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Osteoporosis: The Silent Epidemic

Andrew M. Kaunitz, M.D.
Andrew M. Kaunitz, M.D. is Professor & Assistant Chairman, Department of
Obstetrics & Gynecology, University of Florida Health Science Center / Jacksonville.

Of the 10,000,000 Americans with osteoporosis, nearly 80% are women. It is estimated that between 13 and 18% of postmenopausal white women in the US (4-6 million) have this disease, with an additional 30-50% (13 to 17 million) having low bone mineral density (osteopenia), placing them at increased risk for osteoporosis and fractures. The fact that one out of every two white women will experience an osteoporotic fracture at some point during her lifetime also underscores how common this silent epidemic is. Although osteoporosis is less prevalent among men, African-American, and Hispanic women, this disease is by no means rare in these populations.

After reviewing pathophysiologic issues and risk factors, this article will focus on the clinical and economic impact of osteoporosis and fractures in women. Then, it will detail approaches to the prevention of low bone density and practical issues relevant to screening for and diagnosing this common disorder. Finally, treatment options for osteoporosis in women will be discussed.

Skeletal Homeostasis

Bone is a highly active organ. The process of bone remodeling that maintains a healthy skeleton continually removes older bone, replacing it with new bone. The remodeling process also serves the body's metabolic needs for calcium. Bone loss occurs when the balance between bone removal resorption (osteoclastic activity) and replacement (osteoblastic activity) is altered, causing less bone to be replaced than was removed. In the absence of estrogen, osteoclastic activity predominates. The consequence is reduced bone mass and an increased fracture risk.

The most serious outcome of osteoporosis is hip fracture, which can result in 10 - 20% excess mortality within 1 year from thrombotic, pulmonary and other complications. Additionally, up to 25% of hip fracture patients may require long-term nursing home care, with only one third fully regaining their prefracture level of independence. In Florida, about 20,000 hip fractures occur each year.

Vertebral (spinal) fractures also cause disabling complications including back pain, height loss, and kyphosis. Postural and height changes associated with kyphosis may limit activity, including bending and reaching, and their cosmetic effects may reduce self-esteem. Multiple thoracic fractures may result in restrictive lung disease, and lumbar fractures may alter abdominal anatomy, leading to constipation, abdominal pain, distention, reduced appetite, and premature satiety.

Hip and vertebral fractures can also cause psychological symptoms, most notably depression, as patients face the multiple challenges of pain, physical limitation, and lifestyle changes. The high morbidity and consequent dependency associated with these fractures strain interpersonal relationships and social roles for patients and their families.

Economic Impact Of Osteoporosis

Osteoporotic fractures create a major burden for individuals and society. In 1995, they were the presumed cause of 432,000 hospital admissions, almost 2.5 million physician visits, and about 180,000 nursing home admissions in the United States. Direct medical expenditures alone for osteoporotic fractures in that year were estimated at $13.8 billion. These costs are anticipated to rise with the growing elderly population. Hip fractures incur the greatest osteoporosis-related health care expenditures. By one estimate, the number of hip fractures and their associated costs could more than triple by the year 2040.

Clinical Assessment Of Risk For Osteoporosis

Clinicians will be most effective in preventing and recognizing osteoporosis by remaining alert to risk factors for this condition. At the University of Florida Medicus Bone Density Center, cigarette smoking and chronic use of corticosteroids represent most common risk factors for low BMD in pre and perimenopausal women. Physicians should consider the possibility of osteoporosis and risk of fracture in all postmenopausal women, paying particular attention to the risk factors listed in Table 4.

Clinicians should also be attentive to the secondary causes of osteoporosis (Table 5), and medications which can reduce bone mineral density listed in Tables 6. Although most of these secondary causes can be identified clinically, limited biochemical testing (i.e. TSH, renal and liver function tests, erythrocyte sedimentation rate, calcium, phosphorus and alkaline phosphatase) may be appropriate. When indicated by history/examination, laboratory studies to exclude hypercorticolism, metastatic breast cancer or multiple myeloma should be considered.

