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Vitamin D and Nutritional Status are Related to Bone Fractures in Alcoholics

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Bone fractures are common in alcoholics. To analyse which factors (ethanol consumption; liver function impairment; bone densitometry; hormone changes; nutritional status, and disrupted social links and altered eating habits) are related to bone fractures in 90 alcoholic men admitted to our hospitalization unit because of organic problems. Bone homoeostasis-related hormones were measured in patients and age- and sex-matched controls. Whole-body densitometry was performed by a Hologic QDR-2000 (Waltham, MA, USA) densitometer, recording bone mineral density (BMD) and fat and lean mass; nutritional status and liver function were assessed. The presence of prevalent fractures was assessed by anamnesis and chest X-ray film. Forty-nine patients presented at least one fracture. We failed to find differences between patients with and without fractures regarding BMD parameters. Differences regarding fat mass were absent, but lean mass was lower among patients with bone fracture. The presence of fracture was significantly associated with impaired subjective nutritional evaluation (χ² = 5.79, P = 0.016), lower vitamin D levels (Z = 2.98, P = 0.003) and irregular eating habits (χ² = 5.32, P = 0.02). Reduced lean mass and fat mass, and altered eating habits were more prevalent among patients with only rib fractures (n = 36) than in patients with multiple fractures and/or fractures affecting other bones (n = 13). These last were more closely related to decompensated liver disease. Serum vitamin D levels showed a significant relationship with handgrip strength (ρ = 0.26, P = 0.023) and lean mass at different parts of the body, but not with fat mass. By logistic regression analysis, only vitamin D and subjective nutritional evaluation were significantly, independently related with fractures. Prevalent fractures are common among heavy alcoholics. Their presence is related more closely to nutritional status, lean mass and vitamin D levels than to BMD. Lean mass is more reduced, nutritional status is more impaired and there is a trend to more altered eating habits among patients with rib fractures, whereas multiple fractures depend more heavily on advanced liver disease.
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CLINICAL FEATURES
Vitamin D and Nutritional Status are Related to Bone Fractures in Alcoholics
Emilio González-Reimers1,*, Julio Alvisa-Negrín1, Francisco Santolaria-Fernández1, M. Candelaria Martín-González 1,
Iván Hernández-Betancor 1, Camino M. Fernández-Rodríguez1, J. Viña-Rodríguez1and Antonieta González-Díaz2
1
Servicio de Medicina Interna, Hospital Universitario, Universidad de La Laguna, Ofra s/n, Tenerife, Canary Islands, Spain and
2
Servicio de Medicina
Nuclear, Hospital Universitario, Universidad de La Laguna, Tenerife, Canary Islands, Spain
*Corresponding author: Tel.: +34-922-678600; Fax: +34-922-319379; E-mail: egonrey@ull.es
(Received 4June 2010; in revised form 15 November 2010; accepted 7December 2010)
Abstract Background: Bone fractures are common in alcoholics. Aims: To analyse which factors (ethanol consumption; liver
function impairment; bone densitometry; hormone changes; nutritional status, and disrupted social links and altered eating habits)
are related to bone fractures in 90 alcoholic men admitted to our hospitalization unit because of organic problems. Methods: Bone
homoeostasis-related hormones were measured in patients and age- and sex-matched controls. Whole-body densitometry was per-
formed by a Hologic QDR-2000 (Waltham, MA, USA) densitometer, recording bone mineral density (BMD) and fat and lean mass;
nutritional status and liver function were assessed. The presence of prevalent fractures was assessed by anamnesis and chest X-ray
film. Results: Forty-nine patients presented at least one fracture. We failed to find differences between patients with and without frac-
tures regarding BMD parameters. Differences regarding fat mass were absent, but lean mass was lower among patients with bone
fracture. The presence of fracture was significantly associated with impaired subjective nutritional evaluation (χ
2
= 5.79, P= 0.016),
lower vitamin D levels (Z= 2.98, P= 0.003) and irregular eating habits (χ
2
= 5.32, P= 0.02). Reduced lean mass and fat mass, and
altered eating habits were more prevalent among patients with only rib fractures (n= 36) than in patients with multiple fractures and/
or fractures affecting other bones (n= 13). These last were more closely related to decompensated liver disease. Serum vitamin D
levels showed a significant relationship with handgrip strength (ρ= 0.26, P= 0.023) and lean mass at different parts of the body, but
not with fat mass. By logistic regression analysis, only vitamin D and subjective nutritional evaluation were significantly, indepen-
dently related with fractures. Conclusion: Prevalent fractures are common among heavy alcoholics. Their presence is related more
closely to nutritional status, lean mass and vitamin D levels than to BMD. Lean mass is more reduced, nutritional status is
more impaired and there is a trend to more altered eating habits among patients with rib fractures, whereas multiple fractures depend
more heavily on advanced liver disease.
INTRODUCTION
Bone loss and fractures are common events in alcoholics,
due in part to both direct and indirect effects of ethanol on
bone remodelling (Diamond et al., 1989;Leslie et al., 2003;
Peris et al., 1995;Spencer et al., 1986;Wezeman et al.,
2000; ) in a dose-dependent fashion (Turner, 2000), but also
to the peculiar style of life of the alcoholic, prone to falls,
traffic accidents and violence. The term Battered alcoholic
syndromewas coined >30 years ago by Oppenheim (1977)
to define the situation of a chronic alcoholic who presented
with at least three bone fractures, at different sites and in
different healing stages.
Among alcoholics, probably rib fractures constitute the
most frequently observed ones (González-Reimers et al.,
2005), and in many cases, the patients are not aware of them,
partly due to the anaesthetic effect of ethanol, but also
because of inebriation. Although rib fractures have not been
considered as classic osteoporotic fractures, in a large study
including nearly 6000 elderly men, rib fractures were the most
commonly observed ones, and they were related in most cases
to falls from the standing position (Barrett-Connor et al.,
2010). Importantly, hip bone density was an independent risk
factor for rib fracture, and also, rib fracture was an indepen-
dent risk factor for a new hip fracture. Therefore, at least in
elderly men (Barrett-Connor et al., 2010), rib fracture should
be considered as an osteoporotic fracture, in a similar way as
wrist or hip fractures. A similar conclusion was reached by
Ismail et al. (2006), especially among women. However, falls
from standing height being the main cause of rib fracture,
inebriation, muscle atrophy and/or neuropathy, and the
peculiar style of life of the alcoholic patient surely play a role
in the high prevalence of these fractures. For instance, Keso
et al. (1988) found that thoracic fractures were more com-
monly observed among unmarried, divorced or widowed alco-
holics. However, in addition to these factors, it is clear that
heavy prolonged ethanol consumption also constitutes a risk
for classic osteoporotic fractures, such as hip fracture (Felson
et al., 1988). Indeed, ethanol exerts direct effects on bone syn-
thesis and resorption, leading to decreased bone mass. Besides
these direct effects, altered nutrition (Santolaria et al., 2000),
altered liver function (Chappard et al., 1991;Jorge-Hernández
et al., 1988) and ongoing drinking (Alvisa-Negrín et al.,
2009;Peris et al., 1994) also play a role.
The main objective of this study was to analyse which
factors (ethanol consumption; liver function impairment;
bone densitometry; hormone alterations; nutritional status
and environmental factors related with job, social status and
eating habits) are related to bone fracture in a cohort of 90
heavy-alcoholic men admitted to our hospitalization unit
because of organic problems. Since, as commented, subtle
differences, largely depending on the style of life and social
environment of alcoholics, may exist between the mechan-
isms leading to rib fractures and the classical osteoporotic
fractures in these patients, we have compared all the data
mentioned before among patients with only rib fractures and
patients with other types and/or multiple fractures.
