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© AME Publishing Company. All rights reserved.Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgcIntroduction
Osteoporosis is a progressive bone disease. It affects the bone
strength due to reduction of bone mass and microarchitectural
disruption leading to fragile bones with increased risk of
fractures (1). Patients with osteoporotic fractures have high
morbi-mortality and are a great burden for the health system.
In the United States, 10 million people have osteoporosis and
1.5 million of fragility fractures happen each year (2).
Primary osteoporosis is due to the physiological process of
aging, and is exacerbated by normal menopause. Secondary
osteoporosis denotes bone loss that is caused or aggravated by
other diseases or medications. In patients with osteoporosis,
50-65% of men, 50% of premenopausal women and 30% of
postmenopausal women have a secondary cause for bone loss (3,4).
Smoking, high alcohol intake, glucocorticoids (GC) use,
malabsorption, calcium and vitamin D deficiencies and low body mass index (BMI) are well-known causes of secondary
osteoporosis. Patients with gastrointestinal diseases (GID)
may present multiple risk factors for bone disease. Systemic
inflammation may exacerbate bone loss in diseases such as celiac
disease (CD) and inflammatory bowel disease (IBD).The aim of
this review is to discuss the epidemiology, pathogenesis, screening
and treatment of osteoporosis in the most common GID.
Pathophysiology of osteoporosis
The diagnosis of osteoporosis is established by dual energy
X-ray absorptiometry (DXA) of lumbar spine, proximal femur
or forearm. For postmenopausal women and men aged 50 years
or more, DXA results are compared to those of a young adult
reference population (T score), and a standard deviation (SD)
is generated. Osteopenia is defined as bone mass density
(BMD) between –1 and –2.5 SD, and osteoporosis as BMD Review Article
Osteoporosis in gastrointestinal diseases
Carina Bertoldi Franco
Endocrinology and Diabetes Research Unit, Endocrinology and Diabetes Research Unit, The Canberra Hospital, Medical School, Australian
National University, Canberra 2614, Australia
Correspondence to: Carina Bertoldi Franco. Endocrinology and Diabetes Research Unit, Australian National University Medical School, Building 10,
Level 6, The Canberra Hospital, Yamba Drive, Canberra 2614, Australia. Email: [anonimizat].
Abstract: Secondary osteoporosis is common in patients with gastrointestinal diseases (GID), and
its pathogenesis is multifactorial. Malabsorption, deficiencies of calcium and vitamin D, secondary
hyperparathyroidism, glucocorticoids (GC) use, hypogonadism, low body mass index (BMI) and chronic
systemic inflammation are known causes of metabolic bone disease in patients with GID. Patients with celiac
disease (CD) frequently have abnormal bone mineral density, even in the absence of symptoms. Adherence
to a gluten-free diet increases bone density, following nutritional improvements and reduction of systemic
inflammation. Osteoporosis occurs in up to 40% of cases of patients with inflammatory bowel disease (IBD). In
those patients, the synergism between GC therapy and disease activity is the main reason for bone loss, which
is more intense in Crohn’s disease than in ulcerative colitis. Bariatric surgery, e.g., Roux-en-Y gastric bypass
and biliopancreatic diversion, can be associated with bone loss due to intense weight reduction, increased bone
turnover and nutritional deficiencies. Recent data have also suggested that osteoporosis and fractures may
be enhanced in patients with irritable bowel syndrome (IBS). Osteoporosis and other clinical risk factors for
fracture should be investigated in patients with gastrointestinal diseases. Since atraumatic fractures have a high
morbid-mortality, appropriated treatment should be offered for those at risk.
Keywords: Bone density; gastrointestinal diseases (GID); inflammation; osteoporosis; vitamin D deficiency
Submitted Jun 16, 2014. Accepted for publication Jul 18, 2014.
doi: 10.3978/j.issn.2224-4778.2014.08.01
View this article at: http://dx. doi.org/10.3978/j.issn.2224-4778.2014.08.01

58 Bertoldi Franco. Osteoporosis in gastrointestinal diseases
© AME Publishing Company. All rights reserved.
Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgcof –2.5 SD or below. For other populations, BMD results
are compared to an age- and gender-matched reference
population (Z-scores). Low bone mass is defined as a Z score
of –2 SD or less (5). For each SD below normal, the fracture
relative risk increases by 1.5- to 3-fold (6). However, not only
a low BMD defines the fracture risk.
