An NIH conference ¹ described osteoporosis as a “skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality.” Bone density corresponds to the amount of mineral within an area or a volume, and bone quality depends on architecture, bone turnover, damage accumulation, and mineralization. Compromised bone strength (bone fragility) increases the risk of fractures resulting from moderate trauma, defined as a fall from standing height or less, which has led to the concept of “fragility fracture.” Therefore, osteoporosis is a risk factor for fracture.

The concept of osteoporosis has progressively evolved from criteria based on histology, to fracture occurrence, to assessment of bone mass, and currently to the individual assessment of fracture risk, including history of fracture, clinical risk factors for fracture, and bone mass evaluation. Indeed, a fracture-based diagnosis unacceptably delays intervention in a condition for which prevention of fracture is essential. Changes encountered in osteoporosis can be assessed by noninvasive techniques measuring bone mineral density (BMD), such as dual x-ray absorptiometry (DXA). BMD accounts for 75% to 85% of the variance in ultimate strength of bone tissue ² and is well correlated with the load-bearing capacity of the skeleton in vitro.³ Prospective studies demonstrate that the risk of fragility fractures increases as BMD declines, with a 1.5- to 3-fold increased risk of fracture for each standard deviation (SD) fall in BMD.⁴ The main advantage of a density-based diagnosis is the possibility of an early intervention, before fractures. This approach was carried out by the World Health Organization (WHO) in its definition of osteoporosis in 1994.⁵ In women, osteoporosis can be diagnosed if the BMD or the bone mineral content (BMC) at the spine, femoral neck, or forearm is 2.5 SD or more below the mean value of a reference population of young, healthy premenopausal women, with the following categories:

1. Normal: BMD higher than 1 SD below the young adult mean

2. Osteopenia, or low bone mass: BMD between 1 and 2.5 SD below the young adult mean

3. Osteoporosis: BMD lower than 2.5 SD below the young adult mean

4. Established (or severe) osteoporosis: BMD lower than 2.5 SD below the young adult mean and the presence of one or more fragility fractures

Thus, osteoporosis is defined in practice by a surrogate marker (i.e., BMD), not a health outcome (fracture), even if other factors can influence the likelihood of fractures. The relationship between BMD and fractures is very similar to that between hypertension and stroke and stronger than that between serum cholesterol and coronary heart disease (Fig. 13-1). The gradient of the risk of fracture with decreasing BMD is as steep as that between diastolic blood pressure and stroke.

FIGURE 13-1 Hip fracture incidence as a function of BMD measured at the hip, spine, and forearm in postmenopausal women. (Data from Cummings SR, Black DM, Nevitt MC, et al: Bone density at various sites for prediction of hip fractures, Lancet 341:72–75, 1993.)

It is estimated that with this 2.5 SD threshold, 30% of white women older than 50 years have osteoporosis,⁶ a fraction that is similar to the lifetime risk of fracture at the hip, spine, and forearm for a 50-year-old woman.⁷ By this definition, about 0.6% of young adult women have osteoporosis, and 16% have low bone mass. The prevalence of osteoporosis increases with age because of the decline in bone mass. Not all women who have osteoporosis by the WHO criteria will sustain fractures, and conversely, many women who do not have osteoporosis by this definition may deserve treatment because of other risk factors that will increase their risk of fracture. Thus, this operational WHO definition of osteoporosis provided the concept of osteoporosis as a risk factor for fracture, which is important for assessing the number of affected individuals, but patient diagnosis must include other risk factors for fracture. This is the role of the individual fracture risk assessment of fracture.

Recently, a WHO Scientific Group issued a technical report including hierarchical levels of evidence for the ability of risk factors to identify individuals at risk for fracture.⁸ Those risk factors were validated by meta-analyses of population-based cohorts from Asia, Australia, Europe, and North America. Those risk factors were BMD at the femoral neck, low body mass index, a prior fragility fracture, glucocorticoid exposure, a parental history of hip fracture, smoking, excessive intake of alcohol, and rheumatoid arthritis. The combination of those risk factors allowed for building fracture probability models, providing individual probabilities of fracture that will be the basis for therapeutic decision making, thus shifting the former therapeutic threshold paradigm, which was often based only on the BMD T score.

Epidemiology

Magnitude of The Problem

In women, osteoporosis is rare before menopause. With aging, more and more women are affected by osteoporosis; by the age of 80 years, 27% have low bone mass and 70% have osteoporosis at the hip, spine, or forearm.⁷ Sixty percent of osteoporotic women will experience one or more fragility fractures. In the United States, it is estimated that 16.8 million (54%) of postmenopausal white women have low bone mass, and 9.4 million (30%) have osteoporosis.⁷ These rates of prevalence are lower in nonwhite women and in men. NHANES III (Third National Health and Nutritional Examination Survey) data indicate that 10,103,000 Americans (8,021,000 women and 2,082,000 men) have osteoporosis and that 18,557,000 (15,434,000 women and 3,123,000 men) have low bone mass and thus an increased risk of osteoporosis in comparison to those who do not have low bone mass.⁸ The prevalence of vertebral fractures can vary according to the definition of fracture used. Thus 10% to 25% of women older than 50 years are estimated to have vertebral fractures.⁹^,¹⁰ In 1990, 1.66 million hip fractures were estimated worldwide in those older than 35 years.¹¹

Osteoporosis results in high rates of morbidity. In 1986 in the United States, osteoporosis was responsible for an estimated 321,909 hospitalizations in white women 45 years and older—167,421 for hip fractures, 35,106 for fragility vertebral fractures, 120,636 for wrist fractures, and 20,369 for humerus fractures.¹² Osteoporosis-related fractures also significantly contribute to the economic burden of health care. In 1995, direct costs for osteoporosis fractures were estimated to be $13.8 billion,¹³ whereas it was 5 to 6 billion annually 10 years earlier.¹² Being elderly, patients with hip fractures often have other medical conditions, thus increasing their risk of complications such as pressure sores or infections. Hip fractures often result in admission to nursing homes.¹⁴ The number of hip fractures and their associated costs are expected to sharply increase and could triple by the year 2040. Indeed, the number of elderly people is quickly growing, and fracture incidence rates increase with age.¹⁵ This phenomenon is observed in developed countries, but the projected rapid expansion of the elderly populations of Latin America and Asia could lead to an increase in hip fractures from 1.66 million worldwide in 1990 to 6.26 million in 2050, with only 25% occurring in North America and Europe.¹¹ Osteoporosis is also associated with mortality. For each standard deviation decrease in bone mineral density, the mortality risk is increased 1.5-fold.

The lifetime risk of fractures can be estimated, given the probability of fracture and the odds of reaching a given age. Most data have been generated in white populations of Western countries. The lifetime risk of sustaining an osteoporotic fracture has been estimated in the United States to be close to 40% for women and 13% for men. For vertebral fractures, the estimated risk is 15.6% for women and 5% for men. The risk of hip fracture is 17.5% for women and 6% for men and for wrist fracture, 16% for women and 2.5% for men.⁷

Site-Specific Fractures

Hip Fracture

Hip fracture is the most serious complication of osteoporosis. It results in high morbidity and sometimes mortality. The most striking characteristic of hip fractures is that they are associated with a 12% to 20% reduction in expected survival.¹⁶ Many of the deaths after hip fractures are related to other diseases.¹⁷ Few deaths are actually due to or hastened by the fracture, but the risk of dying of another disease is sometimes increased by the hip fracture. About 5% of women sustaining a hip fracture die during the following year as a consequence of fracture. In women living in nursing homes, 36% of those having a hip fracture will die within a year. Thirty percent to 50% of these patients are unable to regain the level of function they had before the hip fracture. The patient’s physical condition before the fracture may be the best predictor of postfracture functional outcome.

The incidence of hip fracture increases exponentially with age in both genders. In women younger than 35 years, the incidence is 2 per 100,000 person years, whereas it is 3032 per 100,000 person years in women older than 85 years.¹⁸ In men the rates are 4 and 1909 per 100,000 person years, respectively. Most hip fractures occur in elderly people: 52% after age 80 years and 90% after age 50 years.¹⁸ The decline in BMD and the increase in frequency of falls in elderly people are responsible for this high incidence of hip fracture. Only 1% of falls lead to a hip fracture, but 90% of hip fractures are related to a fall from standing height or less.¹⁹ Hip fractures tend to be the consequence of falls on hard surfaces, the fall not being stopped by protective reflexes of upper limbs.²⁰ Fifty percent of the falls leading to hip fractures result from slipping or tripping, 20% from loss of consciousness, and 20% to 30% of loss of balance and other factors.

Vertebral Fracture

The epidemiology of vertebral fractures is less well characterized than that for hip fractures because symptoms after vertebral fracture are unidentified in up to 70% of cases, and standardized radiographic diagnostic criteria for vertebral fractures are lacking. Less than a third of patients with vertebral deformities seek medical assistance, and 2% to 8% need hospital admission.²³ In women, 90% of vertebral deformities are a consequence of mild to moderate trauma, whereas this proportion is only 50% in men.²⁴

The incidence of clinical vertebral fractures increases gradually with age in both genders. The age-adjusted prevalence is thought to be between 8% and 25% in women older than 50 years. The difference in prevalence figures is due to the definition used.²⁴ Early definitions of vertebral fracture were based on the type of deformity and thus had poor precision. New techniques using vertebral morphometry give more reliable results.²⁵ Vertebral deformities are mostly noted in women, with a ratio of 2 : 1, but this ratio becomes narrower in elderly people older than 80 years. It has been suggested in a large epidemiologic study involving 15,570 European men and women that the incidence of vertebral deformities might be equal in both genders. In the same cohort, vertebral fracture incidence in women over 50 was estimated at 10.7/1000 person years in women and 5.7/1000 per person years in men.²⁶ Changes in the gross appearance of the vertebral body encompass a wide range of morphologic characteristics, from increased endplate concavity to complete destruction of the vertebral anatomy in vertebral crush fractures.²⁷ It must be kept in mind that vertebral deformity is not synonymous with vertebral fracture; for example, Scheuermann’s disease is frequently discussed as a differential diagnosis.²⁸

New vertebral fractures, even those not recognized clinically, are associated with substantial increases in back pain and functional limitation due to back pain, at least in elderly women.²⁹ Ten percent to 20% of elderly women with worsening of their functional status because of back pain have had a vertebral fracture. Common complications of vertebral deformities are chronic back pain, back disability, height loss, limitations in activity, emotional difficulties stemming from physical appearance, and more medical consumption. Kyphosis from vertebral fractures adds to the overall back pain. For instance, after adjustment for age, a 15% increase in kyphosis increases the odds ratio of severe upper back pain 2.1-fold. However, no association has been found between the number of fractures and impairment in quality of life. The occurrence of vertebral fracture is predictive of new fracture, with RR = 5 to 11. Vertebral fractures are associated with increased mortality at 5 years, as for hip fracture. The increase in mortality is progressive over this period, as opposed to hip fracture. The risk of death appears to be much higher for clinically apparent vertebral fracture, and the presence of multiple vertebral fractures further increases this risk.³⁰^,³¹

Wrist Fracture

Wrist fractures, also called distal forearm fractures or Colles’ fractures, are very common. The incidence of wrist fracture is hard to calculate because only a minority of patients is hospitalized. A Norwegian study showed that it was the most common fracture responsible for admission to a local university hospital.³² Incidence varies among different ethnic groups. Wrist fracture risk is lower in black people than white people.³³ Increasing incidence was observed between 1950 and 1982,³⁴ but this trend seemed to have leveled off during the second part of the 1980s.

The pattern of incidence of wrist fracture is different from that of hip or vertebral fractures. The age-adjusted female-to-male ratio is 4 : 1, with a linear increase in incidence in women from ages 40 to 60 years, followed by a plateau.³⁵ In men, the incidence is almost constant between the ages of 20 and 80 years, for unknown reasons. Wrist fractures are not associated with an increase in mortality and are usually thought to be free of long-term poor outcome.³⁶ Other data, however, suggest that half of the patients do not report good functional status at 6 months because of complications such as algodystrophy, neuropathies, and posttraumatic osteoarthritis.³⁷

Wrist fractures must be considered as an important predictor of subsequent vertebral and hip fractures. Indeed, it has been shown that men and women with distal forearm fractures have on average a twofold increase in the risk of sustaining a hip fracture.³⁸ Previous wrist fractures are also significant predictors of overall osteoporotic fractures, with a doubled risk. In younger women, the predictive value of a previous wrist fracture for subsequent osteoporotic fractures seems even more important, with a relative risk of 2.67 (1.02 to 6.94) for women aged 40 to 49 years. This predictive value is of the same magnitude as that provided by a 1-SD decrease in BMD measured by bone densitometry.³⁹ Thus, the occurrence of a wrist fracture in an early postmenopausal woman is suggestive of osteoporosis and should trigger appropriate investigation such as BMD measurement.

Other Fractures

Other fractures include proximal humerus, pelvis, proximal tibia, and rib fractures. An excess of these fractures is noted in postmenopausal women, their rates increase with aging, and they are often a consequence of minimal trauma. These fractures are related to low bone mass, similar to hip and vertebral fracture, and they should also motivate BMD measurement because any of them could be the first symptom of osteoporosis.

Variability In Fracture Incidence

The incidence of hip fracture is markedly lower in black and Asian people and varies among different countries and populations. Rates are higher in Scandinavia than in Western Europe and Oceania.²¹ A north-south gradient in age-standardized risk is found in Europe and the United States,²² with a higher rate in the north. The age-adjusted increase in incidence that has been observed in several countries over the past 50 years appears to have leveled off in some of these countries. The incidence increases with socioeconomic difficulties, decreased winter sunlight, and water fluoridation. Fractures are more frequent in winter months. This seasonal trend could be due to altered neuromuscular coordination and vitamin D deficiency in winter months, because most fractures occur indoors and thus cannot be explained only by slippery winter conditions.²² About 80% of hip fractures occur in women, because the age-adjusted incidence in men is two times lower than in women, and more elderly women are alive than are elderly men.

