Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh

Management of osteoporosis in a pre-menopausal woman

Ashok K. Bhalla, MD, FRCP, Consultant Rheumatologist *
Royal National Hospital for Rheumatic Diseases, NHS Foundation Trust, Upper Borough Walls, Bath BA1 1RL, UK

Keywords:
There is no agreed definition of osteoporosis in pre-menopausal
Z-score women. The International Society for Clinical Densitometry
endocrine disorders recommends using Z-score, and women with Z-scores of 2.0 or
anorexia nervosa lower should be defined as having a bone density that is ‘below the
glucocorticoid-induced bone loss expected range for age’. The diagnosis is more readily made in the
primary hyperparathyroidism presence of a low-trauma fracture. The relationship between low
hyperthyroidism bone mineral density (BMD) in young pre-menopausal women and
diabetes mellitus
its associated fracture risk is not the same as in older women with
gastrointestinal disorders
a low BMD. Between 50% and 90% of pre-menopausal women will
liver disease and pancreatic insufficiency
transplantation osteoporosis have an underlying secondary cause, the most common being
drug-related osteoporosis eating disorders, anorexia nervosa and use of glucocorticoids.
pregnancy-associated osteoporosis Management should focus on identifying the underlying cause and
anti-resorptive therapy treating it where possible. The use of pharmacological therapy
anabolic therapy under other circumstances should be considered carefully. Women
with only low BMD and no other risk factors probably require no
pharmacological intervention. Those with low BMD and secondary
causes or with a severely low BMD, or those who have fragility
fractures, may require treatment with anti-resorptive agents,
which can include oestrogen, bisphosphonates, calcitonin, calci-
triol or anabolic therapy with teriparatide. Selective oestrogen
receptor modulators (SERMs) should be avoided as they cause
further bone loss in menstruating women. Alendronate and
risedronate have been licensed for use in glucocorticoid-induced
osteoporosis. These drugs accumulate in the human skeleton and
have been shown to cross the placenta and accumulate in newborn
rats. The effects on human pregnancy are unclear, although normal
pregnancies have been reported.
Pre-menopausal women with osteoporosis should be followed up
until the BMD is stable, which can usually be ascertained by
follow-up scans at 18–36-month intervals.
Ó 2010 Elsevier Ltd. All rights reserved.

* Tel.: þ44 1225 473443; Fax: þ44 1225 473437.

E-mail address: ashok.bhalla@rnhrd.nhs.uk

1521-6942/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.berh.2010.01.006
314 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

Osteoporosis in post-menopausal women has been well studied and documented, whereas that in
pre-menopausal or young women has received little attention due to the lower incidence of the
disorder and limited information to explain its aetiology.
Low bone mass in pre-menopausal women may result from a lower peak bone mass, bone loss after
the attainment of peak bone mass or a combination of the two.

Peak bone mass

This is largely genetically determined (80%) but lifestyle factors can contribute further to max-
imising the genetic potential. Peak bone mass is attained at the end of the second decade. Studies
indicate that body weight, physical activity and normal pubertal development act as independent
determinants of peak bone mass [1–4]. Calcium, vitamin D, mechanical loading and normal pubertal
development are probably the most important determinants not only of peak bone mass, but also of
bone strength and, when optimum, allow for the full genetic potential to be achieved.
Since peak bone mass has a Gaussian distribution, 14% and 2% of women will have values, which are
1 or 2 standard deviation (SD) below the mean. This does not necessarily mean that individuals at the
lower end of the distribution have increased risk of fracture, since the correlation between reduced
bone mass in pre-menopausal women and fracture risk is less robust than in post-menopausal women.

Definition of pre-menopausal osteoporosis

The diagnosis of osteoporosis in pre-menopausal women can be readily made in the presence of
a low-trauma fracture. However, there is no agreed definition of osteoporosis in pre-menopausal
women. In post-menopausal women, the presence of osteoporosis can be determined, in the
absence of a fracture, by assessing bone mineral density (BMD) T-scores. However, this World
Health Organization (WHO) criteria of bone density based on T-scores is not applicable to pre-
menopausal women and should not be used to categorise such women into normal, osteopenic
or osteoporotic groups. Furthermore, since the relationship between T-scores and fracture risk in
pre-menopausal women is less clear than in post-menopausal women, a conservative approach is
needed to arrive at a diagnosis even with low bone density to avoid unnecessary treatment. It is
thus important to have a clear idea when to undertake a BMD estimation in pre-menopausal
women. If BMD is to be measured, then the International Society for Clinical Densitometry
recommends using Z-scores [5]. Women with a Z-score of 2.0 or lower should be defined as having
a bone density that is ‘below the expected range for age’ and a Z-score of above –2.0 should be
categorised as ‘within the expected range for age’. The term ‘osteopenia’ should be avoided in this
age group and a diagnosis of osteoporosis is best made if a BMD is accompanied by a low-trauma
fracture(s). When interpreting BMD, it is important to bear in mind that body size and stature will
influence dual energy X-ray absorptiometry (DEXA) measurements, leading to an underestimation
of true volumetric bone density in people of short stature.