Bone strength is defined by a proper balance between
bone tissue resorption and formation, a process of bone
renovation called remodeling. Bone remodeling disruption,
due to bone formation reduction or enhanced resorption,
or both, may result in osteoporosis. In addition to bone
remodeling, microdamage accumulation, microarchitecture,
mineralization degree, mineral matrix composition and
bone geometry also contribute to fracture risk (7).
Osteoclasts are responsible for bone resorption,
osteoblasts, for bone formation (8), and osteocytes, for
the detection of microdamages, microstructural and
biomechanical alterations in the bone, signalizing the start
of the remodeling process. The communication between
osteoclasts and osteoblasts is intermediated by the receptor
activator of NF- κB ligand (RANK-L), its soluble form
(sRANK-L), and osteoprotegerin (OPG). Osteoblasts
express RANK-L, which links to RANK present on the
osteoclasts surface. RANK-L stimulates the differentiation
and osteoclasts activity, hence initiating bone resorption.
On the other hand, osteoblasts produce OPG, which binds
to RANK, and antagonizes RANK-L action and bone
resorption (9). Many inflammatory cells and cells of the
immune system are able to express RANK-L, a member of
the tumor necrosis factor (TNF) family and an important
link between systemic inflammation and bone health (10).
Besides, pro-inflammatory cytokines contribute to
osteoporosis, by stimulating bone resorption (a mechanism
that is osteoblast-independent). Interleukin (IL)-1 β, IL-6
and TNF α act in synergy with RANK-L, stimulating bone
resorption. Also, TNF- α inhibits bone formation, affecting
the differentiation of osteoblasts (11). Chronic inflammation,
T cells hyperactivation, increased levels of pro-inflammatory
cytokines, and unbalanced RANK-L/RANK/OPG system
are observed in patients with IBD and celiac disease, which
could explain in part their susceptibility to osteoporosis.
Epidemiology and pathogenesis of osteoporosis
in gastrointestinal diseases
Celiac disease
CD is an autoimmune disorder, which causes chronic inflammation of the small intestine due to sensitivity to
gluten. The mucosa of small intestine has an abnormal
architecture with lymphocytic infiltration in the
epithelium. This inflammatory process results in atrophy
of the intestinal mucosa and malabsorption (12). The
prevalence of CD is increasing worldwide, mainly because
the consumption of products with gluten has enhanced,
reaching 0.2-1% in the U.S. and Europe (13-15).
CD has been associated with osteoporosis (16,17), even
in patients without gastrointestinal symptoms or those
following for years a gluten-free diet (GFD) (18). The
prevalence of low BMD is high. Up to 70% of patients
with CD have abnormal DXA (16,19-22). Results of
studies assessing the fracture risk in patients with CD are
divergent, depending on the length of the follow-up, the
compliance to a GFD, the analysis of fracture history, and
intestinal mucosal status. The fracture risk in patients with
CD ranged from 1.3- to 10-fold higher than the general
population (21,23-25). However, other authors did not find
increased risk of fracture in patients with CD (26,27).
The pathogenesis of metabolic bone disease associated
with CD is multifactorial. Chronic malabsorption leads
to nutrient deficiency, secondary lactose intolerance and
low BMI. Calcium absorption is particularly impaired
because CD affects the region of the small intestine where
it is absorbed. Vitamin D-dependent calcium-binding
proteins, which are responsible for calcium uptake by
enterocytes, were absent or diminished in patients with
CD (28). In addition, unabsorbed fatty acid in the intestinal
lumen can bind to calcium and prevent its absorption.
Hyperparathyroidism secondary to deficiency of calcium
and 25OH-vitamin D is common. Elevated PTH increases
bone resorption and turnover, resulting in low BMD
and impaired bone quality, especially in the cortical bone
present in the appendicular skeleton (29).