Costs

In the United States, direct medical expenditures for osteoporotic fractures were estimated at $20 billion in 2000,⁴⁰ two-thirds of which are accounted for by hip fracture alone. An important determinant of rising cost is increased age. The estimated cost for care in the United States during the first year after a hip fracture is $21,000 per person and is much higher in women older than 80 years. If the cost of the subsequent nursing home is attributed to the hip fracture, the cost of care for those who stay in nursing homes after 1 year is $93,378 per person. The average cost for vertebral fracture during the first year is $1200 per patient, and it is $800 for Colles’ fracture. Costs are expected to double in 2050, due to the increasing number of fractures resulting from the aging population.

Osteoporosis: A Neglected Disease

It has been shown in recent years that even after marketing of several effective therapies for osteoporosis, most patients who have sustained an osteoporotic fracture (forearm fracture, vertebral fracture, and even hip fracture) do not receive adequate secondary prevention for future fractures, whereas the risk of repeated fractures is markedly increased, including that of second hip fracture.⁴¹

Pathogenesis

Osteoporosis is a multifactorial disease. Most but not all risk factors influence the level of bone mass. Some may have an impact on bone structure (the so-called quality of bone), and some increase the risk of fragility fracture through extraskeletal mechanisms. One should distinguish risk factors for falls from risk factors for bone fragility.

Clinical Risk Factors

Clinical risk factors can shed light on the pathophysiology of fragility fractures. Bone mineral density is a key risk factor for fracture,⁴² but numerous studies have evaluated other risk factors for fractures.^16,43–50 The use of such factors (Table 13-1) to identify high-risk subjects is frequently advocated. Different types of fractures have different risk-factor profiles.⁴⁴

Table 13-1

Risk Factors for Hip Fracture With and Without Adjustment for Calcaneal Bone Density and History of Prior Fracture

BMD, Bone mineral density.

Data from Study of Osteoporotic Fractures.

Estrogen Deficiency

Estrogen deficiency has been associated with osteoporosis since first suggested by Fuller Albright in the 1940s. It is the main cause of bone loss in women after menopause. Premature menopause—natural or surgically induced—extends the period during which a woman is exposed to a hypogonadal state, thus increasing the total duration of bone loss occurring after menopause.⁵¹ Similarly, late menarche and primary or secondary amenorrhea also increase the risk for osteoporosis.⁵² Luteal deficiency in premenopausal women has been suggested to be associated with bone loss,⁵³ but the evidence is still controversial. Estrogen deficiency is also associated with bone loss during the 3 to 4 years preceding the actual menopause—the perimenopause—with a rate similar to that observed in the early postmenopausal years.⁵⁴ It is likely that women with the lowest concentrations of residual estrogen have faster bone loss and fracture more often, although this might be confounded by the effect of body weight or other sex steroids.^55–57 Also, women receiving aromatase inhibitors as adjuvant therapy for breast cancer lose bone more rapidly and sustain an increased rate of fragility fracture.⁵⁸

Other Factors

Many factors increase the risk of fracture. For instance, the Study of Osteoporotic Fractures ⁴⁹ identified 16 independent risk factors for hip fracture in addition to low BMD (see Table 13-1). Numerous studies have described risk factors such as female gender, white or Asian race, age, previous fractures, thinness, cigarette smoking, family history of hip fracture, use of sedative hypnotics, and impairment in visual and neuromuscular function. Lack of physical activity may also be an important cause of bone loss,⁵⁹^,⁶⁰ and it has been hypothesized that some of the age-related bone loss and the burden of skeletal fragility result from a decline in physical activity, in particular, in Western societies. Black people have less osteoporosis and fewer fractures than white and Asian people do. Excessive alcohol consumption increases the risk of fractures, whereas moderate intake might exert a protective effect. Undernutrition in the elderly may contribute to bone loss, the risk of falling, or the response to injury.⁶¹ It is widely believed that inadequate calcium intake throughout life is a significant risk factor.⁶²

In a cohort of 7575 French women aged 75 years or older, the risk of subsequent hip fracture was significantly increased (even after adjustment for femoral hip BMD) in women with a slow gait speed, in women who had difficulty performing a tandem (heel-to-toe) walk (i.e., neuromuscular impairment), and in women with visual acuity less than 2/10.⁶³ The incidence of hip fracture among women classified as being at high risk because of both a high fall risk status and a low BMD was found to be 29 per 1000 women years. It was 11 per 1000 in women at risk because of either a high fall risk status or low BMD, and the risk was 5.4 per 1000 women years in those at low risk according to both criteria. Even with this combined approach, about a third of women with a hip fracture had not been identified as being at high risk, thus indicating that other factors are important in the pathogenesis of hip fracture. Although these clinical risk factors can be easily assessed with a rapid questionnaire and physical examination, they are probably of limited value in younger women. A personal history of hip fracture is still predictive, but its prevalence is much lower in women younger than 65 years. Fall-related factors have not been tested but are likely to be poor discriminants in younger and healthier women.

Candidate risk factors have been examined by a WHO working group in individual data meta-analyses of 12 prospective population-based cohorts. Data were collected from 60,000 men and women participating in the Rotterdam study in the Netherlands; the European Vertebral Osteoporosis Study and the European Prospective Osteoporosis Study; the Canadian Multicenter Osteoporosis Study; the Dubbo Osteoporosis Epidemiology Study in Australia; the EPIDOS and OFELY cohorts in France; and cohorts from Rochester, Minnesota; Sheffield, England; Kuopio, Finland; Hiroshima, Japan; and Gothenburg, Sweden. Several risk factors have been selected on the basis of the possibility to modify them and ease of use in clinical practice: BMD at the femoral neck, low body mass index, a prior fragility fracture, glucocorticoid exposure, a parental history of hip fracture, smoking, excessive intake of alcohol, and rheumatoid arthritis.64–68 Those factors are modeled to provide individual probabilities of fracture that can be easily calculated using the computer-driven WHO fracture risk assessment tool called FRAX (available at Internet websites such as http://www.shef.ac.uk/FRAX/).⁶⁹

Peak Bone Mass

Peak bone mass is the amount of bone acquired at the end of skeletal growth, and it is followed by bone loss throughout the rest of life. Bone mass at a given age is a function of the peak bone mass achieved and the amount of bone lost as a consequence of menopause and aging. Peak bone mass, which is reached in early adult life, primarily depends on genetic factors. It is also influenced by dietary calcium intake during adolescence and by physical activity.

Blacks achieve higher peak bone mass than whites do, who have greater peak bone mass than Asians, particularly Japanese. Twin studies have shown a strong correspondence of peak bone mass in monozygotic twins, who have closer concordance in BMD than dizygotic twins.⁷⁰ Which genes are the most important is still unknown. It has been reported by Morrison et al. that polymorphism of a noncoding sequence of the vitamin D receptor gene was associated with peak bone mass variance in monozygotic twins, and that these polymorphisms accounted for most of the genetic effect.⁷¹ This association has not been confirmed by most subsequent studies^72–74 but has initiated searches for other candidate genes, including the estrogen receptor, interleukin 6 (IL-6), transforming growth factor β (TGF-β), and type I collagen. For example, the collagen Iα1 Sp1 polymorphism is moderately associated with BMD and fracture, as shown in a meta-analysis of 13 studies involving 3642 patients.⁷⁵ More recently, some variants of LRP5 have been found associated with BMD and fracture.^76–78 Even if many advances have been made in understanding the role of genetic factors in the last 10 years, a great deal of additional research is required to identify the genes relevant to the pathogenesis of osteoporotic fracture. Indeed, most studies so far have been underpowered. In the future, it is likely that a combination of large-scale studies and technologic improvements such as genomewide associations will help identify candidate genes in the regulation of bone strength.^77–79

Dietary calcium intake may be important for attaining optimal peak bone mass. Three placebo-controlled trials in children or adolescents, including one performed in twins, have shown a modest but significant increase in BMD in those receiving calcium supplementation.80–82 Children with very low calcium intake are more likely to benefit from an increase in calcium, preferably from a dietary source.

Other factors may be important, such as those influencing the progression of puberty. Exercise during growth may contribute to the level of peak bone mass. It has been shown that intensive exercise before puberty may enhance bone acquisition that might persist in adulthood,⁸³ but the role of exercise in the normal physiologic range is unknown. In girls, areal BMD gains stop around ages 16 to 20 and in boys around ages 20 to 22. Bone width, however, will continue to increase throughout life, even after linear growth cessation, to maintain bending strength despite areal BMD decline.⁸⁴ Diet, physical activity, and toxic substances exposure, including maternal cigarette smoking during pregnancy (programming), may also influence the level of peak bone mass.⁸⁵^,⁸⁶

Bone Loss With Aging

Changes in bone mass as a function of age are presented in Fig. 13-2. Throughout life, women lose 35% to 50% of their bone mass, depending on the skeletal site. Although osteoporosis is a systemic disease affecting the whole skeleton (with the exception of the bones of the skull and face), the pattern of bone loss differs slightly and depends on the type of bone. It has been generally believed that bone loss starts around menopause. In fact, a recent study showed that trabecular bone loss—assessed at the distal forearm with high-resolution peripheral quantitative computed tomography (HR-pQCT)—starts in young adults of both sexes, accounting for a third of the total trabecular bone loss over the entire life.⁸⁷ Menopause induces accelerated bone loss within 5 to 8 years, followed by a linear rate of bone loss that may accelerate after the age of 75 years.⁸⁸ Because of a much slower rate of bone remodeling, cortical bone loss may start later, but the total amount of cortical bone mass that is lost in women in their 80s is probably similar to the amount of cancellous bone lost. The proportion of overall bone loss related to menopause and to the estrogen-independent aging process is debated, but clearly bone loss in the elderly is still under the influence of estrogen deficiency and can be prevented by hormone replacement therapy (HRT).⁸⁹

FIGURE 13-2 Bone loss during adult life.

Two major mechanisms underlie bone loss in women. First, an age-related decrease in osteoblast activity occurs and leads to an imbalance between the amount of bone resorbed and the amount of bone formed within a remodeling unit (BMU). Second, menopause induces a marked increase in the number of remodeling units activated within the cancellous and cortical bone envelopes per unit of time, which will amplify the small deficits observed at each BMU. This overall increase in bone turnover peaks within the first 2 to 3 years after menopause but persists throughout life, even in women in their 80s, as shown by the sustained increase in bone markers of resorption and formation in elderly postmenopausal women. The mechanism by which estrogen deficiency results in increased bone resorption and bone loss is not yet completely understood, but evidence indicates that estrogens act indirectly through cytokines and growth factors such as IL-1α, IL-1 receptor antagonist, tumor necrosis factor α (TNF-α), IL-7, and TGF-β. Estrogen also stimulates production of osteoprotegerin—a decoy receptor that is a potent inhibitor of osteoclast activity—in osteoblastic cells and is also an inhibitor of receptor activator of nuclear factor κB (RANKL) and RANKL-stimulated osteoclastogenesis, thus explaining a large part of the antiresorptive action of estrogen in bone.90–92 Estrogen results in an increase in IL-7 in target organs such as bone, thymus, and spleen, at least in part through decreases in TGF-β and increased IGF-1 production, leading to a first wave of T-cell activation.⁹³ Those activated T cells release IFN-γ, increasing antigen presentation by dendritic cells and macrophages as a result of up-regulation of MHCII expression through the transcription factor CIIA.⁹⁴ Estrogen deficiency also amplifies osteoclastogenesis and T cell activation by down-regulating antioxidant pathways, resulting in an upswing in ROS, which in turn stimulates antigen presentation and TNF production by mature osteoclasts. As a result, T-cell activation is again amplified and promotes release of the osteoclastogenic factors RANKL and TNF. In addition, TNF stimulates osteoblastic RANKL and M-CSF production, in part by up-regulating IL-1, thus leading to osteoclastic formation.⁹⁵^,⁹⁶ TNF and IL-7 also directly blunt bone formation through their effects on osteoblasts.

Bone turnover in osteoporosis, however, varies widely with patients with high, normal, and low bone turnover.⁹⁷ In osteoporosis, trabecular plates are perforated and transform into rods, leading to thinning of trabeculae and loss of connectivity, with increased risk of fracture as a result. Cortices also thin because of reduced periosteal apposition failing to compensate for bone loss at the endosteal surfaces. Modifications in collagen matrix (e.g., variations in the proportions of various crosslinks and isomerization of C-telopeptide) and the degree of mineralization may also influence bone strength.

Serum intact parathyroid hormone (PTH) levels increase with advanced age in both genders. This hyperparathyroidism is secondary to the calcium and/or vitamin D deficiency commonly found in the elderly, especially in those institutionalized, and may contribute to bone loss in both women and men. A classification of osteoporotic fractures based on clinical features and underlying mechanisms has been used. Type I osteoporosis includes mainly wrist and vertebral fractures, occurring mostly in women younger than 70 years, and is predominantly due to loss of cancellous bone because of estrogen deficiency. Type II osteoporosis includes mainly hip fractures that occur in both elderly men and women as a result of cancellous and cortical bone loss driven primarily by secondary hyperparathyroidism. It has been proposed that this model should be unitary, with bone loss caused by estrogen deficiency in both phases and in both genders.⁴³ In this model, the accelerated phase of bone loss after menopause involves a disproportionate loss of cancellous bone, mainly due to estrogen deficiency. Compared to normal postmenopausal women, osteoporotic women seem to have impaired responsiveness to postmenopausal low levels of estrogen. The subsequent phase of slow bone loss involves proportionate losses of cancellous and cortical bone and is associated with secondary hyperparathyroidism. In aging men, low testosterone and estrogen levels contribute to bone loss. In the elderly, decreased bone formation also contributes to bone loss, probably due to stem cells which tend to differentiate toward the adipocyte lineage rather than the osteoblastic lineage.

