1.0 to 2.5 SD below the mean for young adults. The number of SD from the normal young mean is designated as a T-score on the final DXA report. In the recent past, the diagnosis of osteoporosis was based solely on a bone mass measurement of 2.5 SD or more below this mean i.e., (T-score ≤ 2.5) (See Table 39-1) (6). Another means of expressing bone density is as a comparison to persons of the same age, gender, and ethnicity; this is reported as one’s Z-score and is clinically most useful in following bone mass in children and adults less than 50 years old. In the last decade, however, the financial burden and impact of osteoporotic fractures on quality of life (Table 39-2) became statistically more important in treatment guidelines. As a result, in 2008, the WHO expanded the designation of osteoporosis beyond only statistical determinants to include clinical criteria: those patients with osteopenia who have had a fragility fracture, particularly of the spine or hip, are also now defined as having osteoporosis (7). When osteoporosis occurs without association with other conditions, it is defined as primary osteoporosis; in women, it is referred to as postmenopausal osteoporosis, and senile osteoporosis in men. Osteoporosis is also commonly seen in association with other diseases or conditions (e.g., rheumatoid arthritis, vitamin D deficiency), medications (e.g., phenytoin, corticosteroids), or disuse with immobility. These cases can be called secondary osteoporosis. These conditions have generalized bone mass reduction and increased risk for fracture in common (Table 39-3).
 FIGURE 39-1. Micrographs of biopsy specimens of (A) normal bone and (B) osteoporotic bone. Adapted from Demptster DW, et al. J Bone Miner Res. 1986;1:15-21. |
TABLE 39.1 Defining Bone Loss by BMD | ||||||||||
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TABLE 39.2 Loss of Quality of Life Years in Osteoporosis | ||||||||||||||||||||||||||||||||||||||||||||||
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EPIDEMIOLOGY
General Population and Persons with Disability
The National Osteoporosis Foundation (NOF) estimated in 2008 that more than 12 million people in the United States would have osteoporosis by 2010, and 40 million would have low bone mass, or osteopenia (8). By the year 2020, these numbers are expected to rise to 14 and 47 million, respectively. Unchecked, these changes could double or triple the number of hip fractures in the United States by 2040 (9). It is important to remember that persons with osteopenia far outnumber those with osteoporosis; thus, more fractures occur in the osteopenic population (3). Fractures are also more likely to occur in trauma patients who have pre-existing low bone mass or
osteoporosis (10). Of the 10 million people in the United States estimated to have osteoporosis, women account for 8 million of those affected, and men for 2 million; another 12 million men are estimated to be at risk for the disease (11). When compared with other ethnic/racial groups, risk is increasing most rapidly among Hispanic women (12).
osteoporosis (10). Of the 10 million people in the United States estimated to have osteoporosis, women account for 8 million of those affected, and men for 2 million; another 12 million men are estimated to be at risk for the disease (11). When compared with other ethnic/racial groups, risk is increasing most rapidly among Hispanic women (12).
TABLE 39.3 Classification of Osteoporosis | |
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In the more generalized population, more than 2.0 million fractures per year in the United States in 2005 were directly related to osteoporosis. Of those, approximately 25% were at the hip and pelvis (13) and 30% at the spine (11). One-half of American women and up to 25% of men will have an osteoporotic fracture in their lifetime. The prevalence of osteoporosis at the hip is 17% for white, 14% for Hispanic, and 6% for black postmenopausal women (14). As life expectancy increases, osteoporosis will become more prevalent in men and women. Its importance as a public health problem is underscored by the fact that the lifetime risk of hip fracture in women is larger than the sum of lifetime risks of having breast, endometrial, and ovarian cancer. At present, hip fractures constitute on average 77% of the cost burden of fragility fractures in the United States (15).
Because of lower bone mass accrual in youth, and higher rate of bone loss in mid- and late life, women are more susceptible than men to osteoporosis (16). In the past, osteoporosis has been largely neglected in men, but research shows it is an important clinical and public health problem. Based on current WHO diagnostic criteria for osteoporosis, its prevalence is 4%, 2%, and 3% among white, Mexican-American, and black men age 50 and older, respectively (17). It is now recognized that the prevalence of hip fracture in men is approximately one-third to one-half that of women of similar age. Mortality after fracture in men, however, is consistently higher than that in women (18). Although hip fracture rate in women is two to three times that of men, 1-year mortality after hip fracture for men is nearly twice that of women (19). Although women lose bone mass rapidly during menopause, by age 70, calcium absorption has decreased in both sexes, resulting in an equal rate of bone loss by age 65 in men and women. After the age of 75 years, osteoporosis affects half the population, men and women equally.
The epidemiology of the Women’s Health Initiative identified clinical risk factors and biomarkers for 5-year hip fracture risk in postmenopausal females, and enhanced our knowledge of race and ethnic differences in this population (20). The prevalence of osteoporosis in white women is similar to that of Hispanic and Asian women. However after age 50, 20% of white and Asian women and 7% of men are diagnosed with osteoporosis compared to only 5% of non-Hispanic black females, and 4% of males (14). While African-Americans are less likely to have osteoporosis, once diagnosed, they have the same increased risk of fracture (14). After hip fracture, black women have a higher mortality than white women, thought to be due to in part to more advanced age and differences in medical care (19).
Osteoporosis occurs commonly in the rehabilitation patient population in both its primary and secondary forms. In Greek patients 1-year post-stroke, Lazoura et al. demonstrated that bone loss at the paretic hip relative to the nonparetic hip in males (11.8% at the femoral neck, and 10.4% at the greater trochanter) was less than perimenopausal women of the same age (13% and 12.6%, respectively). However, contrary to U.S. trends, there was no statistical difference between male and female in prevalence of osteopenia (53.3% and 52.2%, respectively), but males were more likely to have osteoporosis (20% vs. 13%) (21).