PATIENTS AND METHODS
Patients and controls
We included 90 alcoholic patients, aged 50.14 ± 10.99 years
(median = 49; inter-quartile range (IR) = 4258), all of whom
Alcohol and Alcoholism Vol. 46, No. 2, pp. 148155, 2011 doi: 10.1093/alcalc/agq098
Advance Access Publication 19 January 2011
© The Author 2011. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved
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were heavy drinkers of more than 100 g ethanol/day (212 ±
79 g/day) for prolonged time periods (29.4 ± 9.7 years) until
the day of admission, and 30 age-matched controls, who
were sanitary workers and drinkers of <10 g/day. The total
amount of ethanol consumed by the patients until the
inclusion in the study was 33.88 ± 16.36 kg ethanol/kg body
weight (median = 33; IR = 1950). In 50 cases, serology for
hepatitis C virus (HCV) and hepatitis B virus (HBV) was
performed, being positive in 10 cases for HCV and in 4 for
HBV (anticore antibodies; surface antigen was negative in
all cases). Patients were also categorized into cirrhotics and
non-cirrhotics according to clinical grounds and ultrasound
findings, and to liver biopsy when clinically indicated. A
total of 40 cirrhotics were included; Childs classification
(based on the presence and characteristics of ascites and
encephalopathy, and on serum albumin, bilirubin and pro-
thrombin activity) was used to assess severity. According to
this score, 2 patients belong to Child A (less severe), 13 to
Child B (moderately severe) and 25 to Child C (most severe)
groups. Strictly speaking, the Child-Pugh score is only appli-
cable to cirrhotics. However, alcoholic liver disease is an
ongoing process, and decompensated liver cirrhosis is the
last stage of it. It is difficult, sometimes, to differentiate
between compensated cirrhosis (i.e. Child A patients) and
non-cirrhotic alcoholic liver disease on clinical grounds only,
as it happens in this study with two patients who did not
undergo liver biopsy, whereas it is relatively easy to clearly
identify decompensated (Child C) cirrhotics. Therefore, we
have also classified our sample in two groups: decompen-
sated (Child C) patients and compensated (non-cirrhotics +
Child A and Child B) ones.
The presence of fracture was recorded by anamnesis and
examination of clinical records and thoracic X-ray. If a rib
fracture was discovered in the X-ray plain film without
having been reported by the patient, the patient and their
relatives were asked again. Forty-nine patients had suffered
fractures at the inclusion in the study: rib fracture, affecting
one or two adjacent ribs, in 36 cases, three or more rib frac-
tures affecting non-consecutive ribs (more than one fracturing
episode), and/or non-simultaneous fractures in other places,
in 9 further cases, 2 cases of hip fracture, distal radius in one
case and multiple simultaneous fractures (traffic accident) in
one further case. We classified our patients in those with
only rib fractures (n= 36) and those with multiple + osteo-
porotic fractures (n= 13).
Following a previously reported protocol (Santolaria
et al., 2000), we also recorded the following: (a) the
eating habits of the patients, asking them where they
usually eat (if at home or in bars or taverns), how many
times a day they eat and what they eat (sandwiches or
snacks, or normal dishes), classifying them in three cat-
egories: normal: the patient eats three times a day (break-
fast, lunch and dinner), usually at home, with the family;
irregular habits (loss of some meals, substitution of some
dishes by snacks); and poor eating habits (usually in bars
or taverns, in the form of sandwiches or snacks, once or
twice daily); (b) the social environment of the patient ,
also classifying it into three categories (the best one: with
stable family and work; deranged: living alone, widowed,
unmarried or divorced, eventually unemployed; and the
worst one: skid-row patients, i.e. lonely, unemployed and/
or homeless patients, usually heavy drinkers).
Nutritional evaluation
In addition, subjective nutritional evaluation was performed
to all the patients, as follows: we examined the muscle
masses of the upper and lower limbs and of the temporal
muscle, defining two degrees of atrophy (severe, moderate)
and absence of atrophy, and assigned 2, 1 and 0 points to
each category, respectively. We also recorded, by physical
examination, the fat loss on the cheek and abdomen,
Bichats fat and subcutaneous fat atrophy, and classified
them in a similar way, and defined a score (SNS), based on
the sum of the assigned points, for which the poorest value
was 10 and 0 the best one was. We further classified our
patients as well nourished (02 points), moderately under-
nourished (34 points) and severely undernourished (510
points), since this classification is related to the prognosis
(Hernández-Plasencia et al., 1991).
We recorded handgrip strength with a dynamometer, body
mass index, triceps skinfold with a Holtain lipocaliper and
brachial perimeter with a tap, and determined serum biliru-
bin, prothrombin activity and serum albumin and other
routine laboratory tests. We also collected blood samples
after overnight fast. Samples were stored at 80°C until the
following hormones and biochemical markers were
determined.
Whole body composition
After informed consent, the 90 patients and 30 controls
underwent assessment of bone mineral density (BMD), as
well as lean mass and fat mass (only 26 controls) at different
body parts, such as arms, ribs, legs, trunk and total body,
with a HOLOGIC QDR-2000 (Waltham, MA, USA). In 85
cases and 28 controls, BMD was assessed at the lumbar
spine and hip, recording BMD and Z- and T-scores (defined
following standard criteria, Cummings et al., 2002) at the
femoral neck, trochanter, Wards triangle, intertrochantereal
area, total hip and lumbar spine (L2L4).
Biochemical parameters
We determined serum osteocalcin (to 79 patients), by immu-
nometric chemiluminiscent assay (recovery = 97121%; vari-
ation coefficients of assays ranging from 3.5 to 7.1%; DPC,
Los Angeles, CA, USA), as a marker of bone synthesis, and
C-terminal telopeptide of type I collagen (CrossLaps), by
one-step enzyme-linked immunosorbent assay (ELISA), with
a recovery ranging from 94 to 107% and an intra- and inter-
assay variation coefficient ranging 4.74.9 and 5.48.1%,
respectively (Osteometer Bio Tech A/S, Herlev, Denmark),
as a marker of bone breakdown in non-cirrhotics. This par-
ameter was determined only to 53 patients. We also deter-
mined serum IGF-1 (Chemiluminiscent assay, DPC, Los
Angeles, CA, USA) to 87 patients; 1, 25 dihydroxyvitamin
D3 to 73 patients (radioimmunoassay, Nichols, San Juan
Capistrano, CA, USA), parathyroid hormone (PTH) to 87
patients; serum free testosterone to 49 patients; serum
RANKL, to 50 patients, by ELISA, with a sensitivity of
0.08 pmol/l and a variation coefficient of 5% or less
(intra-assay) and 9% or less (Immundiagnostik, Bensheim,
Germany); and osteoprotegerin to 64, by sandwich ELISA,
with a sensitivity of 0.14 U/l, and intra-assay and inter-assay
Bone Fractures in Alcoholics 149
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variation coefficients <10% (Biovendor, Brno, Czech
Republic).
The study protocol was approved by the local ethical com-
mittee of our Hospital (2009/23) and conforms to the ethical
guidelines of the 1975 Declaration of Helsinki.
Statistics
The KolmogorovSmirnov test was used to test for normal
distribution, a condition not fulfilled by PTH, vitamin D,
IGF-1 and serum telopeptide. Therefore, non-parametric
tests, such as MannWhitneysUtest and KruskallWallis,
were used to analyse differences of these parameters between
groups. Studentst-test, variance analysis and Pearsons cor-
relation analysis were used with the remaining parameters
(related to bone mass), whereas Spearmans rho (instead of
Pearsons correlation) was utilized in the case of non-
parametric variables.
To assess which parameters the presence of fracture
depends on, we performed stepwise logistic regression analy-
sis between fracture and several variables, which showed a
relation with fractures in the univariate analysis, or which
could be potentially involved in the pathogenesis of fractures,
as commented in the results section, and also, among those
with fracture, a logistic regression analysis to discern which
factors were associated with rib fractures or with multiple
fractures. All these analyses were performed with the SPSS
program (Chicago, IL, USA).
RESULTS
Differences between patients and controls
Differences in clinical and biochemical parameters between
patients and controls, as well as T-score values for lumbar
spine and hip, and BMD at several parts of the skeleton are
shown in Table 1. Decreased BMD was observed in the
included patients, who also showed lower T-scores than con-
trols. In Table 1, we also show data relative to lean and fat
mass. Clearly, patients showed less lean mass, but a similar
amount of fat (besides at the trunk) than controls.