Bone Quality

Bone strength is determined by its material composition and structure.⁹⁸ Bone must be stiff to resist deformation, thereby making loading possible, and it must also be flexible to absorb energy by deforming. Bones shorten and widen when compressed, and lengthen and narrow in tension. When bone is brittle (i.e., too stiff and unable to deform a little), the energy imposed during loading leads to structural failure, initially by the development of microcracks and then by complete fracture. When bone is too flexible and deforms beyond its peak strain, it breaks. Long bones are mainly made of cortical bone, favoring rigidity over flexibility, whereas mainly trabecular vertebrae can absorb more energy by deforming more before breaking. Differences in bone dimensions explain the better tolerance to load in men compared with women and in some races compared with others.⁹⁹ Men and women generally have similar vertebral trabecular volumetric density and similar vertebral heights. The larger vertebral cross-sectional area in men contributes to sex-based differences in bone strength. Black people tend to have wider but shorter vertebral bodies and higher trabecular volumetric density than do white people, owing to thicker trabeculae. The geometry of the hip (hip axis length) influences the risk of hip fractures. Femoral neck length is a predictor of future fracture, and individuals with particularly long femoral necks are more likely to have hip fractures. This feature has been noted in white women from the United States¹⁰⁰ and France.¹⁰¹ The increase in height over the second part of the 20th century could partly explain the increase in the incidence of hip fracture during this period.¹⁰² Bone modeling (construction) produces a change in size and shape of bone when new bone is deposited without previous bone resorption. During bone remodeling (reconstruction), resorption by osteoclasts precedes bone formation by osteoblasts. Bone modeling and remodeling modify the external size and contours of bone and its internal architecture by the deposition or removal of bone from the surface of bone. They result in cortical and trabecular thickening during growth and thinning during aging. Bone loss occurring with menopause and aging is associated with disturbances in bone microarchitecture.¹⁰³ Osteoclastic resorption leads to focal perforations in cancellous bone plates, which results in loss of connection of the horizontal plates, along with detachment of vertical bars throughout the bone marrow cavity. Thus the probability of crush fracture is increased in bones rich in cancellous bone, such as vertebrae. The thickness of cancellous bone plates is about 100 to 150 µm, and osteoclasts dig resorption defects of 50 to 100 µm during normal remodeling. Perforations in cancellous plates can be a consequence of increased osteoclast activity and lead to impairment in bone mechanical properties and therefore to an increased risk of fracture. With continued remodeling, trabeculae perforate and some disappear completely. Active endocortical and intracortical remodeling “trabecularizes” cortical bone (i.e., creates cortical bone with more surface area).¹⁰⁴ Older, more densely mineralized interstitial bone distant from surface remodeling has a reduced number of osteocytes and accumulates microdamage.¹⁰⁵ Both cortical thinning and cortical porosity reduce the resistance of bone to the propagation of cracks, leading to complete fracture in case of a fall. The loss of bone strength due to cortical thinning and porosity is partially offset by deposition of new bone on the external surface (periosteal apposition), so cortical thickness is better maintained than would occur without periosteal apposition (Fig. 13-3).¹⁰⁶^,¹⁰⁷ However, details of changes in periosteal apposition with aging—along with the effects of site, sex, and race—are difficult to evaluate prospectively, given the small magnitude of periosteal apposition throughout adult life. The notion that periosteal apposition is greater in men than in women remains controversial.¹⁰⁸ More recent studies suggest that sex-based differences may occur at some but not all sites.⁹⁹^,¹⁰⁹ Sex-based differences may also vary across races.

FIGURE 13-3 Bone morphology as a function of age and gender.

Role of Falls

Skeletal determinants of bone strength do not reflect all the factors related to fracture risk. For any given bone density, the risk of fracture is greater in the elderly. The increased frequency of falling, the type of fall that occurs among the elderly, and the loss of protective soft tissue may all explain the larger contribution of age and the less important role of bone mass in the elderly. Among postmenopausal women in the United States, the frequency of at least one annual fall rises from about one in five at 60 to 64 years of age to one in three at 80 to 84 years of age.¹¹⁰ Propensity for falling has been assessed in several studies⁴⁸ with parameters such as gait speed, inability to rise from a chair without using one’s arms, and of course, visual impairment. These parameters are associated with a risk of falling. The increase in falling is nevertheless not sufficient to account for the increasing incidence of fractures, because only 5% to 6% of falls result in a fracture (1% of hip fractures and 4% to 5% for other fractures). Fracture risk is also related to the seriousness of the trauma on the femur and the direction of the fall. Indeed, the risk of hip fracture is 13 times higher when the impact is delivered directly over the hip.¹¹⁰ A great amount of force can be dissipated by the thickness of soft tissue over the femur, and patients with low fat mass may be at higher risk of hip fracture.

Clinical Features

Postmenopausal Osteoporosis

The most common clinical form of osteoporosis is postmenopausal. Typically, women sustain a wrist fracture about 10 years after menopause, a vertebral fracture 15 to 20 years after menopause, and eventually, after 75 years of age, a hip fracture.

Wrist fractures or distal forearm fractures are mainly of two types: a Colles’ fracture is a consequence of dorsal angulation, and the less frequent type, a Smith fracture, results from volar angulation. These fractures usually have a favorable outcome, but some patients suffer from algodystrophy, osteoarthritis, or neuropathies.³⁶

Two types of hip fracture are cervical and trochanteric. The femoral trochanter is composed of more cancellous bone than the femoral neck is. It seems that the predictive value of BMD and ultrasonic parameters may be higher for trochanteric fracture than for cervical fracture.¹¹¹ Hip fractures are associated with more morbidity and mortality, and the prefracture functional state is restored in less than half of patients (see earlier in Epidemiology).

Vertebral fracture requires separate consideration. Vertebral fracture results in back pain, which often appears after some strain on the back, such as lifting a suitcase or working in the garden. The pain is commonly severe and often confines the patient to bed. This pain localizes to the back and rarely radiates to the legs; cord compression is exceptional, and in this latter case, one must consider other diagnoses such as metastases or myeloma. Pain from the fracture usually eases over a period of 6 to 8 weeks and disappears. Nevertheless, it has been estimated that about two-thirds of vertebral fractures are not diagnosed at the time they occur because they are considered by patients or physicians as nonspecific back pain. Loss of height is another main feature of vertebral fracture, but often patients do not report it spontaneously, so it needs to be sought by asking about the individual’s height in early adulthood and measuring the current height. Therefore, it is worthwhile to record the patient’s height at each clinical visit. Height loss of 3 cm or more should alert the physician to the possibility of a new vertebral fracture. Detection of asymptomatic vertebral fractures is clinically relevant because they are associated with a threefold to fivefold increased risk of new vertebral fractures, independent of the level of BMD. In addition, the incidence of new vertebral fracture in the year following a vertebral fracture has been estimated to be 20%.¹¹² Kyphosis is generally a consequence of vertebral crush fractures in the thoracic spine and sometimes results in decreased lung capacity. Vertebral fractures in the lumbar spine result in decreased abdominal volume, which causes protrusion of the abdomen and impingement of the costal margin on the iliac crest. This iliocostal contact provokes pain and a grating sensation.

Diseases and Treatments Contributing To Osteoporosis

A variety of disorders are associated with an increased risk of osteoporosis (Table 13-2). In most of these cases, osteoporosis appears to be multifactorial and cannot be attributed to only a specific disease (“secondary osteoporosis”). We will discuss only the most common disorders associated with osteoporosis.

Table 13-2

Diseases and Treatments Contributing to Osteoporosis

Endocrine disorders

Hyperthyroidism

Hyperparathyroidism

Type 1 diabetes mellitus

Conditions associated with hypogonadism

Hemochromatosis

Turner’s syndrome

Klinefelter’s syndrome

Postchemotherapy

Hypopituitarism

Anorexia nervosa

Inflammatory disorders

Rheumatoid arthritis

Ankylosing spondyloarthritis

Lupus erythematosus

Disorders associated with malabsorption

Celiac disease

Gastrectomy

Chronic liver diseases

Total parenteral nutrition

Inflammatory bowel disease

Conditions associated with immobilization

Bone marrow disorders

Multiple myeloma

Mastocytosis

Leukemia

Disorders of connective tissues

Osteogenesis imperfecta

Medroxyprogesterone acetate

Glucocorticoid-Induced Osteoporosis

Consistent evidence indicates that glucocorticoids impair bone formation ¹¹³ by directly inhibiting osteoblastic activity. Osteoblastic synthesis of type I collagen, osteocalcin, and alkaline phosphatase is decreased; the production of insulin-like growth factor 1 (IGF-1) and IGF-2 is also inhibited by glucocorticoids. Measurement of serum osteocalcin provides a good index of this osteoblast inhibition by glucocorticoids. The effect of corticosteroids on bone resorption is less clear. High doses have been associated (in some but not all studies) with an increased rate of bone resorption resulting from decreased intestinal calcium absorption, increased urine calcium excretion, decreased osteoprotegerin levels, and hypogonadism. Glucocorticoids contribute to adrenal and gonadal deficiency because of inhibition of pituitary hormone secretion, with a dose-dependent reduction in free testosterone in men. Consequently, exposure to supraphysiologic doses of glucocorticoids leads to substantial and rapid bone loss in most individuals, especially in the first year of therapy and with doses above 7.5 mg of prednisone. Thus fractures are very common, especially vertebral fractures, which occur in 30% to 50% of corticosteroid-treated patients; the risk of vertebral and hip fractures is generally more than doubled.¹¹⁴ Patients undergoing organ transplantation may have a higher fracture risk than other steroid-treated patients, perhaps because of the preexisting condition and the osteopenic effect of other immunosuppressive drugs. One of the main problems with corticosteroid treatment is the minimal effective dose to avoid side effects. Some evidence suggests that corticosteroid-induced inhibition of bone formation occurs even with low doses of inhaled corticosteroids, with a marked decrease in serum osteocalcin.¹¹⁵ With oral corticosteroids, the increase in fracture risk starts as low as 2.5 mg/day.¹¹⁶ Data from cross-sectional and prospective studies suggest that the bone mass of asthmatic patients treated with inhaled corticosteroids is lower than that of controls, in a dose-dependent fashion.¹¹⁷ The increased fracture risk rapidly offsets on cessation of therapy.¹¹⁸ BMD values are not good predictors of fracture risk in patients on corticosteroids, since the risks start to rise with T score around 0.0.¹¹⁹

Endocrine Diseases

Sex hormone deficiency in both genders results in bone loss. All diseases and drugs that reduce sex hormone levels are associated with bone loss, and the list includes athletic amenorrhea, anorexia nervosa, hemochromatosis, Turner’s syndrome, Klinefelter’s syndrome, numerous chemotherapeutic regimens, hypopituitarism, or treatment with luteinizing hormone–releasing hormone analogs for endometriosis. In type 1 diabetes mellitus, small and variable decreases in bone density have been reported. In type 2 diabetes, BMD seems to be increased, perhaps because of increased body weight and hyperinsulinemia, but fracture risk seems to rise, perhaps due to impairment in bone quality. Cushing’s syndrome leads to bone loss that is reversible after treatment of the disease. Thyroid hormones are major activators of bone remodeling.

Patients with hyperthyroidism are subject to high-turnover osteoporosis with or without mild hypercalcemia, and they have an increased risk of fracture.⁴⁹ The decrease in BMD in thyrotoxic patients is reversible after treatment of the hyperthyroidism.¹²⁰ The deleterious effects of supraphysiologic doses of thyroid hormone on bone may also occur (but to a lesser extent) in patients who receive suppressive doses of thyroxin for the treatment of thyroid carcinomas and nontoxic goiter. Conversely, hypothyroidism does not seem to significantly affect BMD. The potential role of calcitonin deficiency in bone loss after thyroidectomy is unclear.

Studies by DXA in mild primary hyperparathyroidism have shown that bone density is reduced in regions of cortical bone but is normal in areas of cancellous bone. This decrease in BMD is likely to increase the risk of fracture. Skeletal recovery after surgical treatment of parathyroid adenoma is very significant, with an increased BMD of about 6% at the femoral neck and 8% at the spine 1 year after surgery.¹²¹This improvement is sustained 10 years after surgery. These patients were the more severely affected patients whose surgery was dictated by the guidelines of the National Institutes of Health.

Osteoporosis In Young Adults

A few young adults have osteoporotic fractures corresponding to either mild osteogenesis imperfecta or idiopathic osteoporosis. Osteogenesis imperfecta is an inherited syndrome characterized by fragile bones and recurrent fractures that can lead to skeletal deformities.¹²³ Inheritance and phenotypic expression are very heterogeneous. Clinical features of osteogenesis imperfecta also include short stature, blue sclerae, dentinogenesis imperfecta, hearing loss, scoliosis, and joint laxity. Osteogenesis imperfecta generally results from mutations of type I collagen.

Idiopathic juvenile osteoporosis is a very rare condition ¹²³ of children and adolescents before puberty. This disease does not seem to be of familial origin. Vertebral fractures usually occur over a 2- to 4-year period. In severe cases, patients may have deformities of the extremities and kyphoscoliosis.

Idiopathic adult osteoporosis is more often recognized because bone densitometry is more widely available. Although the condition may resemble mild osteogenesis imperfecta, these patients do not have dentinogenesis imperfecta, blue sclerae, or hearing loss. They do, however, have joint laxity and mild scoliosis, and a familial history is sometimes found.¹²³

Osteoporosis In Men

Fractures are more prevalent in men than in women from childhood to middle life, probably because of a higher incidence of trauma. After 40 years of age, fractures are less common in men than in women, but the incidence of fracture as a result of mild trauma increases with aging. The incidence of hip fracture in men rises exponentially with age, as in women. The sex ratio (female to male) is about 2 : 1 in northern Europe, but it may vary in other areas and reflects the lower life expectancy of men. Mortality related to hip fracture is significantly higher in men than in women. Although vertebral deformities are common in men, many of them are unrelated to osteoporosis. Vertebral fractures in men are associated with height loss, kyphosis, and increased disability, as in women. The incidence of osteoporotic vertebral fractures seems to be half that in women.²³ Vertebral fracture in men is associated with lower BMD than in controls.¹²⁴ The incidence of limb fracture begins to rise at a later age in men than in women.

