Osteoporosis

Authors: Erika Tapino, MD, Fellow, Division of Endocrinology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA; Barbara Simon, MD, Fellow, Division of Endocrinology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA; and Serge Jabbour, MD, Assistant Professor of Medicine, Division of Endocrinology, Diabetes & Metabolic Diseases; Department of Medicine, Thomas Jefferson University Hospital; Philadelphia, PA.

Peer Reviewer: Susan Y. Melvin, DO, Director, Family Medicine Residency Program, Long Beach Memorial Medical Center, Long Beach, CA; Clinical Professor, Department of Family Medicine, University of California, Irvine.

Osteoporosis is the most common bone disease. It is a major risk factor for fracture, which leads to considerable morbidity, mortality, and expense.1 Osteoporosis is a global problem that will increase in significance with the growing elderly population. The condition affects both sexes and all races, albeit to different degrees. Bone loss occurs during the normal aging process. Primary osteoporosis results from the involutional losses associated with aging and, in women, with additional losses related to natural menopause. Secondary osteoporosis results from other disorders or medication exposures; it most commonly is found in premenopausal women and in men,2 although it is not limited to these groups. As many as 30% of postmenopausal women with osteoporosis have been found to have other conditions that may have contributed to their bone loss.3 It is important to know the major etiologies and be familiar with the diagnostic investigations in patients suspected of having secondary osteoporosis.

Many therapeutic options now are available to prevent and treat osteoporosis, and consist of non-drug and drug or hormonal therapy. In just one decade, osteoporosis has been transformed from a disorder considered to be an inevitable and irreversible consequence of aging to a disorder in which there now is true therapeutic optimism. Besides calcium and vitamin D, many agents such as sex steroids, calcitonin, bisphosphonates, and, recently, teriparatide can be used in these patients.

This article will discuss the definition, epidemiology, and different causes of osteoporosis. Diagnostic studies, including bone densitometry, will be reviewed as well as the various therapies.—The Editor

What Is Osteoporosis?

As defined by the Consensus Development Conference (CDC), osteoporosis is "a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk."4 Osteoporosis also was defined operationally by the World Health Organization (WHO) in 1994 as a femoral neck bone mineral density (BMD) value 2.5 standard deviations or more below the mean for normal white women, or a T score of -2.5. The National Osteoporosis Foundation (NOF) uses the same criteria to define osteoporosis (www.nof.org). The increasing availability of bone densitometry (DXA) has allowed this definition to be used to assess the prevalence of osteoporosis around the world.5 This stratification of disease by T score will be discussed further in the diagnosis section.

It should be pointed out that the bone deterioration and fragility themselves are not the primary concern when it comes to evaluating a patient for osteoporosis. Instead, attempts to measure bone strength and BMD are more a means to predict fracture risk, as fractures are the consequence of osteoporosis with significant morbidity and mortality.

Epidemiology: Who Gets Osteoporosis?

Classically, osteoporosis has been considered a disease of postmenopausal women of northern European descent, as this is the population with the highest rate of fractures. However, as the population ages, one can expect the frequency of osteoporotic fractures to increase in other populations as well.5

Net bone loss occurs in most populations of aging men and women after the cessation of growth and a period of skeletal "consolidation,"5 but patterns of bone loss differ by skeletal site. For example, femoral bone loss begins at about 20 years of age in both men and women, and continues in a linear fashion during the rest of one’s life. Alternatively, bone loss in the appendicular skeleton begins at the time of menopause in women and at a comparable age in men.6 What is clear is that patterns of bone loss have made changes in the prevalence of osteoporosis predictable. These trends in BMD and osteoporosis are seen clearly in both the Third National Health and Nutrition Examination Survey (NHANES) and a study of Rochester, Minn., women.7,8 One obvious problem with these major studies is that they primarily have focused on postmenopausal white women; we now know that other populations, including men, should be evaluated as well.

Furthermore, the incidence of osteoporosis varies among different ethnic populations, possibly because of variations in skeletal architecture and turnover of bone mass. For instance, bone mass generally is lower among Caucasians and Asians in comparison to people of other races. Conversely, African-Americans classically have a much greater bone density when compared to Caucasians of the same age and sex.9 However, these generalizations need to be interpreted carefully, as racial comparisons of areal BMD are confounded by differences in bone size that are not corrected by taking into account the projected area of the DXA scan. When these differences in bone size have been accounted for, some studies have found that African-American women maintain their advantage in lumbar spine done density.10 On the other hand, differences in bone size seem to account for the differences in bone density initially seen between white and Asian women. Thus, Asian-American women and white women now are believed to have a similar prevalence of osteoporosis.5

Likewise, when looking at the epidemiology of osteoporosis, one cannot overlook the issue of gender. Peak bone mass achieved by men is one-fourth to one-third greater than that achieved by women. However, one again must take into account that male skeletons are larger, and that two-dimensional areal BMD scans do not completely correct for the fact that wider male bones also are thicker. When this is corrected for, men still have greater bone mineral densities; however, the difference is reduced.11 It should be noted that the definition of male osteoporosis still is unclear, and has not yet been made by the WHO. Usually, T scores still are compared to the bone mineral densities of women, as that currently is the standard and the source of the most voluminous data. However, it has been found that the estimates of prevalence of osteoporosis in men increase greatly when male-specific normal values are used.5 Although it has been found that at any given BMD, fracture risk in men resembles that seen in women, it also is known that the age-specific hip fracture rate is lower in men because of their lower prevalence of osteoporosis and reduced risk of falling.5

Etiology: What Are the Different Causes of Osteoporosis?

