Transcript osteoporosis and type 2 diabetes * the link

OSTEOPOROSIS AND TYPE 2 DIABETES – THE LINK
Introduction
 Type 2 diabetes mellitus (T2DM) is one of the common chronic metabolic disorders
across the world having a significant impact on an individual's health 1
 It has been estimated that T2DM affects over 366 million adults worldwide and the
number is expected to rise up to 552 million by 2030 1
 Osteoporosis is a condition where the bones become less dense and are
susceptible to fractures.2,3 Osteoporosis can result in deformity, disability, pain and
even death4
It has now been established that T2DM is an independent
risk factor for osteoporotic fractures.1
1. Rubin MR, et al. Osteoporosis Risk in Type 2 Diabetes patients. Expert Rev Endocrinol Metab. 2013;8(5):423–5. 2. Giangregorio LM, et al. FRAX underestimates fracture risk in patients with diabetes. J
Bone Miner Res. 2012;27(2):301–8. 3. Brown SA, et al. Osteoporosis: An Under-appreciated Complication of Diabetes. Clin Diabetes. 2004;22. 4. Abdulameer SA, et al. Osteoporosis and type 2 diabetes
mellitus: what do we know, and what we can do? Patient Prefer Adherence 2012;6:435–48.
OSTEOPOROSIS AND TYPE 2 DIABETES – THE LINK
Prevalence
 The third National Health and Nutrition Examination Survey (NHANES III) estimated that about
13–18% women over 50 years of age in United States (U.S.) have osteoporosis with 37–50%
having additional risk of low bone mass at the hip 1
 This disease alone causes more than 350,000 hip fractures each year in the U.S. and the
annual number of fractures is expected to double by 2025 1
 The Iowa Women’s Health Study involving 32,089 postmenopausal women revealed that
women with type 1 diabetes mellitus (T1DM) were 12 times more likely to report hip fractures
as compared to women without T1DM. Whereas, in case of T2DM the risk was 1.7-fold higher
as compared to women without T2DM.2
 A review of 16 studies found 140,000 hip fractures among 800,000 patients with type 1
diabetes and review of 12 studies revealed people with T2DM have 70% more risk of hip
fracture3
 A recent study by Xia et al. showed that elderly men with diabetes were more likely to have
lowered bone mineral density and this is likely to be caused by insulin insufficiencies,
decreased insulin sensitivity, and diabetic nephropathy in patients living 4
1. Brown SA, Sharpless JL. Osteoporosis: An Under-appreciated Complication of Diabetes. Clin Diabetes. 2004;22. 2. Hofbauer LC, et al. Osteoporosis in patients withdiabetes mellitus. J Bone Miner Res.
2007;22(9):1317–28. 3. Osteoporosis – Is There A Link With Diabetes? [Internet]. [cited 2015 Sep 3]. Available from: http://iddt.org/related-health-issues/osteoporosisis-there-a-link-with-diabetes 4. Xia J, et al.
The relationship between insulin resistance and osteoporosis in elderly male type 2 diabetes mellitus and diabetic nephropathy. Ann Endocrinol (Paris). 2012;73(6):546–51.
OSTEOPOROSIS AND TYPE 2 DIABETES – THE LINK
 Risk factors particular to patients with diabetes are included in Table 1
Brown SA, Sharpless JL. Osteoporosis: An Under-appreciated Complication of Diabetes. Clin Diabetes. 2004;22. Available from: http://clinical.diabetesjournals.org/content/22/1/10.short?rss=1&ssource=mfc
OSTEOPOROSIS AND TYPE 2 DIABETES – THE LINK
The Diabetes-osteoporosis Association
Diabetes and osteoporosis are both frequent
endocrine disorders. However, they seem to be
interconnected in several ways.1
 Type 1 diabetes is linked to low bone density. Patients with type 1 diabetes are insulin
deficient, which may be required to promote bone growth and strength. 2
 Type 1 diabetes is typically developed at a young age when bone mass is still increasing.
Bone mass is thought to reach its peak by the age of 30 years. Thus, young people with type
1 diabetes may never achieve a normal peak bone density and the maximum strength. 2
 Low peak bone mass may make an individual prone to develop osteoporosis in future life.