Smeltzer et al. demonstrated that community-dwelling American women with disabilities (control group) had a higher incidence of osteoporosis (22.6% vs. 7%) and low BMD (53.1% vs. 40%) than nondisabled postmenopausal women; only 50.9% of the controls were postmenopausal, with mean age of 50.6 (22). This corroborates findings by Nosek et al.
that women with disabilities develop osteoporosis earlier (23). In Smeltzer’s DXA screening of subjects, the highest incidence of osteoporosis was seen in women with spina bifida (69.2%), spinal cord injury (65%), post-poliomyelitis (44.2%), and cerebral palsy (40%). Risk factors included Caucasian race (87.6%), lack of exercise (64.6%), menopausal status (50.9%), and medication-associated risk (44.8%). Estrogen replacement therapy was the most common prescribed treatment (19.7%), with alendronate prescribed for 5.6%. Only one-quarter of these women with disabilities had been previously screened for BMD, and only one third were taking calcium supplementation (22).
that women with disabilities develop osteoporosis earlier (23). In Smeltzer’s DXA screening of subjects, the highest incidence of osteoporosis was seen in women with spina bifida (69.2%), spinal cord injury (65%), post-poliomyelitis (44.2%), and cerebral palsy (40%). Risk factors included Caucasian race (87.6%), lack of exercise (64.6%), menopausal status (50.9%), and medication-associated risk (44.8%). Estrogen replacement therapy was the most common prescribed treatment (19.7%), with alendronate prescribed for 5.6%. Only one-quarter of these women with disabilities had been previously screened for BMD, and only one third were taking calcium supplementation (22).
Secondary osteoporosis is not restricted to disabled adults; children with disabilities, including cerebral palsy and juvenile idiopathic arthritis, are also susceptible (24, 25). Although screening and treatment protocols are not as well studied as in adults, these children are also at increased risk for low bone mass, osteoporosis, and fractures compared to their peers (26, 27, 28, 29). Pediatric patients with cerebral palsy are particularly susceptible to spontaneous fractures (30).
Loss of bone mass with immobilization is most dramatically demonstrated in spinal cord injury patients, in whom sublesional bone mineral loss occurs in the lower limbs and pelvis; in paraplegic patients, and also in the upper limbs in tetraplegic patients. Dauty et al. showed in 2000 that sublesional BMD in spinal cord injury patients decreased 41% relative to controls at 1-year post-injury. It is most prominent at the tibia (−70%) and distal femur (−52%), the most common fracture sites (31). The spine bone mass does not significantly decrease (32).
The morbidity associated with osteoporotic fractures is high (33). In 1995, there were greater than one-half million hospitalizations, and 800,000 emergency room encounters secondary to osteoporotic fractures. Of these, hip fractures are the most devastating (34). Hip fractures account for nearly 50% of all osteoporotic fracture hospitalizations in the United States, compared to 8% for vertebral fractures (35). In terms of resulting disability, WHO data show that, post-fracture, one hip fracture is the equivalent to four vertebral fractures, or twenty fractures at other sites (3). The direct cost of osteoporosis is estimated at $12.2 to 17.9 billion annually in the United States. Because of increased life expectancy, the number of hip fractures could increase three- to eightfold by 2040 (9). Therefore, early screening and implementation of exercise, diet, fall prevention, and pharmaceutical strategies will become even more crucial.
Most of the social and economic burden of osteoporosis relates directly to hip fracture as well (15). Although some fracture patients suffer only temporary disability, many patients face deformity, loss of function, dependence, or institutionalization. Hip fracture almost invariably results in hospitalization and is a strong risk factor for acute complications (36). Fewer than 50% of hospitalized patients with hip fracture recover their prefracture competence in activities of daily living (ADLs); 80% are unable to perform at least one instrumental ADL, such as shopping or driving (37) and only 25% regain previous levels of social functioning (38). Nine of every 100 elderly, white female hip fracture patients will die because of that fracture within 5 years (39). Of those who are ambulatory before hip fracture, studies have shown that 20% require long-term care afterward (11). Hip fractures are now clearly associated with increased mortality as well; approximately 20% of these patients will die within 1 year of their fracture (40).
Although less debilitating than hip fractures, fractures at the spine, wrist, and other sites are more common, and result in considerably more morbidity than hip fractures. Fractures of the vertebra are the most common, more than 700,000 per year in the United States (11), and are largely responsible for the “dowager’s hump” deformity. These fractures, when severe, may cause chronic back pain, loss of height, and disability (41), as well as balance dysfunction, and altered abdominal anatomy, leading to abdominal distention, constipation, pain, and reduced appetite. Multiple thoracic fractures can lead to restrictive lung disease as well (42, 43, 44). Because of adverse changes in the ability to perform ADLs, the resulting impairment may be equal to that seen after hip fracture (45). Wrist fractures more likely to result in short-term disability, such as pain, loss of function, nerve entrapment (particularly carpal tunnel syndrome), bone deformity, and arthritis. Past studies have demonstrated a 30% risk of complex regional pain syndrome with wrist fractures (46, 47).
The WHO has established a quantitative value to the impact of osteoporotic fractures by determining the quality-adjusted life year (QALY) associated with these fractures, with perfect health for 1 year assigned a QALY of 1, and death assigned a QALY of 0. With this measure, a disability that reduces a person’s self-assessed quality of life by half, compared with perfect health, is assigned a QALY of 0.5. A focus group of postmenopausal women generally agreed with determinations made by the NOF Committee from the WHO QALY model. Similarly, the effectiveness of various pharmacologic treatments in preventing fractures and their consequences was based on available evidence from randomized controlled trials. Although effectiveness of rehabilitation strategies was not reviewed, the assumptions of effectiveness coupled with costs enable the calculation of the expected cost per QALY for any interventional strategy. With this methodology, a statistician can determine the likelihood of a particular strategy providing a favorable cost:benefit ratio for the health care system. Table 39-2 provides examples of QALYs assigned to various outcomes after NOF analysis (48).
