Key words
bariatric surgery - bone - sleeve gastrectomy - Roux-en-Y gastric bypass - fractures
Introduction
Obesity is a preventable global health problem that continues to grow at an alarming
rate [1]. According to the World Health
Organization, in 2016, almost 2 billion adults were overweight and 650 million were
obese [2]. Projected estimates from 2017 show
that in 2030, obesity levels could reach huge proportions in some countries, such as
the United States, Mexico, and the United Kingdom, where respectively 47, 39, and
35% of the population is believed to be affected by this chronic disease
[3]. These data gain particular relevance
after acknowledging that obesity is related with multiple associated conditions,
such as type 2 diabetes [4], hypertension
[5], dyslipidemia [6], obstructive sleep apnea, cardiovascular
disease, cancer, and increased mortality [7]
[8]
[9]. The management of this disease and its
associated complications has evolved during the last decade [10], with an increased awareness for the
long-term benefits of a more definitive approaches, such as bariatric surgery [11]
[12].
These benefits (which include durable weight loss, diabetes remission, and the
amelioration of multiple cardiovascular risk factors and other comorbidities) led to
a progressive increase in the number of surgeries performed worldwide [13]
[14].
Despite these advantages, one possible side effect of surgical procedures is their
negative impact on bone health, an important issue that received more attention
during the last decade [15]
[16]. The mechanisms that are responsible for
bone deterioration after bariatric surgery encompass diminished mechanical loading,
malabsorption (calcium and vitamin D, among other nutrients) and altered
gastrointestinal and adipocyte hormone levels [17].
Accordingly, the objective of this narrative review is to analyses the impact of
bariatric surgery on bone metabolism, focusing mainly on the two most performed
procedures worldwide [sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB)]
([Fig. 1]). The review then proceeds to
present the main players in this intricate relationship and to explore new
recognized connections, based on recent data. The main techniques to measure bone
mineral density and predict fracture risk are also discussed, as well as the risk of
a fracture occurring after bariatric surgery.
Fig. 1 Schematic presentation of the connections between bariatric
surgery and bone metabolism. GLP-1: Glucagon-like peptide 1; GLP-2:
Glucagon-like peptide 2; GIP: Gastric inhibitory polypeptide; PYY: Peptide
YY; FGF-21: Fibroblast growth factor 21.
Measuring the Impact of bariatric surgery on bone mass and fracture risk
Measuring the Impact of bariatric surgery on bone mass and fracture risk
Several imagiological and analytical tools have been applied, mainly during the last
decade, to understand how obesity and bariatric surgery affects bone metabolism.
Most of them used dual-energy X-ray absorptiometry (DXA), which is a quantitative
non-invasive technique that is the standard reference method for measuring BMD. DXA
is commonly used to diagnosis and monitor osteoporosis, however it can also have
other applications, such as in evaluating whole body composition [18]. Despite being extensively used as the main
imagery for evaluating bone (even among obese individuals), it does, however, have
various limitations. Up until recently, the tables of DXA scanners were only able to
support a maximum weight of 136–160 kg, depending on the machine
used. Despite the fact that newer models can support heavier weights (up to
205 kg), the problem is that sometimes tables are not wide enough to
accommodate some severely obese patients [15].
In addition, the precision of DXA scans declines with higher BMI and excessive fat
accumulation around bones, which could lead to unpredictable errors in DXA
evaluation of up to 20%. This fact explains the increased difficulty in
obtaining and interpreting measurements from axial sites (lumbar spine, hip) when
compared with those from peripheral ones (such as radius or tibia). Other problems
that lead to imprecisions include differential positioning of adipose abdominal
panniculus and the presence of vertebral fractures, which can also contribute to
erroneous BMD values [19]. The accuracy of BMD
is also affected by significant weight loss, which is a recurrent problem among this
particular population who is submitted to bariatric surgery. This problem seems to
be related with an alteration in the distance between X-ray source and the bone,
owing to the diminished interposition of fat (which can change the evaluation of
bone area, while calculating areal BMD or bone mineral content) [20]. Another handicap of DXA is that it can
only measure two different tissues at the same time (for instance, soft tissue and
bone) and when it measures body composition, a DXA scan tends to make assumptions
about fat/lean tissues ratios to reveal the densities of three different
tissues (lean tissue, fat, and bone). These ratios can be flawed in cases of
significant weight loss. Finally, different manufacturers of DXA machine (GE-Lunar,
Hologic, Norland) employ distinct methods to determinate BMD and adipose tissue
proportion, which makes it impossible to compare results obtained from machines with
different brands [21].
Bearing in mind the limitations of the use of DXA in obese states, other methods for
evaluating have been pursued. One of them is quantitative computed tomography (QCT),
which is a three-dimensional technique that quantifies BMD in several sites, such as
the hip, spine (axial QCT) [22] or forearm,
proximal femur, and tibia (peripheral QCT – pQCT). The strengths of QCT are
the ability to separate cortical and trabecular bone, the determination of 3D
geometric parameters (such as cross-sectional area, dimensions, cortical thickness,
trabecular structure), and enabling the technician to characterize the bone in more
detail. This ultimately leads to a better understanding of bone-related anomalies
associated with the risk of fracture [23].
