Amenorrheic Bone Loss1
Karen K. Miller and
Anne Klibanski
Neuroendocrine Unit, Department of Medicine, Clinical Research
Center, Massachusetts General Hospital and Harvard Medical School,
Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 457B, Boston, Massachusetts 02114.
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Introduction
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THE ASSOCIATION between postmenopausal
estrogen deficiency and osteoporosis has been clearly established for
many decades. In addition, congenital disorders causing estrogen
deficiency, such as Turners syndrome or Kallmans syndrome, may
affect bone mineralization. The deleterious effects of acquired
functional estrogen deficiency on bone metabolism in young women has
only more recently been recognized. Secondary amenorrhea is a common
disorder, and more than 4% of premenopausal women experience episodes
of amenorrhea lasting more than 3 months (1). Estrogen deficiency in
approximately 55% of these women is attributable to hypothalamic
amenorrhea, a state of acquired GnRH dysregulation, including
hyperprolactinemia, which induces a state of functional menopause. (2)
In addition, premature ovarian failure due to autoimmune disease or
secondary to chemotherapy is increasingly diagnosed.
The effects of estrogen deficiency on bone are characterized by an
acceleration of bone turnover with a disproportionate augmentation of
resorption compared with formation (3). Trabecular bone is typically
affected more than cortical. Although the precise means by which
estrogen deficiency causes increased bone turnover is not known,
possible mechanisms include a direct effect on osteoblasts via estrogen
receptors (4, 5, 6, 7); increased osteoclastic activity due to local
bone-resorbing cytokines such as interleukin-1, interleukin-6, and
tumor necrosis factor (8, 9, 10, 11, 12, 13, 14, 15); and an increased skeletal vulnerability
to the effects of PTH (16). This review will focus on the
pathophysiology of osteoporosis associated with premenopausal estrogen
deficiency in women with secondary amenorrhea (Table 1
).
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Acquired GnRH deficiency
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Hyperprolactinemia, excessive exercise, stress, undernutrition,
and anorexia nervosa are all causes of functional acquired GnRH
deficiency and are associated with osteopenia. Functional GnRH
deficiency is characterized by a wide spectrum of disordered GnRH
secretion leading ultimately to ovarian dysfunction and deficiency of
gonadal steroids. The most prevalent pattern of GnRH secretion, as
demonstrated by frequent LH sampling, is a reduced frequency of
pulsations (17). However, several other patterns of GnRH pulsatility
have been documented and include frank apulsatility, recapitulation of
puberty with pulsation occurring at night only (documented in some
women with anorexia nervosa), decreased pulse amplitude, and a pattern
of pulses seen normally in the early follicular phase (17, 18, 19). These
disparate pulsatility patterns all result in a lack of
folliculogenesis, progression to anovulation, and consequent gonadal
steroid deficiencies resulting in osteopenia. In other women with
organic sellar or central nervous system disease, including pituitary
tumors and radiation damage, structural abnormalities may be present
affecting GnRH and/or gonadotropin secretion. Finally, the use of GnRH
agonists for the treatment of endometriosis, uterine fibroids, and
other disorders has resulted in iatrogenically induced estrogen
deficiency.
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Hyperprolactinemia
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Hyperprolactinemic amenorrhea was the first identified model of
functional hypogonadal osteoporosis and is associated with a 17%
decrease in cortical (20) and a 1530% decrease in trabecular
(21, 22, 23) bone density. The importance of estrogen deficiency in the
pathogenesis of bone loss in these young women was demonstrated by
Klibanski et al., who showed that spinal bone mass was
significantly lower in amenorrheic hyperprolactinemic women than that
in their eumenorrheic counterparts despite similar elevations in PRL
levels (24). In addition, patients with a longer duration of amenorrhea
tend to have lower bone density (25). Factors other than menstrual
status also contribute to the pathogenesis of bone loss in this
population. As has been suggested in studies of women with premature
menopause, obesity may be protective against osteopenia. In one study,
a small subgroup of hyperprolactinemic amenorrheic women, 120125% of
ideal body weight, had normal cortical bone density, although their
thinner counterparts demonstrated significant bone loss (25). Moreover,
a significant correlation between spinal bone density and serum
dehydroepiandrosterone sulfate levels has been reported in
hyperprolactinemic women and raises the possibility that adrenal
androgens play a role in the maintenance of normal bone mass in women
(24).