Assessment of fracture risk

In pre-menopausal women with a low BMD, the risk of fracture is not the same as in older women
with a low BMD because pre-menopausal women are oestrogen replete, have greater muscle mass,
thicker cortices, a normal trabecular connectivity, lower bone turnover and fewer falls compared to
post-menopausal women. While the short-term risk of fracture in pre-menopausal women with a low
Z-score, for example, –2.0 is low, the risk may be higher when other risk factors are present.
A low BMD in young women is associated with an increased risk of low trauma and stress fractures
compared with women with normal BMD, even though the relationship between BMD and fracture is
less clear in this age group [6,7].
The diagnosis of osteoporosis is often more secure when there is a history of minimal trauma
fracture and a low BMD.
In pre-menopausal women with a Colles fracture, the non-fractured radius[8] and the lumbar
spine[9] have significantly reduced BMD compared with matched, non-fracture controls. However,
 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327 315

BMD may not be reduced in some young women, especially those on high-dose glucocorticoids for
auto-immune disease [10].

Evaluation of pre-menopausal osteoporosis

In pre-menopausal women with low-trauma fracture or low BMD, an underlying cause is often present
that may have either affected the accrual of optimal peak bone mass, and/or led to increased bone loss
following attainment of peak bone mass. The prevalence of secondary causes may vary depending on the
setting and varies from 50% to 90%. Peris et al [12]. found that 44% of patients referred to an outpatient
rheumatology department had secondary osteoporosis and that 56% had idiopathic osteoporosis.
The most common causes of secondary osteoporosis in pre-menopausal women are shown in
Table 1 and the most important ones are discussed later. In most cases, a thorough medical history and
clinical examination will provide clues about the underlying secondary cause. The history should
include information about family history, previous fractures, onset of menarche, amenorrhoea or oli-
gomenorrhoea, pregnancy and duration of lactation, diet and exercise, gastrointestinal (GI) symptoms,
lifestyle behaviour and medication. An examination of the patient may provide additional clues such as
features of Cushing’s syndrome, height loss or a kyphotic deformity to indicate underlying vertebral
fractures, blue sclerae and hyperelasticity of skin and joints indicative of a connective tissue disorder
such as osteogenesis imperfecta. In those with suspected height loss or kyphosis, there may be a need
for spinal radiographs or DEXA-based vertebral fracture assessment. X-rays should be examined
carefully to see if the vertebral deformities identified represent a vertebral fracture or some other
pathology such as Scheuermann’s disease, which is not associated with an increased risk of fracture. In
many individuals, the history and examination may not offer sufficient clues, in which case it is
important to identify secondary cause by appropriate laboratory tests.

Laboratory tests

Since the occurrence of an underlying secondary cause is high, all young women with minimal
trauma fracture or low BMD with a Z-score of2.0 should be thoroughly evaluated with investigations
shown in Table 2. These will identify individuals with hyperthyroidism, hyperparathyroidism,
Cushing’s syndrome, hypogonadism, osteomalacia, malabsorption, liver disease, coeliac disease and
idiopathic hypercalcuria. If a secondary cause is not identified, a bone biopsy may be indicated in
pre-menopausal women with a history of low-trauma fracture. This may identify unsuspected causes,
such as mastocytosis, and provide clues about bone turnover.

Endocrine disorders, anorexia, eating disorders and amenorrhoeic states

Anorexia nervosa and bulimia have an onset at any time from adolescence through to the fourth
decade of life and are associated with a significant loss of bone mass. Bone density is reduced by more
than 2.5 SD at either the hip or the spine in 38% of women with anorexia nervosa and by more than 1 SD
in 92% of such patients [13]. The loss of bone mass observed in adult women with anorexia is probably
attributed to bone loss. Adult women having anorexia nervosa with disease onset in adolescence have
much lower bone mass than those with adult-onset anorexia nervosa due to an interference with the
normal process of bone mineral accretion, leading to a permanent deficit [14]. Several metabolic
disorders occur in anorexia nervosa that may adversely impact on the skeleton, which include defi-
ciencies in oestrogen, excessive endogenous cortisol production, reduced insulin-like growth factor 1
(IGF-1), protein/energy malnutrition and secondary hyperparathyroidism as a consequence of low die-
tary calcium or vitamin D intake. The degree of low bone mass found in women with anorexia nervosa is
more severe than that seen in women with hypothalamic amenorrhoea who are of normal height [15].
A number of studies, although not all, have suggested that, in anorexia nervosa, bone turnover
markers are characterised by a decrease in osteoblast function (bone formation) and an increase in
osteoclast function (bone resorption), suggesting that bone remodelling is uncoupled [15,16].Domi-
nguez et al. [16], in a longitudinal study, showed that osteocalcin concentration did not differ signif-
icantly from those in the control subjects but after nutritional rehabilitation there was a significant
316 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

Table 1
Secondary causes of osteoporosis.

Endocrine disorders
Amenorrhoea and eating disorders
Cushing’s Syndrome
Hyperthyroidism
Hyperparathyroidism
Hypogonadism
Type 1 Diabetes Mellitus
Vitamin D, Calcium and nutritional deficiency
Hypercalcuria

Gastrointestinal
Coeliac Disease
Inflammatory bowel disease
Malabsorption Syndrome
Severe liver disease

Marrow-related disorders
Amyloidosis
Leukaemia
Lymphoma
Multiple myeloma
Haemochromatosis
Sickle cell anaemia
Thalassaemia

Connective tissue disorders

Osteogenesis imperfecta
Marfan’s Syndrome
Ehlers-Danlos Syndrome
Hypophatasaia

Organ transplantation
Cardiac
Liver
Kidney
Lung

Inflammatory disorders
Rheumatoid arthritis
Ankylosing Spondylitis
SLE

Medication
Glucocorticoids
Immunosuppressants
Anti-epileptic drugs
Heparin
GnRH agonists
Chemotherapy
Thiazolidanediones
Lithium

Lifestyle
Female athlete Triad
Smoker
Alcohol

Idiopathic osteoporosis

increase in serum osteocalcin. In the same population, the resorption marker urinary N-terminal
telopeptides (NTX) was high in anorexic patients compared with controls at admission. Following
nutritional rehabilitation, there was a decrease in NTX concentration and the pattern observed was
that of an initial recovery in bone formation followed by suppression of resorption. Such a pattern
indicates that therapy with anti-resorptive agents, such as oestrogens, may not be effective in this
 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327 317

Table 2
Laboratory investigations.