Lactose intolerance occurs in 30-60% of newly
diagnosed patients, who avoid ingestion of dairy products
and consequently, calcium. Thus, CD may affect calcium
metabolism in many ways. Furthermore, patients with
adherence to GFD may have nutritional deficiencies even
after the reestablishment of a normal intestinal absorption,
since gluten-free products are poor in calcium, vitamin
D, zinc and magnesium. Patients with CD who are newly
diagnosed or have poor adherence to GFD may present
weight loss and low BMI. Low BMI is strongly correlated
with low BMD, and is a predictor of fractures in the
general population (30,31). A longitudinal study with CD
seropositive patients showed that BMI correlated with

59 Translational Gastrointestinal Cancer, Vol 4, No 1 January 2015
© AME Publishing Company. All rights reserved.
Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgcBMD at both diagnosis and follow-up of the disease, and
after 2.4 years there was an increase in body fat, and an
increase in BMD by 10.8% and 7.1% in the spine and hip,
respectively (32). Lower systemic levels of insulin growth
factor (IGF) 1 and leptin, which are associated with the
stimulation of bone anabolism and reduction of mechanical
load are some factors involved in the decrease of BMD
caused by low BMI.
Disease activity evaluated by duodenal biopsy may also
be an important predictor of bone disease in CD. In patients
with follow-up biopsy, persistence of mucosal atrophy was
correlated with fracture of the femur. Risk was increased in
case of subtotal or total mucosal atrophy. In this study, 43%
of patients who had subtotal or total mucosa atrophy at
diagnosis had persistent mucosal atrophy over the following
years (33). This suggests that patients with more severe
disease at diagnosis should be monitored for bone disease.
In corroboration with the relation between CD activity/
severity and bone loss, there are evidences that systemic
inflammation, mainly T-cell-mediated, is involved in
the pathogenesis of low bone mass. Serum levels of pro-
inflammatory cytokines IL-1 β (34), and IL-6 were higher in
patients with CD without treatment, and IL-6 was inversely
correlated with BMD (34,35). GFD was able to ameliorate
the pro-inflammatory profile, with reduction of IL-1 β and
IL-6 and increase of IL-1 receptor antagonist, an anti-
inflammatory cytokine (34).
Besides, circulating levels of RANK-L and OPG were
increased in patients on GFD, as well as in newly diagnosed
CD cases who were not on GFD yet. However, the
RANK-L/OPG ratio was increased only in those with newly
diagnosed CD. BMD Z-score was negatively correlated
with serum IL-6 levels and RANK-L/OPG ratio, but not
correlated with PTH levels. Osteoclasts multiplication and
activity were stimulated in vitro when osteoclasts precursors
from healthy donors were incubated with serum of newly
diagnosed CD patients, with a more robust effect in
osteoclastogenesis increase. Serum from CD patients, on
GFD or not, stimulated osteoblast proliferation and activity
in cell cultures. However, only serum from patients not on
GFD decreased the levels of OPG (35). These pieces of
evidence demonstrate that the pathogenesis of bone loss in
CD may not be restricted to malabsorption and calcium-
vitamin D-PTH disturbances. Inflammation may explain
why even patients without gastrointestinal symptoms
have higher risk of osteoporosis. In those patients, gluten
withdrawal is fundamental for reducing the inflammatory
status.Furthermore, CD is related to other disorders that
contribute to osteoporosis development. About 10% of
patients with type 1 diabetes mellitus (T1DM) present
CD (12). T1DM is a well-known cause of osteoporosis (36).
Among other disorders with high frequency in patients
with CD, delayed puberty, hypogonadism, autoimmune
thyroiditis, primary hyperparathyroidism can negatively
influence bone mass (12).
Inflammatory bowel disease
The term IBD includes Crohn’s disease and ulcerative
colitis (UC), which are characterized by relapsing or
persistent inflammation mediated by a hyperactivation of
T-cells. In Crohn’s disease, the inflammation is transmural
and may affect the entire gastrointestinal tract, whilst
in UC, the inflammation is restricted to the mucosal
layer of the rectum and/or colon (37). The prevalence of
osteoporosis in IBD ranges from 4-40% (38-41), depending
on the population, disease activity and exposure to GC. It
has been shown that the incidence of osteoporotic fractures
was 40% higher in patients with IBD than in the general
population, and 74% higher when specifically analyzing
spinal fractures (42).
Use of GC, chronic inflammation, deficiencies of vitamin
D, K and calcium due to malabsorption or inadequate
dietary intake, hypogonadism and immobility, are among
causes of low BMD in IBD.
