Low bone mineral density in premenopausal women.

Abstract: With the proliferation of bone densitometers, an increasing number of premenopausal women are having their bone density tested. Approximately 15% of premenopausal women have bone mineral density that is more than 1 standard deviation less than the young-adult mean, and approximately 0.6% are more than 2.5 standard deviation below young-adult mean bone density. Most premenopausal women with low bone density have low peak bone mass, stable bone density, and low short-term absolute risk of fracture. The management of these patients involves nonpharmacologic lifestyle measures and reassurances that fracture risk is low. A minority of premenopausal women with low bone density have increased short-term absolute fracture risk with contributing diseases, conditions, or medications that should be identified and treated. Premenopausal women with fractures are at increased risk for fractures later in life. Methods for evaluating these patients and selecting those who require additional care are reviewed.

Key Words: bone mineral density, fracture, osteopenia, osteoporosis, perimenopausal, premenopausal

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In postmenopausal women, the prevalence of low bone mineral density (BMD), the relationship of low BMD to fracture risk, and the efficacy of pharmacologic therapy to reduce the risk of fractures is well established. The World Health Organization criteria (1) for diagnosing osteoporosis and osteopenia are based on epidemiologic data obtained in postmenopausal women. Widely distributed treatment guidelines, such as those of the National Osteoporosis Foundation (2) and the American Association of Clinical Endocrinologists, (3) are targeted for postmenopausal women. However, it is not uncommon in clinical practice to encounter premenopausal women with low BMD and/or fractures. These patients are usually concerned about osteoporosis and future risk of fractures. To address these concerns, health care providers must decide whether or not a disease state is present, estimate the risk of future fractures, and recommend a course of action. The following discussion reviews issues relevant to low BMD in premenopausal women and provides a framework for clinicians to manage these patients. "Premenopausal" is defined as the time between attainment of peak bone mass and the onset of menopause, or approximately age 20 to 50.

Prevalence

Bone density in a population of any age is normally distributed (4) in a bell-shaped Gaussian curve (Fig. 1). With advancing age, bone loss occurs and the curve shifts to the left. Several large studies have shown that bone loss at the femoral neck begins in the mid-20s, soon after peak bone mass is attained, and continues throughout life. (5-7) The rate of femoral neck bone loss in healthy premenopausal women is approximately 3% per decade. There does not seem to be a corresponding loss of bone at the spine or forearm during these same years. (8) When bone density is reported as a T-score (the patient's BMD minus the mean young-adult BMD divided by the standard deviation [SD] of the young-adult reference population), 85% of premenopausal women are predicted to have a "normal" T-score [greater than or equal to]-1.0, whereas approximately 15% have a T-score < -1.0 and 0.6% have a T-score < -2.5. (9) The measured prevalence of low bone density expressed as a T-score is dependent on the population studied, the mean BMD and SD of the young normal reference population, the skeletal site measured, the technology used, and the instrument itself. There is no consensus as to whether it is appropriate to use T-scores in all premenopausal women or a subset thereof. Alternatively, BMD may be reported as an age-matched Z-score (the patient's BMD minus the mean age-matched BMD divided by the SD of the age-matched reference population). Z-score values are very close to T-scores in this population, especially in younger premenopausal women.

[FIGURE 1 OMITTED]

Diagnosis

A clinical diagnosis of osteoporosis can be made if there is a history of fragility fracture, provided that other causes of fracture have been ruled out. This applies to both premenopausal and postmenopausal women. It is preferable to make a diagnosis by bone density testing before a fracture occurs, so that therapeutic intervention can lower the risk of a first fracture. According to the World Health Organization criteria, as interpreted by a panel of experts at a Position Development Conference of the International Society for Clinical Densitometry, (10) osteoporosis is present when a dual-energy x-ray absorptiometry (DXA) study shows a T-score [less than or equal to]-2.5 at the spine, hip, or forearm. Osteopenia is diagnosed when the T-score is < -1.0 and > -2.5. These diagnostic cutoffs apply to postmenopausal women. There is no consensus whether T-scores or Z-scores should be used in premenopausal women, or whether diagnostic cutoffs established for postmenopausal women should be applied to premenopausal women. Peripheral bone density testing of the heel or finger is helpful in assessing fracture risk in postmenopausal women but cannot be used to diagnose osteoporosis or osteopenia or to monitor therapy. (11) The role of peripheral bone density testing in premenopausal women is not established.