Full blood count (FBC), ESR or plasma viscosity

Renal function
Serum calcium, phosphate
Liver function to include gamma-glutamyl transferase (GGT)
Thyroid function
Serum 25-hydroxyvitamin D
Coeliac screen
24 h URINE calcium excretion and cortisol

Additional tests sometimes needed:

PTH
FSH/LH, oestradiol, prolactin
Myeloma screen
Bone tumour marker

condition in the absence of appropriate nutritional therapy and explains why such women taking the
oral contraceptive pill continue to have fractures and fail to show a significant increase in bone density.
With regard to bisphosphonates, Miller et al [17]. administered a 9-month course of treatment with
risedronate to 10 adult women with anorexia nervosa and compared the results with published data
from 40 control women studied by the same group of investigators. They found an increase in the
lumbar spine (but not the hip) BMD in those subjects given risedronate, compared to a decrease in
controls. Golden et al [18]. conducted a double-blind randomised trial comparing alendronate 10 mg
daily with placebo in 32 adolescents with anorexia nervosa, all of whom received calcium and vitamin
D supplementation and multidisciplinary treatment for their eating disorder. Femoral neck and lumbar
spine BMD increased by 4.4% and 3.5%, respectively, in the alendronate group, compared with an
increase of 2.3% and 2.2%, respectively, in the control group. The authors observed that body weight
was the most important determinant of BMD and that BMD was significantly higher in subjects who
were weight-restored compared with those who remained at low weight. However, larger randomised
controlled trials are required to test the efficacy of bisphosphonates in anorexia nervosa and until they
have been done, and the long-term safety assessed, bisphosphonates should not be routinely used in
patients with anorexia nervosa.

Glucocorticoid-induced bone loss

The side effects from the use of glucocorticoids for long periods of time include weight gain, truncal
obesity, proximal myopathy, impaired healing, adrenal insufficiency, steroid withdrawal syndrome,
thinning of the skin with increased fragility and ecchymosis, fluid retention, hyperglycaemia, hypo-
kalaemia, hypertension, hyperlipidaemia, osteonecrosis, osteoporosis and fractures, particularly
vertebral fractures.
Glucocorticoid-induced osteoporosis is probably the most common iatrogenic form of osteoporosis
[19–21]

Mechanism of glucocorticoid-induced bone loss and fractures

Glucocorticoids have both a direct and an indirect effect on the skeleton. The direct effects on the
skeleton include those on the osteoblasts, osteocytes and osteoclasts. Glucocorticoids act on osteoblast
to reduce their number and function; the pool of cells available to differentiate into osteoblasts is
reduced and osteoblast maturation is impaired. These steroid hormones encourage bone marrow
stromal cells, the precursors of osteoblasts, to differentiate towards the adipocyte lineage. The
production of type 1 collagen by mature osteoblasts is decreased, leading to a reduction in bone matrix
available for mineralisation. In addition, glucocorticoids lead to apoptosis of osteoblasts and osteocytes
[22]. Apoptosis of osteocytes will disrupt the mechano-sensory role of these cells by disrupting the
osteocyte–canaliculi network, which repairs bone micro-damage.
318 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

The early direct response of glucocorticoids on mature osteoclasts is to increase osteoclast survival
by decreasing osteoclast apoptosis. This may account for the early enhanced bone resorption with
glucocorticoids [23]. The suggestion that osteoclast function may be increased by secondary hyper-
parathyroidism has not been confirmed [24].
The indirect actions of glucocorticoids, which may stimulate bone resorption, include loss of
gonadal function, reduced intestinal absorption of calcium by antagonising actions of vitamin D,
inhibition of renal tubular reabsorption of calcium leading to renal hypercalcuria, a decrease in growth
hormone (GH) and altered GH/IGF-1 axis.
Bone loss in glucocorticoid-induced osteoporosis is biphasic with a more rapid loss in the first year
followed by a slower annual loss. In the first 12 months of glucocorticoid exposure, bone loss is about
6–12% but may be as high as 20–30% in trabecular bone [25], which may explain why fractures are
more common in cancellous-rich bones such as the vertebral bodies, ribs and femoral neck. Patients on
long-term glucocorticoids have a normal distribution of BMD but with a mean value significantly less
than found in the normal population, indicating that all patients exposed to glucocorticoids are sub-
jected to some degree of bone loss.
Fractures in glucocorticoid-induced osteoporosis occur at higher BMDs than with post-menopausal
women [26], suggesting that bone quality is reduced. The early rapid loss of bone reduces trabecular
thickness and connectivity, which may not be reflected in BMD, and explains why there is no direct
relationship between BMD and fracture risk in glucocorticoid-induced osteoporosis [20].
The true prevalence of fractures in patients on glucocorticoids is not known but cross-sectional
studies indicate that 30–50% of patients taking glucocorticoids chronically will experience a fracture.
As in post-menopausal osteoporosis, vertebral fractures may remain asymptomatic.
Although fractures can occur early following the use of glucocorticoids, the incidence is also related
to the dose and duration of exposure [20]. There is probably no safe dose as an increase in vertebral
fracture is noted with prednisolone doses as low as 2.5 mg per day, but the risk is greater at higher
doses and with longer duration of use [20,25,27].