GC use is the most frequent cause of secondary
osteoporosis. Bone loss in patients exposed to therapeutic
doses of GC is more intense in the first 6 months, leading
to an incidence of osteoporosis in GC users of 50% in this
period (43,44). BMD can decrease in up to 12% in the
first year of GC treatment, with losses of 2-3% per year
afterwards (45). GC stimulate bone resorption through
osteoclasts proliferation, differentiation and stimulation,
and inhibit bone formation by promoting apoptosis of
osteoblasts and blocking their multiplication and function.
GC indirectly affect the skeleton, diminishing the intestinal
calcium absorption and increasing calciuria. Also, GC
decrease muscle mass and suppress growth hormone and
sex steroids, important to maintain the bone mass (45).
About 35% of patients with IBD receive GC during the
first year diagnosis (46). Thus, GC use is a relevant cause of
osteoporosis in patients with IBD, especially for those on
doses equivalent to prednisone >10 mg/d for >3 months (47).
As is observed in CD, hyperactivated immune cells in
IBD may alter the RANK/RANK-L/OPG system, causing

60 Bertoldi Franco. Osteoporosis in gastrointestinal diseases
© AME Publishing Company. All rights reserved.
Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgcmetabolic bone disease (48). Serum levels of sRANK-L and
OPG were increased in patients with Crohn’s disease. Also,
sRANK-L and OPG release was significantly enhanced
in cultures of colon from Crohn’s disease patients. OPG
in supernatant of cultures positively correlated with
histological inflammation and levels of TNF- α, IL-1 β,
IL-6, an anti-inflammatory cytokine (IL-10) and a marker
of tissue destruction (MMP3). The expression of RANK-L
was higher in dendritic cells and in activated macrophages
from the colonic mucosa of patients Crohn’s disease than
of controls (48). In an IL-2 deficient mice model of colitis,
abnormally activated T cells secreted sRANK-L at early
stages of the colonic disease. As they aged, these mice
presented progressive bone loss, with decrease in the levels
of sRANK-L. Conversely, OPG levels raised later in the
course of the bowel disease without reaching a plateau (49).
In spite of the lack of studies that demonstrate the
longitudinal correlation between bone disease, the OPG/
RANK/RANK-L system, and IBD in humans, Moschen
et al. showed results that support this mice model. Serum
levels of OPG and OPG/sRANK-L ratio were significantly
increased in patients with IBD, with the highest levels
observed in Crohn’s disease cases. OPG was inversely
correlated with femur and spine BMD. Lower sRANK-L
levels were found in IBD patients treated with GC alone
or in combination with azathioprine, than in IBD patients
without specific drug treatment. T o confirm the source of
OPG, cytokines secretion from colonic explant cultures
were analyzed. Inflamed colonic regions from patients
with Crohn’s disease and UC presented a 3.4-fold and a
3.8-fold increase of OPG in the media, respectively. There
were no differences between the production of OPG by
non-inflamed areas of IBD patients and healthy controls.
Macrophages and dendritic cells were the primary sources
of OPG, while RANK-L was mainly produced by T-cells.
Although high levels of OPG seem controversial in the
pathogenesis of osteoporosis, the production of OPG
may represent an attempt to cease the progression of
bone loss (50). Indeed, exogenous recombinant OPG was
able to reverse bone loss and decrease T lymphocyte-
induced colonic inflammation in IL-2 deficient mice colitis
model (49). Moreover, other cytokines may contribute
to bone disease in IBD. Circulating IL-6 levels were
increased in children with IBD and were inversely
correlated with BMD (51).
Deficiencies of vitamin D, K and calcium have been
reported in patients with IBD. Particularly in Crohn’s
disease, malabsorption of nutrients and fat due to ileal resection or ileal active disease may contribute to bone
disease (52). Up to 70% of patients with for Crohn’s disease
and up to 45% of UC patients present vitamin D deficiency
(53-57). In a Japanese population, 25OH-vitamin D levels
were lower in patients with long time of disease and in
those in which the disease was active for long periods (58).
25OH-vitamin D is essential for bone mineralization and
has many other physiologic roles. Regarding osteoporosis,
25OH-vitamin improves lower limbs function and body
balance, decrease falls (59) and prevent fractures (60).