ETIOLOGY AND RISK FACTORS
Fracture risk is dependent on the specifics of an individual’s genetic profile, peak bone mass, and strength of bone achieved in one’s lifetime and the subsequent rate of bone loss. There are identified risk factors and causes of low bone mass and osteoporosis that contribute to this fracture risk model. In primary osteoporosis, multiple etiologic factors may act independently or in combination in an individual patient to produce diminished bone mass. In secondary osteoporosis, specific
causes are identified. The presence of one or more of these factors in the elderly increases the risk of accelerated bone loss and subsequent fracture. The “weighting” of each of these risk factors in terms of relative importance as an etiologic factor is not always well defined, although estrogen depletion; calcium, vitamin D, and testosterone deficiency; smoking; advanced age; positive family history; diminished peak bone mass; diminished physical activity; and history of previous fractures are important. Corticosteroid use of 5 mg/day for a minimum of 3 months is also an important risk factor, as are such factors as excessive alcohol intake, cigarette smoking, use of antiseizure medication, and excessive thyroxine replacement and falls (Table 39-4).
causes are identified. The presence of one or more of these factors in the elderly increases the risk of accelerated bone loss and subsequent fracture. The “weighting” of each of these risk factors in terms of relative importance as an etiologic factor is not always well defined, although estrogen depletion; calcium, vitamin D, and testosterone deficiency; smoking; advanced age; positive family history; diminished peak bone mass; diminished physical activity; and history of previous fractures are important. Corticosteroid use of 5 mg/day for a minimum of 3 months is also an important risk factor, as are such factors as excessive alcohol intake, cigarette smoking, use of antiseizure medication, and excessive thyroxine replacement and falls (Table 39-4).
Glucocorticoids reduce bone mass directly by inhibiting bone formation and indirectly by inhibiting the secretion of androgen in the pituitary-gonadal and adrenal systems. Secondary hyperparathyroidism then results from the induced limitation of calcium absorption by the intestine, and calcium reabsorption in the renal tubules. Although vertebral fractures are commonly associated with chronic glucocorticoid use, atraumatic fractures of the ribs and metatarsals can also be found (49).
In senile osteoporosis in men, alcoholism, tobacco abuse, and low testosterone are significant risk factors. Unfortunately, the specific mechanism of progression for osteopenia and osteoporosis in men is difficult to delineate (50). There is early research evidence that smoking cessation increases BMD at the hip; this is significant, as smoking can increases the risk of hip fracture in men and women by up to 30% (51). Of the 30% to 50% of patients requiring chronic glucocorticoids who fracture, the elderly and postmenopausal females are at highest risk.
TABLE 39.4 Risk Factors for Osteoporotic Fractures | |||||||||||||||||||
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Risk factors in persons with disability can differ from the general population. For instance, reduced mobility, vitamin D deficiency, progressive time from onset of disability, and gender in stroke patients have been documented (52). Although the prevalence of osteoporosis in the traumatic brain injury population is not well studied, high risk for hypogonadism and immobility in this population is likely to predispose them to low bone mass (53). Time after onset of spinal cord injury, and associated decrease in mobility, also correlates with increased risk in the lower limbs for low bone mass and fractures (32).
PATHOGENESIS
Osteoporosis is a heterogeneous disease with multiple causes. Although the pathogenesis of bone mass loss in secondary osteoporosis may be readily apparent (e.g., corticosteroid excess, or the lack of muscle effect on bone with subsequent negative bone remodeling in paraplegia), the exact pathogenesis of primary osteoporosis may be more difficult to define. Low bone mass may be attributable to failure to achieve adequate bone mass at skeletal maturity (age 13 to 25 for women) and/or subsequent age-related and postmenopausal bone loss. Although low bone mass is principally associated with fracture, other determinants of fracture include the quality of the bone (e.g., trabecular architecture), the ability to heal trabecular microfractures, and the propensity to fall (54, 55). The pathogenetic basis of inadequate bone mass, particularly in the elderly, also may be considered from the standpoint of tissue, cellular, and hormonal abnormalities.
Tissue Abnormalities
Although cellular and hormonal abnormalities undoubtedly contribute to osteopenia and osteoporosis, the basic abnormality in all types of osteoporosis is a disturbance of the normal bone-remodeling sequence at the tissue level. Therefore, to fully understand the pathogenesis of osteoporosis, knowledge of bone remodeling is necessary.
Bone is constantly turning over (remodeling). The skeleton is a reservoir for 99% of the body’s calcium; remodeling provides calcium to the organism without sacrificing the skeleton. In addition, remodeling allows bone mass to respond to increased and decreased muscle activity (e.g., bone mass is increased in a tennis player’s dominant arm). The initial event in bone remodeling with normal bone turnover is an increase in bone resorption, as mediated by the osteoclast (the cells responsible for bone resorption). This event is typically followed within 40 to 60 days with an increase in bone formation, as mediated by the osteoblast (the cells responsible for bone formation). Bone resorption and formation are normally “coupled”: an increase or a decrease in resorption produces a corresponding increase or decrease in formation, so that the net change in bone mass is zero. In postmenopausal osteoporosis, and possibly in senile osteoporosis as well, bone resorption is increased without a corresponding increase in bone formation, thereby leading to a net loss in bone mass. In this case, bone remodeling is described
as “negatively uncoupled.” In other forms of osteoporosis, particularly those associated with corticosteroid-induced osteoporosis, a primary decrease in bone formation may occur. The end result is the same—a net loss of bone mass, with concomitant increasing risk for fracture as bone density decreases. Abnormalities of bone remodeling at the tissue level will therefore contribute to the pathogenesis of osteoporosis.
as “negatively uncoupled.” In other forms of osteoporosis, particularly those associated with corticosteroid-induced osteoporosis, a primary decrease in bone formation may occur. The end result is the same—a net loss of bone mass, with concomitant increasing risk for fracture as bone density decreases. Abnormalities of bone remodeling at the tissue level will therefore contribute to the pathogenesis of osteoporosis.
