Chapter 25 Osteoporosis
INTRODUCTION
Osteoporosis has reached epidemic proportions, affecting both genders and all races.1,2 In the United States, elderly white women are the at highest risk, and African-American or Hispanic American men may be at lowest risk.3 A 50-year-old white woman has a 40% lifetime risk of fracture and a 14% risk for hip fracture.
The cost of treating fractures is rising.4 Direct costs alone for the treatment of osteoporotic fractures in the United States total greater than $10 billion annually.1,5,6 In a study of over 200,000 postmenopausal women in 34 states in the United States who underwent bone mineral density (BMD) testing using peripheral measurement techniques, almost 40% had low BMD and 7% had osteoporosis.6
Great advances have been made in the past few years in both the diagnosis and treatment of osteoporosis. By the turn of the millennium in the United States, measurement of BMD had become widely available, making the diagnosis of osteoporosis easier. In addition, several biochemical markers of bone turnover allow more precise monitoring of patients on therapy. Newer scoring methods for assessing fracture risk have been developed.7 Lifestyle changes, fall prevention programs, nutritional supplements, and hip pads decrease the risk of fracture.1,8–10 Several medications are currently available that effectively decrease the risk of future fracture.
Unfortunately, despite these advances, studies show that many women age 40 and older have not had the opportunity to discuss management of this disease with their physicians,11 and many patients who suffer from an osteoporotic fracture are not evaluated or treated for their disease.12 Although management of fractures is appropriate, the primary aim for the treating physician should be fracture prevention.
PATHOPHYSIOLOGY
Definition
Osteoporosis is a disease of the skeletal system characterized by decreased bone strength leading to increased susceptibility to fracture.1 Microarchitectural changes result in less bone, which is of poorer quality, thus predisposing the skeleton to fractures that may occur with little or no trauma.1 The first released Surgeon General’s report contains a comprehensive report on osteoporosis.2
Basic Bone Physiology
Early in life, growth and accumulation of skeletal tissue occur. Peak bone mass is reached in adulthood, but the age at which this is achieved varies depending on the skeletal site and measurement techniques used. Currently available evidence suggests this occurs at the hip as soon as the third decade, several years later for the whole body, and maybe even longer in other bones.1,13
Peak bone mass is a major determinant of future osteoporosis risk and optimal achievement is usually multifactorial. Genetic influences account for the majority of variability in BMD and is the most critical determinant of peak bone mass in adulthood.13–16 Daughters of women with osteoporosis, and mothers with hip fractures attain lower peak bone mass than age-matched controls.14,15 Peak bone mass differs among racial groups, with African-American women having the highest BMD and others differing between measured sites and studies.3,17,18 Asian women may have lower BMD than white women but, interestingly, also have lower rates of hip fracture. Differences are likely related to genetic variation between races, local environmental factors, and primarily body weight and bone size.18,19
Basic Mechanisms of Bone Disorders
Uncoupling of bone turnover leading to either increased or decreased formation may result in either net bone gain, as occurs in Paget’s disease of bone, or net bone loss as occurs in postmenopausal women, in primary hyperparathyroidism, and in rheumatoid arthritis.20–23 Most disorders of the skeleton result from excessive osteoclastic activity.20 As a consequence of estrogen deficiency after menopause, there is early and rapid loss of cancellous bone, concomitant with and followed by a more gradual loss of cortical bone. Exogenous estrogen can decrease or prevent this altered skeletal remodeling.24
This bone resorption occurs by two main biochemical pathways: the cathepsin K and the metalloproteinase-dependent pathways. Postmenopausal bone loss is thought to occur mainly via the former.25
Medical Problems Associated with Osteoporosis
Certain medical disorders and medications may significantly impact the attainment of peak bone mass. Malabsorption syndromes, cystic fibrosis, anorexia nervosa, inflammatory arthritis, and other diseases are associated with lower bone mass compared to age-matched controls. Although weight can have a significant impact on the measurement of BMD,18 severely underweight young women have lower BMD and a higher risk of fracture.