As discussed, 25OH-vitamin D deficiency can induce
secondary hyperparathyroidism and increase bone turnover
and resorption. In addition to calcium malabsorption, a
large number of patients with IBD do not have an adequate
intake of calcium (61,62). Furthermore, diarrhea may
lead to magnesium deficiency contributing to calcium
malabsorption. Although less studied, vitamin K sufficiency
is also important for bone health. The prevalence of vitamin
K deficiency in IBD patients was 31% in one study (63).
Vitamin K induces bone formation and mineralization
as well as accumulation of collagen into osteoblasts.
Besides bone formation, vitamin K is able to increase
the production of OPG and alkaline phosphatase by
osteoblasts, and induces the carboxylation and activation of
osteocalcin, a protein produced by osteoblasts involved in
bone mineralization. In addition to bone formation, vitamin
K can inhibit bone resorption and osteoclastogenesis.
However, there is no enough clinical evidence to support
the use of vitamin K to improve the bone mass and prevent
fractures neither in IBD or in the general population (64).
BMD seems to improve after colectomy in patients with
UC, probably through inflammatory reduction and less
need of GC therapy (65-67), whereas in Crohn’s disease,
the role of intestinal resections on osteoporosis is less
clear (27,68).
It is controversial whether IBD per se is able to decrease
the bone mass and increase fracture incidence in clinical
studies. In a study with patients with Crohn’s disease, low
BMD only correlated with GC therapy and disease activity
(defined as levels of C-reactive protein) (69). In patients
with UC and Crohn’s disease with a prevalence of 25% of
vertebral fractures, BMD, disease activity, GC and other
clinical risk were not associated with increased fracture
risk (70). In addition, a study with a follow-up of patients
with Crohn’s disease for 20 years, did not find increased
risk of osteoporotic fractures. The only clinical factor
related with overall risk of fractures was age. Exposure
to GC and intestinal resections were not associated with

61 Translational Gastrointestinal Cancer, Vol 4, No 1 January 2015
© AME Publishing Company. All rights reserved.
Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgchigher risk of fractures (71). In contrast, Crohn’s disease
was associated with osteoporosis after the control of GC use
and other factors known for interfering in the bone mass in
a population-based database of the province of Manitoba,
Canada. However, UC was not related to increased risk of
low BMD in this population (72). Also, the fracture risk was
increased by 2.5-fold in women with Crohn’s disease, but no
enhanced risk was observed in males with Crohn’s disease
or patients with UC. The length of exposure to GC also
determined a higher fracture risk in Crohn’s disease, but not
in UC (73).
The 10-year fracture risk can be estimated in men and
women older than 50 years from femoral neck BMD and
clinical risk factors by the World Health Organization
Fracture Risk Assessment tool (FRAX) (74). The inclusion
of clinical risk factors independent associated with fracture
risk ( T able 1 ) can also predict the fracture risk without using
BMD values (75). Analysing the Manitoba cohort, IBD
was associated with 2-fold higher risk of femur fracture
after controlling for FRAX fracture probability including
the BMD or not. However, the risk of other osteoporotic
fractures combined was related to low BMD and clinical factors, without differences determined by the presence or
absence of IBD (78). Overall, these data suggest that IBD
confers a small independent risk of fractures, probably more
evident in patients with severe disease. The combination
of other clinical factors may have a greater role in the
pathogenesis of fractures in the IBD population.
Bariatric surgery with intestinal bypass
Surgeries that involve intestinal bypass were developed to
produce malabsorption and weight loss. The most common
procedure is the Roux-en-Y gastric bypass (RYGB). Among
60% to 70% of excess body weight is lost after RYGB.
RYGB is a gastrojejunostomy and consists in the creation of
a small gastric pouch attached to a transected jejunum that
connects to a duodenal limb (79).
Data regarding the effects of biliopancreatic diversion
with duodenal switch (BPDDS) on bone metabolism are
scarce. In this surgical procedure, there is a partial vertical
gastrectomy with preservation of the pylorus which is
connected to an alimentary limb; and a long limb bypass
with a portion of the duodenum attached to the pancreas
and gallbladder is connected to a short common duct closer
to the large intestine (80,81). The expected weight loss is
70-80% of the excess weight (82).