Cellular Abnormalities
Conclusive evidence of cellular abnormalities contributing to the pathogenesis of primary osteoporosis is building. In its simplest terms, the rate of growth and activity of osteoblasts falls behind that of osteoclasts, resulting in a loss of bone density. These processes may be separate from abnormalities of bone cells that occur with aging alone. For instance, it may be a failure of the osteoblast, as a result of either decreased cell number, or decreased cell activity, which accompanies advancing age, but is not specific for osteoporosis. Recent investigations of the communication system between osteoblasts and osteoclasts hold promise, particularly the osteoblast CFU-M and RANKL proteins, which stimulate osteoclast activity (Fig. 39-2A), and its protein osteoprotegerin (OPG), which binds RANKL and inhibits osteoclast activity (Fig. 39-2B). The balance between RANKL and OPG production may determine the rate of bone resorption (56). In 2001, a study by Gong et al. associated patients with a dysfunctional receptor (lipoprotein receptor-related protein-5) with severe osteoporosis and pseudoglioma (57); overactivity in this receptor has been shown to form strong bones.
 FIGURE 39-2. Osteoporosis is caused by disruption of normal bone remodeling sequences. (A) Role of RANK and RANKL in bone remodeling. (B) Regulation of RANK/RANKL binding by osteoprotegerin (OPG). (Delmas PD. J Clin Densitom. 2008;11:325-338, Fig. 39-4A. Adapted with permission from Boyle WJ, et al. Osteoclast differentiation and activation. Nature. 2003;423:337-342). |
Hormonal Abnormalities
Many hormonal agents may affect bone cell function and bone mass. Although there are numerous age- and menopause-related alterations in the physiology of these hormones, a specific pathogenetic hormonal abnormality in osteoporosis (excluding the osteopenia associated with hypercorticism and hyperparathyroidism) has not been conclusively defined. Estrogen deficiency remains the most frequently incriminated factor in the pathogenesis of postmenopausal osteoporosis in women, while testosterone deficiency is considered a potential cause in younger men.
Indeed, estrogen deficiency of any etiology, including menopause, early oophorectomy (58), and functional hypogonadism associated with chronic strenuous exercise (female athlete triad [FAT]) (59), should be considered a prime risk factor for bone mass loss. Estrogen deficiency from any cause results in increased skeletal responsiveness to parathyroid hormone (PTH) and increased bone resorption, a transient increase in the
serum calcium level, and a resultant decrease in PTH secretion. With such a decrease, reduced production of the active form of vitamin D, 1,25(OH)2 cholecalciferol would be expected, with a consequent decrease in calcium absorption. A number of these hormonal perturbations are demonstrated in osteoporotic populations; estrogen deficiency alone, however, is an incomplete pathogenetic explanation for osteoporosis because all postmenopausal women are relatively estrogen deficient, but not all develop osteoporosis. The serum level of immunoreactive PTH increases with aging (60) and is increased in about 10% of postmenopausal osteoporotic women. In these women, the increase in PTH may be related causally to bone loss. In most postmenopausal osteoporotic women, however, PTH levels are normal or low compared with those of normal elderly women via the mechanisms noted previously, and in these patients the pathogenetic contribution to osteoporosis is less clear. The situation is complicated by the common finding of vitamin D inadequacy, which may also lead to mild elevations of PTH. Suffice it to say, in all postmenopausal women, bone resorption increases more than bone formation, leading to significant bone loss in some women.
serum calcium level, and a resultant decrease in PTH secretion. With such a decrease, reduced production of the active form of vitamin D, 1,25(OH)2 cholecalciferol would be expected, with a consequent decrease in calcium absorption. A number of these hormonal perturbations are demonstrated in osteoporotic populations; estrogen deficiency alone, however, is an incomplete pathogenetic explanation for osteoporosis because all postmenopausal women are relatively estrogen deficient, but not all develop osteoporosis. The serum level of immunoreactive PTH increases with aging (60) and is increased in about 10% of postmenopausal osteoporotic women. In these women, the increase in PTH may be related causally to bone loss. In most postmenopausal osteoporotic women, however, PTH levels are normal or low compared with those of normal elderly women via the mechanisms noted previously, and in these patients the pathogenetic contribution to osteoporosis is less clear. The situation is complicated by the common finding of vitamin D inadequacy, which may also lead to mild elevations of PTH. Suffice it to say, in all postmenopausal women, bone resorption increases more than bone formation, leading to significant bone loss in some women.
A number of vitamin D abnormalities occur with aging, although an abnormality specific for osteoporosis (rather than simply aging) has not been defined. Decreased levels of 1,25(OH)2 are noted with increasing age. A postulated defect in the osteoporotic elderly person of the renal 25(OH) vitamin D 1-α-hydroxylase enzyme in response to PTH has not been conclusively proven (61, 62). Older people may simply not be able to make vitamin D in response to sunlight, compared to younger people. Nevertheless, calcium absorption does decrease with advancing age, is lower in postmenopausal osteoporotic women, and its decline is associated with increased risk for hip fracture.
There is a great deal still unknown about the pathogenesis of osteoporosis. Other hormones that may play a role in skeletal loss with aging include testosterone, insulin-like growth factor-I (IGF-I), and dehydroepiandrosterone sulfate (DHEAS). A deficiency of the hormone calcitonin also could contribute to on-going bone loss, although it is unlikely that it exerts a major pathogenetic effect in osteoporosis. Calcitonin inhibits the production and activity of osteoclasts, and thus decreases osteoclastic bone resorption. Serum levels of immunoreactive calcitonin decrease with age and are indeed lower in women than in men. In addition, decreased calcitonin secretion in response to calcium stimulation has been noted in some, but not all, osteoporotic populations (63, 64).