Certain medications such as glucocorticoids and phenytoin, vitamin D deficiency, and low calcium diets can also impair skeletal acquisition. Both vitamin D deficiency and low calcium intake are prevalent in our society and increasingly recognized worldwide. Periods of more rapid growth may require higher calcium intake.13,20 Recent evidence suggests that genetic alteration of vitamin D-binding proteins may increase the risk of premenopausal fractures.21
Social Behavior and Bone Mass
Although weight-bearing exercise generally increases BMD, the effects may be short-lived and may return to baseline levels after cessation of exercise regimens.28 Although moderate doses of alcohol have no deleterious effects on BMD, and, in fact, may even be of benefit,29,30 excessive alcohol consumption is associated with lower bone mass and an increased risk of osteoporosis.31 Although not all studies agree, smoking is generally considered to have a deleterious effect on the skeleton and is associated with an increased risk of fracture.24
In young women, eating disorders such as anorexia nervosa and excessive athletic training are associated with loss of BMD or BMD.1,13,26 Young women with anorexia nervosa may have irreversible skeletal changes and have a significantly higher risk of fracture.26 The female athlete triad of intense exercise regimens, with resultant loss of critical body fat and subsequent hypothalamic amenorrhea and low bone mass, are important elements to consider in young active women. This triad is frequently associated with eating disorders that may be further detrimental to skeletal health.
Female athletes weighing less than 50kg have a higher incidence of amenorrhea than those weighing more than 60kg and amenorrheic female athletes have significantly lower BMD than controls and a higher number of fractures. These women may present with stress fractures as the first sign of their disease; thus, every woman with a stress fracture should have a careful dietary, exercise, and menstrual history taken. Importantly, these women may not achieve their peak bone mass if undetected. Bone loss in these young women is likely multifactorial.13,26
Hormonal Influence on Bone Mass
Estrogen
At the cellular level there are two main cell types responsible for the maintenance of skeletal homeostasis: osteoclasts and osteoblasts, influenced by many regulatory genes; several hormones, particularly estrogen, testosterone, parathyroid hormone, and vitamin D; and a variety of cytokines.20,24,32 Estrogen increases osteoclast apoptosis, but its role in osteoblastic function is not fully understood.24
Estrogen decreases osteoclast activity and bone resorption by modulating the production of two essential cytokines that regulate osteoclast number and activity, and possibly osteoblast function as well.20 Estrogen inhibits production of tumor necrosis factor α (TNF-α)33 but increases production of osteoprotegerin (OPG).24 TNF-α promotes bone resorption by decreasing osteoblast activity and directly inducing the differentiation of osteoclast progenitors into mature osteoclasts. TNF-α also appears to induce osteoblastic cells to stimulate osteoclastic bone resorption. Thus, estrogen decreases bone resorption by inhibiting TNF-α production.
In postmenopausal women estrogen therapy inhibits TNF-α release in a dose-dependent manner from peripheral blood mononuclear cells34 and markedly reduces TNF-α mRNA expression in bone biopsy specimens.35,36
In murine models, blockade of TNF-α is not detrimental to skeletal maturation.37 Mice deficient in the p55 TNF receptor are protected against ovariectomy-induced bone loss.38 Surgically induced estrogen deficiency in mice causes significant bone loss, which is mediated via the p55 TNF receptor and can be prevented by blockade of TNF-α.23,37
Mice with excess OPG exhibit increased osteoclastic activity and an osteopetrotic phenotype,39 whereas mice deficient in OPG suffer severe osteoporosis.40 Conversely, OPG protects TNF transgenic mice from generalized bone loss.41 1,25-OH active vitamin D potentiates the action of OPG.
Androgens
Androgens also play a critical role in skeletal development, maturation, and preservation. Differences in estrogen and testosterone production and in tissue sensitivity to these hormones probably account for most of the skeletal differences seen between men and women. At the present time it appears that both are essential for bone health in women and men. Sources of testosterone in women arise mainly from conversion in peripheral tissues but also from central production in small amounts in the ovaries and adrenal glands, whereas in men 95% is derived from testicular secretion, and production of the various isoforms is highly tissue specific. More detailed explanations of the production and removal of these hormones can be found elsewhere in the book.
The precise molecular pathways in bone resulting from androgenic stimulation are less well-described than for estrogens. Many of the effects of androgens on skeletal tissue may be mediated by increased production of transforming growth factor (TGF)-β and decreased production of interleukin-6.24,42 Studies in female rats have shown that blockade of the androgen receptor may result in significant bone loss, and in men androgen deprivation results in bone loss.43,44 The remainder of this discussion applies mainly to female bone health.