As in women, osteoporosis in men can result from an inadequate peak bone mass and/or accelerated bone loss. As discussed later, gonadal status may be critical for the achievement of peak bone mass in the male. Age-related bone loss is less pronounced in men than in women, around 15% to 20% from 30 to 80 years of age. The mechanisms underlying bone loss with aging in men are unknown, but some evidence indicates decreased osteoblastic activity in males with idiopathic osteoporosis.¹²⁵ In elderly men, secondary hyperparathyroidism may contribute to bone loss.

The same risk factors for fragility fractures have been described in men and women and include smoking and excessive alcohol intake; these factors are often combined in a man with osteoporosis. About 50% of men with osteoporosis are considered to have secondary osteoporosis. The most common causes are chronic glucocorticoid therapy, hypogonadism, alcoholism, gastrectomy, and other gastrointestinal disorders. Male hypogonadism has a major influence on the occurrence of osteoporosis. Peak bone mass may be impaired by disorders of puberty, and men with abnormal or delayed puberty have reduced bone mass.¹²⁶ Estrogen status is believed to be critical for the acquisition of peak bone mass in men since the observation that aromatase deficiency in a man, resulting in estrogen deficiency, led to the absence of epiphyseal closure and to osteopenia, abnormalities that can be successfully treated with estrogen.¹²⁷ Androgens are also essential for the maintenance of bone mass in adult men insofar as hypogonadism in men is associated with low bone mass. Osteoporosis is encountered in many forms of hypogonadism, such as hyperprolactinemia, castration, anorexia, hemochromatosis, and Klinefelter’s syndrome. Prolonged abuse of alcohol has detrimental effects on the skeleton, with reduced bone mass resulting mainly from impaired osteoblast activity, nutritional deficiencies, and hypogonadism. Gastrointestinal disorders, particularly gastrectomy, are also associated with osteoporosis in men. Some but not all studies have linked nephrolithiasis or hypercalciuria with reduced bone mass, but their impact on the mechanisms of bone loss remains unclear.

The absolute risk of various osteoporotic fractures is similar in men and women with the same BMD level, but fewer men than women have a low BMD, and men are generally older if they reach such low levels.¹²⁸ This difference in age and biomechanical factors such as bone size may also modulate the influence of BMD on fracture risk. There is currently no consensus on T scores that may be used as thresholds for therapeutic decision making in men. The −2.5 cutoff T score (if the reference values are obtained from a male population) is often used, given the similar relationship between BMD and fracture in men and women. The FRAX calculator⁶⁹ can also be used in men to assess the individual probability of fracture, but the T score to enter in the software must be calculated using a reference curve obtained with women data (NHANES III database).

Pathology

Histomorphometry

Bone histomorphometry of the iliac crest allows an assessment of bone structure and turnover and is usually performed on transiliac bone biopsy samples. The specimen is processed without prior decalcification and analyzed with standardized histomorphometric methods. Histomorphometry is the only method to differentiate the cell and tissue level of remodeling. Nowadays, noninvasive techniques such as DXA and bone markers are sufficient for most clinical situations involving osteoporosis, and very few indications for bone biopsy still remain. Histomorphometry should be restricted to patients whose history, examination, radiographs, or biochemical profile suggests the possibility of atypical osteomalacia, mast cell bone disease, nonsecreting myeloma, sarcoidosis, or other rare conditions.

Diagnosis

Investigation of patients with osteoporosis is intended to fulfill the following purposes:

• To establish the diagnosis and eliminate the possibility of conditions mimicking osteoporosis

• To identify factors contributing to osteoporosis

• To determine the prognosis of the disease, with quantification of bone mass, identification of previous fractures, identification of factors that influence the risk of fractures independently of bone mass, and assessment of the rate of bone loss with biochemical markers

• To select the most appropriate treatment

• To obtain baseline measurements that can be useful for monitoring treatment efficacy

Differential Diagnosis and Causes of Osteoporosis

Evaluation of a patient suspected of having osteoporosis includes an adequate history and physical examination, and it must assess the potential causes of secondary osteoporosis and diseases mimicking osteoporosis. Biological abnormalities are commonly found in osteoporotic women, but few major medical problems are identified with screening,¹²⁹ and routine laboratory testing may not be cost effective.¹³⁰ However, a biochemical profile is necessary in patients with vertebral fractures, including assays of serum calcium, phosphate, creatinine, 25-hydroxycholecalciferol [25(OH)D], and alkaline phosphatase; serum protein electrophoresis; test for proteinuria; urine calcium; and in some cases, urine protein immunoelectrophoresis and blood cell count. Thyroid-stimulating hormone measurement and, in men, total and bioavailable testosterone and prolactin assays may be useful in some cases. In the elderly, 25(OH)D and PTH assays are appropriate when vitamin D deficiency is suspected. Assessment is guided by the clinical findings because some patients with apparent primary osteoporosis turn out to have mild hyperparathyroidism, osteomalacia, systemic mastocytosis, or late appearance of atypical osteogenesis imperfecta.

A complete examination of the spine is often necessary in patients with osteoporosis and includes height measurement and assessment of pain, paraspinal muscle contraction, thoracic kyphosis and lumbar lordosis, scoliosis, and the gap between the costal margin and the iliac crest, as well as the abdomen protrusion that can result from multiple vertebral fractures. Blue sclerae, joint hyperelasticity, and signs in favor of hyperthyroidism or hyperadrenocorticism should be looked for. A general examination is also important to rule out a neoplasm (e.g., lymph node and breast palpation) or other conditions.

Radiologic Evaluation

The estimation of spine BMD on conventional radiographs is insensitive and inaccurate because the subjective assessment is dependent on radiographic exposure, patient size, and film-processing techniques. BMD has to decline by as much as a third before it can be detected on plain radiographs. The radiographic manifestation of osteopenia of the axial skeleton includes increased radiolucency of the vertebrae, sometimes vertical striation, framed appearance of the vertebrae (“empty box” or “picture framing”) and increased concavity of the vertebral endplates resulting from protrusion of the intervertebral disk into the weakened vertebral body (Fig. 13-4).¹³¹ Those signs of osteopenia, however, do not reflect the bone mineral status accurately, so they have been replaced by bone densitometry.

FIGURE 13-4 Reinforcement of the vertical primary trabeculae and loss of the horizontal trabeculae in postmenopausal osteoporosis led to vertical striations on a radiograph of the lumbar and thoracic spine, combined with an overall radiolucency and “empty box” appearance.

Radiographs are important tools to confirm fractures and their potential etiology. Plain radiographs with anteroposterior and lateral views are required for both the thoracic and lumbar spine. Vertebral fractures include wedge deformities, endplate (“biconcave”) deformities, and compression (or crush) fractures (Fig. 13-5). Some vertebral deformities unrelated to osteoporosis include Scheuermann’s disease, malignancies, and osteomalacia. The diagnosis of mild vertebral fracture can be difficult because of the overlap with the normal range of vertebral body shape. Algorithms to define vertebral fractures that were developed for epidemiologic studies and clinical trials have led to a consensus proposal for the radiologic diagnosis of vertebral fractures.¹³²

FIGURE 13-5 Progressive evolution of spinal osteoporosis in a postmenopausal woman with vertebral fracture cascade, at baseline, 10, and 20 years.

Vertebral fracture evaluation, however, may be challenging because of a considerable variability in fracture identification if clinicians or radiologists interpret radiographs without specific training. Several qualitative and quantitative methods have been developed to standardize visual vertebral fracture evaluation, but the most widely used currently is Genant’s semiquantitative assessment.¹³³ Vertebral fractures are distinguished from other nonfracture deformities, and the severity of the vertebral fracture is assessed by visual determination of the magnitude of vertebral height reduction and morphologic change. The type of deformity (wedge, biconcave, compression) is not linked to the extent of vertebral height reduction—that is, the grading of the fracture. Vertebrae from T4 to L4 are graded on visual inspection as normal (grade 0), mildly deformed (grade 1, 20% to 25% in anterior, middle, and/or posterior height), moderately deformed (grade 2, 25% to 40% in anterior, middle, and/or posterior height), and severely deformed (grade 3, >40% in anterior, middle, and/or posterior height) (Fig. 13-6). Semiquantitative interpretation has excellent intraobserver and interobserver precision, provided careful training and standardization have been applied.¹³³^,¹³⁴

FIGURE 13-6 Schematic representations of wedge, biconcave, and crush vertebral deformities with grading normal to severe deformity. The figure illustrates the semiquantitative visual grading system of Genant. (Drawn by C.Y. Wu.)

The axial skeleton is not the only site where changes due to osteoporosis can be observed. Widening of the medullary canal and thinning of the cortices is commonly described in older individuals as a result of longstanding endosteal bone resorption in the appendicular skeleton (Fig. 13-7). Conventional radiographs can also be used to assess the bone structure, with image procedures relying on texture or fractal analyses.¹³⁵

FIGURE 13-7 PA radiograph of the hand in an elderly osteoporotic woman showing severe diffuse cortical thinning, principally by endosteal resorption.

A variety of diseases and medications are associated with bone loss, but some differences can be seen in the appearance of those secondary osteoporoses compared with postmenopausal or senile osteoporosis. The characteristic radiographic appearance of Cushing’s or corticosteroid-induced osteoporosis, in the extreme, consists of a marginal condensation of the fractured vertebral bodies, resulting from exuberant callus formation (Fig. 13-8). Primary hyperparathyroidism may affect all bone surfaces and result in subperiosteal, intracortical, endosteal, subchondral, and trabecular bone resorption. Those signs, however, are seldom encountered because most patients with primary hyperparathyroidism have mild forms of the disease. In osteomalacia, radiographic abnormalities include osteopenia, non-sharp delineation of cortical bone, deformities, and stress and true fractures. Hyperparathyroidism secondary to renal insufficiency associates vertebral osteosclerosis, amyloid deposits, avascular necrosis, and vascular calcifications (Fig. 13-9A,B). The typical radiographic appearance of steroid-induced osteoporosis consists of a marginal condensation of the fractured vertebral bodies secondary to exuberant callus formation. In multiple myeloma, the radiographic appearance of spine radiographs can imitate osteoporosis, and other diagnostic procedures like skull radiographs (Fig. 13-10) or protein electrophoresis will make the diagnosis. Additional imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy may be useful in the differential diagnosis of the various conditions associated with osteoporosis or vertebral fractures (e.g., trauma [Fig. 13-11], multiple myeloma [Fig. 13-12], storage diseases, leukemia, sickle cell anemia, and thalassemia). Bone scintigraphy or MRI are the ideal techniques to diagnose sacrum stress fracture (Fig. 13-13) that may be encountered in elderly patients with osteoporosis or osteomalacia.

FIGURE 13-8 Lateral radiograph of the spine showing diffuse osteoporosis, dense thickened endplate, or marginal sclerosis, all characteristic of Cushing’s- or steroid-induced secondary osteoporosis.

FIGURE 13-9 A, Lateral radiograph of the lumbar spine showing typical changes of renal osteodystrophy with rugger jersey spine. B, PA radiograph of the fingers shows tuft and subperiosteal resorption and vascular calcification.

FIGURE 13-10 Changes in the spine in multiple myeloma (A), here seen with increased radiolucency and vertebral deformities, may easily be confused with osteoporotic changes. However, additional typical lesions at other sites (besides clinical features and relatively typical laboratory values) may reveal the nature of the underlying disease. In this example, multiple osteolytic lesions in the skull (B) support the diagnosis of multiple myeloma.

FIGURE 13-11 Conventional radiographs of the lumbar spine in the anteroposterior (A) and lateral (B) views reveal an old traumatic fracture of the fourth lumbar vertebra, resulting in instability of the lumbar spine and modest spinal stenosis, as shown on the corresponding MRI (C).

FIGURE 13-12 MRI of the spine in patients with multiple myeloma may give information on the infiltration of spinal bone marrow. In this patient, a diffuse infiltration pattern may be seen on T1-weighted spin echo (A) and gradient echo (B) images. In addition, the patient has a pathologic fracture of the first lumbar vertebra.

FIGURE 13-13 Coronal T1-weighted and T2-weighted images of the sacrum show bilateral sacral insufficiency fractures in an elderly osteoporotic woman.

Bone Mass Measurements

Measurement of bone mass is a critical step in the investigation of an osteoporotic patient to (1) confirm the reduction in bone mass and (2) assess the magnitude of bone loss and therefore the risk of further fracture. Some of the terms may be confusing, so they need to be defined.¹³⁶ What is measured with the various densitometric techniques is an apparent density, including the bone itself and the bone marrow. The term bone mineral density is related to the mass of bone tissue. The true bone mineral density—the mass of bone per unit volume, excluding the marrow and non-bone tissue—is not determined. DXA provides an areal apparent bone density because of a two-dimensional image, so the density is expressed as the bone density per unit area, not per volume, in g/cm². Even if QCT provides a volumetric bone density, usually expressed in mg/cm³, it is also an apparent density, because it includes the marrow spaces of vertebrae.

Dual X-Ray Absorptiometry

Technical Principles

The physical principle of DXA is to measure the attenuation of x-rays with two different energies through the body, thus accounting for variable soft-tissue thickness and composition, at sites like the axial skeleton, the hip, and the whole body. The dual x-ray can be generated by either K-edge filters or kVp switching. The preferred anatomic sites for BMD measurement are the lumbar spine (L1 to L4) and the proximal femur (Fig. 13-14), although the whole body and peripheral sites can also be scanned (calcaneus, distal forearm). Measurement of attenuation of the x-ray photons of two distinct energies also allows accurate assessment of body fat content.¹³⁷ The areal density that is measured by DXA is an integral of both cortical and trabecular BMC normalized to the size of the projected area. Scan times have been shortened from about 5 to 10 minutes for pencil-beam scanners to 10 to 30 seconds for the fan-beam systems, which perform a single sweep across the patient instead of a two-dimensional raster scan. Fan-beam systems also allow for easier identification of vertebral structures and artifacts because of better image resolution, but at the expense of greater x-ray exposure.