Many authors have shown BMD loss after bariatric
surgery (83-85). In a RYGB prospective study with 1 year
of follow-up, decreases of 9.2% of femoral neck BMD and
of 8.0% at the total femur were observed. There was a
strong correlation between BMD reduction and magnitude
of weight loss. No changes occurred at spine and forearm
BMD (86). In another study, the risk of fractures was
studied in 258 patients from Olmsted County, Minnesota,
who underwent bariatric surgery. The average follow-up
was almost 9 years; patients were young, with a mean age
of 44 years. The risk was 2-fold higher for osteoporotic
fractures (forearm, vertebra and femur) and 2.3-fold higher
for non-osteoporotic fractures at appendicular regions of
the skeleton, in comparison with the general population.
The estimated risk of any fractures in 10 years in individuals
of this population was 35%. In addition, more than 50% of
fractures occurred after 5 years of bariatric surgery (87).
Many causes play a role in the pathogenesis of metabolic
bone disease after bariatric surgery. There are reports of
increased bone remodelling after surgery. Studies have
demonstrated elevated levels of markers for bone turnover
in the post-operatory period, mainly of the bone resorption
indicator N-telopeptide (86,88).The drastic and fast Table 1 Clinical risk factors for osteoporosis and fractures (75-77)
Risk factors for osteoporosis
Older age
Low body weight
>10% weight loss
Glucocorticoids use
Anticonvulsants use
Immobility
Hypogonadism without treatment
Female gender
Low calcium intake
Independent risk factors for fractures
Older age
Previous fracture
Low body weight
Current smoking
Rheumatoid arthritis
Glucocorticoids use
Secondary osteoporosis
Parental history of hip fracture
Alcohol Intake ≥3 units per day
Gender

62 Bertoldi Franco. Osteoporosis in gastrointestinal diseases
© AME Publishing Company. All rights reserved.
Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgcreduction of BMI leads to decreased mechanical load on the
skeleton, an established cause for losing BMD and muscle
mass (89,90). As explained, BMI has strong a correlation
with BMD.
Calcium and 25OH-vitamin D absorption decrease early
after the surgery (86) and seems to be worse in procedures
with longer Roux limbs (91). Secondary hyperpathyroidism
has been described in bariatric patients (92,93) especially
if supplementation of calcium/25OH-vitamin D is
inadequate. Indeed, those patients usually need higher doses
of elemental calcium due to duodenal and proximal jejune
bypass, and supra physiological doses of 25OH-vitamin D
to avoid secondary hyperparathyroidism (94).
Irritable bowel syndrome
Few authors have investigated the association between
irritable bowel syndrome (IBS) and risk of fractures. The
risk of fractures was increased (OR =1.99, 95% CI, 1.24-
3.19) in comparison with controls in a study that evaluated
the medical records of patients with IBD from a health
maintenance organization (95). Another study, which
included more than 300,000 patients with IBS from the
Nationwide Emergency Department Sample database
showed a higher risk for osteoporosis (OR =4.28, 95%
CI, 4.21-4.35) and fragility fractures (OR =4.28, 95% CI,
4.21-4.35) than patients without IBS (96). The authors
discussed that a possible cause for osteoporosis in patients
with IBS is the elevated levels of serotonin produced by
the gastrointestinal tract. Serotonin may decrease bone
formation mediated via LDL-receptor related protein 5
(LRP5) (97). In addition, elevated circulating levels of
pro-inflammatory cytokines such as IL-6 and TNF- α have
been demonstrated in patients with IBS (98,99). Besides,
patients with IBS may avoid products with lactose because
of gastrointestinal symptoms, limiting the intake of
calcium (96).
T able 2 summarizes the etiological factors for osteoporosis
secondary to GID.