A National Institutes of Health Consensus Development Panel states that osteoporosis is "a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality." (12) The presence of a fragility fracture is presumptive evidence of compromised bone strength. Because there are no reliable clinical methods for evaluating bone quality in individual patients, in the absence of a fragility fracture we must rely on bone density testing as the proxy for bone strength. The relationship between bone density and fracture risk is well established in postmenopausal women, but less so in premenopausal women.

Does a premenopausal woman with a T-score < -1.0 have a disease with clinical consequences, or is she a normal woman with a T-score at the low end of the bell curve and no concern about increased fracture risk? Is there a subset of these women who have increased fracture risk? In the absence of a fragility fracture, is it possible to make a diagnosis of osteoporosis or osteopenia in a premenopausal woman? Should fracture risk be reported as relative risk, short-term absolute risk, or lifetime absolute risk? Which type of fractures should be reported? More study is required to answer these questions with confidence. There may be a T-score or a Z-score below which it is appropriate to diagnose osteoporosis or osteopenia in a premenopausal woman, but that cut-point has not yet been determined. The psychological, social, and economic consequences of diagnosing osteoporosis in a premenopausal woman are unknown. Until guidelines are established or consensus is reached, it may be prudent to limit the diagnosis of osteoporosis to premenopausal women with known high risk of fracture, as demonstrated by a previous fragility fracture; extremely low BMD; or a disease, condition, or medication associated with high fracture risk.

BMD testing should be considered for premenopausal women with a history of fragility fracture and those with a disease, condition, or medication associated with osteoporosis. (10) Routine screening of premenopausal or perimenopausal women with BMD testing cannot be recommended at this time. It cannot be determined from a single bone density test whether a patient has low peak bone mass and is stable or has lost bone since attaining peak bone mass. It is likely that most premenopausal women with low bone density are in the former category.

Fractures

In postmenopausal white women with osteoporosis (T-score [less than or equal to] -2.5), the absolute lifetime risk of osteoporotic fracture is approximately 40% (13) (higher if radiographic and not just clinical vertebral fractures are counted), and the relative risk of fracture approximately doubles with every SD decrease in BMD. (14) Age is an important independent risk factor for fracture, with fracture risk rising with increasing age, even when bone density remains the same (Fig. 2). (15, 16) Although the relationship between BMD and fracture risk is not as well quantified in large populations of premenopausal women, there are small studies that provide some valuable insight. Girls with wrist fractures have lower BMD (17) and higher risk of future fractures (18) than age- and sex-matched controls without wrist fractures. Premenopausal women with a history of any type of fracture have lower BMD than controls with no history of fracture. (19) Perimenopausal women with a history of fracture are at increased risk for new fractures. (20) Postmenopausal women with a history of premenopausal wrist fractures have a higher risk of postmenopausal osteoporosis compared with controls with no history of wrist fractures. (21) The Study of Osteoporotic Fractures showed that women with premenopausal fractures of any type have a 33% higher risk of postmenopausal fractures of all types. (22) Some studies have shown that premenopausal women with stress fractures have lower bone density than women with no stress fractures. (23) The accumulating evidence suggests that low BMD is associated with increased relative risk of fracture in premenopausal women, as it is in postmenopausal women, although the short-term absolute risk of fracture is low compared with an older woman with the same BMD. The lifetime risk of fragility fracture in a premenopausal woman with low BMD is at least as great as a postmenopausal woman with the same BMD, because a younger woman has more expected remaining years of life with longer exposure to fracture risk. Table 1 describes the common methods for expressing fracture risk.

[FIGURE 2 OMITTED]

Etiology

Professor Charles E. Dent once stated, "Senile osteoporosis is a pediatric disease." (24) This brings home the point that insufficient acquisition of bone during the years of skeletal growth shortens the time to the development of osteoporosis later in life. Low peak bone mass is a major risk factor for postmenopausal osteoporosis and fractures. (25) Bone density in adulthood is the result of two factors: peak bone mass and bone loss. Peak bone mass is the maximum bone mass achieved in life, probably occurring in the third decade of life in most individuals. Studies in twins (26) have shown that 60 to 70% of the variability in peak bone mass is genetically determined, as expressed by phenotypes such as ethnicity, sex, and body size. The remaining 30 to 40% of variability is related to environmental factors such as diet, exercise, habits, diseases, conditions, and medications. A study of 668 healthy premenopausal women showed that low body weight, menarche at age 15 years or later, and physical inactivity as an adolescent were independent predictors of low bone mass by both DXA and quantitative ultrasonography. (27) Other studies of low BMD in premenopausal women have identified cigarette smoking, low body mass index, and ethnicity (white, Asian) as risk factors. Patients with congenital disorders, such as osteogenesis imperfecta and cystic fibrosis, are now being more successfully managed in childhood, so that more of them are reaching adulthood with low peak bone mass.