People with type 1 diabetes are associated with celiac disease, which also reduces bone
mass.2
 Cytokines are thought to play a role in the development of both type 1 diabetes and
osteoporosis2
1. Vestergaard P. Diabetes and Bone. J Diabetes Metab. 2011;S:1. doi:10.4172/2155-6156.S1-001. 2. What People With Diabetes Need to Know About Osteoporosis [Internet]. [cited 2015 Sep 3].
Available from: http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/Conditions_Behaviors/diabetes.asp
OSTEOPOROSIS AND TYPE 2 DIABETES – THE LINK

Figure 1 shows the effects of diabetes on BMD at different times of life
1. Initial adolescent accumulation of bone is diminished
2. Therefore, reaching a lower plateau with continued loss associated with
hypercalciuria in early adult life
3. Followed by later onset and retardation of age-related bone loss
Krakauer JC, McKenna MJ, Buderer NF, et al. Bone loss and bone turnover in diabetes. Diabetes. 1995;44(7):775–82.
OSTEOPOROSIS AND TYPE 2 DIABETES – THE LINK
 Depending on the age of onset, stages could overlap
 Type 1 diabetes is associated with hypoglycaemia or low blood sugar reactions, vision
problems and nerve damage which contributes to an increased risk of falls and related
fractures
 Type 2 diabetes was previously believed to provide bone protection. An increased bone
mineral density (BMD) and weight in patients with type 2 diabetes prevented osteoporosis in
such patients.
 However, as with type 1 diabetes, people with type 2 diabetes too have an increased risk of
falling because of peripheral neuropathy, possible hypoglycaemia, nocturia, and visual
impairment. Because many type 2diabetic patients are obese and sedentary, this interferes
with bone health.
What People With Diabetes Need to Know About Osteoporosis [Internet]. [cited 2015 Sep 3]. Available from: http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/Conditions_Behaviors/diabetes.asp
POSSIBLE MECHANISM OF DIABETES-INDUCED OSTEOPOROSIS
 Although, exact underlying mechanism of pathogenesis is still unclear. It has been
established that hyperglycaemia is a significant factor that contributes to the direct and
indirect deleterious effects on osteoblast function and bone formation (Figure 2).
 Diabetes mellitus (DM) promotes osteoclast function but suppress osteoblast function,
thereby leading to accelerated bone loss, osteopenia and osteoporosis
 DM/hyperglycemia induces production of macrophage colony stimulating factor
(MCSF), tumour necrosis factor (TNF)-α and receptor activator of nuclear factor-κB
ligand (RANKL), all of which are osteoblast-derived activators of osteoclast proliferation
and differentiation
 Moreover, DM/hyperglycaemia suppresses osteoblast proliferation and function, in part,
by decreasing runt-related transcription factor (Runx)-2, osteocalcin and osteopontin
expressions
Wongdee K, Charoenphandhu N. Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms. World J Diabetes. 2011;2(3):41–8.
POSSIBLE MECHANISM OF DIABETES-INDUCED OSTEOPOROSIS
 Adipogenic differentiation of mesenchymal stem cells is increased as indicated by the
overexpression of adipocyte differentiation markers, including peroxisome
proliferatoractivated receptor (PPAR)-γ, adipocyte fatty acid binding protein (aP2),
adipsin and resistin
 A decrease in neovascularization may further aggravate bone loss
 Bone quality is also reduced as a result of advanced glycation end products (AGEs)
production, which may eventually result in low impact or fragility fractures
Wongdee K, Charoenphandhu N. Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms. World J Diabetes. 2011;2(3):41–8.
POSSIBLE MECHANISM OF DIABETES-INDUCED OSTEOPOROSIS
Wongdee K, Charoenphandhu N. Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms. World J Diabetes. 2011;2(3):41–8.
T2D ASSOCIATED NON-ENZYMATIC GLYCATION INDUCED
SKELETAL FRAGILITY
 Although high bone mineral density (BMD) and high body mass index (BMI) can be
seen in T2DM patients, they are associated with higher risk of fracture. Several studies
have estimated that T2DM patients are at a 2–3 fold increased risk of hip fracture.