Bone Mineral Density Testing

The majority of women with osteoporosis present without clinical signs and symptoms. Fortunately, BMD assessment can be used to establish or confirm a diagnosis of osteoporosis, predict future fracture risk, and monitor changes in BMD due to medical conditions or therapy. BMD has an inverse relationship to the risk of fracture: the lower the BMD, the greater the risk. For each standard deviation reduction in BMD, the risk of fracture increases 1.5 - 3 fold.

Whenever a postmenopausal woman suffers a fracture, osteoporosis should be suspected, and BMD testing serves to confirm this diagnosis and determine the severity of the disease. Patients with osteoporotic fractures should receive counseling about diet, exercise, and pharmacologic treatment. Such patients are at especially high risk for subsequent fractures, a risk that can be reduced with appropriate treatment, even in elderly patients. Some patients (i.e., those over 70 years of age with multiple risk factors) are at sufficiently high risk for osteoporosis that treatment can be initiated without BMD testing.

BMD Measurement — Practical Considerations

A variety of densitometers are in clinical use and provide reliable assessment of fracture risk. However, hip BMD is the best predictor of hip fractures, and it predicts fractures at other sites as well. Dual energy x-ray absorptimetry (DEXA) assesses BMD of the hip, is rapid, precise, and uses far less radiation than a chest x-ray. For these reasons, DEXA has become the gold standard for measuring BMD.

BMD is expressed as a relationship to two norms: the expected BMD for the patient's ethnicity, age and sex (Z-score), or for "young normal" adults of the same sex (T-score) (Figure 1). The difference between the patient's score and the norm is expressed in standard deviations (SD) above or below the mean. In general, T-scores provide information needed for clinical decision-making and form the basis for the diagnoses osteopenia and osteoporosis (Table 7). A T-score of + 1.0 means the patient's BMD at that site is one SD greater than that of a healthy 20-30 year old woman. In contrast, a T-score of -1.5 means the BMD is 1.5 SD less than that of a healthy 20-30 year old woman (Figure 1). T-scores decline in parallel with the steady drop in bone mass that occurs with aging (Figure 1). Usually, 1 SD equals a 10% to 12% difference in bone density.

Figure 1. Bone Mineral Density, Age, T and Z Scores	Table 7. World Health Organization Definition Of Osteoporosis
	The WHO has established the following definitions based on bone mass measurement in menopausal white women: Normal: BMD is within 1 Standard Deviation (SD) of a "young normal" adult (T-score above -1) Low bone mass (osteopenia): BMD is between 1 and 2.5 SD below that of a "young normal" adult (T-score between -1 and -2.5) Osteoporosis: BMD is 2.5 SD or more below that of a "young normal" adult (T-score at or below -2.5). Women in this group who have already experienced one or more fractures are deemed to have severe or "established" osteoporosis.
The BMD of a 57-year woman is expressed in comparison to a young-normal average BMD (Z-score). Accordingly, this woman has a Z-score of -1 and a T-score of -2.5.

Physicians should recognize that trained technicians are necessary to ensure precise, reliable, clinically useful BMD assessment (Figure 2). Physicians should also recognize that women with osteopenia (BMD does not meet criteria for osteoporosis) may experience fragility fractures when other risk factors for fracture independent of low BMD are present (Table 4).

Figure 2. AP Spine Results  -- Patient: 44 years, 63 inches, 160 lbs.

This 44 year old woman had an abdominal hysterectomy with removal of both ovaries for uterine fibroids at age 41. She discontinued estrogen replacement at age 42. At age 44, the above DEXA BMD study demonstrated spinal osteopenia (T= -1.6). Estrogen was restarted. One year later, spinal BMD had increased 5% with the corresponding T score increasing to -1.2 (follow-up study not shown).

Note that osteophyte formation caused artifactual increase in BMD of L4. The technologist appropriately chose L1-L3 only to assess spinal BMD.