Pregnancy and the Postpartum Period
Significant bone loss occurs during pregnancy, as assessed by BMD testing.45,46 Although earlier reports have suggested that heparin use in pregnancy may result in significant bone loss during pregnancy, a recent randomized trial showed treatment with low molecular weight heparin throughout the course of pregnancy did not result in significantly more bone loss in this study of women with recurrent miscarriages compared to individuals who used only aspirin throughout the course of their pregnancy.49 Breastfeeding in the postpartum period can further exacerbate bone loss, but a recent study shows that the effect may not be sustained, with the majority of women returning to baseline within a year after the birth of their child.46
Age and Postmenopausal Status
With aging, there is an alteration in the rates of bone formation and destruction where the process switches from one of gradual net gain to one of loss. This loss along with microarchitectural deterioration results in significant compromise of bone strength.47 More dramatic changes occur most noticeably during and after menopause. (In contrast, bone loss in men tends to be more constant over time.) Postmenopausal bone loss is biphasic in women (who are not on antiremodeling therapy), with an initial rapid bone loss in the first few years of menopause followed by a more gradual decline in later years.48
Women with higher levels of bone markers lose more bone and have a higher rate of fracture than women with normal or low levels, even after adjustment for BMD and hormonal status. However, postmenopausal women with high bone turnover markers and low estradiol levels have an even higher rate of fracture.48–50
Estrogen therapy preserves BMD and suppresses bone turnover markers, but discontinuation leads to a rapid increase in bone turnover markers and significant bone loss similar to that seen in recently postmenopausal women but greater than age-matched controls.51 Women undergoing surgical menopause may be at higher risk for short-term bone loss compared to women experiencing natural menopause.48
Hyperparathyroidism
Secondary hyperparathyroidism, impaired vitamin D metabolism, and vitamin D and calcium deficiency are also critical elements in age-related bone loss, and their importance and prevalence has been increasingly recognized. Calcium absorption varies among individuals and is influenced by many factors, primarily vitamin D.13,52 Decreased ability to absorb calcium is associated with increased risk of fracture in elderly women.53 Primary osteoporosis is associated with decreased calcium absorption, lower vitamin D levels, and compensatory increases in parathyroid hormone levels.24,54
Vitamin D Deficiency
Vitamin D increases absorption of calcium and phosphorus from the gut, increases their reabsorption from the kidney, and decreases skeletal mobilization of calcium. Deficiency of vitamin D impairs absorption of calcium, which is counteracted by increased parathyroid hormone levels and osteoclastic activity to resorb skeletal tissue to maintain serum calcium level.13,52,54
Vitamin D deficiency is prevalent in elderly women with hip fractures,55 due to decreased skin conversion, decreased sun exposure, and low dietary intake.52
CLASSIFICATION AND GENERAL PRINCIPLES OF INVESTIGATION
Secondary osteoporosis should be considered whenever there is any clinical suspicion of a disorder known to affect bone or calcium metabolism. A careful history, including a list of medications both past and present, is essential given the extensive list of diseases and treatments associated with or known to cause low bone mass or bone loss (Table 25-1).
Category | Specific Examples |
---|---|
Medications | |
Endocrine diseases | |
Inflammatory diseases | |
Malabsorption syndromes | |
Deficiency states | Vitamin D deficiency |
Renal diseases | |
Bone marrow disorders | |
Genetic diseases | |
Prolonged immobilization |
Previous studies have shown that up to 70% of patients with osteoporosis may have other diagnoses contributing to low bone mass.56,57 Secondary causes of low bone mass may be more prevalent in perimenopausal women and in men, although studies are limited on the prevalence of such disorders in postmenopausal women with low bone mass.1,58 An evaluation of possible causes of low bone mass should be undertaken in anyone for whom this is suspected. It is generally recommended that at least basic chemistries are obtained, including complete blood count, thyrotropin level, 24-hour urine for calcium excretion, intact parathyroid hormone level, and a 25-hydroxyvitamin D3 level in all patients.56,59,60
Glucocorticoid-induced Osteoporosis
Glucocorticoid-induced osteoporosis is a distinct form of secondary osteoporosis. Although an extensive list of medications can both directly and indirectly affect the skeleton, glucocorticoid-induced osteoporosis is the most common drug-induced metabolic bone disease.61,62 Glucocorticoids are often prescribed in both young and older individuals for treatment of medical conditions, such as rheumatoid arthritis, asthma, or other chronic obstructive pulmonary disease. Vertebral fractures will develop in 30% to 50% of patients taking chronic glucocorticoids, and patients have an increased risk of fracture at any site compared to nonusers. The risk of fracture is related to the daily dose, duration of therapy, and older age.63
Acute corticosteroid excess leads to decreased calcium absorption from the gut, a marked early increase in bone resorption, and decrease in bone formation with resultant increased excretion of urinary calcium. There can be very significant bone loss during this initial phase. Chronic use leads to other changes, including hypogonadism, resulting in a generalized suppression of skeletal remodeling.62 The American College of Rheumatology has published guidelines for the management of patients with glucocorticoid-induced osteoporosis.63
CLINICAL EVALUATION
History
Osteoporosis is generally a painless and symptom-free disease until fractures occur. Fractures may be very painful or painless, with up to two thirds of vertebral fractures being clinically silent.64 Loss of height is the most common finding in women with osteoporosis. History taking should include questions about height loss, back pain, dietary calcium intake, eating disorder history, age of menarche and menopause, and cycle history during menstrual years. Other risk factors for low bone mass should also be evaluated, including major illnesses, medications (particularly glucocorticoid use), a history of prolonged amenorrhea, and risk factors for fracture such as poor vision, recent falls, and findings of risk on a fall risk assessment.