FIGURE 13-14 Fan-beam dual x-ray absorptiometry (DXA) scan of (A) the hip (oblong box, femoral neck; box, Ward’s area; trochanter, shaft, and total), and (B) regions of interest analyzed in the spine (L1-4).

The x-ray tube, the detectors, and the hardware are never perfectly stable, so there is a need to compensate for day-to-day variations in measurements. A set of stable calibration standards are acquired each day before assessing patient data; some machines have internal calibration systems to monitor the densitometer performance continuously.

The radiation dose to patients is small (0.08 to 4.6 µSv) compared with other techniques using ionizing radiation. Fan-beam technology has increased the dose (6.7 to 31 µSv), which is still acceptable. Measuring vertebral morphometry by DXA also delivers less radiation (<60 µSv) than do lateral radiographs. The greater scatter dose from fan-beam DXA systems approaches limits set by regulatory bodies for occupational exposure.

Diagnostic Use

Several sites can be measured with DXA. The spine measurement is limited to the lumbar spine, because the thoracic spine evaluation would be compounded by air in the lungs and ribs and sternum overlying the scan field. The scan usually includes L1 to L4 (sometimes L2 to L4). The spine should be centered in the scan field and properly aligned. One should remain alert to artifacts such as those induced by patient movement. The presence of vertebral fracture, deformities, osteoarthritis, aortic calcification, or curvature such as scoliosis modifies BMD,¹³⁸ so in individuals older than 65 or 70 years, those commonly affected by osteoarthritis, the spine measurement is often of limited clinical utility. On the DXA report, large differences in vertebral height, area, BMC, and/or BMD suggest fracture or degenerative changes. Affected vertebral bodies should be excluded from the analysis; the entire spine scan is often discarded because of these kinds of artifacts. The hip DXA scan includes the proximal end of the femur and a portion of the pelvis. Only the proximal femur bone is assessed. Small changes in femur rotation can induce significant changes in hip BMD,¹³⁹ so special positioning devices are typically used to position the measured limb at 15 to 30 degrees inward rotation. This way, the femoral neck is visible because it is aligned to the table and perpendicular to the x-ray beam. The right and left hips being similar within an individual, one can choose either side and repeat measurements on the same side. If degenerative changes, previous fracture, localized bone disease (hip osteonecrosis, Paget’s disease of bone, etc,) affect only one hip, the scan will be performed on the opposite side. On the report image, the lesser trochanter should be only slightly visible, indicating an appropriate rotation. Machines evaluate different regions of the hip, including the femoral neck, the trochanteric region, Ward’s triangle, and the total region. The diagnosis relies on the femoral neck and total regions values. The forearm can also be measured, typically on the nondominant side. The radial shaft is a good indicator of cortical bone density. Total body scans mainly reflect the cortical bone and are very precise. They are generally performed to assess body composition parameters such as lean and fat mass.

Several prospective studies have shown that BMD measured by DXA at various skeletal sites (spine, hip, forearm, calcaneus, total body) predicts the risk of fragility fractures, with a relative risk of 1.5 to 3.0 for each 1-SD decrease in BMD.⁴ The prediction of fracture is higher when BMD is measured at the site of fracture—for example, measuring hip BMD for hip fracture. Although BMD is commonly measured at the spine and hip, measuring multiple sites has little advantage.

The most convenient way to describe BMD is by T scores and Z scores. The T score is the number of standard deviations above or below the mean for young adults. The WHO definition of osteoporosis is based on the T score (see earlier). The T score declines with aging. The Z score is the number of standard deviations above or below the mean for people of the same age. The Z score permits a comparison of patients with a reference population of the same age and therefore allows detection of bone loss that is excessive for age. The high prevalence of osteoporosis in the elderly, however, as well as the difficulty in selecting a population adequate to establish a reference range of values in the elderly, limits use of the Z score. From a practical perspective, the diagnostic thresholds proposed by the WHO can be applied effectively to spine and hip DXA measurement. Therapeutic thresholds should include not only the BMD T score but also age and risk factors that predict the risk of fracture independently of BMD.

Observed changes on follow-up should not be due to precision errors. The bone content and area should be checked for consistency. The precision error—expressed as a coefficient of variation (CV)—is usually around 1% at the spine and 1.5% to 2% at the hip. This precision error should be evaluated in a group of subjects representative of the clinic population setting. The precision error can be estimated by measuring a group of 14 individuals, each at least three times, with interim repositioning.¹⁴⁰ The least significant change—the minimal BMD variation considered statistically significant within an individual—is calculated as . Thus, the least significant change in BMD is generally around 3% at the spine and 5% to 6% at the femoral neck. The precision error can also be expressed as an absolute BMD value difference, which is more accurate for extreme BMD values.

Limitations

First, measurement of the spine is often more difficult to interpret in persons older than 65 years because of the high prevalence of degenerative osteoarthritic changes, which will increase the apparent BMD reading without accurately measuring trabecular bone. Second, the accuracy of the technique is reduced in obese subjects. Third, repeated measurements may have limited value in assessing the rate of change in BMD because the expected percent change in BMD is the same magnitude as the precision error of the technique. Variations in technologist performance will adversely affect the precision of the exam. The same scan mode and parameters should be used at follow-up as those on the baseline examination. A 3- to 5-year interval between two measurements may be necessary in untreated postmenopausal women to detect fast BMD losers. In patients treated with antiresorptive therapy, a 2-year interval is usually necessary to detect a significant increase in BMD.

Contraindications

Pregnancy, recent administration of oral contrast media or radioisotopes, spinal deformity, and orthopedic hardware contraindicate DXA. BMD results can also be affected by metal objects such as belts and buttons. Severe obesity and small stature also undermine the interpretation of BMD results.

Other Techniques

Quantitative Computed Tomography

QCT measures the volumetric BMD of the lumbar spine and proximal femur, allows differentiation between cortical and trabecular BMD, and provides a sensitive measure of compartmental changes; however, it has several drawbacks, including relatively high radiation exposure and a higher precision error than that of DXA.¹³⁶^,¹⁴¹ QCT was originally implemented to determine bone mineral density in single slices through the midsections of the lumbar vertebral bodies (Fig. 13-15) or the distal radius.^136,141,142 With the advent of whole body multislice/multidetector (spiral) CT, a technique in which the examination table is continually advanced during data acquisition and one that allows more rapid scanning of large sections of the body, three-dimensional volumetric QCT (vQCT) techniques were developed. These advances improved the precision for measuring spine or hip from approximately 2% to 3% for single-slice to approximately 1% to 2% for volumetric measurements and enhanced the sensitivity and accuracy of the original approach by covering larger volumes.^143–145 As a volumetric technique, vQCT can determine BMD or bone mineral content of the entire bone or of specified subregions and, similar to single-slice QCT, can provide a separate analysis of the trabecular or cortical components. Geometric measurements, such as cross-sectional area or hip axis length, and derivation of mechanical properties, such as cross-sectional moment of inertia, are possible (Fig. 13-16). For further central skeletal analyses, the vQCT data can be used for high-resolution imaging of bone structure¹⁴⁶^,¹⁴⁷ and for finite element analysis (FEA).¹⁴⁸^,¹⁴⁹ This technique computes distributions of mechanical stress and strain throughout the bone under simulated loading conditions in an iterative process. Finite element modeling may improve the assessment of bone strength and the prediction of fracture healing, because it integrates the geometric and densitometric information that has been acquired from the QCT scan.

FIGURE 13-15 Traditional quantitative computed tomography (QCT) with single slice per vertebra is illustrated, along with the scout localization, the simultaneously scanned phantom, and the ellipse region of interest in the vertebral centrum.

FIGURE 13-16 Volumetric quantitative computed tomography of the spine (top) and hip (bottom) may be used to analyze bone mineral density (BMD) in various bone compartments and to accurately measure BMD and geometry. Top left, Segmented vertebral body selected for analysis with removed processes. Top center and right, Integral and trabecular and peeled trabecular volumes of interest along with the traditional elliptical and Pacman volumes of interest (VOIs). Bottom left, Segmented proximal femur. Bottom center and right, Analysis VOIs in the hip.

High-Resolution Peripheral Quantitative Computed Tomography

HR-pQCT allows for three-dimensional evaluation of BMD and quantification of architecture. These devices were introduced more than 10 years ago, but their performance has been improved more recently, with machines evaluating trabecular architecture and volumetric BMD at the distal radius and tibia with a nominal isotropic voxel size of 82 µm (Fig. 13-17). Precision of HR-pQCT measurements was 0.7% to 1.5% for total, trabecular, and cortical densities and 2.5% to 4.4% for trabecular architecture.¹⁵⁰ In the OFELY cohort, postmenopausal women had lower density, trabecular number, and cortical thickness than premenopausal women at both radius and tibia. Osteoporotic women had lower density, cortical thickness, and increased trabecular separation than osteopenic women at both sites. Furthermore, although spine and hip BMD were similar, fractured osteopenic women had lower trabecular density and more heterogeneous trabecular distribution at the radius compared with unfractured osteopenic women.¹⁵⁰ At the distal radius, women with fractures had lower volumetric total (D tot), trabecular (D trab) BMDs, trabecular bone volume (BV/TV), cortical thickness (Cort Th), trabecular number (TbN), trabecular thickness (TbTh), and higher trabecular separation (TbSp) and distribution of trabecular separation (TbSpSd) than controls without fractures. In a logistic model, each SD decrease of volumetric total and trabecular densities was associated with a significantly increased risk of fracture at both sites (ORs ranged from 2.00 to 2.47). After adjusting for aBMD measured by DXA at the ultradistal radius, differences between cases and controls remained significant for D trab, and there was a similar trend for TbN, TbSp, and TbSpSd, with adjusted ORs ranging from 1.32 to 1.50. In postmenopausal women, vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone that can be assessed noninvasively and that are partially independent of aBMD assessed by DXA.¹⁵¹ Assessment of bone mechanical properties by FEA may improve identification of those at high risk for fracture. The three-dimensional data obtained with HR-pQCT may help to achieve this goal. Thus, the proportion of load carried by cortical versus trabecular bone seemed to be associated with wrist fracture independently of BMD and microarchitecture in the same set of women from the OFELY cohort. These results suggest that bone mechanical properties assessed by microFE may provide information about skeletal fragility and fracture risk not assessed by BMD or architecture measurements alone and are therefore likely to enhance the prediction of wrist fracture risk.¹⁵²

FIGURE 13-17 Micro-CT of the distal radial metaphysic at nominal isotropic spatial resolution of 90 microns.

Quantitative Ultrasonography

Quantitative ultrasonography may be a surrogate technique for DXA and may provide additional information on the material properties of bone. Ultrasound velocity (speed of sound) and ultrasound attenuation through bone (broadband attenuation) are recorded at various peripheral bones such as the calcaneus, patella, phalanges, and tibia.¹⁵³ In general, ultrasound devices have a low precision error, but their accuracy is unknown. Both speed of sound and broadband attenuation decrease with age, with a magnitude that varies considerably from device to device. Prospective studies have shown that ultrasound measurement of the os calcis is a valid predictor of hip fracture risk in elderly women.¹⁵³^,¹⁵⁴ Quantitative ultrasonography is a technique for the broad diagnosis of osteoporosis, with the availability of cheap and portable devices. Until each device is adequately validated and precise diagnostic and therapeutic thresholds are defined, quantitative ultrasound should be still considered a research tool.

Who Should Be Screened With Dxa?

Even if BMD is an important predictor of fracture risk, it is too insensitive to be used solely as an indication for treatment, so targeted BMD testing of postmenopausal women who have clinical risk factors for fracture or low BMD is generally recommended, rather than universal testing.¹⁵⁵ The U.S. Preventive Services Task Force has concluded that the benefits of BMD testing are clear for all women 65 and older.¹⁵⁶ The use of other risk factors such as smoking, family history, race, decreased physical activity, alcohol or caffeine use, or low calcium intake could not be used to identify women at high risk. Most North American guidelines consider that BMD testing is appropriate in all women aged 65 and older. In younger women, BMD testing should be limited to those with BMD-independent risk factors. In other regions of the world, specifically in Europe, a case finding strategy is often adopted, so that BMD testing is proposed in women who have risk factors for low bone mass; for example, low BMI, smoking, excessive alcohol consumption, history of steroid use, personal or familial history of fragility fracture, diseases associated with accelerated bone loss (hyperparathyroidism, uncontrolled hyperthyroidism, osteogenesis imperfecta, malabsorption), or premature menopause, regardless of age.

According to the latest recommendations of the U.S. National Osteoporosis Foundation (NOF), the decision to perform bone density assessment should be based on an individual’s fracture risk profile and skeletal health assessment. The results of the test must be able to influence the treatment decision. NOF recommends testing of all women aged 65 and older and men aged 70 and older, regardless of clinical risk factors. Younger postmenopausal women and men aged 50 to 69 with clinical risk factors, adults who sustain fracture after age 50, adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥5 mg prednisone or equivalent for ≥3 months) associated with low bone mass or bone loss should be tested. BMD measurement is not recommended in children or adolescents and is not routinely indicated in healthy young men or premenopausal women. In patients treated for osteoporosis, BMD may be used to monitor treatment effect.