Indications For BMD Testing

The decision to test for BMD should be based on an individual's risk profile (Table 4), and testing should be reserved for clinical settings in which the results could influence a treatment decision.

BMD testing should be performed in:

• Perimenopausal women with risk factors for low BMD, including cigarette smoking, corticosteroid use or others listed in Tables 5 and 6.
• Postmenopausal women undecided regarding hormonal replacement or use of other drugs to prevent/treat osteoporosis.
• Postmenopausal women under age 65 who have one or more additional risk factors for osteoporotic fracture (besides menopause).
• All women aged 65 and older regardless of additional risk factors.
• Postmenopausal women who present with fractures or evidence of reduced BMD on plain x-ray (to confirm diagnosis and determine disease severity).
• Women being monitored during treatment of osteoporosis.

Pharmacologic Prevention And Treatment Of Osteopenia And Osteoporosis

All patients being considered for drug treatment of osteoporosis should also be counseled on risk factor reduction. Patients should be specifically counseled on the importance of calcium, vitamin D, and exercise in addition to pharmacologic treatment for osteoporosis. The decision to treat osteoporosis with a pharmacologic agent should be based on strong evidence that such treatment effectively prevents fractures, that its expected benefits outweigh any potential adverse effects or risks, and that it represents a reasonable use of financial resources. The cutpoints for intervention, which were developed by the National Osteoporosis Foundation, have been derived in part by analysis of treatment cost-effectiveness, and use risk factors listed in Table 4.

Physicians should initiate therapy to reduce fracture risk in menopausal women with BMD T-scores below  -2 in the absence of risk factors and in women with T-scores below -1.5 if other risk factors are present. Women over age 70 with multiple risk factors (especially those with previous nonhip, nonspine fractures) are at high enough risk of fracture to initiate treatment without BMD testing.

The clinical usefulness of biochemical markers of bone turnover, including the urine or serum NTX, remains unclear but is under active investigation. An advantage of such biochemical markers is that they can provide rapid feedback (i.e. 3 months) about current loss of BMD, facilitating clinical decisions regarding initiating, continuing or modifying treatment. In contrast, it is not useful to repeat BMD assessments more frequently than every 12-24 months.

FDA-Approved Drugs For Osteoporosis

Medications FDA-approved for osteoporosis prevention and/or treatment are hormone replacement therapy (HRT), alendronate, risedronate, calcitonin, and raloxifene. The skeletal sites most responsive to these pharmacologic therapies are the spine and hip. This observation underscores the usefulness of central DEXA (hip/spine) rather than peripheral assessment of BMD (e.g. wrist, heel or ankle) in women being treated for osteopenia or osteoporosis.

HRT

Epidemiologic studies of HRT indicate a 50% to 80% decrease in vertebral fractures and a 25% decrease in other fractures with 5 years of use and an anticipated 50% to 75% decrease in all fractures with 10 or more years of use. Based on its effectiveness in preventing and treating osteoporosis, along with other potential benefits for postmenopausal health, HRT provides the greatest benefit relative to its cost. The great majority of postmenopausal women should be counseled to consider HRT or estrogen replacement therapy and assisted in weighing its risks and benefits. A diverse array of oral and transdermal HRT formulations are available, including estrogen-only and combination estrogen-progestin formulations (Tables 8 and 9). Physicians and their patients need to recognize that many years, or even decades of HRT may be necessary in order to derive a substantial reduction in fracture risk. Recent data suggests that very low (lower than the traditional "gold standard" 0.625 mg dose of conjugated equine estrogen) doses of estrogen (including the lowest doses of currently available oral and transdermal formulations, and even the estrogen-releasing ring Estring) may maintain BMD, particularly in elderly women not recently exposed to estrogen.

Women who do not want to receive HRT under any circumstances should undergo BMD testing to facilitate recommendations regarding alternate treatment strategies. Likewise, BMD testing may help women undecided regarding HRT to make a prudent decision.