Generally, osteoporosis is divided into two forms: primary and secondary. The term primary osteoporosis is applied to women who have gone through natural menopause and older men with low sex hormone levels. Correspondingly, secondary osteoporosis is used to describe most other forms of osteoporosis, including the most common, glucocorticoid-induced osteoporosis, and the less common causes like endocrine disorders (most commonly hypo-gonadism), hematopoietic disorders, connective tissue disorders, other drug-induced causes, immobilization, renal disease, and nutritional and gastrointestinal disorders. (See Table 1.)

Primary osteoporosis is the most widely recognized form of osteoporosis. As stated, it generally is applied to postmenopausal women or older men who have no clear cause for their osteoporosis other than estrogen deficiency, calcium deficiency, or age.12 Normally, bone formation and bone resorption are coupled. During childhood and adolescence, both bone formation and bone resorption are increased, but the bone formation rate is higher than the bone resorption rate. Then, once peak bone mass is achieved by about the third decade of life, bone resorption rates surpass bone formation rates, and net bone loss ensues.12 The cause of this imbalance between bone formation and breakdown is not completely understood, but the principal inciting factor is believed to be related to gonadal hormone deficiency. More specifically, increased bone resorption that occurs later in life after peak bone mass is reached is associated with estrogen deficiency, which may lead to osteoclastogenic cytokines. This is thought to lead to more rapid bone loss than in estrogen-replete subjects.13

The term secondary osteoporosis traditionally is applied when specific pathogenetic mechanisms are present, though it is quite common to have coexistent primary and secondary osteoporosis. As previously mentioned, there are many causes of secondary osteoporosis, including hypogonadism, other endocrine disorders (i.e., hyperparathyroidism, hyperthyroidism, etc.), gastrointestinal diseases, transplantation, genetic disorders, and medications.13

As mentioned, exogenous glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. Patients with rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, and transplant recipients make up the majority of chronic glucocorticoid users.14 Patients with chronic diseases like those mentioned often are at additional risk for osteoporosis because of poor nutrition and immobilization. Glucocorticoid-induced osteoporosis is especially common in postmenopausal women, presumably because they already suffer from primary osteoporosis.

The most rapid bone loss in glucocorticoid use occurs during the first 6-12 months of steroid therapy, when there can be a 3-27% decrease in BMD. This initial rapid decrease in bone loss usually slows down two years into steroid treatment, but still remains higher than the rate of loss of the general population.15 Like primary osteoporosis, initial bone loss is trabecular and is followed by losses in cortical bone.15 But there is controversy where trabecular bone is lost more rapidly—in the trochanter vs. in the lumbar spine.

Although not entirely clear, glucocorticoid-induced osteoporosis is thought to be the result of both increased bone resorption and decreased bone formation. Currently, the favored dominant mechanism is decreased bone formation by way of direct inhibition of osteoblast activity. More specifically, steroids decrease the absolute number of osteoblasts by inducing apoptosis. Steroids also modulate the osteoblast response to many growth factors. This osteoblast inhibition is evident clinically by decreases in serum levels of osteocalcin, reduced trabecular wall thickness, and by incomplete repair of bone remodeling lacunae.16 As mentioned, glucocorticoids also are thought to contribute to osteoporosis by increasing bone resorption. Several mechanisms are thought to lead to this increased resorption, including inhibition of gastrointestinal calcium absorption and possible subsequent secondary hyperparathyroidism, increased urinary calcium and phosphate loss, and decreased sex hormone production by means of inhibition of gonadotropin release.15 In addition, exogenous steroids decrease the secretion of corticotropin, thus decreasing the production of adrenal androgens, which are the major precursors of estrogen in postmenopausal women.

There is controversy over whether a safe glucocorticoid dose exists in regard to bone health. Although it generally is agreed that the lower the dose the better, no specific dose has yet been identified as safe. In fact, even a single oral dose of 2.5 mg of prednisone has been demonstrated to almost immediately increase serum osteocalcin levels.17 This elevation in serum osteocalcin reflects increased bone formation and turnover. Even inhaled steroids, although preferred to oral steroids, have been linked to up to a one point standard deviation decrease in bone mineral density T scores when used chronically.18 Thus, whenever possible, patients should have therapeutic glucocorticoids weaned to the lowest possible dose or, if possible, discontinued.