Differences between patients with fractures
and without fractures
As shown in Table 2, 49 patients presented at least one bone
fracture at the time of inclusion. We failed to find differences
between patients with and without fractures regarding BMD
parameters. On the contrary, there were significant differ-
ences regarding lean mass, especially between patients with
rib fracture and patients with other types of fractures and
non-fractured patients. Although there was also a trend
Table 1. Clinical and biochemical parameters in patients and controls. Results are given as mean ± standard deviation and, in those non-parametric variables,
also median (inter-quartile range). Data relative to lean and fat mass include only 26 controls
Patients (90) Controls (30) T (Z); P-value
Age (years) 50.14 ± 10.49 50.11 ± 10.40 T= 0.03; NS
Serum ASAT (U/l ) 114.0 ± 99.5
Serum ALAT (U/l ) 59.4 ± 41.8
Serum GGT (U/l) 302.5 ± 455.5
Osteocalcin (ng/ml ) 3.13 ± 3.18 7.37 ± 2.69 T= 4.73; P< 0.001
Serum telopeptide (nmol/l) 0.603 ± 0.388 0.53 (0.430.65) 0.211 ± 0.095 0.17 (0.140.34) Z= 4.9; P< 0.001
Serum vitamin D (pg/ml ) 28.27 ± 14.68 24.00 (17.037.5) 85.37 ± 27.10 88.39 (59.18112.55) Z= 5.2; P< 0.001
Serum IGF-1 (ng/ml) 106.73 ± 97.82 62.6 (32.6153.0) 192.00 ± 106.13 135.00 (121.38259.9) Z= 4.21; P< 0.001
Serum PTH (pg/ml ) 64.95 ± 86.12 41.80 (25.9075.50) 87.95 ± 141.15 40.84 (19.3765.31) Z= 0.7; NS
Serum free testosterone (ng/dl) 10.06 ± 10.58 7.82 (3.0713.38) 18.09 ± 3.84 18.41 (14.8120.44) Z= 3.79; P< 0.001
Serum cortisol (µg/dl) 14.32 ± 5.58 18.19 ± 4.55 T= 2.66; P= 0.009
Serum osteoprotegerin ( pmol/l) 12.86 ± 6.54 6.83 ± 1.79 T= 3.54; P< 0.001
Serum RANKL (pmol/l ) 0.14 ± 0.22 0.06 (0.010.17) 0.08 ± 0.07 0.08 (0.020.15) Z= 0.03; NS
Subtotal BMD (g/cm
2
) 0.98 ± 0.10 1.08 ± 0.08 T= 4.96; P< 0.001
Pelvis BMD (g/cm
2
) 1.04 ± 0.15 1.18 ± 0.13 T= 4.85; P< 0.001
Right leg BMD (g/cm
2
) 1.22 ± 0.13 1.35 ± 0.12 T= 5.22; P< 0.001
Left leg BMD (g/cm
2
) 1.22 ± 0.13 1.36 ± 0.12 T= 5.38; P< 0.001
Left arm BMD (g/cm
2
) 0.80 ± 0.10 0.85 ± 0.08 T= 2.75; P= 0.007
Right arm BMD (g/cm
2
) 0.81 ± 0.08 0.83 ± 0.07 T= 1.32; NS
Left rib BMD (g/cm
2
) 0.61 ± 0.07 0.70 ± 0.07 T= 6.45; P< 0.001
Right rib BMD (g/cm
2
) 0.60 ± 0.07 0.70 ± 0.06 T= 6.96; P< 0.001
Thoracic spine BMD (g/cm
2
) 0.90 ± 0.13 0.98 ± 0.11 T= 2.94; P= 0.004
Total hip T-score 1.05 ± 1.16 (n= 85) 0.07 ± 1.18 (n= 28) T= 3.48; P< 0.001
Lumbar spine T-score 1.15 ± 1.18 (n= 85) 0.56 ± 0.90 (n= 28) T= 2.12; P= 0.036
Left arm lean (g) 2535 ± 608 3000 ± 448 T= 3.62; P< 0.001
Right arm lean (g) 2781 ± 595 3099 ± 469 T= 2.51; P= 0.013
Trunk lean ( g) 26,301 ± 3655 26,094 ± 3008 T= 0.26; NS
Left leg lean (g) 7191 ± 1596 8187 ± 1135 T= 2.97; P= 0.004
Right leg lean (g) 7467 ± 1563 8467 ± 1024 T= 3.07; P= 0.003
Total lean ( g) 49,951 ± 6984 53,032 ± 5927 T= 1.98: P= 0.05
Left arm fat (g) 1322 ± 749 1429 ± 516 T= 0.69; NS
Right arm fat (g) 1438 ± 916 1536 ± 575 T= 0.52; NS
Trunk fat (g) 8812 ± 5057 11,770 ± 3860 T= 2.76; P= 0.007
Left leg fat (g) 3071 ± 1528 3330 ± 1042 T= 0.81; NS
Right leg fat (g) 3044 ± 1516 3379 ± 1057 T= 1.05; NS
Total fat (g) 18,706 ± 9273 22,366 ± 6364 T= 1.89; NS
150 González-Reimers et al.
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regarding fat parameters, differences were not statistically
significant ( probably due to the higher values of standard
deviations).
When patients with rib and multiple fractures were pooled
together and compared with patients without fracture regard-
ing lean and fat mass, significant differences were observed
only regarding right arm lean mass, lower among those with
fracture (2660 ± 555 g) than among those without fracture
(2925 ± 615 g, t= 2.15; P= 0.034). The presence of fracture
was significantly associated with subjective nutritional evalu-
ation (χ
2
= 5.79, P= 0.016). Indeed, 12 out of 49 individuals
with fracture (24.49 %) were severely undernourished, in
contrast with 3 out of 41 without fracture (7.32%). A non-
significantly higher proportion of patients with multiple frac-
tures (53.85%) were well nourished when compared with
patients with only rib fractures (47.22%).
Among biochemical parameters, only vitamin D (KW =
9.18, P= 0.01; Table 2) was lower among those with frac-
tures, both among those with only rib fractures and among
those with multiple fractures. When all the patients with frac-
ture were grouped and compared with those without fracture,
serum levels of 1, 25 (OH)
2
D3 were significantly lower in
the former (median (IR) = 21 (1527) pg/ml ) than in the
latter (35 (2144) pg/ml; Z= 2.98; P= 0.003). Interestingly,
serum vitamin D levels showed a significant relationship
with handgrip strength (ρ= 0.24, P= 0.046), left arm lean
Table 2. Body composition analysis, including bone mineral density (BMD, in g/cm
2
), lean mass and fat mass and biochemical and epidemiological
parameters in patients with and without fractures. Results are given as mean ± standard deviation and, in those non-parametric variables, also median
(inter-quartile range)
Only rib fracture (n= 36) Hip + multiple fracture (n= 13) No fracture (n= 41)
Left arm BMD 0.79 ± 0.10 0.78 ± 0.09 0.81 ± 0.10 F= 0.82; NS
Right arm BMD 0.81 ± 0.08 0.79 ± 0.08 0.82 ± 0.09 F= 0.62; NS
Left ribs BMD 0.60 ± 0.08 0.62 ± 0.08 0.60 ± 0.07 F= 0.43; NS
Right ribs BMD 0.60 ± 0.07 0.62 ± 0. 09 0.60; ± 0.07 F= 0.50; NS
Thoracic spine BMD 0.89 ± 0.11 0.88 ± 0.15 0.92 ± 0.15 F= 0.84; NS
Lumbar spine BMD 0.95 ± 0.12 0.93 ± 0.18 0.98 ± 0.18 F= 0.44; NS
Pelvis BMD 1.03 ± 0.13 1.04 ± 0.19 1.05 ± 0.16 F= 0.15; NS
Left leg BMD 1.20 ± 0.12 1.20 ± 0.15 1.24 ± 0.14 F= 1.03; NS
Right leg BMD 1.21 ± 0.12 1.20 ± 0.16 1.23 ± 0.13 F= 0.43; NS
Subtotal BMD 0.98 ± 0.09 0.97 ± 0.12 0.99 ± 0.10 F= 0.29; NS
Osteocalcin (ng/ml ) (31/12/36) 2.38 ± 2.01 1.70
(1.102.85)
2.61 ± 1.48 2.40
(1.353.80)
3.95 ± 4.14 2.05
(1.006.45)
KW = 0.65; NS
Serum telopeptide (nmol/l)
(23/9/21)
0.58 ± 0.27 0.54
(0.440.64)
0.75 ± 0.81 0.46
(0.340.75)
0.56 ± 0.20 0.54
(0.420.67)
KW = 0.37; NS
Serum vitamin D (pg/ml)
(28/12/32)
24.06 ± 10.97 24.0
