Osteoporosis

Osteoporosis is characterized by reductions in bone mineral density (BMD) to the extent that fractures occur after minimal trauma. It is a disease process and not a component of normal aging. Nevertheless, the incidence, patient suffering, and economic costs of osteoporosis are very significant as outlined in.(1-6)

Osteoporotic fractures (humerus, pelvic, Colles', and vertebral) in the United States total 1.5 million yearly. Although most vertebral fractures go unreported, 15% of women in their mid 60s have a vertebral fracture, and about 30% to 40% of women have such a fracture by their mid 80s.(4,5) Osteoporosis is preventable and treatable, but there are no warning signs until a fracture occurs. In essence, osteoporosis is a silent risk factor for fracture.

The most common complication of osteoporosis is hip fracture, and it is this event that is responsible for significant cost. The average cost of a hip fracture in the United States is estimated to range as high as $35,000 per patient.(3) The total annual cost reported in is derived mainly from fracture data, and does not include the cost of nursing home confinement or home healthcare.(3) Of this figure, $11 billion is attributable directly to the treatment of women.

Table 1

Aside from the cost, hip fracture is associated with significant mortality and morbidity. Roughly 20% of patients with a hip fracture die within the first month of injury.(7) In fact, most of the deaths from hip fracture occur in the first 3 to 4 months, secondary to heart failure, pulmonary embolism, or pneumonia. Death usually occurs in those who are less medically healthy at the time of fracture.

Because of the magnitude of this disease, and because there are effective therapeutic interventions, the National Osteoporosis Foundation (NOF) recently issued new recommendations for the assessment, diagnosis, and treatment of osteoporosis as listed in Table 2.(8) They provide a complete framework — from counseling to treatment.

Table 2

Osteoporosis and Menopause

The decline in a woman's BMD begins around age 18 and progresses steadily. The amount of bone present in later life is determined by the bone mass accumulated during youth and the rate of bone loss that occurs later. About 50 years ago, an association between osteoporosis and postmenopausal women was noticed. There is now little doubt that estrogen deficiency plays a very important role in the pathogenesis of bone loss. Approximately 20% of bone loss occurs in the first 5 to 7 years after menopause.(9-11)

A number of factors are associated with an increased risk for osteoporosis (Table 3). Women who are traditionally considered at greatest risk are white or Asian with a family history of osteoporosis and a small frame. More specifically, the factors that are associated with attaining maximal peak bone mass are genetic heritage, physical activity, and diet.(12,13) Factors most associated with excessive bone loss include menopause, age-related changes, declining physical activity, impaired absorption of calcium, and adverse effects of other medical conditions or drugs.(14)

White and Asian women are at highest risk of developing osteoporosis. African American and Hispanic women have a lower, but significant risk.(15) Data from the National Health and Nutrition Examination Survey (NHANES II 1998-1991) indicate that non-Hispanic white women have a prevalence that is 1.3 to 2.4 times higher than non-Hispanic black women, and 0.8 to 1.2 times higher than Mexican American women.(16) Despite these differences, it is important that African American and Hispanic women not discount their risk. African American women have higher BMD than whites throughout life, and this fact has erroneously created the impression that osteoporosis is not a concern for African American women. Recent research, however, has supported African American women as a vulnerable population, primarily because of other risk factors, not race. It is estimated that 1 in 5 African American women will be affected by osteoporosis.(17)

Table 3

Lactose intolerance may be a complicating factor in this population as well. As many as 75% of all African Americans are lactose intolerant, which is likely to interfere with the adequate intake of calcium.(18) Moreover, African American women are more likely than white women to die following a hip fracture.(18)

Both artificial and medical menopause represent areas of unrecognized importance in terms of osteoporosis risk. Some 500,000 women in the United States undergo hysterectomy and bilateral oophorectomy yearly and not all receive HRT. Bone loss in these women is likely to be significant. Six months of gonadotropin-releasing hormone (GnRH) therapy produces a 5% loss of bone at the spine, most, but not all, of which is recovered after therapy is stopped. Also, 1 year of Depo-Provera is associated with 8% bone loss, which is recovered in time with young women. Prolonged use, however, may have long-term consequences. Cigarette smoking increases the metabolism of estrogens in the liver, reducing the level of active hormone. Women who smoke are at greater risk for osteoporosis and tend to begin menopause at an earlier age.

Much of this has been confirmed in a recent study, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, which assessed the effects of HRT on bone mineral density in the spine and hip in postmenopausal women.(19) Those assigned to placebo had decreased BMD at the spine and hip, while women assigned to HRT had increased BMD during a 36-month period.

Sites of Bone Mineral Density Measurements

Reduced bone mass, irrespective of the site of measurement, is correlated with an increased risk for future fracture.(20) Thus, bone densitometry is the primary technology for diagnosing and managing patients at risk for, or with, osteoporosis (Table 4).(20,21) lists several densitometry techniques. Densitometry predicts the risk of fracture; it can be used to determine who should be treated (ie, those with low, or decreasing, bone density); and it is useful in monitoring therapeutic response.

Table 4

Such measurements can be made at central sites (spine and hip) where fractures occur. But peripheral measurements can be made as well at the hand, forearm, and heel. However, it is difficult to interpret the density at the spine from a measurement made at the forearm (radius) or heel (calcaneus).