While on the subject of glucocorticoid-induced osteoporosis, it is important to address the closely related transplant-associated osteoporosis. Medical advances have made organ transplantation an increasingly common treatment for end-stage organ disease, including renal, hepatic, cardiac, and pulmonary disease. Recent improved survival rates after transplantation have led to increased awareness of long-term complications of such dramatic interventions. The pathogenesis of osteoporosis in transplant recipients is considered complex and multifactorial. First, many transplant patients are believed to have underlying risk factors for bone loss, including advanced age, postmenopausal status, Caucasian race, vitamin D deficiency, physical inactivity, and tobacco or alcohol abuse. In addition, end-stage renal or hepatic patients may suffer from derangements in mineral homeostasis prior to transplantation. In fact, each specific end-stage organ disease carries with it specific metabolic changes that can contribute to the process of bone loss. However, most transplant patients are exposed to countless medications, including medications that can cause bone loss, like glucocorticoids, loop diuretics, and heparin. But the primary contributing factor to rapid bone loss and subsequent fracture in transplant patients regardless of the underlying organ disease is thought to be immunosuppressive therapy. The main offending medications are glucocorticoids, cyclosporine A, and tacrolimus.13 Rates vary with the immunosuppressive regimen, but it is clear that the most rapid bone loss occurs soon after transplant, usually within the first 6-12 months.13 Thus, practitioners need to be vigilant and aggressive in their evaluation and treatment of transplant associated osteoporosis. Specifically, patients should have their BMD evaluated prior to transplantation, and any patient with a decrease in BMD or definitive osteoporosis should be started on a bisphosphonate regimen and have their gonadal steroids replaced when appropriate. Furthermore, even if a patient does not yet demonstrate bone loss preoperatively, he or she should be given adequate calcium (1500 mg/day) and vitamin D (400-800 IU/day).

It has been easier thus far to link some hormonal disorders with peak bone mass, particularly those involved with skeletal development, including glucocorticoids, growth hormone, thyroid hormones, and gonadal steroids. More specifically, estrogen has been found to have a crucial role in the development of peak bone mass. Estrogen deficiency during adolescence is associated with decreased peak bone mass, as estrogen has an important role in epiphyseal closure and the decrease in bone remodeling after puberty in both men and women. Some disorders associated with such a hypogonadal state include Turner syndrome (XO), hyperprolactinemia, the "female athlete triad" (disordered eating, amenorrhea, and bone loss), and anorexia nervosa (which can increase the risk for osteoporosis by multiple means, including estrogen deficiency, secondary hyperparathyroidism from low dietary calcium and vitamin D, excess endogenous cortisol production, and low levels of IGF-1).13

Like women, men who suffer from any type of either primary (testicular), secondary (pituitary), or tertiary (hypothalamic) hypogonadism can experience rapid bone loss and fragility fractures. This includes men with Klinefelter syndrome (XXY) as well as men with complete androgen insensitivity.19

Hyperthyroidism is associated with increased bone resorption. Epidemiologic studies suggest that thyrotoxic patients are at increased risk for fracture.20 Most studies have found that bone density improves but does not completely recover with successful therapy of thyrotoxicosis.21 Thyroid hormone replacement that is not associated with thyroid stimulating hormone (TSH) suppression does not lead to detrimental effects on bones.20

In hyperparathyroidism, skeletal demineralization may occur, most commonly at sites with a high proportion of cortical bone.22 Spine bone mineral density usually is preserved in mild forms of primary hyperparathyroidism, although a recent study23 found an increased risk of fracture at all sites. Fracture risk normalized within one year of parathyroidectomy.23

Many gastrointestinal diseases, such as celiac disease, postgastrectomy states, inflammatory bowel disease, pancreatic insufficiency, and hepatic disease can lead to osteoporosis and osteomalacia through interference with intestinal absorption of calcium, phosphorus, and vitamin D.24 In hepatic disease, a disruption in 25-hydroxyvitamin D synthesis is an additional factor in the pathogenesis of bone disease.

Rheumatic diseases, mainly through glucocorticoid therapy and decreased mobility, also may lead to osteoporosis. Disorders of bone marrow, such as multiple myeloma, leukemias, and lymphomas, should be in the differential diagnosis when appropriate. Medications such as anticonvulsants, heparin, and methotrexate are important offenders: anticonvulsants increase degradation of vitamin D metabolites; heparin has been shown to stimulate bone resorption, mainly at doses of 15,000 U or greater for at least six months,3 while the data regarding low-molecular-heparin still is scarce; methotrexate has a direct resorptive effect on bones. Other rare causes of secondary osteoporosis are listed in Table 1.

Diagnostic Studies

To appropriately diagnose, work up, and treat osteoporosis, a clinician must be able to identify a patient at risk for osteoporosis, choose the appropriate tests to evaluate for osteoporosis, and know how to interpret the results of any work-up done. Identifying patients at risk for bone loss should begin with a detailed history, including analysis of calcium intake, nutrition, changes in height or weight, physical activity, lifestyle habits including smoking history, menstrual and reproductive history, personal or family history of fragility fractures (defined as appendicular or axial fractures occurring after a fall from standing height or less), and personal or family history of other endocrine disorders that may affect skeletal health. Physical examination should include evaluation of height and spine, and the search for any evidence of thyroid or adrenal disease. Generally, some sources25 recommend screening for osteoporosis in all postmenopausal women older than 65 years, any postmenopausal woman younger than 65 years with other risk factors, and any patient with a fragility fracture. Clearly, a patient with history of any other disorder that imposes risk for osteoporosis should be evaluated as well.

