Overview Page 1

Epidemiology and impact
Osteoporosis is a disease characterized by a reduction in the quantity of bone tissue and a deterioration of the structure or microarchitecture of bone tissue, both of which produce bone fragility and an increase in the risk of fractures throughout the body.

Osteoporosis is very common; it currently affects 4-6 million postmenopausal Caucasian women.¹ Approximately half of all Caucasian women will experience an osteoporotic fracture during their lifetimes. In the United States, there are approximately 1.5 million osteoporotic fractures every year.² Of these, 250,000 are hip fractures, which carry a 24% mortality risk within the first year.³ About one in six Caucasian women will fracture her hip.^4-7 Half of those who suffer hip fractures are unable to walk without assistance² and about 8% require long-term nursing care.⁸ Only 10-15% will return to full, independent activity.

Osteoporosis presents an enormous burden to the healthcare system. The cost of the disease and its associated fractures is estimated to be $14 billion annually. Hip fractures incur the greatest expenditures. Initial hospital care costs an average of $7,000 and the average cost for the first year post-fracture is $21,000. In 1995, hip-fracture treatment costs totalled $8.68 billion.⁹

Vertebral fractures are associated with an increase in mortality that is directly related to the number of fractures as documented on x-ray. Vertebral fractures also have major physical consequences, including loss of height, changes in posture, chronic back pain, difficulty breathing and the so-called Dowager's hump. People with fractures in the lumbar region may experience changes in the abdominal anatomy, abdominal pain, constipation, reduction in appetite, and a feeling of fullness and distension. These changes can have a major negative impact on a patient's quality of life.^10-12 The cumulative burdens of pain, disability, reduced quality of life, and cost represent a serious public health problem.

Risk Factors
During childhood, bone is gained in a relatively linear fashion. At puberty there is a major acceleration in bone acquisition, with a dramatic increase in bone mineral density (BMD). This increase in BMD represents an increase in the dimensions of bone rather than a change in the density of existing bone matrix. In females, the bone acquisition process is nearly complete by age 17; in males by age 20. Maximum BMD is achieved around age 28.

Genetic factors are largely responsible for determining the level of peak bone mass. Nutritional factors (e.g., calcium intake), exercise patterns, age of menarche, regularity of menstrual function, and exposure to alcohol and tobacco also affect peak bone mass. At the time of menopause, all women lose bone. This bone loss is accelerated in the first five years after menopause but continues through the rest of life. Several factors can increase or decrease the rate of bone loss at this stage of life, including exercise, calcium and vitamin D intake, and smoking. A variety of diseases, such as inflammatory bowel disease, multiple myeloma, lupus, and rheumatoid arthritis, can contribute to bone loss. Certain medications, such as glucocorticoids and excessive amounts of thyroid hormone, can also increase bone loss.

Compared with men, women are at higher risk for osteoporosis because of a lower peak bone mass, smaller skeletal size, and the accelerated bone loss that occurs after menopause. Among women, the incidence of osteoporotic fractures is higher in Caucasians than in African-Americans, while women of Hispanic descent have an intermediate risk. There is greater variability within each race, however, than there is among races.

Men have a lower risk for osteoporotic fractures, but the lifetime risk is still substantial – 25% for a 60-year-old man. As with women, the risk of hip fracture rises exponentially with aging, but the age at which this increase begins is typically five to 10 years later in men.

Diagnosis
The diagnosis of osteoporosis requires the assessment of risk factors, measurement of bone mineral density, documentation of fractures, and an evaluation of potential secondary causes of bone loss. The National Osteoporosis Foundation (NOF) recommends that all post-menopausal women age 65 or older have a bone mineral density test regardless of any other risk factors or therapies being used at the time (Table 1). The Foundation also recommends that postmenopausal women under the age of 65 who have one or more additional risk factors for osteoporosis, including secondary causes, should undergo a bone mineral density test. The most important of these risk factors include a history of fractures occurring with minimal trauma, a positive family history of osteoporotic fractures (especially a maternal history of hip fracture), current smoking, being very thin, and frequent falls. In the future, it is likely that recommendations for testing will be broadened to include all postmenopausal women, regardless of the presence or absence of risk factors.

Bone mass accounts for approximately 80% of bone strength; it is the single strongest predictor of osteoporotic fractures. Current bone density measurements employ a variety of techniques that are fast, safe, and accurate. These techniques include single- or dual-energy x-ray absorptiometry (DXA), computerized tomography (QCT), and ultrasound. Densitometers are classified by the skeletal regions they measure; either central (spine and/or hip) or peripheral (forearm, tibia, wrist, finger, or heel). The preferred technique is the hip DXA test, which is the best for predicting hip fracture risk.