Management of glucocorticoid-induced osteoporosis

The use of glucocorticoids in certain clinical situations may be lifesaving and, therefore, obligatory;
however, the dose and duration should be kept to a minimum to reduce the potential toxicity asso-
ciated with these drugs. All individuals administered with glucocorticoids, including pre-menopausal
women, should be given adequate information about the reasons for the use of the drug, the side
effects and complications as outlined earlier and the need to carry either an Alert bracelet or a steroid
card if they are to be on long-term glucocorticoids.

(a) General measures: patients should be given advice about lifestyle factors, the need for weight-
bearing exercise and adequate calcium and vitamin D intake with supplementation if necessary.
(b) Specific therapy: primary prevention and treatment guidelines have been proposed by the Royal
College of Physicians and the American College of Rheumatology (ACR) [28,29]. The Royal College
of Physicians Guidelines recommend bisphosphonates in primary prevention in younger people
with a BMD T-score of less than 1.5 who are to be given oral glucocorticoids for 3 months or more,
irrespective of the dose. In addition, treatment is also recommended if serial BMDs show a loss of
BMD of >4% after 1 year. The ACR recommends primary prevention with bisphosphonate in
patients prescribed glucocorticoids for more than 3 months at a dose of prednisolone 5 mg or
equivalent. In addition, ACR guidelines recommend the use of bisphosphonates in all subjects with
a BMD T-score less than –1.0 on DEXA scanning.

Aminobisphosphonates are the most commonly used drugs in the primary or secondary prevention
of glucocorticoid-induced osteoporosis, which have been shown to have anti-fracture efficacy in
patients with an age range of 18–85 years. However, the number of pre-menopausal women in these
studies has been relatively small and the effect in this population is assumed to be similar to that
observed in the overall population.
 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327 319

Both risedronate 5 mg a day and alendronate 10 mg a day have been shown to prevent bone loss
and reduce vertebral fractures [30,31]. Individuals who cannot tolerate oral treatment, or where
oesophageal disease precludes the use of oral bisphosphonates, then intravenous therapy with
pamidronate, ibandronate or zoledronate can be considered. The use of bisphosphonates, however,
should be considered carefully in women of childbearing age and, where possible, a bisphosphonate
with the shortest half-life should be used. There is no evidence that calcium alone or active vitamin D
analogues either prevent fractures or preserve BMD [32].
Since glucocorticoid-induced osteoporosis is dominated by a reduction in bone formation, then
anabolic therapy with intermittent parathyroid hormone (PTH) would appear to be especially effective
and this has been shown to be the case in an 18-month trial of teriparatide versus alendronate, in
which teriparatide treatment group had fewer vertebral fractures compared with the alendronate
group (0.6% vs. 6.1%, p < 0.004). There were no differences in non-vertebral fractures between the
groups [33].

Other endocrine states

Primary hyperparathyroidism: calcium homeostasis is maintained by PTH through its action on target
tissues of bone and kidney. Primary hyperparathyroidism is a relatively common endocrine disease with
an incidence as high as 1 in 500 to 1 in 1000 and is usually asymptomatic [34]. Primary hyperpara-
thyroidism can occur in all ages but is more frequent in the sixth decade with a female:male ratio of 3:1.
The majority of women are post-menopausal. When primary hyperparathyroidism occurs in children or
younger adults, the possibility that it may be part of the spectrum of a genetic endocrinopathy, such as
multiple endocrine neoplasia type 1 or 2, should be considered. A number of skeletal disorders occur in
primary hyperparathyroidism and include osteiitis fibrosa cystica, where there is subperiosteal resorp-
tion of the distal phalanges, tapering of the distal clavicles, salt-and-pepper appearance of the skull,
brown tumours and bone cysts of long bones. The presence of such abnormalities is uncommon in
asymptomatic patients. However, osteopenia and osteoporosis are probably more common and are
probably the most recognised forms of bone disease in primary hyperparathyroidism.
Primary hyperparathyroidism can be caused from excessive secretion of PTH from one or more of
the parathyroid glands. In 80% of cases, there is a benign solitary adenoma and, in 15–20% of patients,
the cause is hyperplasia of all four parathyroid glands. Parathyroid carcinoma is a very rare disease
(<0.5% of cases).
At the bone level, there is an increase in bone turnover with increase in both osteoclast-mediated
bone resorption and osteoblast activity, leading to a loss of both cortical and cancellous bone.
Substantial loss of bone occurs at cortical rather than at cancellous sites. At the distal radius, an area
rich in cortical bone, bone density was less than 80% that of age- and sex-matched controls; by contrast,
lumbar spine bone density, reflecting cancellous bone, was relatively well preserved [25]. The risk of
fracture in untreated primary hyperparathyroidism is increased.
In 2002, a workshop at the National Institutes of Health (NIH) revised previous guidelines for the
management of asymptomatic primary hyperparathyroidism [35]. Surgery was recommended if there
was symptomatic disease such as overt bone disease or kidney stones, or if the patients had a life-
threatening episode of hypercalcaemia. Asymptomatic patients were recommended for surgery if
there was a significant elevation of serum calcium, marked hypercalcuria, in case of reduced renal
function by 30% compared with age- and sex-matched controls and if BMD was more than 2.5 SD below
young normal control subjects at any site. Patients less than 50 years were recommended for surgery as
they were at greater risk for progression of the hyperparathyroid disease.