How does one screen or begin an evaluation for osteoporosis? Usually a dual energy x-ray absorptiometry (DXA) scan is performed to evaluate bone density and thus predict fracture risk. Although there are many limitations to this test, a clinician needs to know how to interpret the results of bone densitometry. First, one must recall that a T score reflects comparison with young Caucasian women, while a Z score compares the bone density of the patient with age-matched controls. Classically, the T score is used to stratify fracture risk, not the Z score. A T score of 0 ± 1 standard deviations from the mean is considered normal; a BMD T score between 1 and 2.5 less than the mean is termed osteopenia; a BMD more than 2.5 standard deviations below mean is considered osteoporosis; and BMD with T score more than 2.5 standard deviations below the mean with the presence of fragility fractures is considered severe osteoporosis.26

There are many other problems with using the above thresholds and DXA scan in general. Such problems include different bone mineral density measurements from machine to machine, and differences in bone mineral density between central and peripheral sites of measurement. There have been attempts to correct the differences that occur between different machines, including using standard deviations or T scores rather than absolute BMD; however, this has not solved the problem as different manufacturers use different databases. Accordingly, some believe that a new young normal reference database done on all BMD technologies is needed.27 Also mentioned were the differences that occur between central and peripheral sites of measurement, with the peripheral sites being more accurate in measuring bone mineral content per unit volume of bone because of less surrounding soft tissue.27 It is quite a large task to address these problems with bone mineral density measurement, reference populations, central vs. peripheral measurements, and fracture risk. Currently, the NOF and the International Society for Clinical Densitometry (ISCD) are attempting to address some of these issues with the T-score Equivalency Project.27 Other problems include defining osteoporosis in men (currently most databases only use data from women; the ISCD recommends using gender specific databases as references) as well as defining osteoporosis in different ethnic groups (currently there is only multi-ethnic head-to-head prevalence and fracture data from National Osteoporosis and Risk Assessment).27 Until these issues are resolved, it is likely best to continue to use the results and thresholds as they stand, but to use them with caution.

Besides DXA scan, ultrasound of the calcaneus also can be used to predict fracture risk because sound transmission through bone is related to bone density and skeletal strength;28 however, ultrasound does not give much information regarding spinal bone density and is not as precise as DXA.

Quantitative computed tomography is another method for measuring spinal bone density but it seldom is used now since it is more expensive, less reproducible, and requires a higher radiation dose than DXA.

In addition to imaging, one should not overlook the value of laboratory tests in the evaluation of a patient with osteoporosis in cases where bone loss is greater than expected for the patient’s age, gender, race, and menopausal status.13 An intensive investigation is indicated, particularly in all pre-menopausal or peri-menopausal women and in men with low bone density. Laboratory tests (see Table 2) that can help rule out secondary causes for osteoporosis include a complete blood count, renal function, calcium, phosphorous, alkaline phosphatase, liver function tests, TSH, erythrocyte sedimentation rate, intact parathyroid hormone (PTH), 25-hydroxyvitamin D and 24-hour urinary calcium, and creatinine.

Table 2.
Diagnostic Work-up for Secondary Osteoporosis


Other more specialized tests can be performed, depending on clinical suspicion or the results of the above basic testing: urinary free cortisol or overnight dexamethasone suppression test if one suspects Cushing’s syndrome; serum protein and urine protein electrophoresis if one suspects multiple myeloma; antigliadin or anti-tissue transglutaminase antibodies if one suspects malabsorption or celiac disease; and serum iron and ferritin if malabsorption or hemochromatosis is suspected.13

In addition, some clinicians have found that biochemical markers of bone remodeling are quite useful in the diagnosis and follow-up of patients with metabolic bone disease. The underlying premise of following such markers is based on the fact that bone is a metabolically active tissue that undergoes continuous remodeling through the coupling of bone formation and resorption. Cellular and extracellular components of the skeletal matrix recently have been isolated and found to reflect either bone formation or bone resorption, with some overlap.

Biochemical Markers of Bone Formation. Bone specific alkaline phosphatase (ALP) is one of the most commonly recognized markers of bone formation. It is a product of osteoblasts. One needs to be careful, however, in assuming that an elevated ALP reflects increased bone formation, as there are different tissue specific genes producing ALP. Generally, liver and bone each contribute approximately 50% of the serum ALP. Thus, serum ALP can be looked at specifically for bone formation except in the presence of liver or biliary disease.29 In these cases, one can use a monoclonal immunoassay to determine the source of the elevated ALP.

