Osteoporosis

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Chapter 25 Osteoporosis

John Carey, Miriam Delaney, Holly L. Thacker

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.

Osteoporotic fractures are associated with substantial morbidity and increased mortality. Worldwide, there were approximately 1.7 million hip fractures in 1990, and this number is expected to triple by 2050 as the number of persons older than age 50 increases.

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

The skeleton is composed of cortical and trabecular bone. Cortical bone is primarily found in the long bones and trabecular bone in the axial skeleton. The primary function of cortical bone is structural, whereas the primary function of trabecular bone is calcium homeostasis. Skeletal tissue is in a constant state of turnover with destruction of old bone by osteoclasts and formation of new bone by osteoblasts. This process occurs throughout life at various sites in the skeleton termed bone remodeling units

Each bone remodeling unit contains multinucleated osteoclasts formed from fusion of monocytes and macrophages that migrate to different sites in the skeleton from the circulation. Once there, osteoclasts erode cavities deep into the bone surface termed a resorption pit

This process takes several weeks and is slower in cortical bone. Once the resorption pit has been formed, the osteoclasts are replaced by osteoblasts that lay down new bone, repairing the resorption cavities slowly over several months. Under normal circumstances both processes occur concurrently in an intimately regulated fashion known as coupling, which balances functions to maintain a healthy intact skeleton.

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

Estrogen and biomechanical strain appear to be the primary physiologic factors necessary for maintenance of bone mass. Estrogen decreases bone turnover and preserves homeostatic skeletal remodeling.

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 cells ³⁴ 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

The effect of estrogen on OPG is even more complex. Osteoclasts possess transmembrane receptors referred to as receptor activator of nuclear factor-κB, or RANK. Activation of RANK by tumor necrosis factor-related activation-induced cytokine, or TRANCE (also known as RANK ligand) results in increased bone resorption. However, OPG act as “decoy” receptors that prevent TRANCE from binding and activating RANK receptors. Thus, estrogen stimulation of OPG production decreases bone resorption by decreasing TRANCE binding to RANK.

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.

Testosterone receptors are present on several types of osteocytes, in a manner analogous to estrogen receptors. Testosterone actions include decreasing osteoclast and osteoblast apoptosis and stimulating osteoblast proliferation, which overall increases bone formation and reduces bone resorption. However, whereas estrogen opposes periosteal apposition of bone, testosterone promotes it, which may account for why men generally have larger bones than women. In addition, testosterone plays an important role in epiphyseal maturation and closure.

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.

Hormonal Therapy and Osteoporosis

Several drugs that are routinely used in gynecology directly influence bone metabolism and can result in osteoporosis. Gonadotropin-releasing hormone (GnRH) agonists are commonly used for the treatment of endometriosis and are well-known causes of bone loss secondary to hypoestrogenemia.

Depot medroxyprogesterone, a very popular contraceptive agent among adolescents, is also associated with bone loss secondary to hypoestrogenemia. As a result, depot medroxyprogesterone now carries a black box warning issued by the U.S. Food and Drug Administration (FDA) in 2004 reporting bone loss with prolonged use.

Finally, aromatase inhibitors, increasingly being prescribed to women with breast cancer, are associated with a higher risk of fracture compared to tamoxifen.

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 in humans is primarily obtained from ultraviolet light exposure, with a few foods, such as fish oils, containing significant amounts. Many foods and vitamins are now supplemented with vitamin D, but the actual amount in these foods may vary considerably. Vitamin D formed in the skin after exposure of 7-dehydrocholesterol to ultraviolet light is metabolized in the liver to 25-hydroxyvitamin D₃ and further in the kidney to 1,25-hydroxyvitamin D₃, the biologically active form. Vitamin D, required throughout life, influences several important steps in calcium metabolism, maintaining adequate serum calcium levels.

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

Primary osteoporosis is a disease mainly of the elderly. The underlying mechanisms for this appear to be multifactorial, including having lower peak bone mass, experiencing rapid bone loss after menopause, and having an associated condition, such as a hypogonadal state, poor nutrition, and vitamin D deficiency. There is likely a strong genetic predisposition to develop osteoporosis. An evaluation should be undertaken in patients diagnosed with osteoporosis because certain contributing factors to low bone mass are also more common in these women, including vitamin D deficiency, hypogonadism, and thyroid disease.

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).

Table 25-1 Common Associations or Secondary Causes of Low Bone Mass and Secondary Causes of Osteoporosis 56–59,^61,⁷⁴

Category	Specific Examples
Medications	Corticosteroids Depot medroxyprogesterone Heparin Gonadotropin-releasing hormone analogues Aromatase inhibitors Anticonvulsants Thyroxine Cyclosporine and tacrolimus Methotrexate Cyclophosphamide Neuroleptics Lithium Alcohol excess

Endocrine diseases

Hypogonadism

Hyperparathyroidism

Hyperthyroidism

Inflammatory diseases

Rheumatoid arthritis

Ankylosing spondylitis

Psoriatic arthritis

Malabsorption syndromes

Celiac disease

Short bowel syndrome

Cystic fibrosis

Deficiency states Vitamin D deficiency Renal diseases

Renal insufficiency

Renal osteodystrophy

Renal tubular acidosis

Idiopathic hypercalciuria

Bone marrow disorders

Multiple myeloma

Thalassemia

Genetic diseases

Osteogenesis imperfecta

Ehlers-Danlos syndrome

Turner’s syndrome

Prolonged immobilization

Stroke

Quadriplegia

Space flight

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

Whether radiographic imaging or other laboratory studies, such as serum and urine protein electrophoresis, parathyroid hormone level, or cortisol levels should be undertaken is a decision that needs to be taken by the individual physician, because ancillary testing should be based on the clinical impression.

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.

Bone pain, fevers, and weight loss are not features of osteoporosis, and the presence of such symptoms in the absence of a fracture should alert the clinician to the possibility of a different diagnosis. Paget’s disease of bone, malignancy, osteomalacia, and osteomyelitis can all present with bone pain. Back pain can be seen in osteoarthritis and malignancy and is only a feature of osteoporosis patients who fracture. Dental loss is associated with postmenopausal osteoporosis.

Physical Examination

Results of physical examination may be normal. However, more obvious features of osteoporosis include kyphosis, which if marked can give the appearance of a “hump,” increased limb-to- trunk ratio, decreased rib to pelvic brim height in the upright position, and spinal tenderness. Multiple fractures can lead to chronic pain, dyspnea, and depression. Blue sclera are seen in osteogenesis imperfecta, which can present as fragility fractures.

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).