Diabetes Mellitus Does it Affect Bone

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Diabetes Mellitus: Does it Affect Bone?
A. V. Schwartz
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
Received: 23 January 2003 / Accepted: 23 May 2003 / Online publication: 2 October 2003
Abstract. Both diabetes and fractures affect a large
proportion of older adults. Recent cohort studies indi-
cate that diabetes itself is associated with increased risk
of fracture of the hip, proximal humerus, and foot.
Observational studies and animal models suggest that
decreased bone strength in diabetes may contribute to
fracture risk but this remains a controversial issue. Type
1 diabetes is associated with modest reductions in bone
mineral density (BMD) but type 2 diabetes is often
characterized by elevated BMD. This paradox of higher
BMD but increased fracture risk in type 2 diabetes may
be explained by a combination of more frequent falls
and poorer bone quality. Diabetes can impact bone
through multiple pathways, some with contradictory
effects, including obesity, changes in insulin levels,
higher concentrations of advanced glycation end prod-
ucts in collagen, hypercalciuria associated with gly-
cosuria, reduced renal function, lower insulin-like
growth factor-I, microangiopathy, and inflammation. A
better understanding of how diabetes metabolism and
treatments affect bone would improve fracture preven-
tion efforts in older diabetic adults.
Key words: Diabetes mellitus — Fracture — Bone
mineral density
Diabetes mellitus affects nearly 20% of older adults and
has well-known vascular complications. Skeletal health
is also an important issue for older adults in general as
the risk of fracture increases exponentially with age. In
those with diabetes, the morbidity associated with
fractures is likely to be exacerbated by diabetic com-
plications and possibly by slower fracture healing [1–4].
Recent studies indicate that diabetes itself is associated
with increased risk of fracture of the hip, proximal hu-
merus, and foot [5–10]. Evidence from observational
studies and animal models suggests that decreased bone
strength in diabetes may contribute to fracture risk but
this remains a controversial issue. A better under-
standing of the factors that determine bone strength in
diabetes is needed to inform fracture prevention efforts
in this population.
Diabetes could impact bone through several mecha-
nisms, some of which may have contradictory effects.
Obesity, prevalent in type 2 diabetes, is strongly asso-
ciated with higher bone mineral density (BMD) proba-
bly through mechanical loading and hormonal factors
including insulin, estrogen and leptin [11, 12]. Hyperin-
sulinemia may promote bone formation [13]. On the
other hand, low levels of insulin associated with type 1
diabetes and the progression of type 2 diabetes may
cause reductions in BMD. Hyperglycemia generates a
higher concentration of advanced glycation end prod-
ucts (AGEs) in collagen that may reduce bone strength
[14]. Hypercalciuria associated with glycosuria may in-
duce bone loss [15–17]. Insulin-like growth factor-I
(IGF-I) is thought to be anabolic for bone and may be
lower in diabetes [18–20]. An increase in inflammation
and associated cytokines could accelerate bone turnover
and loss of bone [21, 22]. Declining renal function, more
prevalent in diabetes, is associated with lower BMD in
older women [23]. Microvascular complications of dia-
betes and reduced blood flow to bone may contribute to
bone loss and fragility [24–28].
Type 1 diabetes is associated with a modest reduction
in BMD in most [29–36] but not all [37] studies. The risk
of hip fracture appears to be substantially increased al-
though studies of fractures in those with type 1 diabetes
are limited. Two recent cohort studies reported a 4–12-
fold increase in the risk of hip fracture [6, 7]. However,
two previous case-control studies did not find evidence of
increased risk [38, 39]. Bone histology and bone markers
in rat models of type 1 diabetes indicate a low turnover
state of decreased osteoblast activity combined with
normal or decreased osteoclast activity [16, 40]. How-
ever, in humans, most [35, 37, 41, 42], but not all [34, 43],
studies of bone turnover in type 1 diabetes have reported
increased resorption. Reports on formation markers are
inconsistent across studies and markers [34, 37, 44–46].
Correspondence to: A. V. Schwartz; E-mail: aschwartz@
psg.ucsf.edu
Calcif Tissue Int (2003) 73:515–519
DOI: 10.1007/s00223-003-0023-7 Calcified
Tissue
International
� 2003 Springer-Verlag New York Inc.
The reasons for this bone turnover profile and for lower
BMD in type 1 diabetics are not well understood.