Hyperthyroidism

In hyperthyroidism, or states of excessive thyroxine hormone replacement, there are more new
remodelling units with increased remodelling activity. There is stimulation of osteoblastic and oste-
oclastic activity with shortening of the remodelling cycle because of a decrease in the length of bone
formation resulting in an overall failure to replace resorbed bone adequately, leading to bone loss [25].
In thyrotoxicosis, there may also be an increase in the risk of fracture. Following treatment of the
320 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

underlying condition, the decrease in bone density may be reversed. The effects of over replacement of
thyroxine in a hypothyroid patient are unclear; however, with the availability of sensitive assays of
thyrotrophin secretion, this should occur infrequently.

Diabetes mellitus

In post-menopausal women with either type 1 or type 2 diabetes mellitus, there is an increased risk
of fracture [36]. In pre-menopausal women with stable type 1 diabetes mellitus, and who have reached
peak bone mass, most studies suggest a reduction in BMD, which would increase fracture risk [37].
There is no link between BMD and control of glycaemia. Other risk factors that may predispose to
fractures relate to the complications of the disorder such as vision impairment from diabetic reti-
nopathy and poor balance due to neuropathy, leading to an increased risk of falls.

Osteoporosis in gi disorders, liver disease and pancreatic insufficiency

Here, we discuss the impaired absorption of vitamin D, calcium and phosphate from the GI tract
observed in diseases of the GI tract and the liver result in bone loss. Although calcium absorption
occurs throughout the GI tract, the highest rates are in the duodenum. The absorption of calcium is
mediated by the active metabolite of vitamin D (1,25 hydroxyvitamin D), which controls a highly
efficient transcellular pathway. In many of these disorders, there may be secondary hyperparathy-
roidism, which will also accelerate cortical bone loss.

Bone disease and coeliac disease

This auto-immune and lifelong disease is associated with osteopenia, osteoporosis or osteomalacia,
or a combination of the three. Up to 50% of untreated adults may have a reduced BMD at the time of
diagnosis and a small minority may present with features of osteomalacia, including bone pain and
a proximal myopathy [38]. Routine biochemistry is usually normal, although, in some patients, there
may be reduced serum levels of calcium, vitamin D, reduced urinary calcium excretion and elevated
alkaline phosphatase. With the institution of a gluten-free diet, the biochemical abnormalities and
reduced BMD may improve [39]. Adherence to a gluten-free diet is critical, and, even then, there is
reduced fractional calcium absorption [40].

Inflammatory bowel disease

Reduced BMD has been documented in inflammatory bowel diseases such as Crohn’s disease and
ulcerative colitis. The incidence of osteopenia has been estimated to be 32% in patients with ulcerative
colitis, and 36% in those with Crohn’s disease. The incidence of osteoporosis is lower and estimated to
be 7% in those with ulcerative colitis and 15% in Crohn’s disease [41]. The pathophysiology of bone
disease is multifactorial, including the effects of inflammatory cytokines, intestinal malabsorption
caused by disease activity or intestinal resection, the use of glucocorticoids, failure to achieve
maximum peak bone mass when disease starts in childhood, malnutrition, immobilisation, low body
mass index, smoking and hypogonadism [42]. Most patients with Crohn’s disease are relatively young
with the peak incidence of the disease in the second and third decade. It is unclear how the various
factors that could account for low bone mass relate to a reduction in bone mass and fracture risk. There
is uncertainly about increased fractures in inflammatory bowel disease. Bowel resection, particularly
ileal resection, has been identified as the most significant risk factor for osteoporosis in Crohn’s disease
[43]. The prevention of bone disease requires being replete with vitamin D and minimising the use of
glucocorticoids, although, theoretically, the early use of high-dose glucocorticoids may dampen
cytokine-driven bone loss. Bisphosphonates may be effective in preventing bone loss and they are
adequately absorbed from the gut and retained in the skeleton in those patients with reasonably well-
controlled disease activity [44].
 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327 321

Pancreatic insufficiency

Such a status is seen after total pancreatectomy or in individuals with cystic fibrosis (CF). In children
and young adults with CF, reduced BMD not only may result from malabsorption due to pancreatic
insufficiency, glucocorticoids, hypogonadism, recurrent bacterial infections, immobility and lifestyle
behaviour, but also may lead to both failure to achieve maximum peak bone mass and increased loss of
bone mass after peak bone mass has been achieved. The management includes adequate vitamin D and
mineral replacement and lifestyle advice.

Marrow-related disorders

Disorders of the bone marrow will have a profound effect on cancellous and cortical bone. Increased
bone resorption in plasma cell dyscrasia is caused by an increase in bone resorbing cytokines such as
interleukin-1, tumour necrosis factor-alpha (TNFa) and lymphotoxin [25]. Osteoporosis is also seen in
leukaemia, lymphoma, haemachromatosis and systemic mastocytosis. Mast cells release various
mediators, which have the capacity to affect bone cells, particularly the osteoclasts. The skeletal
manifestations range from severe osteolysis or osteosclerosis to osteoporosis, with the latter being the
most frequent observation. Occasionally, osteoporosis may be the sole manifestation of mastocytosis
but it is usually seen with other manifestations of disease such as flushes and GI symptoms. The
diagnosis can be established by the histological examination of bone marrow biopsies and 24-h urinary
excretion of N-methyl histamine.