If untreated, bone loss progresses in patients with hyperprolactinemic
amenorrhea. Biller et al. found that spinal bone density
decreased significantly in a group of hyperprolactinemic women who
remained amenorrheic over a period of 1.7 ± 0.2
(±SEM) yr and resulted in a bone density more than 2
SD below the control mean in 42% of the group. However,
restoration of normal menstrual function with dopamine agonist therapy
results in an increase in bone density in most, but not all, women
treated (Fig. 1
) (26). The largest
increases in bone density occur during the first 612 months of
therapy, and bone density may not return to normal, even after several
years of normal menstrual function (25, 26). Therefore, a significant
number of women with a history of hyperprolactinemic amenorrhea may
enter the menopause with preexisting osteopenia. These data support the
hypothesis that a history of amenorrhea may be associated with a
permanent increased fracture risk despite resumption of menses. The
finding of osteopenia in these young women established amenorrhea as an
important indication for lowering PRL levels sufficiently to restore
ovulation. If dopamine agonist therapy is not effective or not
tolerated, estrogen therapy or surgery can be considered. Estrogen has
been shown to increase PRL messenger ribonucleic acid transcription
in vitro (27, 28) and, in the setting of pregnancy, has been
shown to increase prolactinoma size in a small subset of patients with
microadenomas and in up to 15.5% of patients with macroadenomas (29).
However, these data demonstrated an increase in tumor size in the
setting of endogenous estrogen levels during pregnancy that are
severalfold higher than those in nonparous women. Preliminary data have
not shown a deleterious effect of estrogen replacement on tumor size in
young amenorrheic women treated with estrogen replacement (30).
However, the long term effects of estrogen replacement on
hyperprolactinemic women with microadenomas remain unknown at this
time.

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Figure 1. Bone density of the radial shaft in 32 women
with hyperprolactinemic amenorrhea. Values for group 1 patients are
shown before and after treatment for hyperprolactinemia; the
solid bars represent the mean bone density, which
increased significantly (P < 0.001) after
treatment. Values for group 2 patients are shown before and after
longitudinal follow-up without therapy; bone density decreased
significantly (P < 0.002) in this group.
(Reprinted with permission from New England Journal of
Medicine, 315:544, 1986.)
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Hypothalamic amenorrhea
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Functional hypothalamic amenorrhea due to excessive exercise or
stress has been demonstrated to be associated with a reduction in
trabecular and, to a lesser degree, cortical bone density. One third of
women who have been amenorrheic for at least 6 months due to weight
loss, without anorexia nervosa, or stress have a vertebral bone density
of 2 SD or more below the mean (31). Three to 66% of
female athletes are affected by amenorrhea, depending on the type of
exercise, intensity, duration, and the athletes nutritional status
(32, 33, 34). Although some studies suggest that weight-bearing bones may
be less severely affected than other parts of the skeleton in athletes
(35, 36, 37), bone density is markedly reduced below age-matched norms even
at weight-bearing sites in women who exercise enough to induce
amenorrhea (21, 36, 38, 39, 40, 41). Vertebral bone density is significantly
lower in these amenorrheic athletes compared with that in their
eumenorrheic counterparts (32, 38, 39). Drinkwater et al.
compared 14 amenorrheic athletes to 14 eumenorrheic athletes of similar
age, weight, percent body fat, height, and age of menarche and found
lumbar bone density to be 14% lower in the amenorrheic athletes,
whereas distal radial measurements did not differ between the groups.
The mean vertebral bone density in the amenorrheic athletes (mean age,
25 yr) was equivalent to that of the average woman of 51.2 yr of age
(38). Warren et al. studied 51 classical ballet dancers,
ages 1329 yr, half of whom were amenorrheic. She found that bone
density was significantly lower in amenorrheic dancers compared with
that in their eumenorrheic counterparts at 2 weight-bearing sites, the
spine and metatarsal, even after controlling for age. After controlling
for weight, the difference between the groups disappeared in the spine,
but not in the metatarsal (41). Moreover, amenorrheic athletes are at
increased risk for the development of stress fractures. Warren et
al. studied 75 professional ballet dancers, ages 1836 yr, and
reported that the incidence of stress fractures was twice as high among
dancers with amenorrhea as in those with regular periods (42). Stress
fractures have also been shown to be more common in amenorrheic women
runners compared with runners who cycle regularly (36). In contrast to
anorexia nervosa, spinal compression fractures have not been reported
in young women with hypothalamic amenorrhea due to exercise or stress,
emphasizing the importance of nutritional factors in patients with
amenorrhea due to weight loss.