Premenopausal women are subject to increased risk of low bone density due to the same conditions, diseases, and medications that affect postmenopausal women (Table 2). In a small study (28) of women diagnosed with premenopausal osteoporosis who were seen in a rheumatology clinic for reasons other than inflammatory joint disease, 65% had identifiable contributing factors. These included hypercalciuria, Cushing syndrome, pregnancy, osteogenesis imperfecta, and malabsorption. Female athletes with amenorrhea and young women with anorexia nervosa are at high risk for low peak bone mass with subsequent development of osteoporosis (29) and fractures. (30) Celiac disease is an often-overlooked cause of calcium and vitamin D malabsorption that is associated with osteoporosis. In a study of 13,145 subjects in the United States, the prevalence of celiac disease was 1:133 in not-at-risk groups and 1:39 in those with osteoporosis. (31) It is commonly a silent disease, with only 35% of newly diagnosed subjects having chronic diarrhea.

Hormonal contraception with depot medroxyprogesterone acetate is associated with increased markers of bone resorption (32) and decreased BMD. (33) These appear to be dosedependent (34) and duration-dependent relationships that are greatest in young women who start it before peak bone mass is attained. (35) The negative bone effects of depot medroxy-progesterone may be partially reversible after discontinuation. (36) Tamoxifen, which can prevent bone loss in postmenopausal women, is associated with bone loss in premenopausal women. (37) Premenopausal women treated for endometriosis with gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide, may lose BMD. (38) Bone effects of GnRH agonists are of particular concern in young women who have not yet attained peak bone mass. (39) Anticonvulsant therapy is associated with low BMD. (40) This has best been studied with phenytoin, phenobarbital, and carbamazepine, which may cause vitamin D deficiency due to up-regulation of cytochrome P-450 hepatic enzymes, and with valproic acid, which acts through unknown mechanisms. (41)

Evaluation

In premenopausal women with low BMD, genetic and lifestyle factors associated with low bone mass should be considered. The patient should be asked about family history of osteoporosis and fractures, personal history of fractures, personal history of skeletal or dental deformities, previous history of skeletal surgery, loss of height, age of menarche, oligomenorrhea, amenorrhea, eating disorders, nutrition, smoking, birth control methods, organ transplantation, gastrointestinal dysfunction, thyroid disease, exposure to high-risk medications, and previous bone density tests. Physical examination has limited utility, but helpful findings to note are height (measured with a stadiometer), weight, nutritional status, balance and strength (heel-to-toe walk, "get up and go" test (42)), joints (inflammatory arthritis, hyperelasticity), and sclera (blue sclera with osteogenesis imperfecta). DXA studies should be performed and interpreted by qualified personnel. Radiologic studies should be considered for those with suspected structural abnormalities of the skeleton. Laboratory studies can be divided into those that should be done in almost all patients, those that should be done on most patients, and those that are done on some patients (Table 3). Measurement of markers of bone turnover may help to identify women with high bone turnover who are at risk for rapid bone loss. Although most cases of low BMD can be managed well by the primary care physician, consultation with an osteoporosis specialist should be considered if there are unusual circumstances (Table 4). (3) The workup should be customized to suit the clinical setting, the concerns of the patient, and the skill level of the health care provider.

Perimenopause 

The years immediately before the cessation of menses and the year after cessation of menses are called perimenopause. Hormonal instability during these years may result in menstrual irregularities; symptoms such as hot flashes, night sweats, and vaginal dryness; abnormal hormone levels such as elevated follicle-stimulating hormone and low estradiol; and loss of bone density associated with an increase in biochemical markers of bone metabolism. (43,44) Unfortunately, no one symptom or test can reliably diagnose perimenopause. It has been suggested by some that the diagnosis be based on menstrual history and age. (45) In women who have had a simple hysterectomy, menstrual history is not available and age may be an unreliable marker of perimenopause. Perimenopausal bone loss is a particular concern for women with low peak bone mass. At this time, there are no consensus guidelines for bone density testing or biomarker screening in perimenopausal women, nor are there guidelines for treating low bone density if it is found. Pharmacologic intervention in this group is complicated by a small but real possibility of pregnancy in women who have an intact uterus.