In a study of the spinal cord-injured population, Szollar et al. found that serum levels of calcium and calcitonin could not be correlated with changes in bone mass. However, in this study of patients with spinal cord injuries, the PTH level decreased in the first year after injury and started to increase 1 to 9 years after injury. Osteoblast activity decreased immediately after injury in these patients, with consequent dramatic decreases in bone degradation. In fact, loss of BMD in the proximal femur was measurable at 12 months following injury in all 176 persons with paraplegia or tetraplegia. Of significance, risk for fracture increased between years 1 and 9 after injury in the 20- to 39-year age group, but continued increasing to year 19 after injury in the 40- to 59-year age group before plateau. This study also showed that BMD in the spine actually increased from weight bearing 1 to 9 years after injury in all study participants, though becoming significant only in those with paraplegia in the 20- to 39-year age group 10 to 19 years after injury (32).
Fractures occur in this population most frequently in the pelvis and lower extremities, particularly the tibia, and correlated with sites of most bone density loss. Similar to the general population, women with spinal cord injury tend to develop osteoporosis more frequently than men with spinal cord injury. Research is needed comparing risk of osteoporosis in patients with spinal cord injury of different races.
Genetic Abnormalities
The degree of peak bone mass achieved and the amount of bone loss as we age determine our risk of osteoporosis. Complex genetic and environmental factors determine these contributing factors. It is likely that a cohort of genes contribute to a predisposition to osteoporosis and that they differ among different ethnic backgrounds (65). Definitive identification of all candidate genes is not established, but numerous gene susceptibilities are implicated, including abnormalities in receptors for the active form of vitamin D3 (calcitriol), estradiol, and PTH as well as genes coding for TGF-β and IL-6. These genes are associated with achieving peak bone mass and bone remodeling processes, and are active throughout the lifespan (66).
Spinal Cord Injury
Although disuse is thought to play a role in the development of osteoporosis in this population, neural factors are also implicated, as is an impaired PTH—vitamin D axis and calcium/phosphate metabolism (67). There is no demineralization in supralesional areas following injury, and weightbearing in the spine is thought to limit loss of bone mass in vertebrae. It is likely that some of this increased spine bone density was due to development of osteophytes is suspected as all patients age. Spasticity, degree of injury, female sex, age, and duration after injury negatively influence bone mass. Reduced intestinal absorption and increased renal elimination of calcium, inhibition of sex steroids, pituitary suppression of Thyroid Stimulating Hormone (TSH), and insulin resistance and IGFs may also contribute (68), but the majority of patients with spinal cord injury have decreased bone mass below the lesion. Animal models have demonstrated increased osteoclast activity, with severe bone loss (48% trabecular and 35% cortical), decreased mineral apposition, and growth plate abnormalities consistent with osteoblast dysfunction (69), and elevated RANKL mRNA induction (70).
In his study of the spinal cord-injured population, Szollar et al. found that serum levels of calcium and calcitonin could not be correlated with changes in bone mass. However, in this study the PTH level decreased in the first year after injury and started to increase 1 to 9 years after injury. Osteoblast activity decreased immediately after injury in these patients, with consequent dramatic increases in bone degradation. In fact, loss of BMD in the proximal femur was measurable at 12 months following injury
in all 176 persons with paraplegia or tetraplegia. Of significance, risk for fracture increased between years 1 and 9 after injury in the 20- to 39-year age group, but continued increasing to year 19 after injury in the 40- to 59-year age group before plateau. This study also showed that BMD in the spine actually increased from weight bearing 1 to 9 years after injury in all study participants, though becoming significant only in those with paraplegia in the 20- to 39-year age group 10 to 19 years after injury (32).
in all 176 persons with paraplegia or tetraplegia. Of significance, risk for fracture increased between years 1 and 9 after injury in the 20- to 39-year age group, but continued increasing to year 19 after injury in the 40- to 59-year age group before plateau. This study also showed that BMD in the spine actually increased from weight bearing 1 to 9 years after injury in all study participants, though becoming significant only in those with paraplegia in the 20- to 39-year age group 10 to 19 years after injury (32).
Fractures occur in this population most frequently in the pelvis and lower extremities, particularly the tibia, and correlated with sites of most bone density loss. Similar to the general population, women with spinal cord injury tend to develop osteoporosis more frequently than men with spinal cord injury. Research is needed comparing risk of osteoporosis in patients with spinal cord injury of different races.
CLINICAL EVALUATION FOR OSTEOPOROSIS
Although the first clinical indication of osteoporosis, either primary or secondary, is usually a fracture, it is optimal to screen and treat patients, both male and female, prior to first fracture.
Quantitating Bone Mass
A number of clinical parameters positively correlate with bone mass, such as paraspinal muscle strength in postmenopausal women and grip strength in premenopausal women and men. Although these are useful methods, they do not substitute for precise quantitation (71). Plain radiographs of the spine are relatively insensitive in quantitating bone mass because 30% to 35% of bone mass must be lost before demineralization is detected. They are, however, sensitive and reliable to assess for fractures of the spine when unexpected height loss is noted, or when fractures are suspected in axial or peripheral bone.
Several noninvasive procedures have been developed over the past 50 years to quantitate bone mass (bone density). The current procedure of greatest clinical utility, DXA is noninvasive, quantifies primarily trabecular (cancellous) bone at the spine and hip with an acceptable precision and accuracy, is reasonably simple to perform at a reasonable cost, and is associated with low radiation exposure. Most importantly, it predicts which patients are at risk for subsequent fracture and can be repeated to assess therapeutic response to treatment. The DXA technique also satisfies requirements for ionizing radiation safety to the greatest degree, as bone density measurements can be obtained within 30 seconds to 2 minutes with a radiation exposure of approximately 10 mrad—one-sixth the exposure of a chest x-ray—with 99% precision and approximately 97% accuracy. CT measurements of the spine provide an exclusive assessment of trabecular bone, and actual volumetric density, but the technique is compromised by high radiation exposure and lower precision.