Screening
Celiac disease
There is no consensus among societies regarding
measurement of DXA for osteoporosis screening in CD. Table 2 Summary of etiological factors present in gastrointestinal
involved in bone disease
Disease Causes of low bone mass density
Celiac
diseaseMalabsorption
Calcium and vitamin D deficiencies
Secondary hyperparathyroidism
Low calcium intake
Secondary lactose intolerance
Gluten free products (poor in calcium)
Disease activity
Systemic inflammation
Persistence of mucosal atrophy
Unbalanced RANK/RANK-L/OPG system
Low BMI
Low leptin and IGF-1 levels
Reduction of mechanical load
Association with other disorders
Type 1 diabetes mellitus
Hypogonadism
Autoimmune thyroiditis
Primary hyperparathyroidism
Inflammatory
bowel
diseaseGlucocorticoid use
Disease activity
Systemic inflammation
Increased sRANK-L and OPG levels
Malabsorption (active disease, ileal resection)
Vitamin D, K and calcium deficiencies
Immobility
Bariatric
surgery with
intestinal
bypassIntense weight loss
Increased bone turn-over
Malabsorption
Inadequate calcium/vitamin D supplementation
Calcium and vitamin D deficiency
Secondary hyperparathyroidism
Irritable
bowel
syndromeIncreased systemic serotonin
levels produced by the duodenum
Low intake of calcium from milk
and dairy products
Use of SSRIS
BMI, body mass index; IGF-1, insulin like growth factor 1;
RANK, receptor activator of NF- κB; RANK-L, RANK ligant;
sRANK-L, soluble form RANK-L; OPG, osteoprotegerin;
SSRIS, serotonin antagonist and reuptake inhibitors.

63 Translational Gastrointestinal Cancer, Vol 4, No 1 January 2015
© AME Publishing Company. All rights reserved.
Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgcThe British Society of Gastroenterology recommends DXA
for those at higher risk of osteoporosis, with 2 or more risk
factors: poor adherence to GFD or persistence of symptoms
on GFD for 1 year; weight loss >10%, BMI <20, Age >70, or
prior osteoporotic fracture (76).
According to the American Gastroenterological
Association (AGA), adults with newly diagnosed CD
should have the BMD evaluated with DXA after 1 year
of GFD. In addition, the AGA recommends that levels of
calcium, 25OH-vitamin D and PTH should be assessed
in all newly diagnosed CD patients (41). If osteopenia
or osteoporosis is identified, specific treatment for bone
disease should be offered, as suggested by the guidelines
(e.g., bisphosphonates) with regular follow-up. If BMD is
abnormal without indication of treatment, its measurement
should be repeated after three years. If BMD is normal, its
measurement should be repeated at menopause in women,
and after 55-year-old in males. Other authors recommend
that all patients should have a DXA when CD is
diagnosed (100). In men with osteoporosis, testosterone
levels should be checked (41).
Inflammatory bowel disease
The AGA recommends that DXA scan should be performed
for patients with one or more risk factors for osteoporosis
(T able 1 ), which should be re-assessed in 2 to 3 years. If
the patient is on high dose GC treatment, DXA scan
should be repeated after 1 year. Serum levels of calcium
should be evaluated in newly diagnosed patients. A broader
investigation for secondary osteoporosis (blood count, total
creatinine, 25OH-vitamin D level, protein electrophoresis,
and testosterone level) should be done in those with
osteoporosis or a previous osteoporotic fracture (41).
The British Society suggests that DXA scan should be
performed in patients at higher osteoporosis risk, with at
least 2 risk factors ( T able 1 ). Other authors discuss the use of
the FRAX calculator to estimate the probability of fractures
and to recommend the initiation of treatment (46).
Bariatric surgery
For both RYGB and BPDDS, DXA scan is recommended
at 2 years after surgery. There is not enough evidence
to indicate DXA scan at baseline for all patients, and
the recommendation for osteoporosis screening should
follow the recommendations of the National Osteoporosis
Foundation (www.nof.org). The measurement of 25OH-vitamin D in the preoperatory period is advised, and a
more extensive investigation, including calcium, albumin,
phosphate and PTH in individual patients, is suggested
for those at higher risk. During the routine follow-up,
25OH-vitamin D, iPTH and calcium should be regularly
assessed. It is recommended to evaluate 24-hour urinary
calcium excretion at 6 months after the surgery, and then
annually (94).
Irritable bowel disease
There is not enough evidence to suggest routine evaluation
of BMD and serum levels of 25OH-vitamin D in patients
with IBS. The prevention of fractures should follow the
standards for the general population.