The importance of weight as a determining factor of spinal bone density
in the study by Warren et al. (41) underscores the
significant contribution of body composition and nutritional factors in
the pathogenesis of hypothalamic amenorrhea and amenorrheic bone loss,
particularly in athletes. This is reflected in the term female athlete
triad, which has been used to refer to the disordered eating,
amenorrhea, and osteopenia that is commonly observed in female athletes
attempting to excel at sports (34, 43, 44). The work by Frisch and
McArthur in the 1970s was the first to demonstrate a possible weight
threshold necessary for normal menstrual function (45). Later studies
demonstrated that bone density correlates with weight (46, 47) and that
low body weight is associated with an increased risk of fractures (48)
in premenopausal women with normal menstrual function.
Evidence that estrogen deficiency is involved in the pathogenesis of
bone loss in hypothalamic amenorrhea includes a positive correlation of
bone density with duration of amenorrhea, a negative correlation with
estradiol levels, and a disproportionate loss of trabecular bone, as in
postmenopausal osteopenia (31, 49, 50). Lack of other ovarian hormones,
such as testosterone, may also play a role in the pathophysiology of
osteopenia in this population. Women with hypothalamic amenorrhea have
lower serum free testosterone levels than those in age-matched controls
(24). Moreover, a correlation between spinal bone density and free
testosterone levels has been demonstrated in women with hypothalamic
amenorrhea (31) as well as in larger studies of eumenorrheic
premenopausal women (51, 52), suggesting a possible role for androgens
in the maintenance of bone mass in premenopausal women and for androgen
deficiency in the pathophysiology of bone loss in hypothalamic
amenorrhea.
Hypercortisolism may also contribute to bone loss in this population.
Subclinical hypercortisolism is prevalent in women with hypothalamic
amenorrhea (18, 53, 54). Depression, which is also characterized by
subclinical hypercortisolism, is associated with osteopenia independent
of menstrual status (55). Cushings disease (56) and administration of
supraphysiological doses of glucocorticoids (57, 58, 59) are known to cause
severe osteopenia. Hypercortisolism-associated derangements in calcium
and vitamin D metabolism, including decreased osteoblastic activity,
decreased intestinal absorption of calcium, and increased urinary
calcium losses, have been described (60, 61, 62, 63, 64, 65, 66, 67), providing potential
mechanisms by which hypercortisolism may contribute to bone loss in
hypothalamic amenorrhea.
The timing of the onset of hypothalamic amenorrhea is extremely
important in determining its impact on bone density. Estrogen
deficiency in puberty is particularly devastating because adolescence
is a crucial time for bone formation and for eventual attainment of
peak bone density (68, 69, 70). Although genetic factors are important in
determining peak bone mass (71, 72, 73), hormonal factors clearly play an
important role. Delayed menarche and amenorrhea during adolescence are
associated with decreased peak bone mass, reflecting a critical window
in time during puberty when adequate gonadal steroids are essential for
the attainment of peak bone mass. A strong correlation has been
demonstrated between the age of menarche and fracture development in
professional dancers, with close to 90% of women who had menarche
later than 17 yr of age sustaining fractures (Fig. 2
) (42). In a later study of 51 classical
ballet dancers, aged 1329 yr, age of menarche was the only variable
that correlated with the occurrence of stress fractures (r = 0.28;
P < 0.004). Moreover, the age of menarche in dancers
with stress fractures was significantly higher than that in dancers
without stress fractures (15.2 ± 2.62 vs. 13.8 ±
1.9 yr; P < 0.02) (41).

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Figure 2. Relationship between age at menarche and the
percentage of subjects with fractures and stress fractures (n =
75). (Reprinted with permission from New England Journal of
Medicine, 314:1351, 1986.)