(15.027.0)
24.00 ± 17.45 19.0
(15.024.8)
33.69 ± 15.15 35.0
(21.044.0)
KW = 9.18; P= 0.01
Serum PTH (pg/ml) (35/13/39) 56.63 ± 48.20 40.6
(25.472.4)
125.71 ± 190.67 54.8
(36.691.6)
52.17 ± 41.61 39.5
(24.267.5)
KW = 2.69; NS
Free testosterone (ng/dl) (15/6/28) 7.40 ± 5.31 6.9
(3.212.9)
8.10 ± 6.78 6.90
(2.0512.93)
11.91 ± 12.95 8.27
(2.1717.70)
KW = 0.56; NS
Serum cortisol (µg/dl) (33/12/36) 13.34 ± 4.35 14.24 ± 6.23 15.25 ± 6.31 F= 1.00; NS
Osteoprotegerin (pmol/l)
(27/8/29)
13.60 ± 7.47 12.50 ± 5.24 12.27 ± 5.89 F= 0.30; NS
Serum RANKL (pmol/l )
(19/8/23)
0.15 ± 0.25 0.06
(0.010.21)
0.17 ± 0.30 0.05
(0.0130.23)
0.11 ± 0.16 0.04
(0.020.11)
KW = 0.07 NS
Serum IGF-1 (ng/ml) (33/13/33) 122.9 ± 103.6 94.3
(35.7195)
84.8 ± 81.9 32.6
(25.9148.9)
99.2 ± 97.7 55.4
(41.7127.0)
KW = 3.13; NS
Age (years) 49.22 ± 8.47 52.31 ± 15.11 50.26 ± 11.63 F= 0.38; NS
Total hip T-score (35/13/37) 1.14 ± 1.14 1.14 ± 1.26 0.90 ± 1.11 F= 0.48; NS
L2L4 T-score (35/13/37) 1.13 ± 0.82 1.54 ± 1.58 1.13 ± 1.35 F= 0.65; NS
Left arm lean (g) 2344 ± 539 2745 ± 547 2636 ± 600 F= 3.27; P= 0.04,
1 vs. 2
Right arm lean (g) 2598 ± 529 2830 ± 611 2925 ± 615 F= 3.09; P= 0.051
Trunk lean ( g) 25,094 ± 2742 28,790 ± 3296 26,571 ± 4060 F= 5.62; P= 0.005,
2 vs. 1,3
Left leg lean (g) 6794 ± 1358 7665 ± 1209 7388 ± 1834 F= 2.05; NS
Right leg lean (g) 7130 ± 1381 7778 ± 1292 7664 ± 1758 F= 1.44; NS
Total lean ( g) 47,528 ± 5447 53,576 ± 6259 50,930 ± 7765 F= 4.68: P= 0.012,
1 vs. 2,3
Left arm fat (g) 1101 ± 598 1499 ± 609 1458 ± 867 F= 2.70; NS
Right arm fat (g) 1172 ± 677 1606 ± 684 1618 ± 1105 F= 2.61; NS
Trunk fat (g) 7713 ± 5998 10,614 ± 3595 9206 ± 4386 F= 1.83; NS
Left leg fat (g) 2764 ± 1471 3483 ± 1303 3211 ± 1623 F= 1.38; NS
Right leg fat (g) 2695 ± 1470 3537 ± 1182 3194 ± 1611 F= 1.88; NS
Total fat (g) 16,466 ± 10333 21,725 ± 6653 19,715 ± 8722 F= 2.03; NS
Handgrip strength ( pounds) 142.8 ± 69.3 108.3 ± 60.9 163.7 ± 80.6 F= 2.64; NS
Triceps skinfold (mm) 8.14 ± 5.34 8.69 ± 6.69 8.45 ± 6.07 F= 0.05; NS
Brachial perimeter (cm) 27.46 ± 4.68 26.85 ± 3.65 27.24 ± 4.06 F= 0.10; NS
Daily ethanol consumption ( g) 208 ± 79 213 ± 80 215 ± 81 F= 0.07; NS
Years of consumption 30 ± 8 33 ± 14 27 ± 9 F= 1.73 NS
Body mass index (kg/m
2
) 24.02 ± 3.42 25.99 ± 3.11 25.54 ± 4.03 F= 1.83; NS
Bone Fractures in Alcoholics 151
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mass (ρ= 0.26, P= 0.024), right arm lean mass (ρ= 0.31, P
= 0.004), trunk lean mass (ρ= 0.26, P= 0.024) and total lean
mass (ρ= 0.28, P= 0.017), but not with fat mass.
Irregular feeding habits were significantly associated with
an increased risk of fractures (χ
2
= 5.32, P= 0.021). Also, a
nearly significant association was found between the type of
fracture and eating habits: normal eating habits were
recorded only in 18.2% of the alcoholics with multiple frac-
tures, in 8.82% of those with only rib fractures, but in
40.62% of patients without fractures (P= 0.057).
A non-significant trend was observed between deranged
social environment and fracture (P= 0.14). Social links were
not disrupted in 69.7% of those without fractures, in 63.6%
with multiple fractures and in 52.94% with only rib fractures.
Relationships between type of fracture, liver function,
alcohol intake and tobacco
Thirteen patients were affected by multiple fractures. Of
these, eight were cirrhotics and five non-cirrhotics, However,
neither the association between cirrhosis and type of fracture
(χ
2
= 1.63, P= 0.2) nor the association between cirrhosis and
any kind of fracture (χ
2
= 0.87, P= 0.3; Table 3) were statisti-
cally significant. There were no relationships between both
the type of fracture and the presence of fracture with any of
the variables included in the Child-Pughs score (ascites,
encephalopathy, prothrombin, albumin and bilirubin). We
also failed to find an association between Childs severity
groups and the presence of fracture (χ
2
= 0.04, P= 0.8) or the
kind of fracture (χ
2
= 0.79, P= 0.3). However, when patients
of the Child C groups were compared with the remaining
patients, the proportion of multiple fractures was
significantly higher (32 vs. 7.7%) among Child C patients,
and that of only rib fractures was slightly higher (43.1 vs.
32%) among compensated patients (χ
2
=5; P= 0.025;
Table 3).
Cirrhotics showed in general lower T-score values at the
lumbar spine (t= 3.15, P= 0.003), but not at the femoral neck,
and also lower BMD values at different parts of the skeleton
(Table 4). Cirrhotics showed lower values of vitamin D (Z=
2.54, P= 0.011) and IGF-1 (Z=3.2, P= 0.001) than non-
cirrhotics, but no differences in lean or fat mass.
Significant differences in total BMD (t= 2.15, P= 0.034),
total hip T-score (t= 2.13, P= 0.036) and lumbar spine
T-score (t= 2.42, P= 0.018) were observed between patients
with decompensated liver disease (Child C patients, who
showed lower values of the aforementioned parameters)
and those without decompensated liver disease. In addi-
tion, decompensated patients showed lower IGF-1 (Z= 3.61,
P< 0.001) and testosterone (Z= 2.19, P= 0.028) and also
nearly significantly lower vitamin D levels (Z= 1.91, P=
0.056) than the remaining patients. No differences were
observed in lean and fat mass, except trunk lean mass, which
was significantly higher (t= 2.42, P= 0.018) in decompen-
sated patients (a result which may be in relation with the
presence of ascites).
Among cirrhotics, those with multiple fractures showed, in
general, a tendency to lower BMD and T-score values,
although the only significant difference was observed regard-
ing lumbar spine T-score values, which were lower among
those with multiple fractures (2.06 ± 1.50) than those
without fractures (1.82 ± 0.70) and those with only rib frac-
tures (1.10 ± 0.80, F= 3.4, P= 0.04). On the contrary, no
differences were observed, among non-cirrhotics, between
patients with only rib fractures, multiple fractures or no
fractures.
In 87 patients, tobacco consumption was recorded. No
association was found between smoking and fracture (71.8%
among smokers, 60.4% among non-smokers).