These patients are prone to fall owing to a deficiency in bone microarchitecture and
poor bone quality.
 Thus, diabetic skeletal fragility is attributed to altered bone microarchitecture and/or
poor bone quality. Accumulation of AGEs on collagen of bone extracellular matrix is
thought to be the underlying mechanism for diabetes associated skeletal fragility.
 AGEs can form covalent crosslinks throughout collagen fibrils differentially affecting
collagen stability and mechanical properties of collagen
Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone. 2015. pii: S8756-3282(15)00302-6.
T2D ASSOCIATED NON-ENZYMATIC GLYCATION INDUCED
SKELETAL FRAGILITY
 AGEs are the post-translational modifications of collagen resulting from a spontaneous
reaction between free floating sugars and amino acid residues on collagen fibers.
However, data on AGEs is scarce and inconsistent. Therefore, a study was conducted
to shed light on these areas.
o Authors conducted a literature search in the PubMed database using keywords or
its combination such as “advanced glycation end-products”, “bone”, “collagen”,
“diabetes”, “fracture”, “fracture risk”, “non-enzymatic glycation”, “skeletal fragility”,
etc.
o About 100 relevant articles were reviewed to evaluate an association between
AGEs in bone and bone’s biomechanical properties
o The results of in vitro experiments to simulate a diabetic state were examined and
compared to ex vivo studies conducted in normal and diabetic human bone and
diabetic animal models
Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone. 2015. pii: S8756-3282(15)00302-6.
T2D ASSOCIATED NON-ENZYMATIC GLYCATION INDUCED
SKELETAL FRAGILITY
Findings
Following are the well-known findings regarding nonenzymatic glycation in bone:
 Increase in AGEs was associated with increase in age within a range of ∼20–100 years
 In vitro studies have suggested that AGEs is associated with decreased osteoblast
activity and altered osteoclast behaviour
 AGEs content remain unchanged with a standard clinical dose of bisphosphonate
however, it increases with increase in the bisphosphonate doses and decreases with
parathyroid hormone treatment
 Several studies have noted changes in bone biomechanical properties with in vitro
AGEs. AGEs are also found to have an influence on the type and extent of
microdamage formed.
 AGE inhibitors can decrease AGE accumulation and restore biomechanical properties
in animal models
 Higher AGE content was seen in bone from diabetic rodent as compared to nondiabetic controls with corresponding changes in mechanical properties
Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone. 2015. pii: S8756-3282(15)00302-6.
T2D ASSOCIATED NON-ENZYMATIC GLYCATION INDUCED
SKELETAL FRAGILITY
Recommendations
However, several inconsistent result and unknown points which needs to be investigated are:
 Reasons for drastic differences in levels of AGEs across the various published studies
 Whether there are differences in glycation content between cancellous and cortical bone
as the conflicting results were obtained with two studies
 Effect of chemically-induced versus naturally produced AGEs on bone cell behaviour
 Whether AGE levels modulation can be treated with anabolic or anti-resorptive treatment
Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone. 2015. pii: S8756-3282(15)00302-6.
T2D ASSOCIATED NON-ENZYMATIC GLYCATION INDUCED
SKELETAL FRAGILITY
 Whether AGE inhibitors/breakers can modulate bone biomechanics in animal models
and/or in human bone.
 AGE levels in bones of patients with T2DM and how AGE levels are influenced by
severity and duration of T2DM
Conclusion
The literature review linked diabetic skeletal fragility to altered bone quality. Further studies
among bone tissue from patients with T2DM and assessment of the biomechanical
consequences of accumulation of levels of AGEs are needed to support this association.
Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone. 2015. pii: S8756-3282(15)00302-6.