Osteocalcin is believed to be a sensitive and specific biochemical marker of osteoblast activity. Some problems with following osteocalcin levels include inconsistencies between assays due to protein fragmentation and a circadian rhythm, with highest levels occurring in the morning.29

Less commonly used are the amino- and carboxy-terminal procollagen propeptides of type I collagen, called PINP and PICP respectively.29 Both are believed to be specific products of proliferating osteoblasts and fibroblasts, reflecting the collageneous phase of bone formation. However, these peptides also may not be entirely specific, as other tissues including fibrocartilage, tendon, skin, gingiva, intestine, heart valve, and large vessels may contribute to serum levels of PINP and PICP. Furthermore, like osteocalcin levels, PINP and PICP levels are not influenced by food intake but do follow a circadian rhythm with highest levels occurring in the morning.

Biochemical Markers of Bone Resorption. There are many biochemical markers of bone resorption. Hydroxyproline is an amino acid present in all collagen types and tissues, and is broken down enzymatically and released in the serum. However, only 10% of the total circulating hydroxyproline is excreted in the urine. The rest is reabsorbed, further metabolized, or reused for collagen synthesis.29 But urine measurements of hydroxyproline have proven to be non-specific, as such measurements can reflect both collagen synthesis and breakdown. In addition, measurement of hydroxyproline levels also mandates the inconvenience of abstaining from collagen-rich foods at least 24 hours prior to testing. Thus, hydryoxyproline levels no longer commonly are measured, having been replaced by some more specific markers of bone resorption.

The pyridinium crosslinks, including pyridinoline (PYD) and deoxypyridinoline (DPD) are present in mature collagens only, with highest concentration in cartilage and bone (PYD) and bone only (DPD). Therefore, DPD is considered the more bone-specific marker.29 Functionally, these compounds are the main crosslinks in skeletal tissues, but they act as stabilizers of mature crosslinks in type I, II, and III collagens of all major connective tissues. Advantages of the pyridinium crosslinks over hydroxy-proline include that levels are unaffected by dietary intake. In addition, pyridinium crosslink levels are not affected by breakdown of newly synthesized collagen, which renders them more specific for bone resorption than hydroxyproline. Both can be measured in the serum or the urine.

The crosslinked telopeptides refer to the measurement of type I collagen degradation products associated with the crosslink regions. The immunoreactive epitopes measured are located on peptide fragments derived from the N-terminal (NTX-1) or the C-terminal (CTX-1) telopeptides of the type I collagen molecule.30 Both of these epitopes can be measured in the serum or the urine. Although specific for breakdown or resorption, CTX-1 levels are affected by dietary intake and must be measured in the fasting state.

Now that the major biochemical markers of bone remodeling have been reviewed, sources of variability of the measurement of such markers will be examined. Generally, many factors, including age, gender, ethnicity, recent fractures (up to 1 year), pregnancy, lactation, drugs, bedrest/immobility/remobilization, diet, exercise, temporal variability like time of day or time of menstrual cycle, and other comorbid diseases, can affect the level or measurement of markers of bone turnover.29 Other more technical aspects also can result in variability of marker measurement, including thermodegradation and photolysis, timing and mode of sample, and variation between laboratories.

How are these biochemical markers of bone remodeling clinically useful? It is best to first review the normal changes in bone remodeling seen with aging. Recall that during puberty and growth both bone formation and resorption are increased, reflecting an increase in bone turnover. Thus, one would expect to see an increase in markers of both bone formation and resorption. This rate stabilizes until approximately the third decade of life, and continues unchanged in men until after age 70.30 However, women experience a huge increase in both bone formation and resorption in early menopause, which may be decreased by calcium supplementation at that time. Later on in menopause, it is known that there is an increase in bone resorption, with an uncoupling of bone formation and resorption. These changes in metabolism also can be reflected in measurements of biochemical markers.

It is thought that changes in these markers reflecting changes in bone metabolism can help predict future bone loss as well as future fracture risk.29 In addition, some support the utility of following levels of markers of bone turnover to assess success of therapy. It may be most useful to measure baseline levels at the time of treatment initiation to determine which type of therapy would be most effective. For example, if a patient demonstrates elevated levels of bone resorption markers, then anti-resorptive therapy may be the best. Furthermore, although measuring BMD is more precise, we know that changes in bone mineral density occur quite slowly, making it difficult to detect a therapeutic response sooner than a few years into treatment. Thus, although measurements of markers of bone turnover are imprecise and very variable, they do change much more rapidly than BMD in response to treatment.29 This may render markers of turnover much more useful than BMD in following patients, at least in the immediate or short-term follow-up period. However, none of these concepts has been proven in controlled prospective trials, and the clinical use of these markers in monitoring patients has not been addressed sufficiently. Consequently, no clinical consensus exists as to the use of bone markers in the follow-up of patients with osteoporosis.

Treatment

The goals of osteoporosis treatment are to prevent fractures, stabilize or increase bone mass, relieve symptoms of fracture and skeletal deformity, and to maximize function (to prevent progression of deformity).31

Nonpharmacologic measures that may be instituted include promoting a diet rich in calcium and vitamin D, emphasizing general good nutrition, recommending smoking cessation, advocating weight-bearing exercises, and identifying and reducing fall risks.