WHO recommendations for baseline and follow-up testing are based on DXA measurements at axial sites (spine and hip). For patients in whom the spine cannot be measured, the forearm is substituted. The spine and the distal forearm contain primarily trabecular bone, metabolically more active than cortical bone, and preferentially altered in osteoporosis, thus most affected by medications used in the treatment of osteoporosis. The hip and parts of the forearm also have cortical bone. The vertebrae and hips are also the fracture sites likely to cause the most disability. WHO guidelines are adapted to the epidemiology of individual countries and are well described in special position papers by the NOF Guide Committee (72, 73). As WHO DXA standards were established from research of white, postmenopausal women, some controversy exists in interpretation of DXA for men, premenopausal females, nonwhite populations and children. The International Society for Clinical Densitometry (ISCD), for example, recommends use of a single normative database for all women, and the use of a male normative database to calculate T-scores for men (74, 75). There is increasing consideration being given to the use of Z-score values for assessing bone health in children, as is done in Canada (76). Although peripheral measurements with other techniques such as pDXA, pQCT, and ultrasound may predict hip and spine fracture similar to DXA, they have less clinical utility than axial measurements. Because of low cost, portability, and lack of radiation exposure, peripheral measurements with ultrasound have evolved primarily as a screening tool, which, when positive, instigates further clinical evaluation and DXA screening (77).
Revised 2008 WHO guidelines for DXA screening and treatment shifted from a T-score-only basis for treatment to evidence-based assessment of the 10-year risk for fracture at hip and other sites, based on age, gender, race, bone density values and known osteoporosis and fracture risks. Guidelines were then adapted to demographic and health care profiles of individual countries (72, 73). Interpretation of these guidelines, though, can vary among diverse governmental and medical specialty organizations. All women 65 or older (men perhaps at age 70), and patients with known fragility fractures after age 45, particularly at the hip or spine, should be screened for osteoporosis via DXA. Screening should also be considered for younger adult women and men with at least two known risks, such as early menopause, tobacco abuse, corticosteroid dependence, or testosterone-blocking agents (see Fig. 39-3, Algorithm for Osteoporosis Management). Protocols for DXA and laboratory screening in children and young adults with chronic disability (i.e., cerebral palsy or spinal cord injury), and with medical conditions associated with osteoporosis such as eating disorders and FAT, are not well established, but the ISCD has published recommendations (www.iscd.org/Visitors/positions/OP-Index. cfm) (74). Fragility fractures in these populations warrant at least baseline DXA assessment. Screening, interpretation of results, and treatment for loss of bone density must be individualized until more research can be done in these populations.
The FRAX WHO Fracture Risk Assessment Tool (Fig. 39-4), developed at the University of Sheffield, in England by Kanis et al. assists the clinician in treatment guidelines for patients with low BMD (osteopenia, DXA T-score between −1.0 and −2.5) without previous pharmaceutical intervention (78). After inserting data reflecting patients’ gender, age, race, body weight, and height, known osteoporosis risk factors, and femoral neck bone density (in gm/cm2) with the manufacturer of DXA equipment, the FRAX tool establishes a treatment threshold in accordance with WHO guidelines. In the United States, if the
data indicate a10-year fracture risk at the hip of greater than or equal to 3%, or at other major sites of greater than or equal to 20%, prescription medications should be considered in these populations (79). If the patient is not started on pharmacologic therapy, subsequent screening by FRAX or with DXA is recommended at 2 years, although some low-risk patients can be assessed at much longer intervals. For those patients who are at risk for fracture and begin therapy, a follow-up DXA is suggested at 2 years, to assess response to treatment. If femoral neck BMD is not available (e.g., in a patient with bilateral hip surgery), FRAX tool must determine fracture risk by body mass index (BMI).
data indicate a10-year fracture risk at the hip of greater than or equal to 3%, or at other major sites of greater than or equal to 20%, prescription medications should be considered in these populations (79). If the patient is not started on pharmacologic therapy, subsequent screening by FRAX or with DXA is recommended at 2 years, although some low-risk patients can be assessed at much longer intervals. For those patients who are at risk for fracture and begin therapy, a follow-up DXA is suggested at 2 years, to assess response to treatment. If femoral neck BMD is not available (e.g., in a patient with bilateral hip surgery), FRAX tool must determine fracture risk by body mass index (BMI).
Bone Markers
Serum and urine markers of bone resorption and formation are diagnostic modalities used primarily to monitor efficacy of prescription therapy. In this sense, the markers may be complementary to bone density assessment. Current rate of bone resorption is most commonly assessed with a urinary marker n-telopeptide of type I collagen (NTX), and c-telopeptides of type I collagen (CTX) (80). The n-telopeptide (NTX) measurement results from 24-hour urine calcium collection, normalized for creatinine; urine is collected within 48 hours of routine serum osteoporosis laboratory studies to best define calcium metabolism pathway abnormalities (as are seen in Table 39-5, Laboratory Tests in Disorders of Calcium Metabolism). However, for convenience, a second-void fasting spot urine NTX can be preferred, due to calcium intake variance during a 24-hour period. Serum levels of NTX and CTX can also be tested. It should be noted, however, that all bone turnover markers have considerable day-to-day variability. Thus, many experts use them in only specific cases when knowing the rate of bone turnover is necessary.
Clinical Evaluation of the Patient at Risk for Osteoporosis
Patients at risk for osteoporosis require careful evaluation, consisting of the following elements. A thorough history is required to determine the presence of risk factors for osteoporosis such as menopausal status, family history of hip fracture, and certain medications (Table 39-6), and to exclude medical conditions leading to secondary osteoporoses (see Table 39-3). A separate intake questionnaire for osteoporosis to expand standard intake history intake can be helpful. History of previous fragility fractures and sites of persistent pain (i.e., atraumatic vertebral compression fracture) must be identified. Identify any history of falls or associated risk factors such as poor vision, bladder urgency, or peripheral neuropathy (Table 39-7). Document any loss of height from early adulthood (average loss of 2 to 3 inches from occiput to sacrum is expected between the ages of 40 and 80 (49)), and include in DXA prescription if greater than 1.5 inches. Assess current level of physical activity and exercise, and past history of eating disorders, in all patients. Social behaviors such as tobacco abuse or excessive alcohol are both positively correlated with bone loss and should be noted (81). The importance of the social history cannot be overemphasized, especially in the elderly, who may have history of frequent falls, require assistive devices or personnel in their living environment, or need consideration for transitional care unit placement. Inadequate daily calcium intake and exercise, vitamin D deficiency, corticosteroid use, diabetes mellitus, and multiple
myeloma are common in the elderly. Inquire into pending dental procedures, as dental extractions could delay start-up of bisphosphonates, the most commonly prescribed medication class for osteoporosis, due to risk of osteonecrosis of the jaw (82, 83). History of certain malignancies may be a relative contraindication for teriparatide, a potent anabolic treatment option.