Transplantation osteoporosis

Organ transplantation is increasingly being used to treat end-stage renal, liver, heart, lung,
intestinal and many haematological disorders. Survival in the recipients of transplants has
improved with advances in transplantation techniques and immunosuppressive therapy. Transplant
recipients who survive can develop a number of long-term complications of transplantation, one of
which is bone disease. The pathogenesis of bone disease in transplantation is not completely
understood, with adverse effects on the skeleton occurring before and after organ transplantation.
Heart, renal, lung and liver failure each have their unique adverse influence on bone and mineral
metabolism; for example, chronic kidney disease is associated with some forms of renal osteo-
dystrophy, while patients with end-stage liver disease frequently have abnormalities of mineral
metabolism. Furthermore, end-stage heart failure can be associated with altered function of other
organs, such as the kidney, further exacerbating the bone disease. In addition to the underlying
failure of the organ, these diseases are often accompanied by other factors, such as poor nutrition,
limited mobility, weight loss, gonadal dysfunction and the use of medication as treatment, which
can adversely affect the skeleton, particularly glucocorticoids. Before renal transplantation, many
patients may suffer from secondary hyperparathyroidism and abnormal vitamin D metabolism,
which could contribute to bone loss. In children receiving a heart transplant, there may be failure to
attain peak bone mass. Pre-menopausal women may have reduced gonadal function, which would
lead to bone loss.
Following transplantation, bone loss may occur rapidly during the first 6 months, with an increase
in the risk of fracture, due to uncoupling of bone resorption and formation. Fractures occur at higher
levels of BMD than would be expected in otherwise healthy individuals. Drugs that contribute to this
bone loss include glucocorticoids and calcineurin inhibitors. In the period immediately after trans-
plantation, bone resorption increases (possibly related to calcineurin inhibitors such as cyclosporin)
and bone formation decreases (probably a specific effect of the high dose of glucocorticoids used in the
early stages to prevent rejection). As the prednisolone dose is reduced to below 5 mg day1, osteoblast
function recovers leading to a reversal of the suppressed bone formation. Both formation and
resorption now are coupled and, although, bone remodelling is generally elevated, the rate of bone loss
slows down and there may even be some recovery of BMD. However, if further increase of glucocor-
ticoids is required, then uncoupling may once occur with rapid bone loss and higher fracture rate.
322 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

Prevention of bone loss after transplantation

Prior to transplantation, BMD should be assessed, risk factors for osteoporosis identified, spinal X-
rays undertaken if indicated and vitamin D status and PTH evaluated. If indicated, thyroid and gonadal
function should be checked. Bone markers may also be helpful in assessing the severity of the meta-
bolic disease. Treatment should be instituted pre-transplantation and plans should be made for further
review and management post-transplantation. Pre-transplantation treatment should correct any
metabolic abnormalities identified, and weightage should be given to treatment with anti-resorptive
agents.
Following transplantation, therapy to prevent further bone loss should be instituted as early as
possible. The majority of drugs studied in the prevention of bone loss after transplantation during the
first year have focussed on the use of vitamin D and anti-resorptive therapy primarily with
bisphosphonates [45–47]. In general, patients should be given adequate vitamin D (400–800 units per
day) and calcium (1000–1500 mg day1). Where possible, the lowest dose of corticosteroids and
immunosuppressive agents should be used. In several studies, bisphosphonates have been shown to
prevent bone loss and reduce fracture incidence following transplantation. Vitamin D alone does not
appear effective. A number of trials have considered the role of calcitriol, which may prevent bone loss
at the proximal femur but treatment is associated with hypercalcaemia and hypercalcuria [46].
In a recent trial by Shane et al. [48], 149 patients were randomly assigned to receive either
alendronate (10 mg day1) or calcitriol (0.5 mg day1) within a month of transplantation. Estimates of
bone loss and the incidence of fractures in an untreated patient group was obtained from a reference
group of 27 prospectively recruited patients who received cardiac transplants within the same period
as the intervention group. At 1 year, both therapies reduced the percentage of bone loss at the lumbar
spine and the femoral neck, compared with the control reference group. The incidence of vertebral
fractures did not differ amongst the groups. Hypercalcaemia was more common in the group treated
with calcitriol.

Drug-related osteoporosis

Important drugs that may be associated with osteoporosis are shown in Table 1. This form of
iatrogenic bone loss remains an important cause of osteoporosis.
A number of immunosuppressants may lead to bone loss. Methotrexate, a drug commonly used in
inflammatory arthritis, has been associated with reports of increased numbers of lower limb stress
fractures. However, there is no adverse effect of methotrexate on BMD or the proliferation and
maturation of osteoblasts [49,50]. The use of calcineurin inhibitors (cyclosporin A and tacrolimus) has
been shown in animal models to increase turnover and cause rapid bone loss; but the data in humans
are unclear [47].