This exam can even be recommended for specific groups to maximize the accuracy of
the evaluation of bone features, namely: very large or small patients
(e. g., those with obesity) and older patients with advanced degenerative
disease of the lumbar spine, as well as in cases where high sensitivity is needed
(corticosteroid or parathormone treatment). The limitations of QCT include a
relatively higher dose of radiation when compared with DXA and a limited number of
longitudinal studies have evaluated QCT’s ability to predict fractures [24]
[25].
A study by Yu et al. compared the QCT and DXA measurements of 30 patients with
morbid obesity who had been submitted to RYGB. This study found that both methods
detected a 3% lower incidence of BMD in the spine, but discordant
measurements at the hip, with the detection of a larger decline in total BMD when
the patient was evaluated with DXA (9%), with negligible changes of total
BMD at any site of the hip when measured with QCT (despite having a
3.0–4.5% loss of trabecular bone). The results suggest that one of
these two methods is probably affected by the presence of foreign objects, which
prompts the need for further research in the area of bone evaluation in
obese/bariatric states [26].
The need to prevent bone fractures led the University of Sheffield to launch the
fracture risk assessment tool (FRAX) in 2008, which provides country-specific
algorithms to predict the 10-year probability of hip and major osteoporotic fracture
(spine, hip, proximal humerus, and distal forearm) of a given patient. This tool
evaluated seven different clinical risk factors that impact fracture risk, namely:
previous fragility fracture, systemic glucocorticoid use, mother/father hip
fracture, smoking, excess alcohol consumption, rheumatoid arthritis, and other
causes of secondary osteoporosis. When added to age, sex, and BMI, these factors
provide a 10-year fracture probability estimate that is independent of BMD [27]. This popular tool, which can be easily
accessed through its website [28], includes
the option to measure the BMD of femoral neck to refine the results. The FRAX
estimate also helps physicians to decide whether to intervene therapeutically,
although the various available guidelines differ with regards the treatment of
cutoffs.
Another tool that can be incorporated optionally in the FRAX is the trabecular bone
score (TBS) [29], which is a textural index
that is associated with bone microarchitecture which analyses pixel gray-level
variations in the DXA image of the lumbar spine. By so doing, TBS can distinguish
differences in the 3-dimensional bone microarchitecture, even in 2-dimensional DXA
evaluations with the same BMD levels. One finding that is independent of BMD is the
fact that higher TBS values are correlated with stronger bone microstructure,
whereas low values are correlated with a worse, fracture-prone microarchitecture
[30]. The proposed TBS cutoffs for bone
architecture among pos-menopausal women are: ˃1350 – normal; TBS between
1200 and 1350, which is consistent with partially-deteriorated bone
microarchitecture; and TBS˂1200 – degraded bone microarchitecture. Limits
for other groups of patients (such as male patients) are yet to be defined [31]. One of the main limitations of TBS is its
lower accuracy for extreme levels of BMI, which is only being recommended for those
patients who have a BMI of between 15–37 kg/m2
[29]. When considering the BMI requirements
for bariatric surgery, it is easy to understand that TBS has a limited range for
application in these patients. Despite this fact, recent versions of the software
are less impacted by excessive fat interposition, and at least two articles have
applied this software among bariatric patients to predict fracture risk [32]
[33].
The increase in bone turnover, which occurs in various pathological states
(osteoporosis, among others), is associated with a decay of bone microarchitecture
and with an increase in fracture risk that is independent of BMD [34]. This fact led to the increased popularity
of the markers of bone turnover – biochemical agents evaluated in blood or
urine. These products mirror bone metabolic activity and can be categorized as bone
formation or bone absorption markers ([Table
1]) [35]. Even among bariatric
patients, the most-used markers of bone formation are N-terminal pro-peptide of type
1 collagen (P1NP) and osteocalcin. In turn, the most-used markers of resorption are
C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal telopeptide of type
1 collagen(NTX-1) [19].
Table 1 Summary of the markers of bone formation and
absorption, considering its specific physiological role on bone
metabolism.
|
Bone formation markers
|
|
Bone resorption markers
|
|
|
By-products of the synthesis of collagen
|
|
Collagen degradation products
|
-
Pyridinium crosslinks:
-
pyridinoline
-
deoxypyridonoline
|
|
Osteoblastic enzymes
|
|
Non-collagenous proteins
|
|
|
Matrix proteins
|
|
Osteocyte activity markers
|
|
|
|
Osteoclastic enzymes
|
|
Bariatric surgery techniques and its impact on bone
Bariatric surgery techniques and its impact on bone
Bariatric surgery has become the most effective option among obese patients to lose
weight and for treating some of the related diseases. This surgery is indicated for
those individuals with a BMI≥40 kg/m2, or those
with BMI≥35 kg/m2 and comorbidities such as sleep
apnea, dyslipidemia, hypertension, or type 2 diabetes mellitus. However, despite its
positive effects, bariatric surgery can be detrimental for bone health, as shown by
recent studies [36]
[37]. Interestingly, the impact of bariatric
surgery on bone appears to differ slightly, according to the surgical technique
performed [38]. The two procedures that
together account for more than 80% of the performed bariatric surgeries
worldwide are Roux-en-Y gastric bypass (RYGB) and Sleeve gastrectomy (SG).
Accordingly, only these two procedures are addressed in this review.
The above-mentioned comorbidities lead to food restriction, malabsorption, and
changes in the secretion of several gastrointestinal hormones, which can also impact
on bone metabolism [39]. A meta-analysis in
2014, which focused on patients submitted to RYGB revealed a significant decrease in
circulating calcium levels and a significant rise in PTH serum levels after surgery.