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Untreated hypothalamic amenorrhea is associated with progressive bone
loss during the first 5 yr of amenorrhea, after which the rate of bone
loss may significantly decline, as demonstrated by Biller et
al. in a prospective evaluation of 17 women, aged 2042 yr, with
hypothalamic amenorrhea (31). However, Drinkwater et al.
documented a 6.2% increase in vertebral bone density in a mean
follow-up of 14.4 months after the resumption of menses in 7 athletes,
in contrast to 2 athletes who remained amenorrheic and continued to
lose bone (74). However, bone density did not return to normal (74),
and an extended follow-up of a larger cohort would be necessary to
determine whether normal bone density for age is eventually achieved.
Estrogen therapy is routinely prescribed for young women with acquired
GnRH deficiency because of its theoretic benefits in reducing bone
turnover, as has been demonstrated in postmenopausal estrogen
deficiency. Definitive prospective studies of the effects of estrogen
therapy on bone in women with hypothalamic amenorrhea have not been
conducted. However, a small retrospective series of 8 women with
exercise-induced amenorrhea treated with estrogen replacement therapy
for 2436 weeks showed an increase in vertebral and femoral neck bone
density compared with that in women not receiving hormone replacement
(75). In addition, one randomized, prospective study of 24 women with
hypothalamic amenorrhea demonstrated an improvement in lumbar spine and
total body bone mineral density after 12 months of oral contraceptives
compared with those after placebo treatment (76). Medroxyprogesterone
(10 mg/day) for 10 days a month for 12 months was shown in one double
blind, placebo-controlled study to be associated with an increase in
spinal bone density in premenopausal women (77). Bisphosphonate therapy
has not been studied in premenopausal women, and neither benefits nor
risks specific to this population, including potential deleterious
effects on fetal development and long term effects on skeletal
mineralization, are known. Further study is needed to determine optimal
therapy in this population.
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Anorexia nervosa
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Anorexia nervosa is associated with acquired GnRH deficiency and
LH secretory patterns that resemble those of prepubertal and pubertal
children (19). The osteoporosis associated with anorexia nervosa is
more severe than that seen in other groups with premenopausal estrogen
deficiency, probably reflecting the effects of undernutrition itself on
bone formation and/or resorption. Unlike other forms of premenopausal
osteoporosis, fractures at a variety of skeletal sites are common, with
a 7-fold increase in the risk of developing nonspinal fractures
compared with that in age-matched women (78). The majority of women
with anorexia nervosa have evidence of bone loss, and 50% of women
with anorexia nervosa have bone densities more than 2 SD
below age-matched means (79, 80, 81). Biller et al. reported an
average bone density in 19 young women with anorexia nervosa comparable
to that in an average postmenopausal woman in her seventh or eighth
decade (31). Although both cortical and trabecular bones are affected,
trabecular bone loss is more severe (82). Vertebral bone density has
been reported to be as much as 32% below control values in adult women
with anorexia nervosa (79, 80, 83, 84, 85, 86, 87), whereas radial bone density is
reduced up to 18% below control values (78, 79, 80, 81, 83, 87).
Evidence that estrogen deficiency is important in the pathophysiology
of osteopenia in this population includes the fact that amenorrhea is a
nearly universal feature of anorexia nervosa and the observation that
bone density correlates with the duration of amenorrhea (79, 80, 88).
Undernutrition and insulin-like growth factor I deficiency almost
certainly contribute to the increased severity of the osteopenia in
this population compared with that in other states of estrogen
deficiency (80, 89, 90). The roles of increased cortisol levels,
decreased calcium and vitamin D intake, and excessive exercise are less
clear (78, 91, 92). Women who develop anorexia nervosa before age 18 yr
have significantly lower spinal bone densities than those who develop
amenorrhea later, independent of the duration of amenorrhea, consistent
with the severe impact of this disorder on bone accretion (79).