Anti-epileptic drugs

Several observational studies have shown increased rates of bone loss, reduced BMD and an
increase in fracture risk in individuals on anti-epileptic drugs [51]. The pathogenesis includes an
alteration in the metabolism of vitamin D, particularly 25-hydroxyvitamin D to other metabolites,
increased risk of falls and trauma during a seizure. Osteomalacia and rickets have very rarely been
reported in institutionalised children receiving long-term anti-convulsant therapy. It seems prudent
to offer calcium and vitamin D prophylaxis to all individuals on long-term anti-epileptic
medication.

Gonadotrophin-releasing hormone analogues

Gonadotrophin-releasing hormone (GnRH) analogues are used to treat endometriosis in pre-

menopausal women by causing acute oestrogen deficiency. Bone loss can be rapid within 6 months
of the use of such analogues. Bone loss may be prevented by teriparatide or with oestrogen/proges-
terone as ‘add back’ therapy [52,53].
 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327 323

Long-term use of heparin

Almost only used to prevent recurrence of thrombo-embolism during pregnancy, heparin has been
associated with increased rates of fracture risk. The mechanism of action for heparin remains to be
elucidated as some studies have implicated suppression of bone formation.

Thiazolidinediones (TZDs)

Widely used in type 2 diabetes mellitus, these drugs increase bone loss at the hip and fractures in
post-menopausal women and men. Whether a similar effect would apply in pre-menopausal women
remains to be determined.

Pregnancy-associated osteoporosis

Pregnancy- and lactation-associated osteoporosis is an uncommon disorder, which is characterised

by the occurrence of fragility fracture(s), most commonly involving the vertebral bodies, and which
occur either in late pregnancy or early post-partum. It presents with severe back pain and height loss
and is often not recognised because the back pain is put down to ligamentous laxity induced by
hormones of pregnancy. The disorder tends to occur more commonly in the primagravid women,
although a minority of women will have had previous uneventful pregnancies. The aetiology and the
management of pregnancy-associated osteoporosis are unclear. It is possible that some of these
women had low BMD prior to pregnancy and, in one report, there was a high prevalence of fracture in
the mothers of the affected women compared with controls [54]. In 50% of patients, symptoms started
in the post-partum period, whilst 41% had symptoms in the last trimester with 2% having symptoms at
delivery [55]. O’Sullivan et al [56]. reported that 10 out of the 11 women presented with low-trauma
vertebral fractures at a medium of 1-month post-partum. In nine cases, the fractures were multiple
and ranged from two to five. In nine of the 11 patients, there was at least one recognised risk factor for
osteoporosis such as low body weight, smoking history, family history of osteoporosis/fracture and
vitamin D insufficiency. The mean BMD T-score was –2.8 at the lumbar spine and 1.9 at the proximal
femur. Bisphosphonate treatment was given to nine patients for 24 months. In those women treated
with a bisphosphonate within 2 years of presentation, spinal BMD increased by 17% at 1 year, and by
23% at 2 years. By contrast, patients not treated with a bisphosphonate within 2 years of presentation
had much lower increases of BMD of 2% at 1 year at the spine, and 11% at 2 years. Five women had
subsequent pregnancies with only one sustaining a further fracture in the post-partum period, and this
individual had declined bisphosphonate therapy.

Idiopathic osteoporosis

Pre-menopausal women with either low bone mass and/or low-trauma or atraumatic fractures,
and who are otherwise healthy with no underlying secondary contributing cause, are defined as
having idiopathic osteoporosis. Idiopathic osteoporosis is uncommon with an estimated incidence of
0.4 cases per 100 000 person years, and with almost equal sex frequency [57]. There is histo-
morphometric evidence of reduced osteoblast function [57]. The reason for this is not clear as
reduced serum levels of IGF-1, a major determinant of bone growth and remodelling, have not been
found to be low in women as opposed to men with idiopathic osteoporosis [58]. However, pre-
menopausal women with low BMD had lower oestrogen levels and BMD and oestradiol levels
correlated with each other, indicating that in normally menstruating women, differences in sex
hormone production may affect BMD [58].

Inflammatory rheumatic diseases and bone loss

Rheumatoid arthritis is accompanied by an alteration of skeletal remodelling, giving rise to peri-

articular osteopenia, systemic osteoporosis and focal marginal joint erosions. The earliest abnormality
in rheumatoid arthritis is the periarticular osteopenia, which predicts the subsequent development of
324 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

marginal erosions. In the affected joints, the increased bone resorption and formation is related to the
inflammatory process. Additional bone loss will occur from disuse. Rheumatoid arthritis also shows
a generalised bone loss, which will have multiple aetiologies including physical activity, age, sex,
gonadal status, disease severity and duration and the use of medication, particularly glucocorticoids. Of
all the risk factors for generalised bone loss in rheumatoid arthritis, the most significant is disease
activity [59]. In ankylosing spondylitis, where there is a tendency for excessive bone formation at
inflammatory sites, many patients also exhibit reduced BMD at the spine and hips [60]. As this has been
observed in patients with early disease, who are not immobilised or who have significant bony
ankylosis, the findings suggest that bone loss is related to the adverse effect of the underlying
inflammatory disease on systemic bone remodelling with possible reduction in bone formation [60,61].

Management of pre-menopausal osteoporosis

General

A pre-menopausal woman presenting with low-trauma or atraumatic fractures and/or reduced

BMD (Z-score –2.0 SD or below) should be examined and investigated to exclude an underlying
secondary cause. The range of investigations that can be done are listed in Table 2. The management
should focus on treating the underlying disorder, and addressing lifestyle risk factors [62]. Pre-
menopausal women with osteoporosis should be encouraged to undertake weight-bearing activities,
cease or reduce the amount of cigarettes smoked, reduce alcohol intake to approximately less than 3
units a day and maintain adequate calcium and vitamin D intake with supplementation where
necessary.