In addition to bone density testing, biochemical markers of bone turnover can be useful in predicting fracture risk and also for monitoring osteoporosis therapy. Bone is constantly being remodeled by a cyclic process, during which osteoclasts absorb packets of old bone tissue and osteoblasts produce new bone matrix. Bone loss occurs when the amount of old bone resorbed exceeds the production of new bone. The rate of bone formation and resorption can be assessed biochemically in two ways: by measuring the enzymatic activity of bone cells or by measuring the breakdown products of bone matrix. The most commonly used indicators of bone formation are bone specific alkaline phosphatase and osteocalcin. During bone resorption, pyridinolines and metabolized fragments of type 1 collagen are excreted into the urine; these can also be analyzed through laboratory assays. Biochemical markers reflect rates of bone remodeling, a dynamic state, but cannot confirm the presence or absence of osteoporosis and cannot substitute for bone density testing. However, elevated levels of these markers may be associated with an increase in the risk of fractures; they may be most useful in risk prediction when bone density tests show an intermediate level and a treatment decision isn't clearly indicated.

Biochemical markers can be very useful in monitoring response to antiresorptive therapy. Reductions in biochemical markers of bone formation and resorption of 40-60% can be seen within three to six months of therapy, particularly with bisphosphonates and estrogen, while 12 to 24 months are usually required to evaluate treatment response through bone densitometry.

Treatment
Risk factor reduction
The first area to be considered in the management of osteoporosis is the reduction in risk factors. These may include eliminating smoking and alcohol abuse and reducing the risk of falls. The next step in risk reduction is optimizing nutritional status. Total daily calcium intake, from both diet and supplements, should be 1200-1500 mg. (The American diet typically provides 600 mg/day of calcium.) A daily intake of 400 IU of vitamin D (or up to 800 units in those over 65), will help maintain an optimal skeletal status. The management of osteoporosis should also include an exercise regimen. The exact prescription to be followed is not known, but it should include some weight-bearing, aerobic exercise program, such as running, calisthenics, dancing, stair climbing, or racquet sports. The goal is to strengthen the large muscle groups, with concentration on the back, shoulder, and hip musculature. In addition to helping maintain bone mass, exercise helps maintain muscle mass, which improves coordination and balance, thus reducing the risk of falling and fractures.

While not everyone needs medical therapy, women who have experienced fractures or have T-scores ≤ -2.5 should receive medical therapy. Current NOF guidelines recommend that anyone with a T-score of -2 or below, or with a T-score of -1.5 or below and additional risk factors, should receive medical therapy.

Currently approved medications for osteoporosis management include estrogen replacement therapy, raloxifene, calcitonin, alendronate, and risedronate. Parathyroid hormone may receive FDA approval in late 2002 or 2003.

Estrogen
A large body of clinical trial data has shown that estrogen produces beneficial effects on bone mass in both early and late postmenopausal women and in women who have osteoporosis. Most of the data supporting the antifracture effects of estrogen comes from epidemiological evidence rather than clinical trials. A recent meta-analysis by Torgerson et al, which examined 22 studies, showed that the relative risk of nonvertebral fractures was reduced by 27% in estrogen-treated women compared with placebo-treated women.¹³ This effect was most significant in women who were under 60 years of age or who started estrogen before the age of 60. The Heart and Estrogen/Progestin Replacement Study (HERS) is sometimes cited to strengthen the case against estrogen replacement as an effective treatment for osteoporosis.¹⁴ This study, which used conjugated estrogens plus medroxyprogesterone, showed no beneficial effect of estrogen on hip or other fractures. By contrast, results from the aborted Women's Health Initiative (WHI) trial indicate that hormone replacement therapy (HRT) reduced the risk of hip fracture by 33% and all fractures by 24%, despite the fact that this group was not at particularly high risk for osteoporosis.¹⁵

Many patients refuse to consider estrogen therapy because of a fear of breast cancer. Observational studies suggest that there is an increased risk of breast cancer after long-term estrogen use. Results from the WHI trial confirm that HRT results in an increased risk of breast cancer of about 25%, even within the first five years of therapy.¹⁵ This translates into eight additional cases per 10,000 women per year. These results, which received extensive publicity in the lay as well as the professional press, suggest that HRT, particularly the Premproö formulation, can no longer be routinely recommended for long-term therapy.

SERMs
The selective estradiol receptor modulators (SERMs) produce some of estrogen's multisystemic effects, but do not increase the risk of breast cancer. In fact, the SERMs studied to date, tamoxifen and raloxifene, appear to reduce the risk of breast cancer. Only raloxifene is currently approved for the prevention and treatment of osteoporosis. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene was shown to produce modest effects on bone density and to produce reductions in bone turnover markers.¹⁶ Raloxifene reduces the risk of vertebral fractures, although there are no data confirming that it reduces nonvertebral fractures. Other major effects of raloxifene to emerge from the MORE trial include significant reductions in the incidence of breast cancer and cardiovascular and cerebrovascular disease. Tamoxifen has been used as an adjuvant therapy for breast cancer for several decades and is now used for breast cancer prevention. Tamoxifen is not suitable as a substitute for estrogen in the prevention or treatment of osteoporosis, since it produces estrogenic effects on the uterus, including endometrial hyperplasia and endometrial cancer. It also has undesirable anti-estrogenic effects on the brain, resulting in hot flashes.