IMPROVING INSULIN RESISTANCE AND
REDUCTION IN BONE LOSS
 It is sufficiently evident from studies that there is an increased risk of fractures due to
presence of diabetic vascular complications, advanced glycation of bone collagen,
deranged bone turnover, and possibly certain types of anti-diabetic medications. Thus, a
comprehensive management that includes vitamin D and calcium along with a tight
metabolic control is most useful in diabetic patients with osteoporosis. 1
 It has been strongly emphasized by evidences that patients with type 1 as well as type 2
diabetes have an elevated risk of certain types of osteoporotic fractures. Therefore, it has
been recommended that in diabetic patients regular bone health assessment should be
conducted. In order to prevent fractures, improving bone density can be beneficial in
such subjects.2
 In diabetic patients suffering from osteoporosis, the treatment is similar as compared to
patients without diabetes except for those with nephropathy or gastrointestinal
complaints2
1. Okazaki R. Management of osteoporosis in diabetes mellitus – Japanese article. Nihon Rinsho. 2009;67(5):1003–10. 2. Brown SA, Sharpless JL. Osteoporosis: An Under-appreciated Complication of
Diabetes. Clin Diabetes. 2004;22. Available from: http://clinical.diabetesjournals.org/content/22/1/10.short?rss=1&ssource=mfc
IMPROVING INSULIN RESISTANCE AND
REDUCTION IN BONE LOSS
 Studies have demonstrated that glycaemic control can protect T2DM patients from bone
loss while insulin levels have an important effect on low BMD 1
 The long-term net balance between bone resorption and bone formation is considered as
bone loss. Hence, even if the bone turnover is affected by poor glycaemic control, it may
not show if the duration of poor control is short or if the bone mass is measured when
there is a stable glycaemic control for some time.2
 Many studies have exhibited that serum osteocalcin (OC), a marker of bone turnover is in
fact decreased in patients with NIDDM. In diabetic patients, OC may not present correctly
as the synthesis and secretion of OC from osteoblasts is regulated by the ambient
glucose levels. So, for assessing bone turnover, the sensitivity and specificity of each
biochemical marker must be considered.2
It has been demonstrated that improvement in glycaemic control
may have protective effect on patients with non-insulin dependent
diabetes mellitus (NIDDM/type 2 diabetes mellitus).2
1. Abdulameer SA, Sulaiman SA, Hassali MA, et al. Osteoporosis and type 2 diabetes mellitus: what do we know, and what we can do? Patient Prefer Adherence. 2012;6:435–48. 2.Okazaki R, Totsuka Y,
Hamano K, et al. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab. 1997;82(9):2915–20.
IMPROVING INSULIN RESISTANCE AND
REDUCTION IN BONE LOSS
 Addressing this subject, Okazaki and colleagues conducted a study to examine the effect
of glycaemic control on bone turnover using several specific bone markers. A rigid
management program was given to the poorly controlled NIDDM subjects. Before and 3
weeks after treatment, the bone markers were evaluated.
 The bone resorption markers used were urinary deoxypyridinoline (Dpd) and type I
collagen carboxyterminal telopeptide (CTx) while serum bone type alkaline phosphatase
(BALP) and OC were used as the bone formation markers
 The study enrolled all the NIDDM patients who had a HbA1c level of >8% at the
Department of Metabolism and Endocrinology, Kanto Teishin Hospital. Fasting blood
glucose was obtained on the second day after admission and on the day before
discharge. Pyrilinks-D kit after acid hydrolysis was used to assay urine total Dpd while
urine CTx was assayed using Cross-Laps kit. The samples before and after glycaemic
control were used to measure the metabolic bone markers, intact parathyroid hormone
(PTH)and 1,25(OH)2D.
Okazaki R, Totsuka Y, Hamano K, et al. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab. 1997;82(9):2915–20.
IMPROVING INSULIN RESISTANCE AND
REDUCTION IN BONE LOSS
Results
 After treatment, serum calcium (Ca) levels remain unaffected while serum phosphate (Pi)
levels significantly increased. Glycaemic control was found to significantly decrease the
urinary excretion of Ca and Pi. It was also associated with the decrease in the fractional
excretion of Pi (P<0.0001).
 The mean serum 1,25(OH)2D which were in the normal range before treatment
decreased significantly after treatment. There was no effect of the type of treatment
(insulin or noninsulin) on any change in the markers, except for urinary calcium excretion.
 Improvement in glycaemic control led to a significant reduction the resorption markers
 There was also a significant decrease in the levels of serum BALP and total ALP after
metabolic improvement. On the other hand, serum OC which was low before treatment,
showed a significant increase
Okazaki R, Totsuka Y, Hamano K, et al. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab. 1997;82(9):2915–20.