Logistic regression
By stepwise logistic regression analysis, introducing the par-
ameters of age, cirrhosis, lumbar spine (L2L4) T-score,
total hip T-score, total BMD, total lean mass, total fat mass,
subjective nutritional evaluation, duration of ethanol con-
sumption and the hormones IGF-1, cortisol and vitamin D
(classified in two groups, below or above the median), only
vitamin D (P= 0.034) and subjective nutritional evaluation
Table 3. Fractures in Child C patients compared with the remaining ones,
and among cirrhotics and non-cirrhotics
Multiple
fractures (%)
Rib
fractures
(%)
No fractures
(%)
Advanced liver disease (Child C
patients)
8 (32) 8 (32) 9 (36)
Non-advanced liver disease (Child A
and B + non-cirrhotic alcoholics)
5 (7.7) 28 (43.1) 32 (49.2)
χ
2
5.00; P= 0.025
Cirrhotics 8 (20) 16 (40) 16 (40)
Non-cirrhotics 5 (10.4) 19 (39.6) 24 (50)
χ
2
1.63; NS
Table 4. Differences in BMD between cirrhotics and non-cirrhotics
Cirrhotics (n= 40) Non-cirrhotics (n= 48)
Left arm BMD (g/cm
2
) 0.78 ± 0.08 0.82 ± 0.09 T= 2.10; P= 0.039
Right arm BMD (g/cm
2
) 0.80 ± 0.08 0.83 ± 0.08 T= 1.85; NS
Left ribs BMD (g/cm
2
) 0.59 ± 0.07 0.62 ± 0.07 T= 2.12; P= 0.037
Right ribs BMD (g/cm
2
) 0.59 ± 0.07 0.62 ± 0.06 T= 2.57; P= 0.012
Thoracic spine BMD (g/cm
2
) 0.87 ± 0.12 0.93 ± 0.14 T= 2.15; P= 0.034
Lumbar spine BMD (g/cm
2
) 0.93 ± 0.14 0.99 ± 0.17 T= 1.82; NS
Pelvis BMD (g/cm
2
) 1.01 ± 0.14 1.07 ± 0.15 T= 2.08; P= 0.04
Left leg BMD (g/cm
2
) 1.21 ± 0.14 1.23 ± 0.12 T= 0.93; NS
Right leg BMD (g/cm
2
) 1.20 ± 0.11 1.24 ± 0.13 T= 1.36; NS
Total BMD (g/cm
2
) 1.06 ± 0.09 1.11 ± 0.10 T= 2.33; P= 0.022
Total hip T-score 1.25 ± 0.96 0.80 ± 1.14 T= 1.92; NS
Lumbar spine T-score 1.57 ± 1.01 0.81 ± 1.22 T= 3.15; P= 0.003
152 González-Reimers et al.
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(P= 0.021) showed a significant relation with the presence
or not of fracture in the univariate analysis, although subjec-
tive nutritional evaluation displaced vitamin D in the final
formula (P= 0.019). On the contrary, vitamin D remained
the only parameter related to fracture (P= 0.017), displacing
subjective nutritional evaluation, when variables such as cor-
tisol or IGF-1 (which did not show any relations with frac-
ture in the present study) were removed. Also, vitamin D
remained the only parameter related to fracture (P= 0.019)
even if the variable decompensated liver disease(Child C
patients) was introduced.
Considering only patients with fractures and comparing
those with rib fractures and those with multiple fractures,
introducing the variables age, cirrhosis, lumbar spine (L2
L4) T-score, total hip T-score, total BMD, total lean mass,
total fat mass, subjective nutritional evaluation, duration of
ethanol consumption and the hormones IGF-1, cortisol and
vitamin D (classified in two groups, below or above the
median), the variables which entered the final formula were
total lean mass (P= 0.024), total fat mass (P= 0.029) and
liver cirrhosis (P= 0.046), in this order.
However, the variable decompensated liver disease
(Child C patients) displaces the variable cirrhosisfrom the
final formula. Again, total lean mass was the first parameter
selected (P= 0.031), but decompensated liver diseasewas
the second (P= 0.023) and total fat mass, the third one (P=
0.035). These three parameters remain selected if we remove
IGF-1 and cortisol.
DISCUSSION
In contrast with some population-based studies, which report
a reduced relative risk for hip fracture associated to mild or
moderate alcohol consumption (Berg et al., 2008;Wosje and
Kalkwarf, 2007), but in accordance with other authors who
studied alcoholic patients (Clark et al., 2003;
González-Calvín et al., 1993;Lindholm et al., 1991;Malik
et al., 2009;Peris et al., 1992), we found marked differences
between alcoholics and controls regarding BMD, and total
hip and lumbar spine T-scores. Osteoporosis (T-score <
2.5) was found in nine cases at the lumbar spine and in five
cases at the hip. These are findings similar to others pre-
viously reported by our group and by many others, irrespec-
tive of the method used to assess osteoporosis (Alvisa
Negrín et al., 2009;Crilly et al., 1988;Diamond et al., 1989;
Farley et al., 1985;Feitelberg et al., 1987;
García-Valdecasas-Campelo et al., 2006;González-Calvín
et al., 1993;Jorge-Hernández et al., 1988;Lalor et al., 1986;
Peris et al., 1992;Santolaria et al., 2000, among others). In
our study, decreased bone mass heavily depends on
decreased bone synthesis, estimated on the basis of osteocal-
cin values. Biochemical variables related with bone remodel-
ling, such as PTH and RANKL, were not significantly
different in patients and controls, but serum telopeptide,
which may be influenced by liver collagen metabolism
(Ricard-Blum et al., 1996), was also higher among non-
cirrhotics (0.53 ± 0.27 ng/ml ) when compared with controls
(Z= 4.00; P< 0.001).
More than 50% of the patients analysed showed bone frac-
tures. This is quite a high figure compared with those
reported by other authors, such as Keso et al. (1988),
Wilkinson et al. (1985) or Peris et al. (1995), who found
prevalence figures around 35%, although they focused
mainly in detecting rib fractures or radiologically assessed
vertebral fractures.
Low vitamin D levels and deranged nutritional status were
the main factors associated with fracture. Interestingly,
although, in general, BMD values were lower among those
with fractures, differences were not statistically significant.
This result is in agreement with those reported by Peris et al.
(1995) and Santori et al. (2008) regarding vertebral fractures
assessed by radiological criteria. BMD is the most widely
used technique to define osteoporosis (Cummings et al.,
2002), but it may not accurately estimate the fracture risk,
due to the fact that factors related with bone quality are not
assessed by this technique. Moreover, the accuracy of other
recently introduced parameters seem to be higher than the
classic BMD T-score value < 2.5, at least for prediction of
vertebral fractures (Diacinti et al., 2010). In contrast to
BMD, serum vitamin D (1, 25 (OH)
2
D3) levels were sig-
nificantly lower among those with fractures. Although in
some studies, there were no differences in serum vitamin D
between alcoholic patients with and without fractures
(Wilkinson et al., 1985), a similar result to that reported in
this study was found by other authors, such as Santori et al.
(2008), who reported no differences in BMD in a cohort of
alcoholics with a high prevalence of vertebral and non-
vertebral fractures, but indeed lower vitamin D values in the
former; or Diamond et al. (1989) and Malik et al. (2009),
who found lower 25 OH vitamin D levels in alcoholics than
in controls. It is in this sense worthy of note that low vitamin
D levels have been put in relation with increased risk of
falls, and thus, with bone fractures; in fact, treatment with
vitamin D reduced the risk of falling among older individuals
(Bischoff-Ferrari et al., 2009). In the last decade, it was
shown that a receptor for 1, 25 OH vitamin D3 is present in
human skeletal muscle (Bischoff et al., 2001), activation of
which leads to muscle cell proliferation and differentiation
(Ceglia, 2008), and to an increase in the synthesis of calmo-
dulin (Dittranti et al., 1990), leading to improved muscle
function. Although it was not an aim of our study, it is
important to remark that there was a significant relationship
between handgrip strength and serum vitamin D levels, as
well as between vitamin D and lean mass, fully in accord-
ance with the aforementioned statements, and with the
results of a recently published experimental study in which
we also described a significant relationship between type II
fibre atrophy and serum 1, 25 (OH)
2
vitamin D levels in
rats treated following the Lieber-deCarli model (González-
Reimers et al., 2010).
In addition to impaired nutritional status, statistically sig-
nificant differences were observed regarding several par-
ameters related to lean mass and the presence of fractures.