Vertebral Fracture Assessment

With most recent DXA systems, it is possible to scan the entire thoracic and lumbar spine to evaluate vertebral height.¹⁵⁷ The patient is scanned in supine position if the machine has a rotating arm, or in the lateral position. Vertebral bodies can be assessed qualitatively to screen for vertebral deformities, typically using the semiquantitative scoring method also applied to radiographs.¹³³^,¹³⁴ Those deformities can be quantified with a software that measures the height of vertebral bodies. The computer—or better, the technologist—places three points on the posterior, mid-, and anterior margins of both endplates of each vertebra from T4 to L4 to calculate the vertebral heights. Significant changes in vertebral height are indicative of vertebral fracture. This technique is attractive because evaluation of vertebral fracture prevalence can be performed without a conventional radiograph at the same time as the BMD measurement, thus saving time, unnecessary irradiation, and cost. This is an important advantage because vertebral fractures are often overlooked. The interpretation must be cautious, however, because the image quality is variable across individuals, so the observation of deformities is not synonymous for vertebral fracture and should lead to radiographs for confirmation. In addition, the upper thoracic spine may be difficult to visualize, especially among older individuals, with false-negative readings as a result. The specificity and the negative predictive value remain high despite these limitations, because most vertebral fractures occur at lumbar and lower thoracic levels where the image quality is still acceptable.¹⁵⁸ VFA is now widely used as a screening tool for vertebral fracture.

Biochemical Markers

Different Types of Markers

Bone markers are usually classified as markers of bone formation and markers of bone resorption (Table 13-3), but in diseases in which both processes are coupled and disclose similar variation, markers reflect the overall rate of bone turnover. Markers cannot distinguish between bone turnover changes originating in the cortical or in the trabecular envelopes.

Table 13-3

Biochemical Markers of Bone Turnover

Bone Formation Markers

Markers of bone formation are serum total and bone measurements of alkaline phosphatase, osteocalcin, and procollagen I extension peptides. Serum alkaline phosphatase is the most commonly used marker of bone formation but lacks sensitivity and specificity. New assays have been developed to improve specificity in order to separate bone and liver isoenzymes—in particular, immunoassays using monoclonal antibodies with a cross-reactivity of only 15% to 20%.¹⁵⁹ Thus, bone alkaline phosphatase is a sensitive marker of increased turnover in postmenopausal women, and since it is an enzyme activity and not a protein that is cleared by the kidney, it is also a marker of choice in the evaluation of bone turnover in chronic kidney failure.

Serum osteocalcin, also called bone Gla protein, is a small (49 amino acids) noncollagenous protein that is specific for bone tissue and dentin and produced only by osteoblasts and odontoblasts. Serum osteocalcin levels correlate with skeletal growth during puberty, as well as with increase in bone formation rate in conditions characterized by increased bone turnover, such as primary and secondary hyperparathyroidism, hyperthyroidism, or acromegaly. Conversely, osteocalcin is decreased in hypothyroidism, hypoparathyroidism, and glucocorticoid-treated patients, conditions associated with a decreased rate of bone formation. When resorption and formation are coupled, serum osteocalcin is a good marker of bone turnover. The most robust and sensitive assays measure both the intact molecule and the N-midfragment (which is the largest product of degradation of osteocalcin).¹⁶⁰ Although osteocalcin was discovered 30 years ago, its function remains elusive.¹⁶¹ It might be involved in the regulation of energy metabolism, its action depending on its degree of gamma-carboxylation.¹⁶²

Propeptides of type I procollagen (N-terminal and C-terminal extension peptides of type I collagen [PINP and PICP, respectively]) are cleaved during the extracellular processing of collagen. They also reflect bone formation, because type I collagen is the most abundant organic component of bone matrix. PICP exhibits smaller variations in postmenopausal osteoporosis than other markers, so it is probably less useful. However, it seems valuable in the monitoring of growth hormone treatment.¹⁶³ After the menopause, PINP augments to a similar extent that osteocalcin and bone alkaline phosphatase does. It is the most sensitive marker to monitor PTH treatment.¹⁶⁴

Bone Resorption Markers

Markers of bone resorption are fasting urinary calcium and hydroxyproline, plasma tartrate-resistant acid phosphatase (TRAP), and collagen pyridinium cross-links. Fasting urinary calcium, corrected by creatinine excretion, is the cheapest marker of bone resorption but lacks sensitivity in osteoporosis. Hydroxyproline is derived from the degradation of collagen and has long been used as a routine marker of resorption, but it also lacks sensitivity and specificity.

The most specific of the osteoclasts fraction of TRAP is the b subform of the isoenzyme 5 (TRAP5b). It is the only available marker of the osteoclast metabolic activity. Several drawbacks (e.g., influence of clotting, temperature instability) limit its practical use.

Pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) are nonreducible pyridinium cross-links in the mature form of collagen (Fig. 13-18). This posttranslational covalent cross-linking creates interchain bonds stabilizing the molecule of collagen. Concentration of Pyr and D-Pyr in biological fluids is derived predominantly from bone. Pyr and D-Pyr are released from bone matrix during osteoclastic bone resorption. They are excreted in urine in a free form (around 40%) and in a peptide-bound form (60%). Enzyme-linked immunosorbent assays have been developed against the N-telopeptide to helix (NTX) and against breakdown products of type I collagen C-telopeptide (CTX) in urine and serum. These cross-links are markedly increased at the time of menopause and return to premenopausal levels with estrogen and bisphosphonate therapy.¹⁶⁵

FIGURE 13-18 Degradation of type I collagen and excretion of type I collagen cross-links.

Clinical Use of Bone Markers

Bone Markers for Assessment of Bone Loss

A sharp increase in bone markers occurs after menopause. This increase is sustained long after the start of menopause, even in elderly women, and markers are negatively correlated with bone mass assessed by DXA,¹⁶⁶ which suggests that a high bone turnover rate is associated with increased bone loss. A long-term study suggested that the rate of bone loss measured over 12 years by densitometry is increased in women classified as rapid losers at baseline and significantly higher than that of slow losers.¹⁶⁷ Thus a combination of markers and BMD measurement could be useful in assessment of the risk of osteoporosis.¹⁶⁸

Bone Markers for Assessment of Fracture Risk

It has been reported that women classified as fast losers have a vertebral and wrist fracture risk double that of those classified as normal or slow losers.¹⁶⁹ Large prospective studies have shown that increased bone resorption (i.e., above the premenopausal values) is associated with an increased risk in vertebral and peripheral fractures, independently of BMD.¹⁷⁰^,¹⁷¹ Women with both a low BMD and increased bone resorption had a fourfold to fivefold increase in the risk of hip fracture. Measurements of bone resorption markers may be combined with other risk factors for fracture to calculate individual probability of fracture, but markers do not enter into the calculation of individual probabilities of fracture in the FRAX calculator, because data were not available in most cohorts used in model building.

Bone Markers for Monitoring Treatment of Osteoporosis

Antiresorptive therapies such as calcitonin, estrogen, and bisphosphonates induce a significant decrease in markers, which return to the premenopausal range within 3 to 6 months for resorption markers and within 6 to 9 months for formation markers. The significant decrease in bone turnover seen after treatment of osteoporotic women with a bisphosphonate significantly correlates with an increase in BMD at the lumbar spine after 2 years, with a low rate of false-positive and false-negative results.¹⁷² There is also an association between the decrease in bone turnover markers in response to antiresorptive agents such as bisphosphonates or raloxifene and the degree of reduction in fracture risk.¹⁷³^,¹⁷⁴ Given the precision of bone mass measurement with DXA and the expected change induced by antiresorptive treatment, it is usually necessary to wait for 2 years to determine whether the treatment is effective in an individual patient. Determination of markers after a few months of treatment is likely to provide useful information on efficacy and may improve compliance.¹⁷⁵ Therapies stimulating bone formation, such as teriparatide, may be monitored using bone formation markers (e.g., PINP).

Treatment

Nonpharmacologic Intervention

Lifestyle

Patients who have sustained vertebral fractures need specific guidelines in their daily activities to prevent additional fractures. They should avoid weightlifting and learn how to bend to avoid excessive strain on their spine. All lifestyle factors that might be deleterious to bone metabolism should be corrected. Thus patients should not smoke, they should consume moderate amounts of alcohol, and conditions predisposing to osteoporosis should be treated. Although no controlled trial has shown that cessation of smoking increases BMD or reduces the risk of osteoporotic fractures, sufficient evidence indicates that smoking is a risk factor for vertebral and hip fractures.⁴⁸ Drugs predisposing to osteoporosis should be avoided as much as possible.

Nutrition

No universal consensus has been reached on the daily calcium requirement by age, but according the Dietary Reference Intake (DRI) published in 1997,¹⁷⁶ 1300 mg/day is the recommended dose for adolescents, 1000 to 1200 mg/day for adults up to 70 years, and 1200 mg/day after the age of 70 years. Although most studies have shown a beneficial effect of calcium supplementation, as discussed later, the long-term effect of high dietary calcium intake on bone health is unknown. Conversely, there seems to be a threshold of calcium intake—around 400 mg/day—under which increasing calcium intake appears to be beneficial and necessary, both in children and in women older than 60 years.

Several nutritional factors influence the calcium requirement, such as sodium, protein, caffeine, fiber, and vitamin D status. The effect of fiber and caffeine is relatively small, whereas sodium and protein intake may be more relevant because they increase urinary excretion of calcium. A sodium-rich diet has been associated with increased incidence of kidney stones. The effects of phosphorus and fat intake do not substantially influence bone metabolism. Vitamin D promotes calcium absorption and thereby influences calcium requirements. Vitamin D status commonly deteriorates in older people, with serum levels of 25(OH)D lower than those in young adults because of low vitamin D intake and decreased sunlight exposure (see Chapters 3 and 15). NOF recommends an intake of 800 to 1000 international units (IU) of vitamin D per day for adults aged 50 and older. This intake will bring the average adult’s serum 25(OH)D concentration to the desired level of 30 ng/mL (75 nmol/L) or higher.^176–179 The low levels of 25(OH)D commonly seen in the elderly, especially those institutionalized, contribute to secondary hyperparathyroidism, which may play a role in bone loss in the elderly.

Exercise

Immobilization induces bone loss, as documented after prolonged bedrest, space flight, paralysis from spinal cord injury, and casting of limbs. The beneficial effect of exercise on bone mass and bone strength in normal and osteoporotic individuals, however, is still unclear. Several controlled trials have looked at the effect of various exercise programs on BMD, including walking, weight training, aerobics, and high-impact and low-impact exercise. Most of them show a small (1% to 2%) increase in BMD in comparison to either baseline or the control group at some but not all skeletal sites; the increase is not sustained once the exercise program is stopped. Both clinical trials and observational studies suggest that load-bearing exercise is more effective in preserving or increasing bone mass than other types of exercise are. The dominant arm of tennis players or the limbs of gymnasts usually have higher bone mass than other sites do.¹⁸⁰ Skeletal sites must be directly strained to be affected by exercise. In addition, it is likely that fitness might indirectly preserve individuals from fractures by improving mobility and reducing the risk of falls. No randomized controlled trial has been conducted to assess the effect of exercise on fracture risk. Because of the many nonskeletal benefits of exercise, it seems appropriate to recommend regular and moderate exercise in postmenopausal women, but it cannot replace pharmacologic prevention. After vertebral fracture, a supervised exercise program to maintain strength and flexibility of the thoracic and lumbar spine is recommended in the elderly.

It is critical to develop specific interventions aimed at preventing falls and their consequences in the elderly. So far, few studies have shown that specific strategies prevent falls. For example, one trial has shown that older men and women trained to practice tai chi regularly (better balance training) were less prone to fall than untrained counterparts.¹⁸¹

Given the multifactorial etiology of falls, interventions have to be multidimensional. An adequate exercise program may decrease the risk of falling in the elderly, who should be encouraged to walk at least half an hour per day. Indeed, a sedentary lifestyle leads to low muscle mass, postural alterations, and deconditioning of lower limbs and increases the incidence of falls. Visual impairment is a risk factor for falls and fractures because it results in tripping or slipping accidents and decreases postural stability. Therefore, glasses should be checked regularly and cataracts detected early. Whenever possible, the use of drugs that increase the risk of falling should be reduced; such drugs include benzodiazepines, hypnotics, antidepressant agents, and medications that can induce hypotension. Patients should be instructed to avoid slippery floors and to have adequate lights and handrails in bathrooms and on stairs at home.

Experimental studies have shown that the soft tissues covering the hip may have an impact on energy absorption of the fall. Some clinical trials have shown that hip protectors substantially decrease the risk of hip fracture in elderly people living in institution (up to 80%), but those results were not found in all trials, and poor compliance remains an issue in all studies.¹⁸²^,¹⁸³

Pharmacologic Intervention

Evaluation of Drug Efficacy

The goal of therapy is to prevent fragility fractures, and drugs for osteoporosis should demonstrate their ability to significantly decrease the incidence of fractures in adequately powered, prospective, randomized placebo-controlled studies. Conducting such placebo-controlled trials has been debated, but they remain the cornerstone of sound drug evaluation.¹⁸⁴ The diagnosis of nonvertebral fractures is easy, whereas the diagnosis of existing and new vertebral fractures requires adequate morphometric evaluation of spinal radiographs to exclude vertebral deformities unrelated to osteoporosis. Changes in BMD are commonly monitored and are usually seen as a surrogate marker of treatment efficacy. Actually, most drugs that inhibit bone turnover induce a small increase in BMD (i.e., 2% to 10% according to the skeletal site of measurement) that does not account for their marked reduction in fracture rate (i.e., 30% to 50% for vertebral fractures). In addition, some drugs—such as fluoride—may induce a marked increase in BMD without decreasing the fracture rate. Bone turnover markers are another surrogate for treatment efficacy of antiresorptive drugs. Their diminution in response to antiresorptive therapies is associated with the decreased fracture rate. High bone turnover is associated with an increased risk of fractures that is independent of the level of BMD,¹⁷⁰ and antiresorptive therapy such as raloxifene and bisphosphonates induces a dose-dependent decrease in bone markers that is sustained throughout treatment. Anabolic therapies such as PTH induce a substantial increase in markers of bone formation (e.g., PINP).