Surprisingly, no difference in serum 25-OH vitamin D was found, although there was
also a significant decrease in BMD after RYGB. With regards bone markers, there were
significant increases in urinary and serum NTX and in bone-specific alkaline
phosphatase (BSAP) [37]. A recent trial on
bone marker variation after RYGB found similar results, with increased CTX-1, P1NP
and BSAP 2 years after surgery [40]. Another
study addressing bariatric type 2 diabetic patients found that there was a
significant 280% increase in osteoblast activity, and a significant decrease
in BMD of lumbar spine (−4.0%, p<0.05) one year after RYGB
[41]. Several studies to date have focused
on BMD variation after RYGB, where most of them used DXA measurements and detected a
prominent areal Bone Mineral Density (aBMD) decline at the proximal femur during the
first year after surgery, with decreases that range from 6 and 11% [42]. This deterioration at the hip BMD (that is
consistent among studies) can be overestimated by DXA, as articles addressing
volumetric hip BMD by QCT found smaller declines [43]
[44]. On the other hand, DXA
assessments of the lumbar spine found that most of the worse aBMD values were after
RYGB, albeit not with the same magnitude of the decline in hip aBMD. When
considering all the studies addressing spinal BMD, it is evident that there appears
to be a decrease in spine bone mass after RYGB which is underestimated by DXA when
compared to QCT [42]
[43]
[44]
[45]. The appendicular skeleton
is also affected, with diminished total and ultradistal radius aBMD detected 12
months after RYGB. The decline of tibial and radial volumetric BMD (vBMD) values is
less marked than that observed at spine and hip, however, experiments with HR-QCT
suggest that this method may underestimate vBMD variation in states of decreasing
adipose mass [45]
[46]. With regards the radius, the decrease in
trabecular vBMD is responsible for the decline in total vBMD, which occurs due to
changes within the cortical or both compartments, just as in the case of the tibia
[43]
[45]
[47]. A recent study followed
patients submitted to RYGB for seven years and found that BMD continued to decrease
progressively, regardless of the bone site evaluated (hip, spine, radius, and
tibia), and even after weight stabilization [48].
In addition, it is thought that SG also interferes in the production of multiple
gastrointestinal hormones that regulate appetite, such as ghrelin [49]. As this technique is relatively new when
compared with RYGB, it is not surprising that the data regarding its effects on the
skeleton are still limited. Despite this fact, a recent systematic review and
meta-analysis revealed that, after surgery, those patients submitted to SG presented
an increase in serum calcium, serum 25-hydroxyvitamin D, and serum phosphate, while
showing a decrease in serum Parathormone (PTH) levels. No change in serum alkaline
phosphatase was seen after SG. Furthermore, a significant decrease in hip BMD and
femoral neck BMD was reported. Interestingly, no changes in lumbar spine BMD were
detected after surgery [50]. The authors of
this recent review also pronounce on the observation that the magnitude of the
reductions of BMD among those submitted to SG appear to be lower than those reported
elsewhere for RYGB [37]. It is important to
stress that the majority of all the articles included in the analysis had a
follow-up period of 12 months, and that only one study presented a follow-up greater
than one year (60 months) [50]. A recent
observational study followed 48 patients submitted to SG for a period of four years.
At year 4, the rates of bone loss were: 8.1±5.5% for the femur neck,
2.0±7.2% for the lumbar spine; 7.7±6.4% for the
total hip, and 2.4±5.5% in for whole body BMI. This study, which
also followed 47 individuals submitted to RYGB, concluded that bone loss at four
years was comparable between procedures, although SG was associated with less bone
deterioration for total hip BMD [51]. Another
meta-analysis published in 2020 compared the changes in bone metabolism between SG
and RYGB. It found that, among SG patients, the circulating levels of calcium were
higher than those from RYGB, whereas those of phosphorus were lower. The alterations
in 25-hydroxyvitamin D after SG were also less significant than those detected after
RYGB. No differences in BMD were observed between the two groups regardless, of the
area evaluated. 8 of the 13 studies included had a follow-up of 12 months, 1 of 6
months, and only 4 presented a follow-up longer than a year [52]. Another recent study addressing
postmenopausal women found no significant differences between SG and RYGB in total
and regional BMD after surgery. However, despite this fact, there was a clear
decrease in the BMD of ribs and spine after surgery in both groups, which suggests
that DEXA could have an important role postoperatively among high-risk women [53].
Despite the increasing body of evidence to support the deleterious effects on bones
of both SG and RYGB, the currently-available data has several limitations. For
instance, most of the studies are small, with an average population of fewer than 30
patients, with short follow-ups. For these reasons, further research is required to
clarify not only the impact of SG on bone metabolism, but also the various other
differences in outcomes between these two bariatric procedures [54].
Bone fractures and bariatric surgery
Bone fractures and bariatric surgery
The most significant clinical consequence of bariatric surgery on the skeleton is
bone fracture – a condition which is associated with increased morbidity and
mortality [55]. Considering that bariatric
surgery (and malabsorptive procedures in particular) appears to be associated with
increased bone loss, it became crucial to understand whether this resulted in the
occurrence of fractures. The first steps were taken to clarify this relationship
during the decade of 2010 to 2020 [56].