According to the NOF, pharmacologic treatment of osteoporosis is indicated for a BMD T score below -2.0 with no risk factors, a BMD T score below -1.5 with the presence of other risk factors, patients in whom nonpharmacologic preventive measures are ineffective (i.e., bone loss continues or low-trauma fractures occur),31 or patients with prior vertebral or hip fractures.32 Discussion of the pharmacologic agents used to treat osteoporosis are outlined below.

Calcium and Vitamin D. Calcium is required to obtain peak bone mass and to maintain bone health. If dietary calcium intake is inadequate, bone tissue is resorbed from the skeleton to maintain normal serum calcium levels. Up to the age of 70, fewer than 1 in 10 females (and fewer than 1 in 100 older than age 70) meet their calcium requirement through diet.33 If the amount of dietary calcium is inadequate, use of supplements is recommended.

Vitamin D is required for calcium absorption. It is obtained by ingestion of certain foods or produced endogenously through a cutaneous photosynthetic reaction. Vitamin D is not widely available in natural food sources unless the food is specified as vitamin D fortified (such as milk, cereals, and breads).

Calcium and vitamin D supplements can reduce the rate of bone loss in postmenopausal women. Most organizations recommend 1200 mg of calcium and between 400 and 800 IU of vitamin D per day for postmenopausal women and all people older than age 50. The larger dose of 800 IU of vitamin D daily is recommended for the elderly and those at risk of vitamin D deficiency (i.e., chronically ill, housebound, or institutionalized individuals). Between the ages of 19 and 50, most guidelines recommend 1000 mg of calcium and 400 IU of vitamin D per day.

Calcium carbonate is the most commonly used supplement and should be taken with meals to minimize side effects and enhance absorption. Some experts prefer calcium citrate because it may be better absorbed than calcium carbonate.34 Side effects include constipation and gas. Many calcium preparations contain vitamin D, but not at the recommended daily dose. Separate vitamin D supplements are available.

Estrogens and Hormone Replacement Therapy (HRT). Any estrogen deficiency (most commonly from menopause, but also from gonadotrophin releasing hormone [GnRH] agonists, chemotherapy, and amenorrhea induced by athletics or eating disorders) leads to loss of trabecular bone. This bone loss may be related to an increase in cytokines which stimulate osteoclastic activity when estrogen levels decrease.35

Estrogen therapy and HRT are effective and FDA-approved antiresorptive therapies for postmenopausal bone loss, providing increases in BMD and reductions in the incidence of fractures. The Women’s Health Initiative (WHI) found a 34% reduction in hip and vertebral fractures after five years of treatment with HRT.36 However, recent evidence from the WHI has shown that HRT may increase the incidence of cardiovascular events, strokes, and breast cancer in postmenopausal women. Estrogen treatment also is associated with increased incidence of deep venous thrombosis and pulmonary embolism. The FDA recommends that when these agents are being considered for use solely for prevention of osteoporosis, other non-estrogen agents should be considered first.

Selective Estrogen Receptor Modulators (SERMs). SERMs were developed after the observation that tamoxifen, a breast cancer agent, had estrogenic effects on the skeleton.35 Raloxifene is the first SERM to be available for the treatment of osteoporosis. Raloxifene is approved by the FDA for both prevention and treatment of osteoporosis in postmenopausal women. A dose of 60 mg per day has been shown to decrease bone loss, to increase BMD by 2-2.4%, and to reduce the incidence of new vertebral fractures by 30-50%. Currently, there is no evidence that raloxifene significantly reduces risk of non-vertebral fractures.32

Patients taking raloxifene were shown to have a 75% reduction of the incidence of breast cancer.37 Raloxifene has not been shown to have estrogenic activity on the uterus35 and, therefore, no gynecologic surveillance is necessary. There may be a slight increase in incidence of venous thromboembolism to a degree similar to that observed with estrogens. Side effects include hot flashes and leg cramps.

Bisphosphonates. The bisphosphonates reduce osteoclastic bone resorption, resulting in increased BMD. Use of bisphosphonates also is associated with a decrease in bone turnover markers. There are two FDA-approved bisphosphonates for the treatment of osteoporosis.

Alendronate is FDA-approved for prevention of bone loss in recently menopausal women, for treatment of established osteoporosis and for treatment of glucocorticoid-induced osteoporosis. Alendronate increases bone mass and reduces the incidence of vertebral, hip, and all non-vertebral fractures by 50%. Dosage is 5 mg/day or 35 mg weekly for prevention of postmenopausal osteoporosis, and 10 mg/day or 70 mg/wk for treatment of post-menopausal osteoporosis.

Risedronate (5 mg daily and 35 mg weekly) is approved by the FDA for the prevention and treatment of postmenopausal osteoporosis and for treatment of glucocorticoid-induced osteoporosis. It has been shown to prevent corticosteroid-induced bone loss in patients beginning steroid therapy, as well as to improve BMD in patients who already suffer from steroid-induced bone loss.38 Risedronate increases BMD by 3-6%, reduces the incidence of vertebral fracture by 40%, and reduces non-vertebral fractures by 30%.