Although bone density increases with weight recovery and resumption of
menses, significant osteopenia may persist (Fig. 3
) (78, 93, 94, 95). Vertebral bone density
is reduced within 1 yr of diagnosis of anorexia nervosa; therefore,
early intervention is critical (80). Postmenopausal replacement doses
of estrogens have not been proven to reverse osteopenia in anorexia
nervosa. In a randomized controlled prospective study of 48 women with
anorexia nervosa, no significant increase in spinal bone density was
demonstrated after 1.5 yr of treatment with conjugated equine estrogen
(CEE; 0.625 mg) and provera compared with that in the control group. In
a subset of estrogen- and progestin-treated women less than 70% of
ideal body weight, there was a mean 4.0% increase in bone density
compared with that in controls of similar low weight who showed a
20.1% decrease in bone density. These data suggest that the response
to estrogen replacement therapy may differ according to weight and
disease severity, although the study was not designed to address this
question specifically (94). Surrogate markers of bone formation have
been shown to be decreased in this population (90), consistent with the
hypothesis that severe undernutrition may have a selective marked
deleterious effect on osteoblast function. Therefore, therapeutic
strategies to increase bone formation may have a particular rationale
in this population.

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Figure 3. A, Initial and final individual trabecular
bone density measurements in six women with anorexia nervosa who had
spontaneous resumption of menses. There was a significant
(P = 0.01) increase in bone density. B, Initial and
final individual trabecular bone density measurements in women with
anorexia nervosa who remained amenorrheic. These was a significant
(P < 0.0001) difference between the initial and
final bone density measurements. The shaded area
represents the normal mean bone density ± 1 SD. (Reprinted
with permission from Journal of Clinical Endocrinology and
Metabolism, 80:902, 1995.)
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Iatrogenic gonadotropin deficiency
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The increasing use of medications that induce hypoestrogenemia
through acquired gonadotropin deficiency have also been implicated as
causes of osteopenia in young women. GnRH agonist therapy, used to
treat severe endometriosis and uterine myomas, has been shown to be
associated with a decline in spinal bone density after 6 months of
therapy (96, 97, 98, 99, 100). The loss of trabecular bone density appears to be
nearly or totally reversible if treatment is limited to a 6-month
course (97, 100, 101). Moreover, use of add-back norethindrone (10
mg/day), norethindrone (2.5 mg/day) plus cyclical sodium etidronate,
norethisterone (1.2 mg/day), or postmenopausal doses of estrogen plus
medroxyprogesterone may reduce or arrest bone loss, although hormonal
add-back regimens may reduce the effectiveness of GnRH agonist therapy
(96, 98, 99, 102, 103). Progestin therapy, however, is associated with
a decrease in high density lipoprotein levels and an increase in low
density lipoprotein levels (96, 103). Finkelstein et al.
showed that intermittent PTH administration, an experimental therapy,
increases bone density in the spine 2.1 ± 1.1%
(±SEM) and prevents bone loss in the hip when used for 1
yr (104).
Despite the possible osteotropic effects of progestins (77, 105, 106),
long term use of depot medroxyprogesterone acetate may also lead to a
decline in bone density (107, 108, 109, 110), presumably by inducing a state of
estrogen deficiency. However, the possibility of other risk factors for
osteopenia in patients using depot medroxyprogesterone acetate has not
been excluded. In the largest study addressing the issue of depot
medroxyprogesterone acetate-induced bone loss, Cundy et al.
compared spinal bone densities of 200 women who had been using depot
medroxyprogesterone acetate for 226 yr with those in 350
premenopausal healthy controls and found that bone density was
significantly lower in the depot medroxyprogesterone acetate users. In
addition, women who had used depot medroxyprogesterone acetate for more
than 15 yr had lower z-scores than women who had used it for a shorter
time, implying that increased duration of use may result in more severe
bone loss. Moreover, women who starting depot medroxyprogesterone
acetate before the age of 21 yr had lower z-scores than their
counterparts who started later, possibly reflecting a negative impact
on attainment of peak bone mass (107). Although bone density increases
after discontinuation of depot medroxyprogesterone acetate, recovery
may not be complete. In a prospective study, the spinal bone densities
of 14 women were measured before and after discontinuation of depot
medroxyprogesterone acetate. Twelve months after discontinuation of the
contraceptive, there was a mean 3.0% increase in spinal bone density,
and after 24 months, bone density had increased a mean of 6.4%.
Nevertheless, even 24 months after cessation of depot
medroxyprogesterone acetate use, bone density remained 9.0%
lower than that in a group of 18 age-matched controls who had never
taken the medication (110).