The first meta-analysis on the subject of bone fracture comprised five studies and it
revealed that obese patients who have been submitted to bariatric surgery have a
higher risk for all types of fracture when compared with non-surgical control
individuals (note: this finding was even more pronounced in non-vertebral sites,
such as the upper limbs). In addition, it was also found that subjects submitted to
mixed procedures (with a component of restriction and another of malabsorption, such
as RYGB) had a tendency to present increased fracture risk in comparison with those
who underwent restrictive procedures [57].
Another systematic review consisted of 15 studies and was published the following
year, revealing that bariatric surgery patients were associated with a higher risk
of fracture when compared with individuals not submitted to surgery (but having a
similar baseline weight). This fact was seen most often among those submitted to
malabsorptive procedures. Three of these studies found that the fractures reported
were mainly located in the lower limbs (involving the tarsal, metatarsal, and
phalangeal bones). Interestingly, the meta-analysis of these trials did not exhibit
an increased risk of fractures among bariatric surgery patients (contrary to what
happened in purely observational studies) [58]. One of the explanations for this difference is the length of the
follow-up period. For to be able to accurately evaluate the long-term fracture risk
in such patients, it is essential that the length of follow-up periods is
sufficiently long enough for fractures to occur. This becomes evident when comparing
the results of observational studies which have more than five years follow-up [59]
[60]
[61]
[62]
[63]
with the first observational study, which had a shorter follow-up [64]. The most recent meta-analysis addressing
this issue was published at the end of 2020. It included 11 articles and states
that, on average, bariatric patients had 1.41 times more fracture risk when compared
with the non-surgical control group. Another relevant conclusion was that fracture
risk after surgery was site-specific, affecting more the upper limbs, spine, and hip
[65], which differs from the previous
systematic review [58]. These divergences
regarding fracture sites need to be clarified by carrying out with trials with
longer follow-up periods (in order to maximize fracture occurrence), although this
is an ideal scenario, which is difficult to achieve owing to increased follow-up
losses as time progresses [66]. Finally, the
risk of fracture associated with bariatric surgery continued to increase, even
during the 5th postoperative year, when surgical-induced weigh loss is no
longer occurs [65].
In conclusion, all the evidence to date seems to indicate that fracture risk after BS
varies according to the procedure, with consistent evidence implicating that RYGB
leads to an increased risk of clinically important fractures on one hand, while on
the other hand, studies on SG found that the risk of fracture after this type of
bariatric surgery is not greater than RYGB and could indeed potentially be even
less. Despite these facts, more research is needed on fracture risk after SG. Other
pertinent finding is that fracture risk appears to mainly occur two or more years
after surgery, and then increases during the following years. Finally, fractures
related with BS tend to occur at a much younger age than age-related fractures. Our
review thus highlights that fracture risk should be included as another factor for
consideration when deciding whether to opt for BS, especially among older patients
[56].
Bone loss after bariatric surgery: which factors need to be considered?
Bone loss after bariatric surgery: which factors need to be considered?
The detrimental effects of bariatric surgery on bone metabolism appear to have
multiple etiologies which are discussed below in this section ([Table 2]).
Mechanical factors
One of the first mechanisms to be proposed as a link between bone loss and BS was
mechanical unloading. For it is known that the skeleton adapts to the mechanical
strain, leading to alterations in bone mass and microarchitecture when weight
loading changes [67]. After being submitted to
BS, body weight decreases up to 30%, and this lower mechanical load can
contribute to reduced bone formation, augmented bone resorption, and decreased BMD
[16]. These effects seem to be mediated,
at least partially, by the increased secretion by osteocytes of sclerostin –
a negative regulator of bone formation [68].
However, mechanical factors cannot be cited as the cause of the continued loss of
bone mass, despite weight stabilization [47],
or even for altered bone architecture after BS in non-loading-bearing bone sites
[61]. This gap can be partially filled by
factors which are related to nutritional status.
Table 2 Effects of various players on bone and its variation
in obese states and after bariatric surgery.
|
Parameter
|
Overall action on bone
|
Variation of the plasmatic level
|
|
Obese vs. lean state
|
After surgery
|
|
SG
|
RYGB
|
|
Leptin
|
It is likely that leptin has an overall positive effect on bone.
The bone effects of leptin can be different, according to the
area of the skeleton studied [152].
|
↑
[153]
|
↓
[154]
|
↓
[154]
|
|
Adiponectin
|
Has a dual action with opposite outcomes on bone metabolism,
which makes its global effect uncertain [155].
|
↓
[153]
|
↑
[156]
|
↑
[156]
|
|
Ghrelin
|
Clinical data presents variable results, with some studies
finding a positive association between ghrelin and BMD [109], while others present
no significant association [96]
[110] or
even a deleterious effect on bone [111].
|
=/↓
[122]
|
↓
[122]
|
↓
[122]
/may be ↑ in the long
term
[108]
|
|
Resistin/Visfatin
|
Insufficient data to draw any clear role of these hormones on
bone.
|
↑
[153]
/=
[157]
|
?
|
?
|
|
Vitamin C
|
Positive correlation with BMD in multiple bone sites and an
association with decreased risk of BMD-independent fractures
[76]
[77].
|
↓
[158]
|
?
|
?
|
|
Vitamin E
|
Insufficient data. Seems to favor a net increase in bone mass and
to promote structural integrity of the skeleton [81].
|
?
|
?
|
?
|
|
Vitamin D
|
Overall positive effects on bone. Prolonged and severe vitamin D
deficiency leads to rickets in children and osteomalacia in
adults [159].