The NOF guidelines for diagnosis and treatment are based on the World Health Organization (WHO) definition of osteoporosis, namely T-scores measured at the hip (Figure 1).(8) A T-score is obtained by comparing the patient's BMD to the expected BMD for "young normal" adults of the same sex. Although BMD measurements at any skeletal site have value in predicting fracture risk, hip BMD is the best predictor of hip fractures, and it predicts fractures at other sites.

However, WHO also uses spine T-scores. A Z-score results from a comparison to the average BMD for women of the patient's age.

Figure 1

ERT/HRT for Osteoporosis

Figure 2

The most recent results from the PEPI trial (3-year longitudinal study) show significant benefits of estrogen therapy (0.625 mg of conjugated equine estrogen or CEE) in terms of maintenance of bone density at the spine.(19) The PEPI population was age 52 on average. Figure 2 presents only those patients who were adherent to the prescribed regimen. Consistent therapy can produce about a 5% increase in spine density. Also, continuous progesterone (medroxyprogesterone acetate or MPA) therapy resulted in significantly higher BMD compared to cyclic progesterone therapy. Similar results were seen at the femoral neck, where consistent adherence produced about a 2% increase in BMD.

Table 5

Estrogen therapy should be initiated as soon as possible after menopause or ovarian failure because lost bone mass may never be recovered. A placebo-controlled study of 16 years' duration dramatically showed the effects of estrogen deficiency on bone loss in oophorectomized women.(22) Several results of the study were noteworthy. Metacarpal mineral content decreased 20% over 15 years in women who did not take estrogen. Estrogen therapy retarded bone loss irrespective of whether the treatment was started at 0, 3, or 6 years after oophorectomy. And lost bone mass was not replaced. Thus, the earlier estrogen replacement therapy is started after menopause, the more protective its effect on bone density. Moreover, it is never too late to start HRT and gain improvement. It is important to note that the effective dose of estrogen varies according to the type of estrogen compound (Table 6).

Table 6

In addition to having a role in the prevention of osteoporosis, estrogen is beneficial in treatment. A number of studies have examined the ability of HRT to reduce the incidence of fractures. Because the highest incidence of radial and vertebral fractures occurs mainly between 50 and 75 years of age, the effect of estrogen on these fracture rates is easier to detect than its effect on hip fractures, which start in the late 70s. Relative risk (RR) is defined in Table 7. The relative risk graph in Figure 3 shows several case-control and cohort studies that have compared estrogen use in hip fracture cases with estrogen use in controls. These studies showed reductions in fracture risk of 20% to 60%.(23)

Figure 3

Table 7

Therapeutic Alternatives for Osteoporosis

Figure 4 shows a prevention trial that involved a direct comparison of placebo, alendronate, and HRT.(28)

The women who received placebo lost BMD, whereas those treated with alendronate had a mean increase of 3.5% at the spine, and 1.9% at the hip. The responses to HRT were 1% to 2% greater than responses to alendronate. Another prospective study involved about 2,000 women who were randomized to either placebo or alendronate.(29) Significantly fewer women in the alendronate group had vertebral fractures (RR 0.45 [0.27-0.72]). The RR of hip fractures among the treated group was 0.49 (0.23-0.99).

Figure 4

The newest SERM, raloxifene, is also approved to treat osteoporosis. It produces an increase in BMD of about 1% at the hip,30,31 which is lower than the increase seen with estrogen. Although there is a 2% difference between raloxifene and placebo, this SERM is not as effective as estrogen on bone density.

Calcitonin is another therapeutic alternative that slows bone density loss, but it is not as effective as the other agents previously mentioned. There are 2 major US studies that show the effect of calcitonin in postmenopausal women. One showed that in the early menopause, that is, within 4 years, calcitonin was no better than placebo in preventing bone loss.(32) The other study suggests that in late menopause (>10 years since menopause) there is some evidence that calcitonin prevents bone loss.(33) Therapy with this agent produced increases in BMD of 1% to 2%.

The evidence available for elemental calcium supplementation shows only a very modest beneficial effect on osteoporosis. However, habitual dietary intake influences the efficacy of supplementation. Women with low intake to begin with benefit the most. In early menopause calcium supplementaion is ineffective,(34) but in late menopause it reduces bone loss by 25% to 30%.(35,36) RDA nutritional requirements and recommendations from the NIH consensus statement suggest 800 mg of elemental calcium premenopause and 1500 mg postmenopause. The NOF recommends 800 mg before menopause and 1200 mg after. Among the current options for treating osteoporosis, CEE and alendronate are the most potent, but not all treatment options have equal preventive and treatment efficacy. Although bone density may be increased or maintained by several therapies, not all treatments have been shown to reduce fracture rates (Table 8). Fluoride treatment shows the largest increase in BMD, yet the effect on fracture rates is unproven, perhaps because of changes in the quality of bone. Thus, increases in BMD do not always equate with fracture prevention efficacy.

Table 8

Effect Of HRT On Tooth Loss

In addition to ameliorating osteoporosis, estrogen may provide benefit for another condition that involves the skeletal system, that is, tooth loss. Approximately 32% of US women aged 65 have no teeth. Although the prevention of periodontal disease is the most important factor in maintaining teeth, it has been hypothesized that some tooth loss may occur as a result of resorption of the alveolar bone and therefore reflects osteoporotic bone loss. There is some evidence that bone mineral density in postmenopausal women is correlated with the number of teeth.(37-39) The 3 studies in the RR risk graph in Figure 5 show that estrogen therapy is associated with a decreased risk of tooth loss in both past users and current users.(40-42)

Figure 5

Comprehensive Approach To Osteoporosis