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Dr. Maria Michailidou



Introduction: Osteoporosis & Glucocorticoid-Induced Osteoporosis

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, microarchitectural disruption of bone tissue, and compromised bone strength leading to an increased risk for fracture.1

1NIH Consensus Statement, Osteoporosis Prevention, Diagnosis, and Therapy, Office of the Director, Vol 17 (1), p.5, 2000.

Osteoporosis is commonly encountered in primary care settings in the management of postmenopausal women. It is often clinically silent until a fragility fracture occurs.

Osteoporotic fractures are common in postmenopausal women. Hip fractures are the most devastating osteoporotic fractures in terms of medical, psychosocial, and financial consequences. The lifetime probability of sustaining a hip fracture in a 50-year-old white woman is 14%; it is much lower (6%) in a 50-year-old African American woman.

Osteoporosis is being recognized with increasing frequency in older men with height loss, nontraumatic fractures, hypogonadism, and other risk factors. Fractures in men are an important public health problem. Approximately 150,000 hip fractures occur each year in men in the United States, accounting for about one-third of all hip fractures. The mortality from hip fractures in men at 1 year is 30%.

Patients receiving long-term glucocorticoid therapy are at risk for bone loss and should have prevention and treatment approaches implemented. It is important that the primary care provider decides whom to screen for osteoporosis. The decision should be based on an assessment of that individual's risk factors for bone loss and an understanding of disease pathogenesis.

Classic Presentations

Postmenopausal Osteoporosis

Essential Features

Altered microarchitecture. Decreased bone strength. Reduced bone mineral density.

General Considerations

Clinically, osteoporosis is diagnosed when bone mineral density (BMD) is reduced and fractures occur due to skeletal fragility. The most common osteoporosis-related fractures occur in the thoracic and lumbar spine, hip, and distal radius.

Bone loss in women begins before the onset of menopause. Typically, women lose bone mass beginning in the late third and early fourth decades. The process accelerates for the 5 to 10 years around the menopause. Postmenopausal osteoporosis results from estrogen deficiency–induced changes in the production of several key cytokines. Ultimately, this leads to an imbalance between bone formation and resorption so that resorption is favored over formation. After the increased rates of bone loss immediately surrounding the menopause cease, a less aggressive phase of bone loss ensues that continues into the eighth and ninth decades. Estrogen deficiency as well as other factors related to aging (reduced osteoprogenitor population, nutritional deficiencies, malabsorption, etc) play a role in this phase of bone loss.

Osteoporosis can be diagnosed clinically with bone densitometry or by the presence of fragility fractures in a patient at risk for the disease. Bone densitometry has become widely available as a diagnostic tool in recent years. Several techniques for quantifying BMD have been developed. They include dual-energy x-ray absorptiometry (DXA), single-energy x-ray absorptiometry, quantitative computed tomography, quantitative ultrasound, and radiographic absorptiometry. DXA is, by far, the best standardized technique and is preferred for diagnosing osteoporosis and monitoring responses to therapy.

BMD by DXA has been used by the World Health Organization (WHO) to define osteopenia and osteoporosis. Their criteria are based on a large body of data on postmenopausal white women  

In addition to age and BMD, a number of other clinical risk factors have been associated with an increased incidence of osteoporotic fractures  The National Osteoporosis Foundation has categorized these factors as modifiable and nonmodifiable. Nonmodifiable risk factors include gender, ethnicity, age, and family and/or personal history of fracture. Modifiable risk factors include smoking, alcohol consumption, use of long-term glucocorticoid therapy, low dietary calcium intake, poor eyesight, and others.

Despite extensive information on risk factors for fracture and low BMD, no single combination—or weighting—of risk factors adequately predicts the prevalent BMD or fracture risk or can substitute for the measurement of BMD. Risk factor assessment in current practice is helpful in understanding the basis for ongoing bone loss and pointing to strategies for slowing it.

Despite the value of BMD measurements using DXA in assessing fracture risk, DXA instruments are not available everywhere, and testing can be expensive. This has led to the need for guidelines in recommending BMD testing. A variety of professional organizations have published guidelines on the use of BMD testing in postmenopausal women and in patients receiving long-term glucocorticoid therapy (). Most of these indications are based on clinical risk factors obtainable from the initial evaluation of the patient.