All bisphosphonates should be taken on an empty stomach with water, at least one half-hour before food or beverages, otherwise absorption is severely reduced. Patients should remain upright for 30 minutes. This method of administration avoids side effects such as esophageal irritation, heartburn, and dysphagia, which may occur in 10% of patients. The availability of once weekly dosing has reduced the incidence of these side effects.

Contraindications to usage are inability to follow dosing regimen, hypocalcemia, and esophageal abnormalities that might delay transition of the tablet. Upper gastrointestinal tract disease is a relative contraindication.

Salmon Calcitonin. Calcitonin is secreted by the C-cells of the thyroid gland, and exerts hypocalcemic effects by directly inhibiting osteoclast resorption.39 Salmon calcitonin is FDA-approved for the treatment of osteoporosis in women who are at least five years postmenopausal. There are limited data regarding the efficacy of calcitonin, and at best it produces only modest increases in BMD (1-2%) in postmenopausal women.39 Small controlled clinical trials indicated that calcitonin decreased the vertebral fracture rate by 54%, however, in the single large trial performed, it lowered vertebral fracture risk by 21%.32 There have been no data to support a reduction in hip fracture. However, calcitonin is unique in that it has an analgesic effect on the acute pain of vertebral fracture.

Calcitonin is available as a nasal spray (200 IU per spray) or as an injection. The recommended dose is one spray nasally per day in alternating nostrils or 100 IU parenterally. Side effects are minimal and include rhinitis and, rarely, epistaxis with usage of the nasal spray, and flushing, nausea, and vomiting with the parenteral form.

Parathyroid Hormone. Teriparatide (PTH 1-34) is available for treatment of osteoporosis as daily subcutaneous injections. PTH, when given intermittently, works anabolically to build cortical bone. This is in opposition to chronic elevations of PTH, as in primary hyperparathyroidism, which cause a greater degree of osteoclastic bone resorption and lead to osteoporosis. PTH treatment has been shown to improve lumbar spine BMD by approximately 9.7%.40 After 18 months of use, PTH may reduce the risk of vertebral fractures by 65% and it may reduce the risk of nonverterbral fractures by 54%.32,40

PTH is well tolerated, with the most common side effects being dizziness and leg cramps. PTH therapy should not be used in patients with primary hyperparathyroidism or hypercalcemia, patients with renal impairment, or patients with an increased risk of osteosarcoma (i.e., patients with open epiphyses, a history of skeletal radiation therapy, Paget’s disease, and bony metastases).32,41 PTH caused an increase in osteosarcoma in rats,41 although no human cases of osteosarcoma have been observed in PTH treated patients. PTH is available in a pen injection device, and the recommended daily dose is 20 mcg subcutaneously. The FDA-recommended treatment period is 24 months, as PTH use for more than two years has not been investigated. PTH treatment is more expensive in comparison to other treatments.

Patients who are candidates for PTH are postmenopausal women and men at high risk for fracture (i.e., patients who fracture while on antiresorptive therapies or patients who do not respond to or cannot tolerate antiresorptive agents).

Recent evidence suggests that PTH should not be used in combination with bisphosphonate therapy, as combination therapy was less efficacious on BMD than PTH alone.42,43

Monitoring Treatment. Most physicians will monitor central DEXA scan every 1-2 years during pharmacologic treatment. In Medicare patients, the Bone Mass Measurement Act allows for BMD measurement at 12 months after starting a new therapy.

Pharmacologic therapy may be reducing fracture risk even though increases in BMD are not apparent. There also is a precision error inherent in BMD testing, and therefore changes of less than 2-4% in the vertebrae and less than 3-6% in the spine can be due to error.32 It is important to remember that a goal for treatment is to stabilize BMD (prevent further decreases) and not necessarily to increase the BMD.

References

1. Wolinsky FD, Fitzgerald JF, Stump JF. The effect of hip fracture on mortality, hospitalization, and functional status: A prospective study. Am J Public Health 1997;87:398-403.

2. Harper KD, Weber TJ. Secondary osteoporosis: Diagnostic considerations. Endocrinol Metab Clin North Am 1998;27:325-348.

3. Orlic ZC, Raisz LG. Causes of secondary osteoporosis. J Clin Densitom 1999;2:79-92.

4. Consensus Development Conference. Am J Med 1993;94:646-650.

5. Melton LJ III. Epidemiology worldwide. Endocrinol Metab Clin North Am 2003;32:1-13.

6. Melton LJ III, Khosla S, Atkinson EJ, et al. Cross-sectional versus longitudinal evaluation of bone loss in men and women. Osteoporos Int 2000;11:592-599.

7. Looker AC, Orwoll ES, Johnston CC Jr, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res 1997;12:1761-1768.

8. Melton LJ III, Atkinson EJ, O’Connor MK, et al. Bone density and fracture risks in men. J Bone Miner Res 1998;13:1915-1923.