Alendronate

Well-conducted controlled clinical trials utilizing the biphosphonate alendronate indicate that treatment reduces the incidence of fracture at the spine, hip, and wrist by 50% in patients with osteoporosis. Accordingly, this medication represents an important option for those women who meet BMD criteria for treatment but who are unwilling or unable to take HRT, including breast cancer survivors. Alendronate may also be used when HRT treatment fails to improve BMD. Women prescribed alendronate must understand and follow the instructions described in Table 10. Women who take alendronate and do not follow these instructions risk suffering upper gastrointestinal symptoms (chest pain, heartburn, painful or difficult swallowing), and rarely, esophageal ulceration. The 5 mg dose has been approved by the FDA for prevention of osteoporosis, and the 10 mg dose has been approved for treatment. In contrast with HRT, several years of alendronate therapy may be sufficient to reduce fracture risk. Nonetheless, longer term use of alendronate appears to provide ever greater protection from fractures. A recent trial found that alendronate in combination with HRT had a more favorable impact on BMD in menopausal patients with osteoporosis than HRT alone.

Risedronate

A newer biphosphonate, risedronate, appears to have a favorable impact on bone density and fracture reduction similar to alendronate, possibly with fewer gastrointestinal symptoms. Originally marketed for the treatment of Paget's Disease, risedronate received FDA approval for the prevention and treatment of osteoporosis in April 2000.

Calcitonin

Salmon calcitonin, a hormone that inhibits bone resorption, is FDA approved for the treatment of osteoporosis. It is most commonly administered as a single daily intranasal spray that provides 200 units of the drug (Table 10). The efficacy of calcitonin in stabilizing or increasing BMD and preventing fractures is lower than that of HRT or biphosphonates. Consequently, calcitonin is generally considered to be a safe but somewhat less effective intervention for osteoporosis. It may be used as an alternative to HRT or biphosphonates for patients who meet the criteria for other osteoporosis treatments but are unable or unwilling to take them. Calcitonin also provides effective treatment for pain associated with vertebral compression fractures.

Raloxifene

This drug is in a class of compounds called selective estrogen receptor modulators (SERMs), which have been developed to provide the beneficial effects of estrogens without their potential disadvantages. Raloxifene, approved by the FDA for prevention and treatment of osteoporosis, is another alternative for postmenopausal patients (Table 10). Raloxifene has been shown to prevent bone loss, and preliminary data in women with osteoporosis show that it reduces the risk of vertebral fracture by some 40 _ 50%. In contrast to HRT and biphoshonates, no scientific data currently indicate that use of raloxifene use prevents hip fractures. Raloxifene increases the risk of deep vein thrombosis to a degree similar to that observed with estrogen. In addition, an increase in hot flashes is observed. Furthermore, use of raloxifene does not prevent or treat genital atrophy. Therefore, raloxifene is not used to treat menopausal symptoms.

Androgens and Progestins

Although not FDA approved to prevent or treat osteoporosis, a growing body of evidence suggests that testosterone combined with estrogen replacement therapy has an effect on BMD more positive than estrogen alone. Although estrogen-progestin formulations are currently available in two strengths (Estratest HS: esterified estrogen 0.625 mg/methyltestosterone 1.25 mg, and Estratest: 1.25/2.5), current BMD evidence favors the use of the higher dose combined formulation (Estratest) (Table 10).

Progestins derived from testosterone, including norethindrone acetate and norgestimate, are increasingly being used in HRT. Clinical trial data suggest that norethindrone acetate therapy in combination with estrogen replacement may have a more positive impact on BMD than estrogen alone.

Conclusion

Osteoporosis is by no means a new disease. However, new technologies such as BMD assessment have revolutionized our ability to evaluate fracture risk just as new knowledge and medications have dramatically improved our ability to prevent and treat low BMD. Primary care physicians who counsel women regarding bone-healthy lifestyle choices and appropriately use the diagnostic and pharmacologic measures described in this article can play a major role in reducing this silent epidemic of women.

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May, 2000 (Supplement)/ Jacksonville Medicine

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