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Ovarian failure
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Premenopausal bone loss associated with hypogonadism was first
recognized in women with a history of surgical oophorectomy (111). In a
study investigating the long term effects of oophorectomy in young
women, the identified decrease in bone density was accompanied by an
increase in fracture risk (112). It was later appreciated that the
premature onset of menopause from other causes, including autoimmune or
idiopathic (21, 49) and chemotherapy (113, 114, 115), results in a decline
in bone density. Bone loss from premature ovarian failure is becoming a
more important public health problem as an increasing number of women
in the premenopausal age group undergo chemotherapy for treatment of
malignancies. Some chemotherapeutic regimens result in a greater than
50% incidence of amenorrhea, primarily attributed to ovarian failure,
although hypothalamic amenorrhea has also been reported (116, 117, 118).
Although all bone compartments may be affected in women with premature
ovarian failure, trabecular bone is more severely reduced than cortical
bone, and this preferential bone loss has been identified in other
states of amenorrheic premenopausal bone loss (111). Cann et
al. demonstrated that women with premature ovarian failure have an
average vertebral bone density 21% below that of age-matched
eumenorrheic women (21). Obesity, however, may confer some protection
against bone loss. Although Bagur et al. confirmed
significant spinal and hip bone loss in 28 women with premature
menopause from a number of causes, including oophorectomy and
idiopathic cessation of menses, he also reported normal bone density
for age in a small group of obese women with a body mass index greater
than 30 kg/m2 (119). It is not clear what degree of obesity
may be necessary for maintenance of bone mass in the absence of normal
menstrual function, and this finding needs to be confirmed in a larger
population. Nevertheless, the fact that obesity may protect against the
bone loss associated with premature menopause raises the interesting
question of whether this effect derives from an increased conversion of
androgens to estrogens and/or from the mechanical effects of the weight
itself.
Although no large prospective randomized trials have been conducted, a
variety of small studies suggest that estrogen replacement therapy, in
doses shown to be of therapeutic benefit to older postmenopausal women,
may increase or prevent a decline in bone density in women with
oophorectomy and chemotherapy-induced premature ovarian failure
(120, 121, 122, 123, 124, 125, 126). In the largest prospective study, Prior et al.
randomized 41 oophorectomized women to receive CEE at a dose of 0.6
mg/day or medroxyprogesterone at a dose of 10 mg/day. CEE prevented
bone loss at the spine and hip, whereas those women receiving
medroxyprogesterone lost bone at all sites (Fig. 4
) (126). In women with premature ovarian
failure, CEE (0.625 mg/day) plus medroxyprogesterone (5 mg for 10 days
each month) prevented bone loss at the distal forearm compared with
that in a self-selected group of women who did not receive hormone
replacement therapy (120). A retrospective analysis reported that
lumbar bone density was higher in 12 oophorectomized women than that in
18 women who had not taken estrogen (123). Two other small uncontrolled
studies also reported an increase in spinal bone density with estrogen
therapy in women with premature menopause secondary to oophorectomy or
chemotherapy (121, 124). In the largest prospective observational
study, Byrd et al. followed 1,016 women, aged 2278 yr, who
had undergone oophorectomies and had been receiving estrogen therapy
for at least 3 yr for a total of 14,318 patient-yr. The majority of
these women were taking 1.25 mg/day CEE. The researchers reported a
lower incidence of forearm fractures than expected as determined by
previously published data using age-matched women (122). For women with
chemotherapy-induced ovarian failure and estrogen-responsive tumors,
estrogen therapy is typically contraindicated. Selective estrogen
agonist-antagonists and bisphosphonates have been shown to be of
therapeutic benefit in postmenopausal women with estrogen
deficiency-associated bone loss (127, 128, 129, 130) and may have a role in this
population, but to date they have not been tested in premenopausal
women.

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Figure 4. Six- and 12-month percent change
(±SD) in bone density after premenopausal ovariectomy,
determined by dual energy x-ray absorptiometry in the femoral neck by
randomized blinded therapy with CEE (0.6 mg/day) or medroxyprogesterone
acetate (MPA; 10 mg/day). Annual bone loss was not significant during
CEE treatment, but was significant at all sites during MPA therapy. At
12 months, bone density was different between CEE- and MPA-treated
women (P = 0.02). (Reprinted with permission from
Journal of Bone and Mineral Research, 12:1856 1997.)
