SYMPOSIUM ON OSTEOPOROSIS

Preview

Osteoporosis is considered a disorder of postmenopausal women because bone mineral loss and accompanying fragility fractures are common in this group. However, certain premenopausal women are also at risk for osteoporosis. Because of a lack of screening and treatment guidelines for premenopausal women, it can be difficult to determine whether a low bone mineral density correlates with a disease such as osteoporosis and to predict the potential risk of a fracture and formulate the correct course of action. In this article, Dr Derk identifies high-risk groups, presents an approach to judicious screening, and recommends prevention and treatment strategies.

Most osteoporosis research, classification criteria, and treatment guidelines have centered on postmenopausal women, because osteoporosis and fragility fractures are most common in this group. Classification criteria and treatment guidelines for premenopausal women with osteoporosis are clearly lacking.1

An estimated 15% of premenopausal women have a bone mineral density (BMD) lower than 1.0 standard deviation (SD) below the young-adult mean, and 0.6% have a BMD lower than 2.5 SD below the same mean.2 However, World Health Organization (WHO) criteria for diagnosis of osteoporosis and osteopenia are based on BMDs derived from data on postmenopausal women (table 1).3 The correlation of BMD measurements with osteoporosis and osteopenia in premenopausal women has not been established. Healthcare providers are left to decide whether a low BMD in a premenopausal woman correlates with a disease such as osteoporosis, to predict the risk of a fracture, and to determine the best approach to management.

Interpretation of BMDs in premenopausal women

Peak bone mass in women is usually attained in their mid 20s. Soon after, BMD declines 3% per decade at the femoral neck in healthy premenopausal women; this rate does not appear to apply to the lumbar spine and forearm.4,5 It is important to understand that peak bone mass is individual and is influenced by both genetics and environmental factors. Thus, peak bone mass data are normally distributed in a bell-shaped curve. This distribution needs to be considered when interpreting BMDs in premenopausal women.

During bone growth, three-dimensional changes such as increased bone size and periosteal changes, which confer great structural integrity, are not reflected by the two-dimensional measurement of dual-energy x-ray absorptiometry (DXA). When interpreting BMDs in a relatively young woman, it is important to consider that peak bone mass is not attained at all sites at the same time. Peak bone mass appears to be attained earliest in the proximal femur and the vertebral bodies and later at other sites (ie, wrist and skull).6 Bone loss is believed to progress in the same way during premenopause, meaning that BMD measurements at different sites (ie, femoral neck, wrist, lumbar spine, and skull) may be discordant. In a study of BMDs in premenopausal women,7 20% to 24% of women 20 to 29 years old had a difference of 1.0 SD at the different sites; this incongruity occurred in 32% to 46% of women 30 to 45 years old.

Interpretation of BMD studies in premenopausal women may not be as clearly defined as in postmenopausal women, and there is no consensus about whether T-scores should be used in all or in only a subset of premenopausal patients. A T-score compares a patient's BMD with the average score of a healthy young adult at peak bone density. Z-scores, which are also included on DXA reports, compare the BMD with that of others in the same age-group and of the same race and gender and may be more accurate in young patients?\especially those younger than 30 years old.

Mass screening with peripheral bone density, which measures bone density in the limbs, such as heel or wrist, has become popular at health fairs. However, screening should be limited to postmenopausal women because, as previously described, standard criteria for BMD measurements in premenopausal women have not been established. Mass BMD screening in premenopausal women could create unnecessary anxiety for patients and lead the healthcare provider to order a full DXA study and possibly take a course of action based on data from postmenopausal women.

Who should be screened?

BMD testing in premenopausal women should be limited to patients who have fragility fractures (fractures resulting from mechanical forces that would not ordinarily cause fracture), who have a history of eating disorders, who are taking medications associated with osteoporosis, or who have a disease that can lead to osteoporosis (eg, endocrine, gastrointestinal, connective tissue disorders).8

Evaluation

The National Osteoporosis Foundation26 recommends BMD screening for all postmenopausal women younger than 65 who have at least one risk factor for osteoporosis (in addition to being female and postmenopausal) (table 2), all women 65 and older, and postmenopausal women who have fractures. Special attention needs to be paid to estrogen-deficient women at risk for fractures, women with vertebral abnormalities or primary hyperparathyroidism, those taking or planning to take long-term glucocorticoid therapy, and those being monitored for response to osteoporosis therapy.

The International Society for Clinical Densitometry27 recommends screening for women older than age 65, postmenopausal women younger than age 65 who have risk factors, men aged 70 or older, adults with fragility fractures, adults who have a disease or are taking medications related to low bone mass or bone loss, and any patients who are being considered for osteoporosis therapy or are receiving therapy (to assess response).

WHO criteria should not be applied in diagnosis of osteoporosis in premenopausal women, and Z-scores rather than T-scores should be used. The International Society for Clinical Densitometry27 states that diagnosis of osteoporosis in this group requires low BMDs and a secondary cause; diagnosis should never be based on BMD scores alone.

Secondary causes of osteoporosis need to be addressed in premenopausal women being evaluated for osteoporosis. Age at menarche and regularity of the patient's menses need to be considered, because amenorrhea and its precipitating causes can lead to bone loss.