Clinical & Laboratory Evaluation

The evaluation of perimenopausal or postmenopausal women for osteoporosis or a low BMD begins with the clinical assessment. This includes the medical history with careful attention to the history of medication use (especially glucocorticoids), smoking, alcohol intake, dietary calcium intake, and family history of osteoporosis and fractures. The physical examination is focused on signs of bone pain or deformity, anemia, hyperthyroidism, hypercortisolism, malnutrition, or disorders that cause secondary forms of osteoporosis

In postmenopausal women, it is unusual to diagnose a secondary cause of osteoporosis. Most commonly estrogen deficiency is at fault. It has become apparent, however, that vitamin D deficiency and subtle forms of calcium malabsorption (eg, due to celiac sprue) are more common than previously thought and should be considered in patients with impressively low bone mass with or without fractures. In addition, multiple myeloma can be relatively "silent" clinically and present with osteoporosis, bone pain, pathologic fractures, or anemia. This diagnosis should be considered if BMD is remarkably low for age or an unexplained anemia or elevated erythrocyte sedimentation rate is present. Multiple myeloma can be easily excluded by a serum and urine protein electrophoresis. Establishing this diagnosis is important because it redirects therapy.

There has been considerable debate about what the appropriate and cost-effective laboratory work-up should be for postmenopausal women with low BMD or osteoporosis. There is no consensus. At a minimum, laboratory evaluation should include a complete blood cell count, serum chemistry panel, liver function tests, and serum thyroid-stimulating hormone and calcium determinations. Measurements of serum 25-hydroxyvitamin D and urinary calcium and creatinine excretion can be extremely helpful. Subtle and overt vitamin D deficiency are relatively common in elderly patients and extremely difficult to diagnose on clinical grounds alone. Vitamin D deficiency is likely to contribute to bone loss because it interferes with the mineralization of bone matrix. High levels of urinary calcium excretion suggest idiopathic hypercalciuria. This can be associated with renal stones and low BMD. In addition, a urinary calcium measurement in a patient already taking calcium supplements can be informative as to the adequacy of therapy. If the urinary calcium excretion is low, then underlying malabsorption or an extremely low calcium intake must be considered. Postmenopausal women as a group are commonly affected by primary hyperparathyroidism (prevalence ~3 per 1000). A serum calcium determination adequately screens for this diagnosis. If it is elevated, serum intact parathyroid hormone should be measured.

It is estimated that 10–20% of postmenopausal women have additional secondary causes for their bone loss although this may be a conservative estimate. Given the costs and patient commitment required for years of treatment for osteoporosis, it is imperative that underlying causes—especially those that require different management approaches—be properly diagnosed.

Imaging Evaluation

The ideal study to assess BMD in a postmenopausal woman is a DXA measurement of the lumbar spine and hip. In many patients over age 65, spinal BMD measurements can be spuriously elevated due to aortic calcifications, arthritis, and degenerative disc disease. In such persons, only measurements of the total hip and femoral neck are reliable enough for diagnostic purposes.

Disease Course & Complications

Postmenopausal osteoporosis can progress silently over years to a dangerously low BMD and markedly reduced bone strength to a degree that the fracture threshold is reached. Osteoporosis in patients taking glucocorticoids long term is characterized by even more rapid bone loss. After this process progresses, fragility fractures can occur with minimal impact. Fractures are the dreaded complication of osteoporosis. Fractures of the spine cause pain but are generally self-limited. After multiple fractures, height is lost. With that can come reduced thoracic expansion capacity, difficulty with breathing, progressive spinal deformity called kyphosis, and ultimately increased frailty. As noted above, frailty is also a risk factor for fractures.

Hip fractures have a more dramatic course, and prognosis in the elderly osteoporotic patient is guarded. These fractures require hospitalization and surgery. Because of the underlying frailty of most of these patients, their comorbid conditions and advanced age, and the prolonged immobilization and rehabilitation required, patients who fracture their hips face decreased life expectancy. It is estimated that the overall mortality in the first year after a hip fracture is 20%. In men, the risk of death is three-fold greater than in women. Women fracture their hips at earlier ages and have fewer comorbidities than men. It has also been reported that men require longer hospitalizations and have more complicated courses after their hip fractures, mostly due to infections.

In addition to the medical and financial ramifications of the immediate treatment of the hip fracture, there are substantial long-term human consequences. It is estimated that 50% of patients who sustain a hip fracture do not live independently afterwards. Hip fractures are life-altering events for elderly people. Thus, it is imperative to recognize osteoporosis early and intervene with treatment strategies that reduce fracture risk. In view of the rapidly rising mean age of populations in the developed world, it is critical that interventions for osteoporosis be made expeditiously

Glucocorticoid-Induced Osteoporosis

General Considerations

Glucocorticoid therapy is associated with an array of potential side effects. The most serious and disabling of these are the skeletal complications osteonecrosis and osteoporosis. Skeletal adverse events are estimated to occur in approximately 50% of patients taking long-term glucocorticoid therapy. Although there is debate about the exact dose of prednisone required to increase the risk of bone loss and fractures, the weight of evidence supports the idea that oral doses of 7.5 mg/d (or its equivalent) are associated with an increased risk of both vertebral and hip fractures. In addition to drug dosage, the underlying disease often contributes in important ways to the pathogenesis of bone loss in patients taking glucocorticoids long term through changes in circulating hormones or inflammatory cytokines, concomitant drug therapy, nutritional issues, or inactivity. Men and women of all ages and even children can lose bone while taking long-term glucocorticoid therapy and deserve to be considered for the prevention and treatment strategies outlined below.