Treatment

Prevention is always preferable to treatment. A healthy lifestyle, beginning early in life, with particular attention to adequacy of calcium, vitamin D, and exercise, may help to maximize peak bone mass and slow the inevitable bone loss that occurs with aging. Lifestyle measures to improve peak bone mass may help to prevent osteoporosis later in life. Indeed, there is evidence that calcium supplementation, (46) vitamin D supplementation, (47) and weight-bearing exercise (48) in infancy or childhood can have beneficial effects on bone density and bone geometry. Exercise in premenopausal and postmenopausal women has been shown to have beneficial effects on bone density as well. (49) Patients often need reassurance that their low bone density may be largely of genetic origin, as is height or eye color; that absolute risk of fracture is probably very small; and that they can lead full and active lives.

Diseases, conditions, and medications associated with osteoporosis should be identified and treated when possible. Patients with celiac disease may have large increases in BMD and reduction in markers of bone turnover in response to a gluten-free diet. (50) Pharmacologic doses of vitamin D may be required in patients with anticonvulsant bone disease due to impaired vitamin D metabolism. Large doses of calcium and vitamin D, sometimes given parenterally, may be necessary in patients with other malabsorption states. Parenteral bisphosphonate therapy has been shown to benefit children and adolescents with osteogenesis imperfecta, thereby allowing them to enter adulthood with improved peak bone mass. (51) Pharmacologic therapy in premenopausal women is indicated for the prevention and treatment of glucocorticoid-induced osteoporosis, (52) and perhaps for very low BMD or documented fragility fractures. The long-term effects of pharmacologic therapy in premenopausal women are unknown. There is particular concern with bisphosphonate therapy in women of childbearing potential, because the long bone half-life of these medications may result in fetal exposure, with unknown consequences, many years after medication is discontinued. The temptation to use pharmacologic therapy for a condition that may be due to low peak bone mass with low absolute risk of fracture should be resisted until more supporting data become available.

There is evidence that low-dose oral contraceptives may reduce bone turnover and stabilize BMD in women who are in the late reproductive or perimenopausal years. (53,54) The effect of oral contraceptive use in younger premenopausal women on BMD later in life is less clear, with some studies showing improved BMD (55) and others showing lower BMD. (56) The data are mixed regarding oral contraceptives and reduction of fracture risk, with some studies suggesting reduction of fracture risk (57) and others not. (58) Interpretation of the body of literature on oral contraceptives and bone disease is problematic due to differences in study design, the use of different types of oral contraceptives in varying doses, study subjects having different age ranges and hormonal status, different methods for measuring bone density, and lack of large randomized controlled trials. Hormone replacement "add-back" therapy may have a protective effect on bone for premenopausal women treated with GnRH agonists for endometriosis and premenstrual syndrome. (59) Despite the common practice of prescribing hormone replacement therapy to patients with anorexia nervosa and amenorrhea, there is no convincing evidence that this has a beneficial effect on BMD. (60)

Better clinical tools are needed to identify those premenopausal women with low BMD who are at the highest risk of fracture, and who are therefore possible candidates for pharmacologic therapy. With further study, it may be possible to establish intervention thresholds based on absolute fracture risk, as has been proposed for postmenopausal women. (61)

Conclusion

Low BMD (T-score < -1.0) occurs in approximately 15% of premenopausal women. Most of these women have low peak bone mass due to genetic and/or environmental factors. The relative risk of fracture may be elevated in premenopausal women with low BMD, but absolute fracture risk remains low in most cases. If the BMD is very low or there is a history of fragility fractures, a thorough evaluation for contributing diseases, conditions, and medications should be done. All correctable or avoidable factors should be identified and treated. Pharmacologic therapy is rarely indicated but may be helpful for the management of glucocorticoid-induced osteoporosis, some inherited diseases, and in those with extremely low BMD or fragility fractures. The long-term effects of pharmacologic therapy in young women are unknown. Potential adverse effects of therapy on fetal development should be considered. Further study is suggested to learn more about fracture risk in premenopausal women with low BMD, to develop methods for identifying those who are at high risk for fracture, and to evaluate the risks and benefits of pharmacologic therapy in this population.

