Update on Hormone Replacement: Sorting Out the Options for Preventing Coronary Artery Disease and Osteoporosis

, Ohio State University

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Perhaps the widest-ranging social, physical, and economic impact of estrogen deficiency is on bone density, which may lead to osteoporosis, a disease affecting many older women. Of those affected by osteoporosis, 80% are women, and there is a nearly 40% lifetime fracture risk among women who are age 50.[11] Osteoporotic fractures may present as vertebral crush fractures, Colles' wrist fractures, and/or hip fractures.

In women, osteoporosis may be associated with estrogen deficiency or it may be a natural resultof age-related bone loss. Bone mass usually peaks at age 30 to 35 and gradually declines thereafter. In the postmenopausal period, bone loss accelerates, sometimes by as much as 4% to 5% per year. In many women, both age and estrogen deficiency contribute to osteoporosis.

Clinical risk factors for osteoporosis include female sex, premature menopause, and family history of osteoporosis. However, clinical risk factors are not very sensitive indicators in determining which women will actually develop osteoporosis. Postmenopausal estrogen use and past estrogen exposure have been strongly correlated with higher bone mineral density.[12] Secondary causes of osteoporosis include multiple myeloma, hyperparathyroidism, hyperthyroidism, Cushing's syndrome, and hepatobiliary diseases. Some medications, particularly glucocorticoids, predispose to osteoporosis.

Testing for osteoporosis. Accurate diagnosis of osteoporosis technically requires bone tissue examination. Radiographic examinations are only able to ascertain osteopenia, which may be osteoporosis (loss of bone matrix and mineral) or osteomalacia (loss of bone mineral related to vitamin D deficiency). Therefore, the technique of choice for bone mass measurement is DXA of the spine and hip. (See Figure 1.) Forearm and total body bone density can also be assessed. Results of DXA are expressed in g/cm2. Values are given for the patient compared with age- and sex-matched controls, as well as with young normals. A normal value is no more than 1 standard deviation below the young reference mean peak value. Low bone mass, or osteopenia, is more than 1 standard deviation but less than 2 standard deviations below peak value. The World Health Organization defines osteoporosis as greater than or equal to 2.5 standard deviations below the mean for young, healthy adults at any site (spine, hip, or mid radius).[13] Use of ultrasound of the calcaneus for osteoporosis assessment is still investigational.

Figure 1. Bone densitometry with dual energy x-ray absorptiometry (DXA) uses x-ray source to measure bone mineral density. DXA of hip and spine is useful to indicate osteoporosis related to estrogen deficiency in postmenopausal women.

Bone mineral density testing helpsto confirm the diagnosis of osteoporosis, assess the severity and rate of bone loss, and monitor the effects of therapy. Low bone mass is the single most accurate predictor of an increased fracture risk.[14] One standard deviation below the young normal value at the spine confers almost 2 times the fracture risk. One standard deviation below young normals at the hip is associated with a fracture risk that is 2.4 times the normal risk.

Indications for bone density testing include evidence of vertebral deformity and prior nontraumatic fracture of the hip, spine, or wrist, which may provide useful information for postmenopausal women concerned about their risk of osteoporosis (particularly if these findings would affect their decision to institute HRT). Routine bone density testing for all menopausal women is not recommended. Tests for biochemical markers of bone remodeling are available but not yet recommended for routine evaluation.

Treatment options for osteoporosis. Efforts to prevent falls that could result in fractures are crucial. Treatment for established osteoporosis includes the palliative measures of analgesics, physical therapy, and weight-bearing exercise. Nutritional supplementation with adequate calcium (1.5g/day after age 55 for women not taking HRT and 1.0g/day for the woman on estrogen replacement) and adequate vitamin D (400-800 IU daily) is important and may help to reduce bone loss and the risk of osteoporosis. Pharmacologic treatment of established osteoporosis includes ERT, bisphosphonates (alendronate sodium), or salmon calcitonin (in parenteral form or the newer, intranasal spray).

Parenteral salmon calcitonin is indicated for the treatment of hypercalcemia, Paget's disease, as well as postmenopausal osteoporosis. Parenteral calcitonin has been used for nearly 2 decades and has been shown to increase vertebral bone mass. Intranasal salmon calcitonin is now available in the US for the treatment of osteoporosis in women with documented low bone mass who are 5 or more years postmenopausal. The nasal formulation is easier to use and less expensive than the parenteral form. The efficacy of calcitonin is based on increases in spinal bone mineral density. Calcitonin also appears to have some analgesic affect on the pain associated with micro fractures of the bone that can be clinically beneficial, although this is not an FDA-approved indication. The parenteral formulation is associated with some nausea, flushing, and occasional allergic reaction. The intranasal form has been associated with nasal symptoms and, rarely, nasal ulceration. The dosage is 200 IU sprayed into 1 nostril daily. Alternate nares should be used.

The newest class of drugs for treating established osteoporosis in postmenopausal women is the bisphosphonates; these bind to hydroxyapatite, a mineral in the bone matrix. They are potent inhibitors of bone resorption with a long half-life. Alendronate sodium is the only FDA-approved bisphosphonate available for the treatment of osteoporosis. Alendronate reduces bone loss, results in an increase in bone mass, and most importantly, reduces the incidence of vertebral and hip fractures. Because of the low oral bioavailability, alendronate should be taken in the morning with water only at least 30 minutes before meals, other beverages, or other medication. Elimination of the drug is exclusively renal, and it is incorporated into the bone. Gastrointestinal irritation and disturbances are the most frequent adverse reactions with alendronate. Because of esophageal irritation, the patient should remain upright for at least 30 minutes after taking alendronate.

For the treatment of established osteoporosis, alendronate (Fosamax) 10mg PO qd can be prescribed along with adequate calcium and vitamin D supplements and weight-bearing exercise. Owing to a lack of clinical experience with alendronate, it is not recommended that it be prescribed along with other antiresorptive agents, such as HRT. To date, however, no adverse events have been attributed to the concomitant use of estrogen and alendronate. Safety of treatment for more than 4 years has not been studied. Extension studies are ongoing. Alendronate is contraindicated in patients with renal insufficiency and gastrointestinal disease, particularly current peptic ulcer disease.


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