9. Looker AC, Wahner HW, Dunn WL, et al. Updated data on proximal femur bone mineral levels of US adults. Osteoporos Int 1998;8: 468-489.

10. Melton LJ III, Marquez MA, Achenbach SJ, et al. Variations in bone density among persons of African heritage. Osteoporos Int 2002;13: 551-559.

11. Beck TJ, Looker AC, Ruff CB, et al. Structural trends in the aging femoral neck and proximal shaft: Analysis of the Third National Health and Nutrition Examination Survey dual-energy x-ray absorptiometry data. J Bone Miner Res 2000;15:2297-2304.

12. Raisz LG, Rodan GA. Pathogenesis of osteoporosis. Endocrinol Metab Clin North Am 2003;32:15-24.

13. Stein E, Shane E. Secondary osteoporosis. Endocrinol Metab Clin North Am 2003;32:115-134.

14. Mudano A, Allison J, Hill J, et al. Variations in glucocorticoid induced osteoporosis prevention in a managed care cohort. J Rheumatol 2001;28:1298-1305.

15. Saag KG. Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin North Am 2003;32:135-157.

16. Weinstein RS, Jilka RL, Parfitt AM, et al. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblast and osteocytes by glucocorticoids. J Clin Invest 1998;102:274-282.

17. Nielsen HK, Charles P, Mosekilde L. The effect of single oral doses of prednisone on the circadian rhythm of serum osteocalcin in normal subjects. J Clin Endocrinol Metab 1988;67:1025.

18. Israel E, Banerjee TR, Fitzmaurice GM, et al. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 2001;345:941-947.

19. Marcus R, Leary D, Schneider DL, et al. The contribution of testosterone to skeletal development and maintenance: Lessons from the androgen insensitivity syndrome. J Clin Endocrinol Metab 2000;85: 1032-1037.

20. Baran DT. Secondary causes of osteoporosis: Thyrotoxicosis and weight bearing. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia: Lippincott, Williams, and Wilkins; 1999: 305-307.

21. Jodar E, Munoz-Torres M, Escobar-Jimenez F, et al. Bone loss in hyperthyroid patients and in former hyperthyroid patients controlled on medical therapy: Influence of aetiology and menopause. Clin Endocrinol (Oxf) 1997;47:279-285.

22. Parisien M, Silverberg SJ, Shane E, et al. Bone disease in primary hyperparathyroidism. Endocrinol Metab Clin North Am 1990;19: 19-34.

23. Vestergaard P, Mollerup CL, Frokjaer VG, et al. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321:598-602.

24. Bikle D. Osteoporosis in gastrointestinal, pancreatic, and hepatic diseases. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego: Academic Press; 2001: 237-258.

25. Eddy D, Johnston C, Cummings SR, et al. Osteoporosis: Review of the evidence for prevention, diagnosis and treatment and cost-effectiveness analysis. Osteoporos Int 1998;8:S7.

26. WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Geneva, Switzerland: World Health Organization; 1994.

27. Miller PD. Bone mineral density—clinical use and application. Endocrinol Metab Clin North Am 2003;32:159-179.

28. Bauer DC, Gluer CC, Cauley JA, et al. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. A prospective study. Arch Intern Med 1997;157: 629-634.

29. Seibel MJ. Biochemical markers of bone remodeling. Endocrinol Metab Clin North Am 2003;32:83-113.

30. Beardsworth LJ, Eyre DR, Dickson IR. Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. J Bone Miner Res 1990;5:671.

31. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Prevention and Treatment of Postmenopausal Osteoporosis: 2001 Edition, with Selected Updates for 2003. www.aace.com/clin/guidelines. Accessed 2-25-2004.

32. National Osteoporosis Foundation. National Osteoporosis Foundation Physician’s Guide to Prevention and Treatment of Osteoporosis. www.nof.org/physguide. Accessed 2/25/2004.

33. Dawson-Hughes B. Calcium and vitamin D. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 5th ed. Washington, DC: American Society for Bone and Mineral Research; 2003:349-352.

34. Heller HJ, Greer LG, Haynes SD, et al. Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women. J Clin Pharmacol 2000;40:1237-1244.

35. Gallagher JC. Effect of estrogen on bone. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, DC: American Society for Bone and Mineral Research; 2003:327-330.

36. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen and progestin in healthy postmenopausal women. JAMA 2002;288:321-333.

37. Cummings SR, Eckert S, Krueger KA, et al. The effects of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 1999;281:2189-2197.

38. Watts NB. Bisphosphonates for treatment of osteoporosis. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, DC: American Society for Bone and Mineral Research; 2003:336-341.

39. Silverman SL, Chesnut CH. Calcitonin therapy for osteoporosis. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, DC: American Society for Bone and Mineral Research; 2003:342-344.

40. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density on postmenopausal women with osteoporosis. N Engl J Med 2001;344: 1434-1441.

41. Deal C, Gideon J. Recombinant human PTH 1-34 (Forteo): An anabolic drug for osteoporosis. Cleve Clin J Med 2003;70:585-601.

42. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-1215.

43. Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003;349:1216-1226.