Anticatabolic Agents

Estrogen: Several controlled trials have shown that estrogen stops bone loss in early and late postmenopausal women by inhibiting bone resorption and that it results in a small increment in BMD (5% to 10% over a period of 1 to 3 years). Estrogen reduces bone turnover and increases bone density in postmenopausal women of all ages, as well as improving calcium homeostasis. Results from observational studies ¹⁸⁵ and randomized placebo-controlled trials^186–188 show that estrogen decreased the risk of hip fracture by about 30% and the risk of spine fracture by 30% to 50%. So, HRT has been a standard treatment for prevention and treatment of postmenopausal osteoporosis for years. The reduction in fracture risk exceeds that expected by BMD alone. Calcium supplements enhance the effect of estrogen on BMD.¹⁸⁹ When HRT is stopped, bone loss resumes at the same rate as after menopause. In the Study of Osteoporotic Fractures,¹⁹⁰ the relative risk for nonspinal fracture was 0.66 in postmenopausal women currently taking HRT as compared with those not taking HRT, but it was not decreased in previous users regardless of the duration of treatment. This positive effect was not affected by age and was more significant for women who started HRT soon after menopause (within 5 years).

The long-term risks of HRT, however, outweigh the benefits, as has been shown in a large randomized placebo-controlled trial, the Women’s Health Initiative (WHI) randomized trial.¹⁹¹ Indeed, among more than 16,000 women aged 50 to 79 followed for an average 5.2 years, treated using conjugated equine estrogen and medroxyprogesterone acetate, although hip fracture and colon cancer risks were reduced,¹⁹¹ increased risks of coronary heart disease (CHD) (nonfatal myocardial infarction or death due to CHD),¹⁹² stroke,¹⁹³ breast cancer,¹⁹⁴ and dementia¹⁹⁵ were observed. In addition, in this trial, estrogen plus progestin did not have clinically meaningful effect on health-related quality of life, such as sleep disturbance or vasomotor symptoms.¹⁹⁶ Those results in primary prevention are consistent with those obtained in secondary CHD prevention in a well-conducted randomized placebo-controlled trial.¹⁹⁷ More recent subgroup analyses from the WHI trial have suggested that women who initiated hormone therapy closer to menopause (<10 years) tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend did not meet strict criteria for statistical significance. A similar non-significant trend was observed for total mortality, but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms.¹⁹⁸ The fall in HRT prescription observed after the release of the WHI results has been associated with a decline in new breast cancer incidence in several countries.¹⁹⁹ Thus, estrogen replacement therapy is no longer recommended as a first-line therapy for prevention and treatment of osteoporosis. It should be used only to relieve menopausal symptoms for as short a time and at the lowest dose possible.

Bisphosphonates: Bisphosphonates are stable analogs of pyrophosphate characterized by two P-C-P bonds. By substituting for hydrogens on the carbon atom, a variety of bisphosphonates have been synthesized, the potency of which depends on the length and structure of the side chain. Bisphosphonates have a strong affinity for bone apatite, both in vitro and in vivo, which is the basis for their clinical use. Bisphosphonates are potent inhibitors of bone resorption and produce their effect by reducing the recruitment and activity of osteoclasts and increasing their apoptosis. This activity varies greatly from compound to compound and ranges from 1 to 10,000. The mechanism of action on osteoclasts includes inhibition of the proton vacuolar ATPase of some phosphatases and alteration of the cytoskeleton and the ruffled border. Aminobisphosphonates also inhibit several steps of the mevalonate pathway, thereby modifying the isoprenylation of guanosine triphosphatate–binding proteins.²⁰⁰

Oral bioavailability is low, between 1% and 3% of the dose ingested, and is impaired by food, calcium, iron, coffee, tea, and orange juice. Bisphosphonates are quickly cleared from plasma, about 50% being deposited in bone and the remainder excreted in urine. Their half-life in bone is very prolonged. Aminobisphosphonates can induce a 24- to 48-hour period of fever when administered intravenously and, rarely, esophagitis when given orally.

Etidronate, given in an intermittent regimen, has led to an increase of about 3.5% in spine BMD after 2 years, with a reduction in the vertebral fracture rate,²⁰¹ but this reduction in vertebral fracture rate was no longer significant after 3 years of treatment. Etidronate does not appear to be effective in preventing bone loss at the hip and in reducing nonvertebral fractures.²⁰² Inhibition of mineralization can occur when etidronate is given in high dose.

Alendronate at 5 mg/day is effective in preventing bone loss in postmenopausal women to nearly the same extent as HRT.²⁰³ In women with vertebral fractures, alendronate given for 3 years resulted in an 8.8% increase in BMD at the lumbar spine and hip²⁰⁴ (Fig. 13-19). This treatment reduced the incidence of new vertebral, wrist, and hip fractures by half and prevented height loss. Alendronate also reduces fracture risk in postmenopausal women at the highest risk of fracture (i.e., those older than 75 years or those with very low BMD).²⁰⁵ In women without preexisting vertebral fracture but with a hip T score lower than 2.5, alendronate is able to decrease clinical fractures of all types.²⁰⁶ Alendronate is approved in most countries for the treatment of osteoporosis at the 10-mg/day dose and for the prevention of osteoporosis at the 5-mg/day dose in the United States. Alendronate is safe but can induce mild upper gastrointestinal tract disturbances and heartburn; on rare occasions, these side effects are related to the esophagitis sometimes caused by inappropriate administration of the drug. The antifracture efficacy of another oral nitrogen-containing bisphosphonate, risedronate, has been established in randomized placebo-controlled trials. This compound has been able to halve the rate of vertebral fracture in postmenopausal women in two studies.²⁰⁷^,²⁰⁸ A trial in elderly women has shown a reduction of about a third of the incidence of hip fracture in women with hip BMD in the osteoporosis range, whereas women selected using clinical risk factors for fracture—and who generally were not osteoporotic—did not benefit from the treatment.²⁰⁹ Although these drugs were developed with daily dosages, they are now prescribed to be taken only on a weekly basis. Compliance has been slightly improved by weekly regimens, using 70 mg for alendronate and 35 mg for risedronate.

FIGURE 13-19 Effects of alendronate (aln) on the risk of fragility fracture. (Data from Black DM, Cummings SR, Karpf DB, et al: Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures, Lancet 348:1535–1541, 1996.)

Ibandronate, given either daily (2.5 mg) or intermittently (20 mg every other day for the first 24 days, followed by 9 weeks without the treatment) has reduced the incidence in vertebral fracture of about 50% in a randomized trial involving postmenopausal osteoporotic women.²¹⁰ It has been marketed as a monthly 150-mg tablet and a 3-mg, every-3-months IV injection.

Intravenous zoledronate (e.g., 4 mg once a year or 1 mg every 3 months) has been shown to decrease bone turnover and increase BMD with the same magnitude as alendronate in a randomized phase II trial.²¹¹ Two phase III trials have been published on the antifracture efficacy of annual IV zoledronic acid 5 mg. In the HORIZON Prevention Fracture Trial,²¹² the rate of vertebral fracture was reduced by 65% at 3 years, hip fracture by 40%, and nonvertebral fracture by 25%. In the Recurrent Fracture Trial,²¹³ men and women with a recent hip fracture who received annual 5 mg zoledronic acid had a 35% reduction in clinical fractures and a 28% reduction in all-cause mortality. Other bisphosphonates have been studied in the treatment of osteoporosis. Pamidronate can increase BMD, but no valuable data on its antifracture efficacy have been presented. Clodronate may have an antifracture efficacy, but no adequate data have been published so far.²¹⁴

Bisphosphonates can also be used in secondary osteoporosis, such as corticosteroid-induced osteoporosis. Etidronate prevents bone loss at the spine in men and women receiving corticosteroids, but not entirely at the femoral neck.²¹⁵ At a dose of 5 or 10 mg/day, alendronate is an effective therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, preventing bone loss at all skeletal sites in men and women and reducing the rate of new vertebral fractures in postmenopausal women.²¹⁶ Risedronate (5 mg daily) also increases BMD in patients receiving long-term treatments with corticosteroids and may have favorable effects on fracture rate.²¹⁷ Annual IV zoledronic acid has also shown favorable effects in prevention of steroid-induced osteoporosis.

Selective Estrogen Receptor Modulators: Selective estrogen receptor modulators (SERMs), also called estrogen analogs, act as estrogen agonists or antagonists, depending on the target tissue. Tamoxifen, which has long been used for the adjuvant treatment of breast cancer, is an estrogen antagonist in breast tissue but a partial agonist on bone, cholesterol metabolism, and endometrium. Tamoxifen does not entirely prevent bone loss in postmenopausal women and increases the risk of endometrial cancer, which precludes its use in healthy postmenopausal women. Raloxifene is a benzothiophene that competitively inhibits the action of estrogen in the breast and the endometrium and also acts as an estrogen agonist of bone and lipid metabolism. In a large 2-year randomized placebo-controlled trial of raloxifene in postmenopausal women,²¹⁸ raloxifene increased lumbar spine (2.4%), total hip (2.4%), and total body (2.0%) BMD and significantly reduced markers of bone turnover. Serum cholesterol concentrations and its low-density lipoprotein (LDL) fraction were reduced without stimulation of the endometrium. Results of the MORE trial (Multiple Outcomes of Raloxifene Evaluation),²¹⁹ performed in 7705 osteoporotic women randomized to receive either raloxifene or placebo, showed that the incidence of estrogen receptor–positive breast cancer is reduced by two-thirds in postmenopausal women. In this study, raloxifene also lowered the incidence of vertebral fractures in osteoporotic women with (−30%) or without (−50%) existing fracture but had no significant effect on nonvertebral fractures.²²⁰^,²²¹ In a post hoc analysis of women with prevalent vertebral fractures that were at highest risk of subsequent fractures, raloxifene has decreased the risk of both vertebral and nonvertebral fractures.²²² In another subgroup post hoc analysis of this trial,²²³ women at higher cardiovascular risk were also protected by raloxifene compared to those on placebo; but in the RUTH trial,²²⁴ in which the primary endpoint was cardiovascular events, raloxifene did not reduce cardiovascular events or mortality in a high-cardiovascular-risk population of postmenopausal women. In addition, two trials with incidence of breast cancer as the primary endpoint have confirmed the reduction in receptor-positive breast cancer incidence that was suggested in the MORE trial.²²⁴^,²²⁵

In a 3-year randomized trial,²²⁶ arzoxifene was compared to placebo and raloxifene among 6847 postmenopausal osteoporotic women. A vertebral fracture risk reduction of 42% was obtained with arzoxifene compared to placebo, which was similar to that observed with raloxifene. It is only in a subgroup analysis of patients at high risk that nonvertebral fracture risk was diminished. The incidence of breast cancer was low and did not differ between groups. The adverse events profile was comparable to that of raloxifene.

In a 5-year randomized placebo-controlled trial,²²⁷ lasofoxifene 0.5 mg/day use was associated with a 42% reduction in vertebral fracture risk and a 22% reduction in nonvertebral fracture risk. The risk of estrogen receptor–positive breast cancer decreased by 67%.

Denosumab: Denosumab is a human monoclonal anti-RANKL antibody. It is a potent antiresorptive agent which is administered by a 60-mg subcutaneous injection every 6 months. In a large randomized placebo-controlled trial involving postmenopausal women with osteoporosis,²²⁸ denosumab has been shown to reduce the risk of vertebral fracture by 68% at 3 years. The risk of hip fracture was diminished by 40% and nonvertebral fractures by 20%. The compound was well tolerated. In a trial among 1189 postmenopausal osteoporotic women randomized to receive either weekly alendronate or denosumab 60 mg every 6 months, the increase in BMD and the decrease in markers of bone resorption was larger in the denosumab group than in the alendronate group.²²⁹ In a trial conducted in 252 women at high risk of rapid loss because of an antiaromatase inhibitor therapy prescribed for nonmetastatic breast cancer over 24 months, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall adverse events rates similar to those of placebo.²³⁰ In another trial, postmenopausal women with low BMD were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly.²³¹ After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then reinitiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. The main finding was that the effects on bone turnover were fully reversible with discontinuation of denosumab, and its effects were restored with subsequent retreatment.

Calcitonin: Calcitonin, a peptide produced by thyroid C cells, reduces bone resorption by inhibiting osteoclast activity. It is traditionally given by subcutaneous or intramuscular injection, with poor tolerance (nausea, facial flushes, diarrhea). The development of intranasal salmon calcitonin has made this therapy more acceptable, with fewer side effects. The minimum intranasal dose to have an effect on BMD is 200 IU/day. Calcitonin is less effective in preventing cortical bone loss than cancellous bone loss in postmenopausal women.²³² A small controlled study in osteoporotic women suggested a reduction in new vertebral fractures.²³³ In the PROOF (Prevent Recurrence of Osteoporotic Fractures) study,²³⁴ which is a 5-year double-blind, randomized, placebo-controlled study of 1255 postmenopausal women with osteoporosis, 200 IU/day of intranasal salmon calcitonin significantly reduced the rate of vertebral (but not peripheral) fractures by about 30% in comparison to placebo, but doses of 100 and 400 IU had no effect, and no consistent effect on BMD and bone turnover markers was seen in this trial with a high dropout rate. Thus the role of nasal calcitonin in the management of postmenopausal osteoporosis is not yet clearly documented.²³⁵ Studies examining the effect of oral calcitonin are ongoing.

Anabolic Agents

Parathyroid Hormone: When administered intermittently, PTH stimulates bone formation. It can be administered as the intact hormone (1-84) or as the 1-34 fragment (teriparatide). Teriparatide increases osteoblast birth rate and prevents osteoblasts apoptosis, thereby increasing the number of osteoblasts and the rate of new bone formation. When given once daily subcutaneously, teriparatide increases BMD and improves trabecular architecture, cortical geometry, and strength. In a randomized placebo-controlled trial involving 1637 postmenopausal women with severe osteoporosis, the risk of vertebral fracture was reduced by 65% in those receiving 20 µg/day compared to those on placebo, and their reduction in peripheral fracture risk was of 53% after a median duration of treatment of 21 months (see Fig. 13-16).²³⁶ Treatment was well tolerated, with a transient rise in serum calcium in fewer than 10% of patients.