|
↓
[160]
|
↑
[161
]
(but depends on the efficacy of the
supplementation)
|
↑
[161]
(but depends on the efficacy of the supplementation)
|
|
Irisin
|
Overall positive effects in bone considering the available
evidence: low levels correlated with vertebral fractures; higher
levels associated with increased BMD/bone strength [128].
|
↑
[162]
[163]
|
?
|
?
|
|
Bile acids
|
Insufficient data. Positively correlated with BMD and negatively
correlated with bone turnover biomarkers reflecting bone
absorption in postmenopausal women [140].
|
↑
[164]
|
↑
[139]
|
↑
[139]
|
|
FGF-21
|
Insufficient data, with conflicting results. Some articles show
adverse effects on bone while one article on humans states that
FGF21 can increase bone mass in women through paracrine
mechanisms in the bone-adipose interface [165].
|
↑
[166]
|
↑/=
[146]
|
↑(post-prandrial)
[167 ]
/↓
[166]
|
|
GLP-1
|
Directly affects bone cells and regulates bone turnover by
increasing formation and decreasing resorption [115].
|
↓
[168]
|
↑
[107]
[169]
|
↑post-prandrial=fasting
[ 170]
|
|
GLP-2
|
Inhibits bone resorption with only minimal effects on bone
formation. Four months of treatment with GLP-2 increased hip BMD
in post-menopausal women [115].
|
↓
[171]
|
↑
[112]
|
↑
[112]
|
|
GIP
|
GIP has a direct effect on regulation on bone metabolism with
anabolic effects on osteoblasts and anti-resorptive effects on
osteoclasts [115].
|
=
[122]
|
=(fasting)
[107]
↑(post-prandrial)
[122]
|
?
[172]
|
|
PYY
|
PYY can play a role in bone mass regulation as evident from
association studies in populations with altered energy balance
(supported mostly from rodent studies) [115].
|
↓
[122]
|
=/↑ fasting [122]
↑postprandrial
[107]
|
=/↑ fasting
↑ postprandial [122]
|
=: Stable levels; ↑: Increased levels; ↓: Decreased
levels; ?: Findings need clarification; Note that this data is based upon
several papers, but many areas are still controversial, and studies have had
conflicting results. For that reason, the associations may change in the
future depending on the new findings in the area. This table aims to present
a summary of the most consistent patterns.
Nutritional factors
After BS, there is a reduction of the intake of various nutrients which have a
crucial role in maintaining bone mass, such as proteins, calcium, and vitamin D.
This diminished intake is also aggravated by malabsorption issues which arise after
surgery (mainly after RYGB, but also after SG), which thus paves the way for
alterations in bone metabolism and for presumably related fractures [19]
[21].
These post-surgical nutritional factors can also exacerbate pre-existing alterations
in phosphocalcium metabolism (such as vitamin D deficiency), which further
contributes to the development of secondary hyperparathyroidism (SHPT) [69]
. As a matter of fact, Vitamin D
insufficiency has been reported before surgery in up to 80% of bariatric
patients. In addition, several studies had demonstrated that, despite being
supplemented, patients presented calcium and vitamin D levels that were usually
below or in the lower end of the normal range after surgery [70]. Previous data revealed that patients with
stable or increased vitamin D levels had less bone loss at the femoral neck compared
to patients whose vitamin D level had declined [71]. Furthermore, patients who were randomized to take a high dose of
this vitamin presented less hip bone loss than those who received 800 IU daily [72]. This data supports the hypothesis that
maintaining normal vitamin D levels is essential to preserve hip bone after surgery.
Another study reported that, despite achieving vitamin D serum
levels˃30 ng/ml and a calcium intake of
1200 mg/daily, fractional calcium absorption decreased from
33±14% before BS to 7±4% in patients after RYGB,
leading to a reduction of the absolute amount of calcium absorbed daily (from
392±168 mg to 82±45 mg) [73]. In addition, recent research in
pre-menopausal women showed that calcium absorption was impaired after surgery
– not only among those submitted to RYGB, but also in those patients
undergoing SG (when calcium absorption was significantly reduced from
36.5±2.0% before SG, to 21.0±2.3% and
18.8±3.4% at 12 and 24 months after SG) [74]. This calcium malabsorption is believed to
be one on the main reasons for the increased levels of parathormone (PTH) after
bariatric surgery that has been described in several studies [16]
[37]
[71]. Interestingly, some data
report that the overall PTH action on bone metabolism could change according to the
type of bone (cancellous vs cortical). One study reported that in patients with
post-operative increases in PTH levels, lumbar spine BMD remained stable. In
addition, other studies where PTH was stable or decreased, showed that BMD
decreased, which supports the hypothesis that PTH can have a protective effect on
the cancellous bone of the lumbar spine. On the other hand, augmented PTH levels
appear to be associated with increased cortical bone loss in the tibia [70]
[75].
The true impact of secondary hyperparathyroidism after bariatric surgery on bone
metabolism is still a matter of debate nowadays and more studies are needed to
clarify this intricate relationship [67].
Another nutritional factor, which could also play a role in bone metabolism after
bariatric surgery is vitamin C. It is well known that scurvy (the lack of vitamin C)
is characterized by lower values of BMD and bone mineral content. Most research on
the impact of vitamin C on bone health in humans has reported a positive correlation
with BMD in multiple bone sites and also an association with decreased risk of
BMD-independent fractures. The effects of vitamin C include the stimulation of
osteoblast maturation and the inhibition of osteoclast activity [76]
[77].