myeloma are common in the elderly. Inquire into pending dental procedures, as dental extractions could delay start-up of bisphosphonates, the most commonly prescribed medication class for osteoporosis, due to risk of osteonecrosis of the jaw (82, 83). History of certain malignancies may be a relative contraindication for teriparatide, a potent anabolic treatment option.
TABLE 39.5 Laboratory Tests in Disorders of Calcium Metabolism | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 39.6 Etiologic Factors Contributing to the Risk of Osteopenia/Osteoporosis | ||
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TABLE 39.7 Major Risk Factors for Falls | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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A thorough physical examination establishes cognitive status, assesses oral hygiene and hydration status, and excludes causes of secondary osteoporosis (e.g., hemiplegia, rheumatoid arthritis, anorexia, spinal cord injury). One must assess for preexisting fractures; for example, multiple vertebral fractures can induce severe kyphosis, with anterior-posterior widening of the rib cage, increasing its proximity to the iliac crests, and inducing abdominal protuberance (49). Document any risks for fall (i.e., visual disturbance, neurologic deficits, contractures, leg length discrepancy, poor balance with transfers, gait abnormalities, and improper use of assistive devices). Evaluate the potential for safe weight-bearing and resistive exercise (i.e., cognitive status, cardiopulmonary status, posture, degree of kyphosis, balance and pain with active and resisted motion).
Document height and weight, contracture limitations and leg length discrepancies after measurement. Assess the general mobility of spine and joints of the extremities, as well as abdominal, spinal, and extremity muscle strength. Verify sites of pain (i.e., vertebrae T8-L2 are associated with osteoporosis, whereas fractures at T6 or above are more likely associated with malignancy) (49). Assess for tibial tenderness in thin, female runners, especially with irregular or absent menses, as seen in FAT. Identify any risks for intolerance of prescription medications; for instance, poor dentition, history of gastric disorder such as GERD, gastritis or peptic ulcer, or diffuse myalgias can delay or preclude bisphosphanate use.
Proximal muscle weakness and chronic corticosteroid use will require special exercise focus. Proprioception, balance, transfers and gait must be evaluated. Proper use and design of assistive devices should also be addressed. Specific physical performance measures that correlate with higher bone mass density in hip and spine, wrist or whole body in postmenopausal women include longer step length, normal and brisk gait speeds and step length, longer single leg stance and grip strength (84).
Evaluation of these parameters and improving where possible with resistive exercises may improve bone mass parameters.
Evaluation of these parameters and improving where possible with resistive exercises may improve bone mass parameters.
TABLE 39.8 Basic Osteoporosis Laboratory Tests | |||||||||
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A basic laboratory evaluation is listed in Table 39-8. In primary osteoporosis, results of laboratory tests typically are normal (except 25-hydroxyvitamin D); the primary role of blood and urine tests is therefore to exclude other diseases and in a few cases of urinary NTX, to establish baseline bone turnover rate. For example, multiple myeloma should be suspected with anemia, abnormal serum protein electrophoresis (SPEP), and elevated B-cell population in complete blood cell count. Vitamin D deficiency is best evaluated by serum 25-hydroxyvitamin D. Serum IgA antitissue transglutaminase and IgA endomysial antibody, if positive, can be an indication of malabsorption (i.e., celiac disease). Low urinary calcium to creatinine ratio or a 24-hour urinary calcium are less specific measures of malabsorption in some cases.
 FIGURE 39-3. Osteoporosis Management Algorithm.* *This algorithm is an overall plan for evaluation of women for osteoporosis. It is generally based on the 2008 NOF Clinician’s Guide to Prevention and Treatment of Osteoporosis. Each patient must be assessed individually. Clinical judgment remains very important in the assessment and management of osteoporosis. |
Vitamin D deficiency may lead to secondary hyperparathyroidism. Severe vitamin D deficiency causes osteomalacia, with bone pain and poor mineralization of bone. More commonly, milder degrees of vitamin D deficiency lead to decreased gut absorption of calcium and in some cases secondary hyperparathyroidism, causing loss of bone mineral. Many osteoporosis patients have some degree of vitamin D inadequacy. Vitamin D deficiency also has an effect on muscle, leading to decreased lower body strength and increased propensity to fall. If 24-hour urine calcium value is low, inadequate calcium intake or absorption, or vitamin D deficiency, is likely. If urine calcium value is high, either dietary calcium excess or idiopathic hypercalciuria is a possibility. If the serum calcium is elevated, measurement of PTH is the most important test to do. Primary hyperparathyroidism leads to bone loss and must be differentiated from familial hypocalciuric hypercalcemia (FHH), a benign abnormality of the calcium receptor. Patients with FHH have mild elevations of serum calcium and PTH but very low urinary calcium excretion. It should be noted that patients with primary hyperparathyroidism may have vitamin D deficiency, leading to secondary hyperparathyroidism as well. See Table 39-5, Laboratory Tests in Disorders of Calcium Metabolism.