PTH is prescribed mostly in patients with severe osteoporosis. Those women, however, have often received other therapies for osteoporosis (e.g., raloxifene or bisphosphonates) before PTH may be started because they continue to fracture. In an observational prospective study, Ettinger et al.²³⁷ have treated osteoporotic women who had been either on raloxifene or alendronate for 18 to 36 months, with teriparatide 20 µg/day for 18 months. They found that teriparatide stimulated bone turnover in patients pretreated with raloxifene and alendronate, but the increase in markers of bone formation was blunted during the first months among those on prior alendronate. Moreover, among those on prior raloxifene, the teriparatide-induced increase in BMD was comparable to that reported in treatment-naïve patients, whereas prior treatment with alendronate delayed increase in BMD, particularly during the first 6 months. One may think that activated bone resorption is a prerequisite for an effect of PTH on bone formation. Thus, in old female sheep treated with the bisphosphonate tiludronate, PTH, or PTH and tiludronate, it has been shown that in the combined-therapy PTH and tiludronate group, the anabolic effect of PTH—as assessed using biochemical markers of bone formation and bone histomorphometry—was abolished.²³⁸ Comparable findings have been made in clinical trials in humans. In postmenopausal women treated with both alendronate and PTH(1-84), the increase in volumetric density was comparable to that observed in those receiving alendronate alone and significantly lower than that of women taking PTH alone, suggesting that concurrent use of alendronate and PTH may reduce the anabolic effects of PTH.²³⁹ Similar findings have been made in men taking alendronate, PTH(1-34), or PTH plus alendronate.²⁴⁰

Such results suggest that PTH and bisphosphonates should not be prescribed simultaneously because the bisphosphonate reduces the anabolic effect of PTH. In contrast, in patients who have taken raloxifene before, the effect of PTH does not appear to be modified, and in those who have taken a bisphosphonate before, the anabolic effect of PTH is still obtained but delayed. This initial blunting of anabolic effect seems to depend on the potency of the antiresorptive agent preceding the PTH treatment, (1) since the increase in markers of bone formation is greater in patients who have taken risedronate previously compared to those who have taken alendronate ²⁴¹ and (2) because there is no blunting after raloxifene.²³⁷^,²⁴²

The antifracture efficacy of intact PTH(1-84) has also been tested. In a trial among 2532 postmenopausal women with mildly severe osteoporosis, PTH could reduce the risk of vertebral fracture by 40%, but not that of nonvertebral fracture. Study results interpretation was hampered by a high dropout rate. The incidence of hypercalcemia among patients on PTH was 23%.²⁴³ This form of PTH is marketed in some European countries but not in the United States.

Other Medications

Calcium: Calcium partially decreases the rate of bone loss, especially in women in late postmenopause. It is generally prescribed as an adjunct to other drugs such as bisphosphonates, and in most clinical trials, both the active and placebo groups receive calcium supplements.

Calcium is likely to be partially effective in preventing bone loss, particularly in older women and those with low calcium intake. Two studies ²⁴⁴^,²⁴⁵ have shown a slight reduction in the incidence of fractures in patients receiving calcium supplements. In one study,²⁴⁶ women older than 60 years were supplemented with 1200 mg/d when their calcium intake was below 1000 mg/d, and this regimen resulted in prevention of bone loss from the forearm over a 4-year period and decreased the rate of vertebral fractures by 59% in women who had vertebral fractures at baseline but not in those without existing vertebral fractures. Calcium supplementation on the order of 500 to 1500 mg/day is safe. Mild gastrointestinal disturbances such as constipation are commonly reported. The risk of kidney stone disease related to hypercalciuria appears to be minimally increased. Bioavailability is greater during meals and varies with different calcium salts, but this factor is probably of little clinical significance.

Vitamin D: In a French study of 3270 institutionalized women with a mean age of 84 years who were treated with calcium (1200 mg/d) and vitamin D (800 IU/day) for 1.5 years, the risk of hip fracture and other nonvertebral fractures was decreased 43% and 32%, respectively, when compared with the placebo group.¹⁷⁸ Treatment increased serum 25(OH)D, decreased serum PTH, and increased femoral neck BMD. However, in a Dutch study of 2578 women of similar age treated with 400 IU of vitamin D or placebo for 3.5 years but without supplemental calcium because of higher dietary calcium intake, the rate of hip fracture was the same in the two groups.²⁴⁷ These women were healthier and more ambulatory, and the hip fracture rate was much lower than in the French study. In a more recent smaller study, 389 men and women older than 63 years were treated with vitamin D (700 IU/day) and calcium (500 mg/day); the study noted a trend toward a decrease in nonvertebral fractures.²⁴⁸ Another study showed a decrease in nonvertebral fractures when vitamin D was given annually by intramuscular injection.²⁴⁹ These studies show the utility of adequate calcium (500 to 1500 mg/day) and vitamin D (700 IU or equivalent) in calcium-deficient and vitamin D–deficient elderly women and probably men. A reduction of about 25% has also been found in men and women aged 65 and older living in the community, after receiving 100,000 IU of vitamin D every 4 months for 5 years.²⁵⁰ In elderly women recovering from a first hip fracture, a supplement in vitamin D has been able to increase BMD and reduce the incidence of falls, these effects being more marked with the addition of calcium.²⁵¹

Vitamin D should be used routinely in institutionalized patients because they have low vitamin D intake, low sunshine exposure, and impaired vitamin D synthesis in the skin. When compliance is reduced, oral or intramuscular dosing of 150,000 to 300,000 U can be administered twice a year. Vitamin D is safe and does not require monitoring. The utility of calcium and vitamin D supplementation in healthy elderly persons with adequate intake and normal BMD has not been established.

Strontium Ranelate: Strontium ranelate is a compound containing two atoms of non-radioactive strontium; it improves bone mass by inhibiting bone resorption while preserving bone formation. Strontium ranelate prevents bone loss induced by estrogen deficiency and immobilization in animal models and also improves bone strength in those models. In phase II trials, this compound has been able to prevent bone loss at the dose of 1 g/day.²⁵²^,²⁵³ In a randomized placebo-controlled trial conducted in 1649 postmenopausal women with osteoporosis (mean age 69) treated for 3 years, strontium ranelate use has been associated with a 41% reduction in vertebral fracture risk, this diminution being apparent as early as the first year.²⁵⁴ In another randomized trial, the primary endpoint being incidence of nonvertebral fracture, all peripheral fractures were significantly but slightly reduced (−16%). The reduction in the incidence of hip fracture did not reach statistical significance in the intent-to-treat analysis but only in a per-protocol analysis (−41%, P = 0.025).²⁵⁵ In those trials, strontium ranelate has been well tolerated. An analysis based on preplanned pooling of data from these two international phase III, randomized, placebo-controlled, double-blind studies included 1488 women between 80 and 100 years of age followed for 3 years. In this study, treatment with strontium ranelate reduced the risk of vertebral (−59%) and nonvertebral (−41%) fractures in women 80 years and older with osteoporosis.²⁵⁶ Strontium ranelate is not approved by the U.S. Food and Drug Administration.

Others: Ipriflavone is a synthetic compound that belongs to the family of isoflavones. In a large randomized placebo-controlled trial, it failed to demonstrate prevention of bone loss.²⁵⁷ In addition, a sizeable proportion of women on ipriflavone had lymphopenia.

Tibolone is a synthetic analog of anabolic steroids with estrogen-like, androgen-like, and progestin-like properties. It is marketed in some countries and generally used as HRT in postmenopausal women. It prevents postmenopausal bone loss and has positive effects on hot flashes. In the randomized LIFT study,²⁵⁸ 4538 women who were between the ages of 60 and 85 years and had a BMD T score of −2.5 or less at the hip or spine or a T score of −2.0 or less and radiologic evidence of a vertebral fracture were assigned to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Tibolone reduced the risk of vertebral fracture (−45%), nonvertebral fracture (−26%), and invasive breast cancer (−68%) and possibly colon cancer, but increased the risk of stroke.

Growth hormone has been used for its alleged bone and muscle anabolic properties. However, growth hormone has produced conflicting results in the prevention of bone loss in postmenopausal osteoporosis.²⁵⁹

Thiazide diuretics reduce tubular reabsorption of calcium and slow cortical bone loss in normal postmenopausal women, so they should not be used as a monotherapy in the treatment of postmenopausal osteoporosis.²⁶⁰

Who Should Be Treated?

Indications

Therapeutic recommendations for women rely on results of clinical trials whose main endpoint was the reduction in fracture risk.²⁶¹ There was no clinical trial in which the main endpoint was reduction in fracture risk in men, although bisphosphonates clearly increase BMD, reduce levels of biochemical markers, and are likely to reduce fracture risk to the same extent as in women. Similarly, teriparatide has shown beneficial effects in men with surrogates, but without the fracture outcome. The decision-making process should be based on an analysis of the patient’s individual risk of fracture and the efficacy and tolerance of the drugs to be prescribed. This decision should rely on age, the existence of clinical risk factors, the magnitude of bone loss as assessed by the level of BMD, and the presence or not of previous fragility fractures.

Most recent therapeutic recommendations rely at least partly on the use of the FRAX algorithm. Each country can adapt the available models to its public health priorities. For example, in the United Kingdom, a cost-effectiveness analysis using the probabilities of fracture calculated with the FRAX algorithm at various ages and the cost of medications in the United Kingdom found that treatment is cost effective at all ages when the 10-year probability of a major fracture exceeds 7%.²⁶² The intervention threshold at the age of 50 years corresponds to a 10-year probability of a major osteoporotic fracture of 7.5% and rises progressively with age up to 30% at the age of 80 years, so that intervention is cost effective at all ages. The use of these thresholds in a case-finding strategy would identify 23% to 46% as eligible for treatment, depending on age. The same threshold can be used in men.

In a United States–specific cost-effectiveness analysis,²⁶³ osteoporosis treatment was considered cost effective when the 10-year hip fracture probability reached approximately 3%. Although the RR at which treatment became cost effective varied markedly between genders and by race/ethnicity, the absolute 10-year hip fracture probability at which intervention became cost effective was similar across race/ethnicity groups and tended to be slightly higher for men than for women. The new WHO fracture prediction algorithm has been combined with an updated economic analysis to evaluate existing NOF guidance for osteoporosis prevention and treatment.²⁶⁴ The WHO fracture prediction algorithm was calibrated to the U.S. population using national age-, sex- and race-specific death rates and age- and sex-specific hip fracture incidence rates. Thus, it is cost effective to treat patients with a fragility fracture and those with osteoporosis by WHO criteria, as well as older individuals at average risk and osteopenic patients with additional risk factors. However, the estimated 10-year fracture probability was lower in men and nonwhite women compared to postmenopausal white women. This analysis generally endorsed existing clinical practice recommendations and concluded that specific treatment decisions must be individualized. So, in the latest NOF recommendations, postmenopausal women and men aged 50 and older presenting with the following should be considered for treatment:

• A hip or vertebral (clinical or morphometric) fracture

• T score ≤−2.5 at the femoral neck or spine after appropriate evaluation to exclude secondary causes

• Low bone mass (T score between −1.0 and −2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture ≥3% or a 10-year probability of a major osteoporosis-related fracture ≥20% based on the U.S.-adapted WHO algorithm.

Which Drug For Which Patient?

Patients With Previous Fragility Fractures

The existence of a previous fragility fracture requires, as an initial diagnostic step, investigation of the differential diagnosis and measurement of BMD. The first-line treatment, based on the current evidence for antifracture efficacy, may be a second-generation bisphosphonate (alendronate, risedronate, ibandronate, zoledronic acid), strontium ranelate, or raloxifene. Calcitonin might be another option, although evidence of efficacy is limited. In patients with severe osteoporosis (low bone mass and several prevalent fractures) teriparatide may be indicated. General measures including fall prevention and adequate nutrition should be implemented. The potential benefits of osteoporosis therapy may be limited if life expectancy is short, and the decision may be to not treat in very elderly women. Whatever the treatment option, adequate calcium and vitamin D supplementation is warranted.

Patients Without Fractures

Women with a T score lower than −2.5 at the spine and hip have osteoporosis and should be treated as indicated, unless their life expectancy is short, and therefore their lifetime risk of fracture is low. For example, women older than 80 years with no additional risk factor for fractures may be treated with calcium and vitamin D alone. Women with a T score above −1 have normal BMD and should not be treated.

Management of women with a low bone mass, that is, with a T score ranging between 1 and 2.5, is more complex. The decision to treat or not is based on the individual’s probability of fracture, as assessed in FRAX, which depends on the magnitude of the deficit in BMD (the fracture risk at a T score of −2 is double the risk of fracture at a T score of −1) and on additive risk factors such as age, parental history of hip fracture, low body weight, history of steroid therapy, and rheumatoid arthritis. Increased bone resorption as assessed by a biochemical marker may also be of interest in some patients. Although treating elderly women with low bone mass might be more cost effective than treating younger ones, treating women in their late 50s and 60s who have a high lifetime risk of fracture is recommended. Raloxifene, strontium ranelate, or bisphosphonates may be proposed.

Treatment Monitoring

Monitoring of Treatment With Densitometry

Whether the long-term antifracture efficacy of antiosteoporotic drugs will depend on the extent to which treatment can increase or maintain BMD is controversial. In one meta-analysis, 16% of vertebral fracture risk reduction after treatment with alendronate was attributed to an increase in BMD at the lumbar spine.²⁶⁵ For patients treated with risedronate or raloxifene, changes in BMD predict even more poorly the degree of reduction in vertebral (raloxifene) or nonvertebral (risedronate) fractures. In women taking alendronate and losing BMD (0 to −4%) at the spine during the first or second year of treatment, the effect of alendronate on vertebral fracture risk reduction is similar to that observed in those women who gained BMD.²⁶⁶ For bone-forming agents, increases in BMD account for approximately one-third of the vertebral fracture risk reduction with teriparatide.²⁶⁷ Further data are needed on the role of BMD in monitoring patients treated with bone-forming agents, but it appears to be of greater value than its use with inhibitors of bone resorption.