Also a trend was observed to lower values of handgrip
strength among patients with fracture. Both findings are also
in accordance with the relation observed between fractures
and nutritional status, and in accordance with the current
knowledge about this item (Huang et al., 1996). Nutritional
status was evaluated in our patients with a subjective scale
and it was related with fracture. Also, those with the worst
nutritional status showed the lowest vitamin D levels (χ
2
=
4.25; P= 0.039). Therefore, the presence of fracture in our
population was related with vitamin D, subjective nutritional
Bone Fractures in Alcoholics 153
by guest on December 29, 2015Downloaded from
evaluation and lean mass, but vitamin D is related to nutri-
tional status.
Some differences did exist between patients with only rib
fractures and patients with other types of fractures. In
general, patients with rib fractures showed worse nutritional
parameters, especially lean mass parameters, than patients
with other types of fractures, although there were no differ-
ences in BMD and in biochemical parameters. Rib fractures
are among the most commonly suffered by alcoholics, so
that they have been considered as markers of alcohol con-
sumption in patients affected or not by chronic liver disease
(Israel et al., 1980;Lindsell et al., 1982). As stated before,
rib fractures are frequently observed in elderly, frail individ-
uals, prone to falls (Barrett-Connor et al., 2010). In this
sense, the alcoholics with rib fractures share some of these
characteristics: they are those with less lean and fat mass,
and also with the more deranged eating habits, also showing
a trend to a more intense social margination. Nutritional
status is in part related to bizarre eating behaviour in alco-
holics (Santolaria et al., 2000). Usually, the heavy drinker
disrupts his social links, become divorced or separated, and
his eating habits evolve to more irregular ones. This may
explain why we found an association between irregular
feeding habits and bone fractures, and also the trend to an
association of irregular eating habits and rib fracture. A
similar finding was also reported by Keso et al. (1988),who
showed that socio-economic status did not influence the
prevalence of fractures, but thoracic fractures were more
commonly observed among unmarried, divorced or widowed
alcoholics.
It may seem counterintuitive that patients with multiple
fractures showed, in general, better nutrition, reduced lean
mass and a trend to more fat mass, and a even a trend to
better social and familial environment, than those with only
rib fractures. However, these findings may be interpreted in
several ways. One explanation may consist in the fact that rib
fractures may appear even after minor trauma, such as falling
from a standing position, something which is very common
in the advanced alcoholic patient, with muscle atrophy and
reduced lean mass, severely impaired nutritional status, and,
perhaps, accompanying polineuropathy and/or cerebellar
atrophy, whereas multiple fractures may occur after major
trauma, fighting and violence among less fragile alcoholics,
with preserved lean and fat mass, and, in general, better
environmental conditions.
However, an association was found between multiple frac-
tures and liver cirrhosis and/or decompensated liver disease.
These patients showed lower values of hormones directly
involved in bone homoeostasis, such as vitamin D, IGF-1
and testosterone, decrease in which may play a role in the
frequency of fractures. A third factor which must be con-
sidered is that the variables trunk and total lean mass, which
were higher among cirrhotics and decompensated patients,
are in fact measuring also water retention and not just
muscle mass. Indeed, ascites is one of the criteria of decom-
pensation of liver disease, and, as expected, it is by far more
frequent among decompensated patients than among com-
pensated ones (χ
2
= 13.7; P< 0.0001).
Thus, our study shows that prevalent fractures are
common among heavy alcoholics, but their presence is
related more closely to impaired nutritional status and
reduced lean mass (especially among alcoholics with only
rib fractures) and low serum vitamin D levels, than to BMD.
Interestingly, a relation was found between vitamin D levels,
handgrip strength and lean mass, in accordance with the
described effects of vitamin D on muscle structure and func-
tion. Multiple fractures depend more heavily on the presence
of decompensated liver disease, with decreased levels of
IGF-1, testosterone and vitamin D. In our study, these
patients showed a trend to a more preserved nutritional status
than those with only rib fractures.
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Bone Fractures in Alcoholics 155
by guest on December 29, 2015Downloaded from
... Since the skeleton undergoes continuous turnover (Frost, 1990), bone loss associated with chronic alcohol abuse may be caused by decreased bone formation and/or increased bone resorption. Most observational studies suggest that chronic alcohol abuse lowers the rate of bone formation (Gonzalez-Calvin et al., 1993;Gonzalez-Reimers et al., 2011;Maurel et al., 2012a), but more variable effects have been reported for bone resorption (Cheung et al., 1995). There is strong evidence that comorbidities, including poor nutrition and disease, contribute to alcohol-associated reductions in bone mass and quality (Gaddini et al., 2016), and some, but not all, studies suggest that comorbidities are essential for alcohol-induced bone loss (Kim et al., 2003;Laitinen et al., 1993). ...
... These include calciumregulating hormones that mediate mineral homeostasis (e.g., Vitamin D and PTH), growth hormones (e.g., growth hormone and IGF-I), and reproductive hormones (e.g., estrogen and androgens; Chen et al., 2009;Gaddini et al., 2016;Ronis et al., 2007;Shankar et al., 2008;Turner, 2000;Turner et al., 2012). In addition, malnutrition is often associated with chronic alcohol abuse and may lead to further mineral and hormone imbalances (Gonzalez-Reimers et al., 2011). Further study will be required to determine the Effects of EtOH consumption on (A) plasma carboxyterminal cross-linking telopeptide of type 1 collagen (CTX), a marker of global bone resorption, and (B) plasma osteocalcin, a marker of global bone formation, in male rhesus macaques. ...
Article
Full-text available
Background Chronic heavy alcohol consumption is an established risk factor for bone fracture, but comorbidities associated with alcohol intake may contribute to increased fracture rates in alcohol abusers. To address the specific effects of alcohol on bone, we used a nonhuman primate model and evaluated voluntary alcohol consumption on: (i) global markers of bone turnover in blood and (ii) cancellous bone mass, density, microarchitecture, turnover, and microdamage in lumbar vertebra. Methods Following a 4‐month induction period, 6‐year‐old male rhesus macaques (Macaca mulatta, n = 13) voluntarily self‐administered water or ethanol (EtOH; 4% w/v) for 22 h/d, 7 d/wk, for a total of 12 months. Control animals (n = 9) consumed an isocaloric maltose–dextrin solution. Tetracycline hydrochloride was administered orally 17 and 3 days prior to sacrifice to label mineralizing bone surfaces. Global skeletal response to EtOH was evaluated by measuring plasma osteocalcin and carboxyterminal collagen cross‐links (CTX). Local response was evaluated in lumbar vertebra using dual‐energy X‐ray absorptiometry, microcomputed tomography, static and dynamic histomorphometry, and histological assessment of microdamage. Results Monkeys in the EtOH group consumed an average of 2.8 ± 0.2 (mean ± SE) g/kg/d of EtOH (30 ± 2% of total calories), resulting in an average blood EtOH concentration of 88.3 ± 8.8 mg/dl 7 hours after the session onset. Plasma CTX and osteocalcin tended to be lower in EtOH‐consuming monkeys compared to controls. Significant differences in bone mineral density in lumbar vertebrae 1 to 4 were not detected with treatment. However, cancellous bone volume fraction (in cores biopsied from the central region of the third vertebral body) was lower in EtOH‐consuming monkeys compared to controls. Furthermore, EtOH‐consuming monkeys had lower osteoblast perimeter and mineralizing perimeter, no significant difference in osteoclast perimeter, and higher bone marrow adiposity than controls. No significant differences between groups were detected in microcrack density (2nd lumbar vertebra). Conclusions Voluntary chronic heavy EtOH consumption reduces cancellous bone formation in lumbar vertebra by decreasing osteoblast‐lined bone perimeter, a response associated with an increase in bone marrow adiposity.
... Alcohol consumption is detrimental to the integrity of bone tissue, with direct interference in bone repair (Lima et al. 2011), and is an important risk factor for osteoporosis (Santori et al. 2008). Consumption does not only harm bone structure, it leads to metabolic changes, vitamin D deficiency, and the adoption of inappropriate eating habits, increasingly compromising bone integrity (González-Reimers et al. 2011). ...