Two of the studies carried out on levels of Vitamin C in bariatric patients showed
an increased level of this vitamin after RYGB (one and five years after surgery)
[78]
[79], while another study demonstrated that there was a significant
reduction in serum vitamin C levels 24 months after RYGB [80]. The role of this vitamin in bone
metabolism after bariatric surgery still needs clarification, as few papers have
been published on this issue, and those that have present conflicting results.
Vitamin E – a lipophilic vitamin with antioxidant properties, seems to favor
a net increase in bone mass and ensure structural integrity of the skeleton [81]. A review by Lewis et al. found no
significant changes to the prevalence of Vitamin E deficiency at 12 months, compared
to baseline. Despite this fact, one of the papers included in their review presented
a statistically significant decrease in average serum vitamin E levels at six months
after BS, and two other papers found a statistically significant decrease in average
vitamin E plasmatic levels at 12 months (both compared to baseline) [82]. A more recent systematic review showed
that patients undergoing malabsorptive procedures (such as RYGB) are at higher risk
of developing vitamin E deficiency, although clinical manifestations of this
deficiency are rarely reported [83].
Considering the apparent lower levels of Vitamin E after BS and its bone protective
effects, one can hypothesize that this vitamin is another link between BS and its
prejudicial effects on bones.
Dietary protein ingestion among bariatric patients after BS tends to be inadequate,
which can potentially lead to a decrease in lean body mass, diminished metabolic
rates, and physiological damage [84]. A study
carried out on a population of 30 women submitted to RYGB revealed that most amino
acids increased as early as three months after surgery, which probably reflects
muscle catabolism [85]. Recent evidence from a
study of 184 patients undergoing SG showed that the proportion of patients with
sarcopenia increased one year after surgery (8% before surgery vs
32% one year after) [86]. Considering
that sarcopenia (reduced muscle mass) is associated with a decrease in BMD and with
osteoporosis among human subjects [87]
[88], it becomes clear that muscle-bone unit can
also play a role in bone metabolism after BS. In addition, other papers have shown
that adequate protein intake after BS minimizes muscle and bone loss [32]
[89]
and raises awareness for the need for a personalized nutritional plan, which can
ultimately protect the skeleton of these individuals after surgery, considering
patients’ metabolic needs.
Hormonal factors
Despite the important role of mechanical and nutritional factors, hormonal changes
resulting from anatomical alterations and weight loss also have an impact on bone
metabolism after BS. One of the involved hormones is leptin – an adipokine
which is released in amounts that are proportional to whole body adipose tissue
[90]. Previous data demonstrated that
leptin promotes osteoblastogenesis and inhibits osteoclastogenesis through various
central and peripheral pathways, and that it also favoring osteoblast
differentiation and matrix mineralization [91]
[92]. In addition, a decrease in
this adipokine after RYGB was inversely correlated with increased levels of markers
of bone formation and resorption. The raise of resorption markers was more evident,
which indicates an overall effect toward bone loss [93]. This suggests that leptin has a net positive impact on BMD that is
then lost – at least partially – as its levels decline after surgery
(which is not only observed after RYBG, but also after SG) [94]. Interestingly, impaired leptin signaling
in the hypothalamus was found to be a predictor of decreased cortical bone mass and
overall BMD or content, albeit with a presumably related increase in trabecular bone
formation [95]. Apart from the overall
positive effect (supported by a meta-analysis by Biver et al. [96]), there is also evidence that leptin can
have a negative impact on bone, due to a central effect through a sympathetic
pathway, however further research on this issue is required [92].
Another potential link between BS and bone health is adiponectin – a bone
marrow fat-derived hormone which, similar to leptin, does not have a clearly
understood role in this relationship. Its serum levels – which are
negatively correlated with adipose mass – increase after BS [97]. Circulating adiponectin has been
associated with an overall anti-osteogenic effect on bone cells through indirect
stimulation of osteoclast formation [98].
Other possible mechanisms that result in bony deleterious effects originate from
adiponectin’s ability to bind growth factors and decrease plasmatic insulin
concentrations, which ultimately counteract the anabolic effects of these hormones
on the skeleton [21]. A meta-analysis of 59
papers demonstrated that adiponectin was negatively associated with BMD, independent
of peripheral fat mass parameters, menopausal status, and gender [96]. This association was also supported by a
prospective study of 42 women 12 months after RYGB [99]. Despite these findings, a correlation between the change in
adiponectin and increased plasmatic markers of bone turnover was not found in
another study of 20 patients who had been submitted to RYGB [93].
The effects of the other two adipokines – visfatin and resistin – in
this context are largely unknown. In the case of visfatin, no association between
BMD and its circulating levels has been found in the metadata or in other
cohort-independent studies [100]. Previous
data in non-bariatric patients revealed that resistin was a significant determinant
of lumbar spine BMD among middle-aged men [101], and that high serum resistin levels were found to be independent
contributors to low BMD in postmenopausal women [102]. Further research is required to clarify whether these adipokines
play a role in bone metabolism after BS. Another possible connection between BS and
bone loss is estrogen – a sex hormone that can be produced in adipose tissue
due to the conversion of testosterone into estradiol under the control of the
aromatase enzyme. This is the main process of estrogen generation in both men and
postmenopausal women. After BS, levels of estradiol were diminished in both men and
women with the expected weight loss and adipose tissue reduction [103]. Considering that estrogen acts to promote
bone formation and suppress bone absorption [104]
[105], the reduction of its
levels after BS could be another explanation for metabolic bone changes after
surgery.