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Other causes of osteopenia in premenopausal women
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This review focuses on osteopenia associated with estrogen
deficiency due to secondary amenorrhea. However, other etiologies
should be contemplated when considering the differential diagnosis of
premenopausal osteopenia in amenorrheic women. These fall broadly into
two categories: medication use and systemic illness. A common cause of
osteopenia in this population is glucocorticoid administration. The
incidence of atraumatic fractures in patients receiving long term
glucocorticoid therapy is 3050% (57, 58, 59). Moreover, regular use of
inhaled steroids for asthma can result in a dose-related reduction in
bone density (131). Glucocorticoids decrease osteoblast activity and
intestinal calcium absorption and may have effects on calcium
regulatory hormones (58, 61). Animal studies suggest that secondary
hypogonadism may also contribute to the osteopenia seen in
glucocorticoid-treated patients (132). Although every other day steroid
regimens may help preserve the hypothalamic-pituitary-adrenal axis,
they do not appear to protect the skeleton (133). Cyclosporine A causes
increased bone turnover and severe osteopenia in rats (134, 135). When
added to glucocorticoid regimens in transplant patients, the risk of
osteopenia rises sharply, with one report of a 44% fracture rate in
less than 3 yr (136).
Other medications have also been implicated as causes of bone loss.
Anticonvulsants reduce bone density through their effects on vitamin D
metabolism (137, 138) as well as by directly affecting bone turnover
(139, 140, 141). Heparin administration is associated with a reduction in
bone density in premenopausal women, including pregnant women, and no
correlation with dose or duration of therapy has been demonstrated
(142, 143, 144, 145). Ethanol abuse has been shown to decrease bone formation
markers, but not bone density, in premenopausal women. (146).
Hyperthyroidism is known to be associated with osteopenia. Although
suppressive doses of levothyroxine appear to decrease bone density in
postmenopausal women not taking estrogen, prolonged levothyroxine
therapy does not appear to be associated with bone loss in eumenorrheic
premenopausal women (147).
Cushings syndrome, like glucocorticoid administration, results in
bone loss. The resultant osteopenia may be completely reversible with
cure of the syndrome (148, 149). Hyperparathyroidism is also associated
with bone loss. However, in contrast to osteopenia associated with
estrogen deficiency, cortical bone mass is preferentially lost (150).
Therefore, radial bone density determinations are of more use in
hyperparathyroidism than spine or hip density measurements. Treatment
of the underlying condition results in an 812% increase in bone mass
in the first 24 yr after surgery (151). Both childhood- and
adult-onset GH deficiencies are associated with a reduction in bone
density (152, 153, 154). GH treatment of patients with adult-onset GH
deficiency increases bone density (155, 156). However, there are few
data available regarding gender-specific effects of acquired GH
deficiency in young women and the relationship between GH deficiency
and gonadal steroids in this group.
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Conclusions
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The association of estrogen deficiency and bone loss in young
women is well established. Hypogonadism can be a result of premature
ovarian failure or acquired GnRH deficiency and results in a reduction
in bone density, with preferential trabecular bone loss. Estrogen
deficiency during puberty can impair the attainment of normal peak bone
density, thereby making women vulnerable to skeletal fractures earlier
in life due to abnormalities in bone accretion as well as bone loss. In
a eumenorrheic premenopausal woman with osteopenia, a number of
systemic diseases and medication use must be considered as possible
etiologies of the osteopenia. Because osteopenia in premenopausal women
is associated with considerable morbidity due to increased fracture
risk, both short term and later in life as the osteopenia progresses,
clinical awareness and further research in this area are clearly
needed. In addition, abnormal bone accretion in amenorrheic adolescents
makes evaluation particularly important in this age group. A better
understanding of the pathogenesis of bone loss in young amenorrheic
women will be critical in the development of early effective
therapeutic strategies to prevent permanent osteopenia.
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Acknowledgments
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The authors thank Dr. Joel Finkelstein for his helpful
comments.
 |
Footnotes
|
---|
1 This work was supported in part by NIH Grants M01-RR-01066 and
R01-DK-52625. 
Received November 20, 1998.
Revised February 4, 1999.
Accepted February 9, 1999.
 |
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