Pharmacological

Adolescents with late-onset menarche should be investigated as should women with menstrual
irregularity. The goal should be to attempt a resumption of menses and, when this is not possible,
treatment with hormone replacement therapy should be considered, although there are no set
guidelines. It is important to bear in mind that evidence for the use of hormone replacement in
amenorrhoea secondary to anorexia nervosa has been disappointing. The treatment of this particular
condition should be focussed on correcting nutritional abnormalities, encouraging a proper diet and
weight gain. A preliminary study indicates that the use of recombinant human IGF-1 alone, or in
combination with an oral contraceptive pill, led to an increase in BMD which was more significant in
the combined group than in the IGF-1 group alone. By contrast, women given the oral contraceptive
pill lost a small amount of bone mass [63]. The use of other agents, such as bisphosphonates, is
currently under investigations but there is some evidence that bone loss may be halted to a slight
extent.
The use of GnRH agonists in endometriosis is associated with reduced bone density, which can
reverse within 24 months of discontinuation of therapy. As previously indicated, administration of PTH
may prevent bone loss associated with GnRH agonists as can ‘add back’ therapy with oestrogen and
progesterone [52,53].
Stress fractures, with highest incidences in young athletes and military recruits, occur when bone is
repeatedly loaded over short periods without sufficient time for repair. In female Navy recruits,
treatment with 2000 mg calcium and 800 IU vitamin D daily reduced the incidence of stress fractures
by 20% [64].
The use of other anti-resorptive drugs, usually bisphosphonates, should be reserved for special
circumstances as evidence for efficacy is not compelling. Pharmacological therapy is not justified in
pre-menopausal women with just a borderline low BMD. Considering pre-menopausal women with
borderline bone density and a secondary cause or those with a very low BMD with or without
a secondary cause or those with fragility fractures regardless of BMD, the underlying secondary cause
should be addressed first. If this is not possible, then some of these women may need treatment with
anti-resorptive drugs, which could include oestrogen, calcitonin, bisphosphonates and calcitriol, or
with anabolic agents such as teriparatide. Selective oestrogen receptor modulators (SERMs) are
 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327 325

contraindicated in pre-menopausal menstruating women as they block the oestrogen action on bone
and can lead to enhanced bone loss. Bisphosphonates in pre-menopausal women should be used with
caution as they accumulate in the skeleton, as they have toxic effects in rats and cross the placenta
accumulating in foetal rat bone. Their effect on the human foetus is unknown, although normal
pregnancy outcomes have been documented. However, in certain circumstances where rapid bone loss
occurs (e.g., transplantation and post-transplantation osteoporosis), the use of these agents may be
justified. The most efficacious treatment of pre-menopausal osteoporosis may be with the use of an
anabolic agent such as PTH, although these are not licensed for such use. Their efficacy in preventing
bone loss and reducing fractures has not been established in this population, and neither has the long-
term safety of their use in young women. Similarly, there is no evidence that strontium ranelate is
effective in this age group.
The follow-up of women with pre-menopausal osteoporosis should continue until it has been
established that BMD is stable. This can usually be ascertained by follow-up DEXA scans at 18–
36-month intervals. When BMD is stable, and no further intervention is required, there is no need for
continued follow-up scans unless new risk factors develop.

Practice points

 Low BMD in pre-menopausal women is not associated with the same fracture risk as low
BMD in older women.
 BMD should be defined using Z-scores.
 BMD with a Z-score of 2.0 or lower is defined as ‘below the expected range for age’.
 Between 50% and 90%, pre-menopausal women with osteoporosis will have a secondary
underlying cause.
 The most common secondary underlying causes are endocrine (eating disorders and anorexia
nervosa) and the use of glucocorticoids.
 In women where underlying cause is not found, the term ‘idiopathic osteoporosis’ is used.
 A borderline BMD is most commonly due to lack of full attainment of peak bone mass
potential or small bone size.
 Transplantation osteoporosis is becoming a greater issue and requires more evaluation.
 Pregnancy-associated osteoporosis is often not recognised.
 The aetiopathogenesis of idiopathic osteoporosis is unclear and requires further evaluation.
 Inflammatory rheumatological diseases, such as rheumatoid arthritis and ankylosing spon-
dylitis, can be accompanied by generalised bone loss and an increased risk of fractures.
 All pre-menopausal women should have general advice about lifestyle risk factors, exercise,
maintenance of adequate calcium þ Vitamin D intake with supplementation if necessary.
 The goal of treatment in amenorrhoea secondary to anorexia nervosa should be to correct
nutritional abnormalities and encourage a proper diet and weight gain. The use of oestrogen
replacement therapy is disappointing. The use of other anti-resorptive drugs should be
reserved for special circumstances as evidence for efficacy is not compelling.

Research agenda

 Need to identify the cause of osteoporosis in healthy young women (idiopathic osteoporosis).
 Further research is required to identify factors that may be important and contribute to bone
loss in anorexia nervosa and could lead to improved pharmacological intervention.
 Clinical research is required to identify when it may be appropriate to treat isolated low BMD
in pre-menopausal women and at what level of low bone mass should such an intervention
take place.
326 A.K. Bhalla / Best Practice & Research Clinical Rheumatology 24 (2010) 313–327

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