In turn, the role of ghrelin in BS is still not very clear. This hormone –
which is produced in the gastric antrum and fundus – is thought to be an
important player in the long-term maintenance of energy stores as it stimulates
appetite and decreases energy expenditure [106]. A meta-analysis of 28 studies by McCarty et al. revealed that
fasting serum ghrelin levels decreased after SG [107], while another by Xu et al. of 16 papers showed that levels of
ghrelin decreased in the short term (≤3 months), and increased in the long
term (>3 months) after RYGB [108].
While studies in animals suggest an overall anabolic effect of this hormone on bone,
clinical data presents variable results, with some studies finding a positive
association between ghrelin and BMD [109],
while others present no significant association [96]
[110], or even a damaging effect
on bone [111]. Accordingly, the impact of
ghrelin on bone after BS remains still remains to be determined [21]. The glucagon-like peptides GLP-1 and GLP-2
– which are produced by intestinal L cells in response to food intake
– are two hormones whose postprandial circulating levels are increased after
RYGB and SG [112]
[113]. Similar to teduglutide, GLP2 receptor
agonists are used in the treatment of short bowel disorders, as they increase both
the bowel surface area and absorption [114].
The few papers to date on the effects of GLP-2 on human bone in vivo have showed
that GLP-2 inhibits bone resorption (measured as CTX), with only slight effects on
bone formation (measured as P1NP or osteocalcin). Research carried out on
post-menopausal women found conflicting results, with one study demonstrating that
four months of GLP-2 treatment increased hip BMD [115], while another found no association between GLP-2 activity and
osteoporosis [116]. In turn, studies in humans
concluded that GLP-1 has benefic effects on bone metabolism, probably through
augmented bone formation. No effect on serum CTX concentration was seen [117]. One of these investigations was conducted
in weight reduced women with obesity (after diet induced weight loss) and found that
treatment with a long-acting GLP-1 receptor agonist increased bone formation by
16% and prevented bone loss after weight loss following a low-calorie diet
[118]. This fact gains even more relevance
when we consider that GLP-1 receptor agonists are therapeutic options not only
before but also after bariatric surgery [119].
Studies in rats also support the positive impact of GLP-1 on bone strength and
quality, which sheds some light on the presumed role of this incretin in protection
against bone loss [115]
[117]. Despite these facts, recent evidence from
the meta-analysis shows that treatment with GLP-1 receptor agonists does not alter
the risk of bone fracture, when compared with treatment with other antidiabetic
drugs among patients with type 2 diabetes [120].
The gastric inhibitory peptide (GIP) – which is produced by the k-cells in
the proximal small intestine after food ingestion – is a hormone with
apparently positive effects on bone [67].
Evidence from studies in humans show that GIP reduces CTX independently of insulin,
and that a loss-of-function of GIP receptor is associated with decreased BMD,
together with an increased risk of fracture. Studies in vitro found that GIP also
inhibits osteoclast formation and resorption, while it reduces osteoblast cell death
[115]. One interesting article from
Torekov et al. also found an association between a functional GIP receptor
polymorphism Glu354Gln (rs1800437) and BMD and fracture risk, suggesting the
involvement of GIP in the regulation of bone mineral density [121]. Considering several studies have found
that the fasting and postprandial levels of this hormone decreased after RYGB, GIP
could be another connection in the complex influence of BS on bone. Interestingly,
GIP levels after SG were stable, or even increased – which raises several
unanswered questions about this issue [122].
Another gut hormone is Peptide YY (PYY) – a regulator of food intake that is
secreted by the enteroendocrine L cells of the distal gastrointestinal tract. It is
known that postprandial PYY levels are increased after RYGB and SG, although it
remains unclear whether the same happens during fasting [21]
[122].
Studies of the impact of GIP on bone in humans found an inverse relationship between
plasmatic GIP and BMD in populations with weight loss (↑PYY and ↓BMD
among patients with anorexia nervosa or submitted to RYGB). There is also evidence
for the direct effect of PYY on osteoblast and osteoclast activity, with a negative
association between PYY and osteoclast activity. In addition, mice without PYY
receptors presented an increase in bone mass and strength, although more research is
required to clarify the existent controversies regarding the effects of PYY on bone
[115].
Acknowledged factors for future lines of research
Acknowledged factors for future lines of research
During the last decade, the impact of microbiota in multiple aspects of metabolic
health of the human host has been established with ample evidence [123]. It is known that microbiota are
profoundly affected by BS, with an increase of Bacteroides and Proteobacteria, and a
decrease in Firmicutes post-operatively in most studies [124]. It is only now that the first steps are
being taken to study the influence of microbiota on bone and its related diseases
[125]
[126]. Interestingly, it is known that several members of the
Proteobacteria (augmented after BS) are associated with osteoporosis [125]. Despite this fact, the only paper that to
our knowledge exits which addresses the relationship between microbiota and BMD
found that gut microbiota presents little relevance for BMD [127]. Considering the lack of information
regarding the impact of changes microbiota after BS on bone, it is still too early
to state whether gut bacteria have a clear role in this issue.