The pathogenesis of glucocorticoid-induced osteoporosis is complex. In the initial phase of such therapy (first few weeks), there is an increase in bone resorption. Within this phase, patients can lose considerable bone mass. In addition, glucocorticoids antagonize the actions of vitamin D, especially in the intestine, leading to reduced calcium absorption. This limits the amount of calcium available to form bone matrix properly. Glucocorticoids also promote calcium excretion by the kidney. In some cases, marked hypercalciuria can be seen. Glucocorticoids act on the pituitary to suppress gonadotropin production, rendering patients hypogonadal. Many women afflicted with the systemic illnesses that require chronic glucocorticoid therapy are amenorrheic secondary either to their underlying illness or its therapy. Impaired gonadal steroid production in both men and women, therefore, figures importantly in the pathogenesis of glucocorticoid-induced bone loss.

However, after a few months and continuing for years, the deleterious effects of glucocorticoids are on the lifespan and functional capacity of osteoblasts and osteocytes. Osteoblasts form new bone, and osteocytes are involved in mechanosensing. Apoptosis (programmed cell death) in these populations is promoted by long-term glucocorticoid therapy. This means that ongoing bone resorption is not answered by increased bone formation, and the sensing of normal mechanical forces and physical loading may be impaired. Overall, an imbalance in bone remodeling is favored, and in the end, resorption predominates. When glucocorticoids are discontinued, bone can recover. Whatever bone mineral has been lost, however, is unlikely to be fully restored. Hence, the prevention of bone loss is the ideal initial strategy.

Patients taking glucocorticoids long term are subject to an increased risk of fractures in the spine, hip, and other sites. It has been suggested that glucocorticoid-treated patients fracture at higher BMDs than other groups of patients, but this notion has been challenged. Needless to say, numerous patients who have had fractures while taking glucocorticoids have BMD measurements that are not extremely low. In such situations, it is important to recall that many of these patients may have had BMD values, prior to the onset of illness and glucocorticoid therapy, that were well above a T-score of –1. Since BMD determinations are often not done prior to the initiation of therapy, baseline BMD values are typically unknown.

The majority of patients receiving glucocorticoids are taking these drugs orally. Other routes of administration (inhaled, intranasal, or topical) are far less likely to have the deleterious skeletal consequences of oral therapy unless particularly high doses of long-acting glucocorticoid preparations are used. In addition, for unclear reasons, not all patients taking high doses of glucocorticoids suffer adverse skeletal consequences. As noted above, only 50% of patients receiving long-term glucocorticoid therapy experience bony complications. What protects the other patients remains unknown. It seems clear that the most vulnerable patients are postmenopausal women. Many of the diseases for which they receive glucocorticoids long term (eg, rheumatoid arthritis) are also especially deleterious to bone. Rheumatoid arthritis induces systemic as well as local (periarticular) bone loss. Therefore, the underlying disease is likely also to be an added risk to skeletal integrity.

Differential Diagnosis

The differential diagnosis of low bone mass or a low BMD measurement is narrow. It is either due to osteoporosis or osteomalacia. Any primary or secondary form of osteoporosis described in this chapter could cause this picture. Osteomalacia causes low bone mass or low BMD because the mineralization of the matrix is defective. Mineral content of the skeleton (not the protein content) is reduced in osteomalacia. A host of different conditions cause osteomalacia. These need to be considered seriously if there is any abnormality in the levels of serum calcium, phosphorus, alkaline phosphatase, or 25-hydroxyvitamin D. Patients with osteomalacia may also have bone pain, pathologic fractures, muscle weakness, and difficulty walking, especially when osteomalacia is moderate or severe and the diagnosis has been delayed. Because the disease is difficult to detect early in its course, the astute clinician must be aware of the manifestations of this less common bone disease and not ignore subtle clinical and laboratory features that hint at the presence of osteomalacia.


The essentials of management for most forms of osteoporosis include the following:

Lifestyle modifications. Nutritional interventions. Pharmacologic therapies.