The effect of type 2 diabetes on bone is more con-
troversial. Increased risk of fracture has not tradition-
ally been considered one of the consequences of type 2
diabetes. In 1980, a large case-control study using Mayo
Clinic records reported that diabetes was not associated
with increased risk of fracture except at the ankle [38]. In
addition, type 2 diabetes is associated with increased
weight, a factor that provides protection from most
fractures. However, more recent cohort studies have
reported increased risk of hip fracture with type 2 dia-
betes [5–9]. Diabetes appears to increase fracture risk at
some other sites, including the proximal humerus, foot,
and possibly ankle, but not the distal forearm or wrist
[5, 6, 10]. In contrast, one large cohort study, the Rot-
terdam study, found a decreased risk of fracture in older
diabetic women, considering all nonvertebral fracture
sites combined [47]. These results are not necessarily
discrepant, however, when we take into account the
preponderance of wrist and forearm fractures in the
Rotterdam study. These fracture sites were not associ-
ated with increased risk in other studies. Taken together,
these studies suggest that there is an increased risk of
fracture at specific sites for older adults with type 2
diabetes.
Bone mineral density is a strong predictor of fracture.
In contrast to the studies of type 1 diabetes that have
generally found a modest decrement in BMD, studies of
type 2 diabetes have reported a broader range of results
that do not suggest a pattern of lower BMD. These re-
sults are somewhat surprising given the increased frac-
ture risk associated with type 2 diabetes. Most, but not
all [15, 36, 48–51], cross-sectional studies have found
average [29, 32, 52], or even somewhat elevated [47, 53–
56], BMD in type 2 diabetes, even after accounting for
larger body size. The disparities in results may be due in
part to variations in the severity, duration and treatment
of diabetes represented in the different studies. Two of
the studies that reported elevated BMD identified dia-
betes using the glucose tolerance test in addition to self-
report and therefore probably included a greater pro-
portion of newly diagnosed diabetics [47, 55]. Possible
contributing factors to higher BMD in type 2 diabetes,
in addition to obesity, include hyperinsulinemia and, in
women, increased androgen levels associated with lower
levels of sex hormone-binding globulin [57, 58].
This paradox of higher BMD but increased fracture
risk in type 2 diabetes might be explained in two ways
[59]. First, diabetics are more likely to fall and may
therefore be exposed to more incidents that could pro-
duce a fracture. Additionally, diabetes may be associ-
ated with poor bone quality that is not captured in
cross-sectional BMD measurements.
Type 2 diabetes is associated with a moderate (50–
60%) increase in the risk of falling [60–62], with some
evidence that type 2 diabetic women using insulin have a
two to three times greater risk of falling than those
without diabetes [60]. Those with diabetes also have an
increased prevalence of risk factors for falls and for in-
jury in a fall, including poor vision, peripheral neurop-
athy, and stroke. Hip and proximal humerus fractures in
particular are almost always caused by a low trauma fall
in older adults, and a history of fallspredicts risk of
these fractures. The risk of sustaining a fracture once a
fall occurs is influenced by the orientation and point of
impact of the fall, by the faller’s neuromuscular ability
to attenuate the force of impact, and by the strength of
the bone [63]. Intrinsic factors that increase the risk
of fracture or other injury in a fall include history of
stroke, lower cognitive function, lower body mass index,
and poor balance and gait performance [64–66]. With
the exception of lower body mass index, these intrinsic
risk factors for injury in a fall are more prevalent among
those with diabetes. Thus, it is likely that increased risks
of falling and of sustaining an injury in a fall due to
physical frailty account for some of the increased risk of
fracture in diabetes. However, in observational studies
that have considered falls and risk factors for falls and
injurious falls, these factors have not fully explained the
association between diabetes and fracture.
In the Study of Osteoporotic Fractures, a prospective
study of women aged 65 years and older, the association
between diabetes and fracture risk persisted after ad-
justing for a history of falls and for risk factors for falls
and injurious falls, including history of stroke, ben-
zodiazepine use, poor vision, walking speed, and pe-
ripheral neuropathy [5]. Forsen et al. [7], using data
from the Nord-Trondelag Health Survey of men and
women aged 50 years and older, found an increased risk
of hip fracture that was partly accounted for by fall risk
factors, including physical inactivity, impaired vision,
impaired motor abilities and history of stroke. This
study did not include a direct measure of falls. Similarly,
Ottenbacher et al. [9], in a study of older Mexican-
American men and women, reported a 50% increased
risk of hip fracture even after adjustment for history of
stroke, poor physical performance and impaired vision,
but was not able to adjust directly for falls. Other studies
of diabetes and fracture have not adjusted for falls or
fall risk factors. While our current evidence is unfortu-
nately limited, it indicates that increased falls and higher
risk of injury given a fall do not fully account for the
greater risk of fracture in diabetes. It is likely that de-
creased bone strength is the other key contributor to
increased fracture risk.