A thorough nutritional history should address in detail the patient's intake of calcium-rich food and presence of eating disorders or lactose intolerance. History taking should also include previous inflammatory or allergic disorders, glucocorticoid use (including dose and duration), heavy tobacco or alcohol use, fractures (including the cause), kidney stones, and renal colic.

Because secondary causes of osteoporosis are more common in premenopause than postmenopause, laboratory evaluation needs to be much more extensive in premenopausal women. It should include measurement of serum calcium, phosphorus, magnesium, thyroid and parathyroid hormones; a complete blood cell count; a complete metabolic profile (including kidney function and liver enzyme levels); and tests for serum 25-hydroxyvitamin D3, celiac sprue autoantibodies, and 24-hour urinary calcium excretion. Other laboratory studies may be included in the initial evaluation, depending on the characteristics of each patient.

Treatment

There are many different guidelines for osteoporosis treatment. The National Osteoporosis Foundation,26 which updated its guidelines in 2003, recommends treatment for postmenopausal women who have T-scores below ?|2.0 with no other risk factors, who have T-scores below ?|1.5 and other risk factors, or who have vertebral or hip fractures. The American College of Obstetricians and Gynecologists28 has similar guidelines and recommends bisphosphonates, the selective estrogen receptor modulator raloxifene (Evista), and estrogen as first-line preventive agents. First-line treatments per the National Osteoporosis Foundation guidelines are bisphosphonates, raloxifene, calcitonin, and synthetic human parathyroid hormone 1-34. There are no recommendations for premenopausal women in these guidelines.

Diseases and conditions associated with osteoporosis in premenopausal women should be identified and treated, if possible. Recommended calcium supplementation for children and young adults is about 1,000 mg a day. Doses of 1,500 to 2,000 mg of calcium a day and 400 to 800 IU of vitamin D a day are recommended for patients with osteoporosis.29 Data on the effects of low-dose oral estrogen-based contraceptives on bone turnover are mixed. Two studies suggested that use of these contraceptives improved BMDs and decreased risk of fractures, whereas other studies suggested the reverse.30,31

Raloxifene has antiresorptive properties that improve BMDs at both the cortical and trabecular bone, although it has been shown to decrease risk of fractures of only the trabecular bone. A study of uterine leiomyomas in 100 premenopausal women32 showed reduced bone loss related to use of a gonadotropin-releasing hormone agonist. Raloxifene is contraindicated in women who are pregnant or may become pregnant because it may harm the fetus. The safety of raloxifene in premenopausal women has not been established.

Bisphosphonates are a class of antiresorptive agents. The most popular bisphosphonates are the second-generation alendronate sodium (Fosamax) and the third-generation risedronate sodium (Actonel). Only the portion of bisphosphonate that binds tightly to hydroxyapatite crystals in the resorption lacunae of bone extends an antiresorptive effect. The skeletal retention can last up to 10 years. These agents have significantly benefited children with osteogenesis imperfecta. The 2001 American College of Rheumatology guidelines14 recommend bisphosphonates for the prevention and treatment of glucocorticoid-induced osteoporosis in premenopausal women. Counseling on the importance of using appropriate contraception during bisphosphonate therapy is required.

The long-term effects of bisphosphonate therapy in women of childbearing age are unknown, although adverse fetal effects have occurred in animal studies. Safety concerns have arisen because these agents are released back into the systemic circulation for many years after their discontinuation; also, they can readily transverse the placenta, deposit in the fetal skeleton, and lead to skeletal abnormalities and other problems.

Intranasal calcitonin (salmon) (Miacalcin Nasal Spray) is recommended as a second-line agent in the 2001 American College of Rheumatology guidelines for treatment of glucocorticoid-induced osteoporosis for patients who cannot tolerate bisphosphonates.14 Calcitonin is classified as a class C drug for pregnant women because of animal study findings, and its use in women of childbearing age needs to be approached with caution.

Synthetic human parathyroid hormone 1-34 is a potent anabolic agent that was approved in 2002. It leads to skeletal remodeling and higher BMDs. Although it initially causes increased cortical bone porosity and an early decline in BMDs, it subsequently leads to new periosteal bone formation and increased cross-sectional area. Episodes of hypercalcemia, nausea, and headaches have been associated with this agent on rare occasions. It is classified as a class C agent for pregnant women.

Conclusion

Population-based screening for osteoporosis in premenopausal women is not supported at this time; therefore, it should be limited to postmenopausal women. Premenopausal women at high risk for osteoporosis should be screened, although the relative importance of BMDs and their correlation with fracture risk are not well established. BMD criteria for diagnosis of osteopenia and osteoporosis in premenopausal women are clearly needed. Pharmacologic therapy may be helpful for glucocorticoid-induced osteoporosis. Otherwise, pharmacologic therapy is rarely indicated for premenopausal women, because its long-term effects in this group are unknown.

Dr Derk is assistant professor of medicine, division of rheumatology, department of medicine, Thomas Jefferson University, Philadelphia.
Correspondence: Chris T. Derk, MD, Division of Rheumatology, Department of Medicine, Thomas Jefferson University, 613 Curtis Bldg, 1015 Walnut St, Philadelphia, PA 19107. E-mail: chris.derk@jefferson.edu.

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