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Excessive alcohol consumption is considered a risk factor for bone health, as it causes a reduction in mass and increases the risk of fracture. However, the determination of bone mineral density (BMD) has not always been an adequate predictor of bone fragility. Thus, the hypothesis arises that chronic alcohol consumption interferes with collagen synthesis and the quality of bone trabeculae, with consequent bone fragility. Groups: Control (n = 6; water intake only during the entire study period); Ethanol (n = 6; ingestion of ethyl alcohol according to the protocol for inducing chronic alcohol consumption). The chronic alcohol consumption model did not cause a significant change in BMD, but there was a significant reduction of 20% in the thickness of the bone trabeculae and of 1.56% in the collagen located in the neck region of immature rat femurs. Although there was no significant change in the mineral matrix, the changes in the organic matrix were able to provide a significant reduction in bone strength. The results suggest harmful effects of alcohol intake on the bone quality of young adult animals and draw attention to the need to also consider methods for the diagnosis of collagen as an element of bone fragility.
... Previous studies that focused on bone mineral density (BMD) measurement in ALD patients reported inconsistent findings. Namely, some authors found no significant BMD changes in proximal femora of ALD patients [10][11][12], while others reported a decrease in bone density and geometrical features among ALD [13][14][15][16] and ALC individuals [17]. In contrast, some authors observed increased BMD values among men who were prone to heavy alcohol consumption [18]. ...
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Although increased hip fracture risk is noted in patients with alcoholic liver disease (ALD), their femoral microstructural and mechanical properties were not investigated previously. The present study aimed to analyze the associations between subregional deteriorations in femoral mechano-structural properties and clinical imaging findings to explain increased femoral fracture risk among ALD patients. This study analyzed proximal femora of 33 male cadaveric donors, divided into ALD (n = 13, 57 ± 13 years) and age-matched control group (n = 20, 54 ± 13 years). After pathohistological verification of ALD stage, DXA and HSA measurements of the proximal femora were performed, followed by micro-CT and Vickers microindentation of the superolateral neck, inferomedial neck, and intertrochanteric region. Bone mineral density and cross sectional area of the femoral neck were deteriorated in ALD donors, compared with healthy controls (p < 0.05). Significant ALD-induced degradation of trabecular and cortical microstructure and Vickers microhardness reduction were noted in the analyzed femoral regions (p < 0.05). Still, the most prominent ALD-induced mechano-structural deterioration was noted in intertrochanteric region. Additionally, more severe bone alterations were observed in individuals with an irreversible stage of ALD, alcoholic liver cirrhosis (ALC), than in those with an initial ALD stage, fatty liver disease. Observed osteodensitometric and mechano-structural changes illuminate the basis for increased femoral fracture risk in ALD patients. Additionally, our data suggest bone strength reduction that may result in increased susceptibility to intertrochanteric femoral fracture in men with ALD. Thus, femoral fracture risk assessment should be advised for all ALD patients, especially in those with ALC.
... Excess alcohol intake has a detrimental effect on skeletal health. In addition to its direct toxic effect on osteoblast function, there are additional adverse effects on gonadal function, protein metabolism, calcium metabolism, physical activity and falls risk [32][33][34]. A metaanalysis conducted by Kanis and colleagues showed that drinking above 2 units of alcohol a day is associated with an increased risk of fracture [35]. ...
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... [ [63][64][65] Dietary deficiencies Malnutrition or dietary deficiencies frequently occur in patients with CLD (12% of OLT patients), due to altered nutritional requirements during ascites or other complications. [66,67] Alcohol consumption Ethanol affects bone directly via a toxic effect on osteoblasts and indirectly by altering PTH, vitamin D, testosterone, IGF-1, cytokines (e.g., TNF or IL-6) and cortisol levels. ...
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Almost all patients with chronic liver diseases (CLD) show altered bone metabolism. Depending on the etiology, this manifests in a severe osteoporosis in up to 75% of the affected patients. Due to high prevalence, the generic term hepatic osteodystrophy (HOD) evolved, describing altered bone metabolism, decreased bone mineral density, and deterioration of bone structure in patients with CLD. Once developed, HOD is difficult to treat and increases the risk of fragility fractures. Existing fractures affect the quality of life and, more importantly, long-term prognosis of these patients, which presents with increased mortality. Thus, special care is required to support the healing process. However, for early diagnosis (reduce fracture risk) and development of adequate treatment strategies (support healing of existing fractures), it is essential to understand the underlying mechanisms that link disturbed liver function with this bone phenotype. In the present review, we summarize proposed molecular mechanisms favoring the development of HOD and compromising the healing of associated fractures, including alterations in vitamin D metabolism and action, disbalances in transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signaling with histone deacetylases (HDACs) as secondary regulators, as well as alterations in the receptor activator of nuclear factor kappa B ligand (RANKL)–osteoprotegerin (OPG) system mediated by sclerostin. Based on these mechanisms, we give an overview on the limitations of early diagnosis of HOD with established serum markers.
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Osteosarcopenia is a complex geriatric syndrome characterized by the presence of both sarcopenia and osteopenia/osteoporosis. This condition increases rates of disability, falls, fractures, mortality and mobility impairments in older adults. The purpose of this study was to analyze the Fourier Transform Infrared (FTIR) spectroscopy diagnostic power for osteosarcopenia in community-dwelling older women (n = 64, 32 osteosarcopenic and 32 non-osteosarcopenia). FTIR is a fast and reproducible technique highly sensitive to biological tissues and a mathematical model was created using multivariate classification techniques that denoted the graphic spectra of the molecular groups. Genetic algorithm and support vector machine regression (GA-SVM) was the most feasible model, achieving 80.0% of accuracy. GA-SVM identified 15 wavenumbers responsible for class differentiation, in which several amino acids (responsible for the proper activation of the mammalian target of rapamycin) and hydroxyapatite (an inorganic bone component) were observed. Imaging tests and a low availability of instruments that allow the observation of osteosarcopenia involves high health costs for patients and restrictive indications. Therefore, FTIR can be used to diagnose osteosarcopenia due to its efficiency, low cost and to enable early detection in the geriatric services, contributing to advances in science and technology that are potential "conventional" methods in the future.
Chapter
The molecular mechanisms of osteoblast-osteoclast interplay, which occur at several differentiation stages, represent one of the main issues in bone cell biology. This chapter aims to setup an overall image of the remodeling process and the coupling mechanisms ensuring the preservation of bone biomechanical integrity. Therefore, the first section deals with the origins, the function, and the differentiation process of bone cells, the second section reviews the sequential remodeling phases within the BMU, the third section focuses on the actors and factors of the intercellular signaling pathways and coupling mechanism, and the fourth section presents the factors affecting bone biology.
Chapter
Alcohol is one of the most widely used drugs around the world, with many adverse health consequences well known to healthcare providers. This chapter provides an overview of the metabolism of alcohol and its short- and long-term effects. The socioeconomic factors impacting alcohol use are explored and consideration is given to variations in global consumption. Alcohol is a risk factor for many negative health behaviours and diseases, including violence, injury, sexually transmitted infections, cancer, cardiovascular disease and gastrointestinal pathology. There is a threshold of alcohol consumption above which the level consumed is linearly associated with adverse health outcomes. Guidelines regarding the safe level of intake vary around the world.
Chapter
Male osteoporosis is a health problem of multifactorial origin. Bone mineral density evaluation (BMD) by X-ray densitometry allows diagnosis, while stratification of risk fracture is usually done through useful diagnostic tools (i.e., FRAXc). The risk of osteoporotic fracture results from a combination of modifiable and unmodifiable factors. Lifestyle factors are the modifiable factors that can greatly impact on overall health and well-being, including bone health. Many lifestyle factors such as physical activity, diet, alcohol abuse, and smoking can have substantial effects on bone metabolism. Nowadays, the crucial role that lifestyle factors play in the development of male osteoporosis has generated a growing interest in this field of study. Male osteoporosis prevention (or non-pharmacological intervention) should be based on the elimination of specific modifiable risk factors (alcohol abuse, smoking, environmental risk factors for falls, etc.) by means of regular physical activity and an adequate nutritional supply of calcium and vitamin D. Non-pharmacological interventions for the prevention and treatment of osteoporosis are recommended for all subjects.