Rodent models provide support for the hypothesis
that diabetic bone has poorer quality that is not ac-
counted for by lower density. Studies in spontaneously
diabetic rats and in those with streptozotocin-induced
diabetes have found decreased bone strength [67–69].
Verhaeghe et al. [40] reported that femoral bones in
516 A. V. Schwartz: Diabetes and Bone
spontaneously diabetic rats had decreased torsional
strength, angular deformation and energy absorption
although the BMD and BMC of the diabetic bones were
not significantly decreased.
Diabetes may produce a similar effect in human bone.
One possible explanation for decreased bone strength in
diabetes is the accumulation of advanced glycation end
products (AGEs) in bone collagen. AGEs are formed
through a series of nonenzymatic reactions between
glucose and proteins resulting in a stable cross-linked
product. AGEs accumulate with age, are elevated in
diabetes, and are thought to contribute to the vascular
complications of diabetes by reducing the elasticity and
increasing the permeability of the blood vessels [70].
AGEs are found in tissues throughout the body, in-
cluding bone collagen. Accumulated AGEs in bone
collagen may increase bone fragility. In human cadav-
eric bone, Wang et al. [71] found that a higher concen-
tration of AGEs was associated with decreased strength.
The mechanism for AGE’s effect on bone strength is not
clear. The presence of AGEs may directly alter the
physical properties of bone collagen [72]. Cell line
studies indicate that AGEs also affect the metabolism of
bone cells. AGEs in collagen are reported to inhibit
phenotypic expression of osteoblasts [73], increase os-
teoclast-induced bone resorption [74], and stimulate
interleukin-6 production in human bone-derived cells
[75]. AGE-specific receptors have been identified in os-
teoblast-like cells [76]. The role of AGEs in bone fra-
gility and related increases in fracture risk is an
important but difficult area to study as we do not yet
have established methods for assessing AGEs in bone
that are minimally invasive.
Another possible explanation for decreased bone
strength in diabetes is an accelerated bone loss in older
adults with diabetes. More rapid bone loss may cause
decreases in bone strength beyond what would be pre-
dicted from the absolute BMD [77]. Little information is
available on longitudinal changes in bone mass in those
with type 2 diabetes. In a study of 19 patients with type 2
diabetes, Krakauer et al. [48] found no loss of BMD at
the radius over 12 years of follow-up. However, among
older women in the Study of Osteoporotic Fractures
(SOF), those with diabetes lost bone more rapidly than
those without diabetes [78]. This was explained in part
by greater weight loss, a strong predictor of bone loss, in
the diabetic women. Greater weight loss has been re-
ported in other studies of older diabetic women and
men [79, 80]. Even among women in SOF who did not
lose weight, diabetes was associated with greater bone
loss. Possible mechanisms that could lead to bone loss
in older diabetic adults, in addition to weight loss,
include hypercalciuria [17], impaired renal function [23],
lower endogenous insulin levels as diabetes progresses
[58], microvascular complications [81], and elevated
cytokines [21].
Those who care for older diabetic adults should be
aware that both type 1 and type 2 diabetes are associ-
ated with an increased risk of certain fractures. The in-
crease in risk is partially accounted for by a greater
tendency to fall, and fall prevention measures should be
a consideration with older diabetic patients. However,
the current state of the evidence suggests that there may
be impairments of bone strength that are not captured
by measurements of BMD. We do not know if current
treatments shown to reduce fracture risk in older adults
will produce a similar reduction in fractures among di-
abetics. However, there is some initial evidence that
antiresorptive treatments known to preserve bone in
older women also have a similar effect on BMD among
those with diabetes [82, 83]. Those with diabetes and
osteoporosis should be provided treatment similar to
that recommended for osteoporosis in general. It is not
known whether treating diabetes and diabetic compli-
cations aggressively can alter skeletal health.
The accumulating evidence that older adults with
diabetes have an increased risk of certain fractures has
given a new impetus to investigations focused on dia-
betes and bone. Future studies need to clarify the impact
of different aspects of diabetes metabolism, improved
glycemic control, and specific treatments for diabetes on
bone. Assessments of bone quality will need to include
the standard measurements of BMD and the develop-
ment of novel approaches such as measures of collagen
glycosylation. A better understanding of how diabetes
affects bone will improve our ability to protect bone
health and prevent fractures in the growing population
of older adults with diabetes.
Acknowledgements. This work was supported by an American
Diabetes Association Junior Faculty Award.
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