DXA screening is of value in the individual patient with history of spine or hip fragility fracture, or two or more risk factors for low bone mass. (See Fig. 39-3, Osteoporosis Management Algorithm for defining DXA screening candidates.) If osteoporosis is found by DXA, treatment is indicated. For those patients with osteopenia, the WHO FRAX questionnaire (Fig. 39-4) can be used to determine if prescription medications are needed for improving bone mass. If DXA/FRAX analysis indicates that fracture risk is 3% or more at the hip, or 20% or more at other sites, more aggressive prophylactic therapy (e.g., bisphosphonate) is recommended. If bone mass measurements at the spine, hip, and wrist are normal by DXA, increased exercise, a diet rich in calcium, and calcium and vitamin D supplements may be sufficient fracture prophylaxis, in conjunction with fall reduction training. Such patients should have a repeat DXA in 2 years, with recalculation of the fracture risk via the FRAX tool at that time if osteopenia persists.
 FIGURE 39-4. FRAX WHO Fracture Risk Assessment Tool to assess 10-year probability of fracture (%). (A) 57 y.o. female (B) 77 y.o. female with same risk factors, BMI and T-score. Note increase in fracture risk with age as only factor. Current tobacco use would increase 57 y.o. female major osteoporotic fracture risk to 9.9% and hip fracture risk to 1.9%, and 77 y.o. female hip fracture risk to 5.3%, without increase in risk of other major osteoporotic fracture. Adapted with permission of Kanis, WHO Collaborative Centre for Metabolic Bone Diseases, University of Sheffield, UK. Available at: http://www.shef.ac.uk/FRAX/tool.jsp. |
Iliac crest bone biopsy is used primarily to exclude osteomalacia or other metabolic bone diseases, such as is seen with late-stage renal failure. Although such biopsies can be used to define high and low bone turnover, this is not usual practice at this time for the typical patient with osteoporosis.
Educational materials can be provided to all patients to reinforce the importance of maintaining bone health, understanding the sequelae of untreated osteoporosis, identifying sources of dietary calcium, and improving fall risk in the home at the time of office visit (http://www.nof.org/).
PREVENTIVE STRATEGIES FOR PATIENTS AT RISK
In the last decade, efforts to improve bone health have focused on prevention and treatment protocols. Prevention programs focus on adequate nutritional status, including optimization of calcium, vitamin D and protein intake, and monitoring for excessive fats or carbohydrate intake. Avoidance of lifestyles known to result in bone loss, including cigarette smoking, excessive alcohol, and possibly carbonated beverage intake is also important. Weight-bearing and strengthening exercises, and fall prevention strategies in the home and community, are equally important.
Because bone mass is the principal, although not the only, determinant of fracture risk, preservation or improvement of bone mass via pharmacologic means is associated with a reduced risk of fracture. The rationale of the various therapeutic agents available for preserving or improving bone mass density or bone mass is based on knowledge of bone remodeling. In normal bone, there is no net change in the amount of bone mass present, as on-going bone remodeling is a balance between bone resorption, and the process of bone formation. In most forms of osteoporosis, however, a perturbation of bone remodeling occurs. Bone resorption increases over normal levels, and bone formation does not compensate for this increase, with a net loss of bone mass overall.
Nutritional Adjuncts
Calcium
Dietary and supplemental calcium intake is a mainstay of osteoporosis prevention and treatment. The Surgeon General’s Report on Bone Health and Osteoporosis (2004) recommends calcium intake of 1,200 mg/day in two or more doses for both men and women more than 50 years of age; children require 500 to 1,300 mg/day, dependent on age (Table 39-9). Food sources such as dairy products, dark green vegetables, salmon, and enriched cereals are rich in calcium (85). (See Table 39-10, Selected Food Sources of Calcium, for a more detailed list of food and beverage sources of calcium.)
Calcium supplementation alone has been documented to produce sustained reduction in the rate of loss of total body BMD in healthy postmenopausal women (86). In healthy, older, nonosteoporotic men, a recent study documented less falls and increased BMD of 1% to 1.5% at all sites in men receiving 1,200 mg calcium supplement daily over those receiving placebo. However, vascular events tended to be more common in the experimental group during the 2-year study (87). Calcium supplementation is inexpensive, relatively simple to ingest, and generally safe for most patients (i.e., in the absence of end-stage renal disease, a history of previous kidney stones, or idiopathic hypercalciuria). Despite the relative ease of obtaining daily calcium requirements, average dietary intake is approximately 700 mg/day (86). In past studies, no more than 1% of men and women more than 70 years of age are meeting their calcium requirements from food sources (88). The immobilization that occurs with hemiplegia and paraplegia, if coupled with excessive calcium intake, may result in elevated urinary calcium levels. A predisposition for kidney stones and nephrolithiasis may then be seen. In general, a urinary calcium excretion of up to 250 mg/day is acceptable in individuals without a history of kidney stones (89, 90, 91, 92). High sodium intake, as is commonly seen in the United States, can lead to increased urinary calcium loss. Early studies of calcium metabolism suggest that one additional gram of sodium per day above Recommended Daily Allowance (RDA) decreases bone density by 1% per year in women (93, 94).
TABLE 39.9 Recommended Daily Calcium Intake | |||||||||||||||||||||||
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TABLE 39.10 Selected Food Sources of Calcium | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Vitamin D
Vitamin D facilitates absorption of calcium and mineralization of bone. It is found in liver, fatty fish, egg yolks and as an additive in foods such as milk, orange juice, and cereals. It can be taken as a supplement and is also synthesized in the skin through sunlight exposure. As many experts believe that the recommended dietary intake should be higher for children and younger adults, the Institute of Medicine is likely to raise the Recommended Daily Allowance for this vitamin, with final recommendations expected in 2011. Current recommendation for daily intake among experts in the field is 800 to 1,000 IU/day of vitamin D3 for men and women age 50 or older (95). The active form of vitamin D (1,25-dihydroxy vitamin D or calcitriol) is also beneficial in osteoporosis and is commonly prescribed as a supplement for patients who lack the 1-α-hydroxylase enzyme because of severe renal impairment. Cholecalciferol (vitamin D3) is probably the preferred form of vitamin D supplement, but ergocalciferol (vitamin D2
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