During the past few years, the relation between irisin and bone has been often in the
spotlight [128]
[129]
[130]. Irisin is a molecule that is produced and released by myocytes, which
appears to have an overall positive effect in bone metabolism. The available
evidence shows that low levels of irisin are associated with vertebral fragility
fractures among post-menopausal women, and that levels of irisin are correlated
positively with BMD among geriatric men [128]
[131]. It is also known that
this molecule is associated positively with BMD and bone strength in athletes, and
research carried out on children described a positive association between serum
irisin and bone status in healthy children [128]. These benefic effects could be explained, at least in part, by the
stimulating effect of irisin on osteoblast proliferation and differentiation [132]. Intriguingly, evidence also exists that
treatment with irisin increases sclerostin production by osteocytes (leading to bone
resorption) and that the deletion of FNDC5 (precursor of irisin) prevents
ovariectomy-induced trabecular bone loss [133]. Another article which supports these findings concluded that irisin
directly stimulates both osteoclastogenesis and bone resorption in vivo and in vitro
[134]. With regards the levels of irisin
after SG, it was found that irisin levels increased after six months [135], while another study found no change in
its levels after surgery [136]. A third study
stated that circulating irisin levels decreased after SG and RYGB in comparison to
the baseline [137]. Similar to SG, post-RYGB
irisin levels also present conflicting results in several papers [67]. Accordingly, the impact of irisin on bone
still needs enlightenment, and this issue represents a promising area of research
among bariatric patients.
Bile acids (BA) are another player that has gained increasing attention over the
decade of 2010 to 2020 [138]. Accumulating
evidence has shown that levels of total fasting and postprandial plasma BA increase
after SG and RYGB and it is thought that these changes contribute to improved lipid
and glucose homeostasis, insulin sensitivity, and energy expenditure after BS [139]. BA also seem to have a metabolic effect
on bone, with a study in postmenopausal women revealing that total serum BA was
positively correlated with BMD, and negatively correlated with bone turnover
biomarkers of bone resorption [140]. In
addition, studies in mice found that the activation of the FXR BA receptor
significantly promoted osteoblastic differentiation and that FXR agonists suppressed
osteoclast differentiation from bone marrow macrophages. A histological study of
mice lumbar spine also demonstrated that FXR deficiency impaired bone formation
rate, as well as trabecular bone volume and thickness [141]. Interestingly, different types of BA can
have differing effects on bone. Ursodeoxycholic acid inhibits apoptosis and
increases survival and differentiation of human osteoblasts, thus neutralizing the
detrimental effects of lithocholic acid in these processes [142]. The effects of BA on bone among patients
submitted to BS are still not known, and this could be another interesting line of
future research.
FGF-21 is a hormone that is produced in the liver and adipocytes, which is positively
associated with poor metabolic health, being related with obesity, diabetes,
mitochondrial diseases, and ageing. It is also known that FGF-21 has several
musculoskeletal effects and that it is involved in muscle atrophy, bone loss and
reduced BMD [143]. One of the few studies
addressing FGF-21 levels after BS showed a significant increase in fasting FGF21,
especially one month after surgery [144],
while other stated that there was a 63% reduction in FGF-21 levels six
months after SG [145]. A paper from Khan et
al. reported that fasting and 120-minute postprandial FGF21 levels at one month were
increased, although these levels returned to baseline values three months after SG
[146]. In turn, Gómez-Ambrosi et
al. found that FGF21 levels were reduced one year after SG-induced weight loss, but
not after RYGB [147]. Therefore, the limited
evidence regarding FGF-21 and its impact on bone after BS presents new opportunities
for research in bariatric patients.
Other possible interesting line of research is the effect of diet-induced weight loss
effects on bone mass. A recent systematic review and meta-analysis of clinical
trials found that, in patients with overweight and obesity not submitted to
bariatric surgery, a single diet-induced weight-loss intervention leads to a small
decrease in total hip BMD (with decreases of 0.010 to
0.015 g/cm2), but not in lumbar spine BMD (in which
was not observed any statistically significant effect of diet-induced weight loss,
the same happening with whole body BMD) [148].
A subsequent paper, addressing this issue among older adults with obesity, stated
that several prospective observational and interventional studies confirm the
negative effects on skeletal health outcomes of intentional weight loss achieved by
lifestyle changes. These effects seem to be modest but persistent in the long term
[149]. So, it would be interesting to know
if different long-term dietary patterns after bariatric surgery can modulate bone
metabolism and these effects on bone mass.
Bariatric surgery is also an option for several patients with heterozygous mutations
of genes related with genetic obesity (such as MC4R, POMC, PCSK1, SIM1, or PTEN)
[150]. Patients with mutations in MC4R
gene had higher BMD than matched control participants, underlining a probable
influence of genes in these relationship between obesity and bone metabolism (that
can, in theory, be also a factor to consider after bariatric surgery) [151].
Conclusion
The impact of bariatric surgery on bone is field of research that has seen a
significant breakthrough over the last decade of 2010 to 2020. Several factors that
have an impact of bariatric surgery on bone health have been identified, however,
how they interact to regulate bone metabolism after metabolic surgery is still
largely unknown. For this reason, we believe that this area of research will
progress positively and advances the frontier of knowledge over the next decade.
Understanding these relationships is crucial to avoid bone loss and to decrease
fracture risk after BS and raises awareness of this problem and can possibly lead to
improving therapeutical options.