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Background HIV infection is now largely a chronic condition as a result of the success of antiretroviral therapy. However, several comorbidities have emerged in people living with HIV (PLWH), including alcohol use disorders and musculoskeletal disorders. Alcohol use has been associated with lower bone mineral density, alterations to circulating bone turnover markers, and hypocalcemia. The pathophysiological basis of bone loss in the PLWH population is unclear but has been suggested to be linked to oxidative stress and inflammation. To test the hypothesis that PLWH consuming excessive alcohol have altered markers of bone turnover and/or calcium homeostasis in association with oxidative stress, we correlated measurements of alcohol consumption with markers of oxidative stress and inflammation, serum calcium concentrations, and measurements of bone turnover, including c‐terminal telopeptide cross‐links (CTX‐1) and osteocalcin. Methods Data were drawn from cross‐sectional baseline data from the ongoing New Orleans Alcohol Use in HIV (NOAH) study, comprised of 365 in care PLWH. Alcohol consumption measures (Alcohol Use Disorders Test, 30‐day timeline follow‐back calendar, and phosphatidylethanol [PEth]) were measured in a subcohort of 40 subjects selected based on highest and lowest PEth measurements. Multivariate linear regression was performed to test the relationships between alcohol consumption and systemic oxidative stress (4‐hydroxynonenal; 4‐HNE) and inflammation (c‐reactive protein; CRP). Results Serum calcium and CTX‐1 did not differ significantly between the high and low‐PEth groups. Individuals in the high‐PEth group had significantly lower serum osteocalcin (median low‐PEth group: 13.42 ng/ml, inter‐quartile range [IQR] 9.26 to 14.99 ng/ml; median high‐PEth group 7.39 ng/ml, IQR 5.02 to 11.25 ng/ml; p = 0.0005, Wilcoxon rank‐sum test). Osteocalcin negatively correlated with PEth (Spearman r = −0.45, p = 0.05) and self‐reported measures after adjusting for covariates. Alcohol consumption showed mild, but significant, positive associations with serum 4‐HNE, but not with CRP. Osteocalcin did not correlate with either 4‐HNE or CRP. Conclusions In this subcohort of PLWH, we detected significant associations between at‐risk alcohol use and osteocalcin, and at‐risk alcohol use and serum 4‐HNE, suggesting suppression of bone formation independent of increased systemic oxidative stress with increasing alcohol consumption.
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Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D3 concentration (25(OH)D concentration: <60 nmol/l v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.
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To study the causes and consequences of radiologically confirmed rib fractures (seldom considered in the context of osteoporosis) in community dwelling older men. Prospective cohort study (Osteoporotic Fractures in Men (MrOS) Study). 5995 men aged 65 or over recruited in 2000-2 from six US sites; 99% answered mailed questionnaires about falls and fractures every four months for a mean 6.2 (SD 1.3) year follow-up. New fractures validated by radiology reports; multivariate Cox proportional hazard ratios were used to evaluate factors independently associated with time to incident rib fracture; associations between baseline rib fracture and incident hip and wrist fracture were also evaluated. The incidence of rib fracture was 3.5/1000 person years, and 24% (126/522) of all incident non-spine fractures were rib fractures. Nearly half of new rib fractures (48%; n=61) followed falling from standing height or lower. Independent risk factors for an incident rib fracture were age 80 or above, low bone density, difficulty with instrumental activities of daily living, and a baseline history of rib/chest fracture. Men with a history of rib/chest fracture had at least a twofold increased risk of an incident rib fracture (adjusted hazard ratio 2.71, 95% confidence interval 1.86 to 3.95), hip fracture (2.05, 1.33 to 3.15), and wrist fracture (2.06, 1.14 to 3.70). Only 14/82 of men reported being treated with bone specific drugs after their incident rib fracture. Rib fracture, the most common incident clinical fracture in men, was associated with classic risk markers for osteoporosis, including old age, low hip bone mineral density, and history of fracture. A history of rib fracture predicted a more than twofold increased risk of future fracture of the rib, hip, or wrist, independent of bone density and other covariates. Rib fractures should be considered to be osteoporotic fractures in the evaluation of older men for treatment to prevent future fracture.
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To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1alpha-hydroxyvitamin D(3) (1alpha-hydroxycalciferol) or 1,25-dihydroxyvitamin D(3) (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D(3) concentration (25(OH)D concentration: <60 nmol/l v >or=60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.
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The aims of this study were to assess bone mineral density (BMD) and content (BMC), osteocalcin, serum telopeptide, PTH and vitamin D in alcoholics, and to determine if a 6-month period of abstinence leads to changes in these parameters. Serum osteocalcin, insulin-like growth factor 1 (IGF-1), telopeptide (40 patients) and 1,25 dihydroxyvitamin D, were measured in 28 controls and 77 alcoholic patients, 48 of whom were evaluated again 6 months later. All patients underwent whole-body assessment of BMD by a Hologic QDR-2000 (Waltham, MA, USA) bone densitometer, at the beginning of the study and 6 months later. Patients showed higher serum telopeptide levels (0.59 +/- 0.40 versus 0.19 +/- 0.10 nmol/100 ml, P < 0.001), lower IGF-1 [median = 49, interquartile range (IQR) = 31-121 ng/ml versus 135, IQR = 116-237 ng/ml, P < 0.001], vitamin D [26.5, IQR = 17.0-37.8 pg/ml versus 82.4 (IQR = 60.9-107.4 pg/ml, P < 0.001] and osteocalcin (2.1, IQR = 1.1-3.6 ng/ml versus 6.65, IQR = 4.9-8.8 ng/ml, P < 0.001) than those in controls. Patients also showed lower BMD values, Z- and T-scores at many levels of the skeleton and reduced total BMC. After 6 months, those who continued drinking showed a loss of bone mass, whereas those who abstained showed either no change or increase, differences being especially marked at pelvis, right arm and total BMD and BMC. Simultaneously, abstainers showed a significant increase in osteocalcin (versus a decrease among those who continued drinking). Serum telopeptide increased in both groups. Ethanol consumption leads to osteopenia, and decreased serum osteocalcin, which improve with abstinence, whereas those who continue drinking show a worsening of both parameters.
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In a pilot study, the prevalence of metabolic bone disease was found to be low in male alcoholics attending an alcohol problems clinic, and did not appear to account for their high prevalence of fractures. The alcoholics with clinical signs suggestive of neuropathy or liver damage did not have a higher prevalence of metabolic bone disease and fractures than those without such signs. However, future research on this topic will have to be based on methods of greater reliability and validity
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Evaluation of osteoporotic vertebral fracture risk is currently based on measurement of bone mineral density (BMD), but bone strength depends also on bone quality parameters. Aim of this study was to evaluate the validity of a new vertebral morphometric index, the Anterior Vertebral Heights sum (AHs) in discriminating women at high risk of vertebral fracture, comparing its diagnostic accuracy with that of BMD measured at lumbar spine (LS-BMD) and femoral neck (FN-BMD). A total of 163 Caucasian post-menopausal women (age range 46-74 years, mean age+/-SD=63.8+/-7.1 years), who did not present prevalent fractures at baseline evaluation, were observed at longitudinal follow-up. X-ray of the thoracic and lumbar spine, LS-BMD and FN-BMD measurements were obtained in all patients at baseline and repeated at the second follow-up visit 18-24 months later (mean 21+/-1.7 months). Radiographs of spine were analysed in order to identify vertebral fractures using a visual semiquantitative method (SQ) and vertebral morphometry as well as by calculating the AHs morphometric index. During follow-up, 21/163 patients (12.9%) sustained a new vertebral fracture; 95.2% (20/21) of fractured patients but only 4.9% (7/142) of non-fractured women had reduced AHs values. As regarding BMD, 66.6% (14/21) and 61.9% (13/21) of women with incident fracture were osteoporotic at lumbar spine and femoral neck baseline evaluation , whereas among non-fractured women, 38% (54/142) at LS-BMD and 33.1% (47/142) at FN-BMD were osteoporotic . Analyses of Receiver Operating Characteristic (ROC) curves showed that AHs discriminated vertebral fractures almost perfectly (AUC 0.97; 95% CI 0.95-0.99). On the other hand, the AUC for LS-BMD was only 0.73 (95% CI 0.64-0.81) and for FN-BMD was 0.72 (95%CI 0.63-0.80), showing that the diagnostic accuracy of AHs was significantly higher compared to that of LS-BMD (p<0.001) or FN-BMD (p<0.001). A modified Poisson regression model for binary data was used to assess the independent role of AHs in predicting vertebral fracture. The effect of AHs remained statistically significant (p<0.001) after adjusting by FN-BMD, age, weight and body height. Results of this study indicate the validity of this new morphometric index in evaluating the risk of osteoporotic vertebral fractures thus suggesting that AHs should be considered a valid parameter in clinical practice to assess the need for primary prevention of vertebral fractures.