Diagnostic Imaging
Any history of a fragility fracture should immediately alert the physician to consider a diagnosis of osteoporosis. Although microarchitectural changes seen on bone biopsy specimens definitively diagnose osteoporosis, this is not a practical approach for most women. The need for noninvasive methods to measure bone strength has led to the development of dual energy absorptiometry (DXA) techniques that measure BMD of the skeleton. BMD accounts for the majority of bone strength. Studies show that measurements obtained by this technique have a strong linear correlation with fracture risk.6,65,66 Additional factors influencing bone strength include bone size and quality. Osteoporosis may be diagnosed with findings of low BMD on DXA in postmenopausal women. Lastly, newer methods for assessing fracture risk and bone strength continue to be developed, with exciting techniques such as virtual bone biopsy using microcomputed tomography or magnetic resonance imaging appearing very promising.
Dual Energy Absorptiometry
The advent of DXA has revolutionized our ability to quickly and accurately measure bone mass noninvasively. Results are expressed in grams per centimeter squared and as T- and Z-scores, which are expressions of BMD in standard deviations compared to a normally distributed reference population. The T-score compares the results to young, healthy white women at peak bone mass, whereas the Z-score compares subjects to age-matched, and usually sex-matched and racially matched, controls (depending on the DXA machine used). A strong linear relationship exists between BMD and fracture risk, such that for each standard deviation below 1 there is an approximately doubling of fracture risk.1,6,65,66
A low BMD is the best individual predictor of future fracture risk in postmenopausal women without prior fracture.6 Women with low BMD and previous fractures have a much higher risk of future fracture.7,64 The addition of age66 and other risk factors such as estrogen deficiency greatly increases the utility of BMD testing to predict fracture risk.7,65 Although World Health Organization criteria can be applied to BMD measurements to diagnose osteoporosis,67 they reflect a consensus of expert opinion, and significant problems exist using such a method as the sole means of diagnosing osteoporosis68 (Table 25-2).
Bone Mineral Density T-Score | World Health Organization Classification |
---|---|
≥ −1.0 | Normal |
−1.1 to −2.4 | Osteopenia |
≤ −2.5 | Osteoporosis |
≤ −2.5 and the presence of a fragility fracture | Severe (established) osteoporosis |
Although these criteria may be used to identify individuals at increased risk for fracture, they are not a panacea for either diagnosis or treatment of this disease. First, most fractures occur in individuals who do not have osteoporosis using these criteria. Second, these criteria were established for use with central DXA technology; their application to other modalities used to measure BMD remains unclear. Third, they were intended for use primarily in postmenopausal white women; their applicability to other populations such as premenopausal women is less clear. Some of these shortcomings were evident in a recent very large study of postmenopausal women in the United States, in which Asian and Hispanic women had significantly lower BMD at one measured site than white women but a similar risk of fracture.6 Finally, other fracture risk factors may be significant, such as age or prior fractures, and the addition of such factors to fracture risk assessment greatly increases the prediction of future fracture risk.7,65,66,68 (Table 25-3).
Prior fragility fracture |
Low bone density (particularly T-score ≤ − 1.7)4 |
Maternal history of osteoporotic fracture |
Low body mass index |
Smoking history |
As a result, attempts have been made to clarify how to best use DXA technology to diagnose osteoporosis in different populations and using different technologies,69 and also how to predict increased fracture risk.7,65 In conclusion, although a useful measure for predicting increased fracture risk, BMD measurement is only one assessment tool for such predictions, and an overall clinical assessment of an individual’s fracture risk should be used when assessing whether a woman is likely to sustain an osteoporotic fracture. A T-score of ≤ –1.7 appears to be an important cutpoint for fracture risk.4
Because osteoporosis is an asymptomatic disease (until a fracture occurs), screening with DXA should be considered in certain individuals, such as postmenopausal women with additional risk factors for osteoporosis. Presently the International Society for Clinical Densitometry recommends BMD testing for the following groups of people:69