Treatment and prevention of metabolic bone
diseases
Celiac disease
GFD is the main treatment for bone disease associated
with CD. It improves bone mass, but may not normalize
BMD in all patients. Response depends on when the GFD
is implemented. Patients with untreated CD in the two first
decades of life may not reach their bone mass peak. In this
situation, bone mass is unlikely to recover completely. In
adults, particularly in postmenopausal women and men
>55 years, BMD response will be related to the magnitude
of bone damage at the diagnosis. BMD increases in an
average of 5% in the first year of GFD, and is more evident
in axial than appendicular skeleton. The increment of BMD
will be lower in the subsequent years (77). It is important to
emphasize that the reduction of the fracture risk in patients
following the GFD is not only due to the BMD increase,
but also because the overall nutritional status, body
composition, BMI, and bone architecture are improved, and
risk of falls is decreased (18).
Celiac disease and IBD
It is recommended a minimum intake of elemental calcium
of 1,000 mg per day, and up to 1,200-1,500 mg per day for
postmenopausal women and men >55 years. The intake of
25OH-vitamin should be 400-800 IU per day. Higher doses
should be prescribed if necessary to maintain the 25OH-
vitamin D levels >25 ng/mL (41,76), especially in those with
fat malabsorption. General recommendations of weight

64 Bertoldi Franco. Osteoporosis in gastrointestinal diseases
© AME Publishing Company. All rights reserved.
Transl Gastrointest Cancer 2015;4(1):57-68
www.amepc.org/tgcbearing exercise, alcohol and tobacco avoidance should
be enforced. In patients with osteoporosis at high risk of
fractures (e.g., for patients who will be on GC treatment
for ≥3 months) or with a previous fracture, treatment
with bisphophonates (e.g., alendronate, risedronate),
raloxifene or teriparatide should be prescribed. In men with
osteoporosis and hypogonadism, testosterone should be
offered (41). In patients with Crohn’s disease, it is advised
to avoid oral GC and initiate alternative medications less
aggressive for bone such as anti-TNF α and azathioprine if
possible (41,76).
Bariatric surgery
All patients submitted to RYGB should receive calcium
citrate, 1,200-1,500 mg/d early after the surgery. Citrate
is the first choice because of hypocloridria caused by
gastrectomy. All patients who had BPDDS and RYGB
should be prescribed at least 3,000 UI/d of vitamin D. The
dose should be titrated to maintain serum levels >30 ng/mL.
The aim of calcium and 25OH-vitamin D supplementation
is to avoid secondary hyperparathyroidism without inducing
hypercalciuria (94).
In patients with osteoporosis or atraumatic fracture with
calcium/vitamin sufficiency, bisphosphonates should be
offered. The best options are intravenous bisphosphonates
(zoledronate and ibandronate) since the absorption of oral
bisphosphonates is impaired with hypocloridria. Also, oral
bisphosphonates may cause anastomotic ulceration (94).
Conclusions
GID can lead to significant impact on bone health and
are frequent causes of secondary osteoporosis. Normal
intestinal function is essential for an adequate calcium
metabolism. Malabsorption of calcium and vitamin D with
consequent secondary hyperparathyroidism may occur in
patients with CD, Crohn’s disease and bariatric surgery.
Low calcium intake due to avoidance of milk and dairy
products is also common in patients with GID, not only
in those with malabsorption, but also in patients with
disorders associated with chronic abdominal pain, altered
bowel habits and abdominal bloating such as IBS and colitis
ulcerative. Calcium and vitamin D status should be analysed
and supplementation ensured when necessary. Use of GC,
weight loss, disease activity, systemic inflammation and
immobility present in patients with GID also play roles in
the pathogenesis of bone disease. There is not enough evidence to determine the
independent risk of each GID for fractures. However,
patients with GID frequently present multiple risk factors
for bone disease. Since osteoporosis in general progresses
slowly and bone loss is not always completely reverted with
treatment, a high level of suspicion is required to prevent
advanced bone loss and fractures. Thus, prompt evaluation
and diagnosis are important for patients at risk of bone
disease. Control of the primary GID, reinforcement of a
healthy lifestyle and prescription of drugs which negatively
affect bone metabolism with parsimony are good strategies
to prevent bone disease. In the future, the validation of
diagnostic tools, such as FRAX, in subgroups with specific
GID will optimise the clinical judgement and indication of
osteoporosis treatment, especially for patients who are not
clearly at high risk of osteoporosis and fractures.
Acknowledgements
Disclosure: The author declares no conflict of interest.
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