Table 1. Common methods for expressing fracture risk (a)

Absolute fracture risk
  Definition: Incidence or prevalence rate of fracture for a specified
    time period.
  Application: Used for fracture risk reporting in some clinical trials.
    Proposed by some to replace T-score thresholds for therapeutic
    intervention.
  Comment: Usually given as 5-yr or 10-yr absolute risk.
  Example: An 80-yr-old woman with a T-score < -1.0 has a 14.6% 10-yr
    probability of hip fracture. (16) Absolute fracture risk in a
    healthy premenopausal woman with low bone mineral density is low
    compared to an elderly woman with the same bone density.
Relative fracture risk
  Definition: Ratio of absolute fracture risks for two groups per SD
    change in bone mineral density.
  Application: Most common method for expressing fracture risk in
    clinical trials.
  Comment: This is an intuitive but sometimes misleading way of
    expressing fracture risk to patients. A high relative risk may not
    be clinically important if the absolute risk remains small.
  Example: In postmenopausal women, the relative risk of hip fracture
    increases by a factor of 2.6 for every 1 SD decrease in femoral neck
    bone mineral density. (14) If the same relative risk is applied to
    healthy premenopausal women with low bone mineral density, it may
    appear that fracture risk is high, although absolute fracture risk
    is likely to be low.
Lifetime fracture risk
  Definition: The risk of fracture during the expected remaining
    lifetime for a person at a specified age.
  Application: Primarily used with statistical modeling for public
    health care planning.
  Comment: Lifetime risk usually decreases as age increases, due to
    decreased life expectancy.
  Example: A 50-yr-old white woman has a 40% lifetime risk of fracture
    of the hip, spine (clinical fracture), or forearm. (13) A 30-yr-old
    woman would be expected to have a lifetime risk the same or slightly
    higher.

(a) Any of these methods may be used to show "global" risk (the risk of
any type osteoporotic fracture) or "site-specific" risk (the risk of
fracture at a specified skeletal site.

Table 2. Possible causes of low bone density (a)

Inherited                Nutritional            Endocrine

Osteogenesis imperfecta  Malabsorption          Hypogonadism
Homocysteinuria          Chronic liver disease  Hyperthyroidism
Marfan syndrome          Alcoholism             Cushing syndrome
                         Calcium deficiency     Hyperparathyroidism
                         Vitamin D deficiency   Anorexia nervosa

Medications      Other

Glucocorticoids  Multiple myeloma
Anticonvulsants  Rheumatoid arthritis
Heparin          Mastocytosis
Excess thyroid   Immobilization
GnRH agonists    Hypercalciuria

(a) GnRH, gonadotropin-releasing hormone.

Table 3. Laboratory evaluation of low bone density (a)

All patients          Many patients         Some patients

Complete blood count  24-h urinary calcium  Intact PTH
Calcium               25-OH-vitamin D       24-h urinary free cortisol
Phosphorous           Celiac antibodies     Follicle-stimulating hormone
Creatinine                                  Prolactin
Thyroid-stimulating                         Serum protein
  hormone                                     electrophoresis
Urinalysis                                  Urine protein
                                              electrophoresis

(a) PTH, parathyroid hormone.

Table 4. When to refer to an osteoporosis specialist (a,b)

Referral to an osteoporosis specialist is appropriate when the patient
  is in any of the following circumstances:
1. Has osteoporosis that is unexpectedly severe or has unusual features
   at the time of initial assessment
     Has very low BMD (a T-score < -3.0 or a Z-score < -2.0)
     Has osteoporosis despite young age (premenopausal)
     Has fractures despite borderline or normal BMD
2. Has a suspected or known condition that may underlie the osteoporosis
   (eg, hyperthyroidism, hyperparathyroidism, hypercalciuria, Cushing
   syndrome, or hypogonadism)
3. Is a candidate for combination therapy
4. Is intolerant of approved therapies
5. Fails to respond to treatment
     Takes estrogen yet has low baseline BMD
     Is undergoing treatment yet shows an apparent loss of BMD on serial
     studies
     Has fractures on treatment

(a) BMD, bone mineral density.
(b) Adapted from Hodgson et al. (3)

Acknowledgment

I thank Lance A. Rudolph, MD, for manuscript review.

Accepted April 22, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0544

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RELATED ARTICLE: Key Points

* Low bone mineral density (BMD) (T-score < -1.0) is present in approximately 15% of premenopausal women.

* Most premenopausal women with low BMD have low peak bone mass because of genetic and/or environmental factors.

* Premenopausal women with fragility fractures or extremely low BMD should have a thorough medical evaluation for contributing diseases, conditions, or medications.

* Pharmacologic therapy is rarely indicated in premenopausal women with low BMD.

E. Michael Lewiecki, MD, FACP 

From the New Mexico Clinical Research & Osteoporosis Center, Inc., Albuquerque, NM.

Reprint requests to E. Michael Lewiecki, MD, FACP, Osteoporosis Director, New Mexico Clinical Research & Osteoporosis Center, Inc., 300 Oak Street NE, Albuquerque, NM 87106. Email: [e-mail]