IMPROVING INSULIN RESISTANCE AND
REDUCTION IN BONE LOSS
 There was a significant correlation between the changes in Dpd and CTx and all the
indices of glycaemic control such as HbA1c, mean blood glucose (MBG), and urinary
sugar (US), urinary Ca and serum 1,25(OH)2D
 A correlation also existed between serum BALP and changes in glycaemic indices and
urinary Ca (Table 2)
Okazaki R, Totsuka Y, Hamano K, et al. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab. 1997;82(9):2915–20.
IMPROVING INSULIN RESISTANCE AND
REDUCTION IN BONE LOSS
Conclusion
 It can be elucidated from this study that in poorly controlled NIDDM patients,
improvement in glucose control is associated with a decrease in markers of bone
resorption and formation except OC
 Irrespective of treatment (diet, oral hypoglycaemic agents, insulin or combination),
metabolic improvement has similar effects on the bone turnover
 These observations laid stress on the fact that good diabetic control may not only prevent
microvascular complications but also osteoporosis by reducing bone loss
Okazaki R, Totsuka Y, Hamano K, et al. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab. 1997;82(9):2915–20.
MANAGEMENT OF OSTEOPOROSIS WITH
VITAMIN D IN DIABETES
 A relatively consistent association between low vitamin D status and prevalence of
T2DM is shown in a meta-analysis by Kulie et al. A low vitamin D level which is evident
in T2DM is an established risk factor for osteoporosis. 1 Thus, an important way of
management in T2DM patients who are at the risk of developing osteoporosis is
improving vitamin D level.
 Low bone mass, decreased bone strength and an increased risk of low-energy
fractures are the characteristic of osteoporosis 2
 The Rotterdam study, the largest study on BMD in T2DM, confirmed that the presence
of treated T2DM carries an increased fracture risk 3
1. Kulie T, Groff A et al. Vitamin D: an evidence-based review. J Am Board Fam Med. 2009;22(6):698–706. 2. Lupsa BC, Insogna K. Bone Health and Osteoporosis. Endocrinol Metab Clin North Am.
2015;44(3):517–30. 3. Hofbauer LC, Brueck CC, Singh SK, et al. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res. 2007;22(9):1317–28.
MANAGEMENT OF OSTEOPOROSIS WITH
VITAMIN D IN DIABETES
 Four randomized, placebo-controlled clinical trials were carried out to evaluate role of
vitamin D3 in the treatment of fractures (Table 3)
Vieth R. The role of vitamin D in the prevention of osteoporosis. Ann Med. 2005;37(4):278–85.
MANAGEMENT OF OSTEOPOROSIS WITH
VITAMIN D IN DIABETES
 All four the studies using approximately 20 μg/day of vitamin D3 showed a reduction in
fracture risk. A vitamin D3 dose of 20 μg/day is the lowest dose which has shown
fracture reduction in randomized clinical trials. This is the only nutrient with a
demonstrable effect on fractures.1
 A randomized, double-blind, controlled clinical trial was conducted for the duration of 1
year including 192 women, to determine if early changes in bone markers could predict
long-term response in BMD after calcium and vitamin D supplementation in ambulatory
elderly women with vitamin D deficiency (25(OH)D <12 ng/mL). They were randomized
to receive either the supplementation (n=95) or a placebo (n=97). Supplementation
significantly increased BMD and normalized 25(OH)D when compared to placebo. 2
 A strong improvement in lower extremity function based on walking speed and sit-tostand speed and in serum 25(OH)D levels was seen in NHANES analysis. Thus,
vitamin D supplements help in the management of fall prevention, which in turn may
reduce osteoporotic fractures.3
1. Vieth R. The role of vitamin D in the prevention of osteoporosis. Ann Med. 2005;37(4):278–85. 2. Grados F, Brazier M, Kamel S et al. Prediction of Bone Mass Density Variation by Bone Remodeling Markers
in Postmenopausal Women with Vitamin D Insufficiency Treated with Calcium and Vitamin D Supplementation. J Clin Endocrinol Metab. 2003;88(11):5175–9. 3. Nieves JW. Osteoporosis: The role of
micronutrients. Am J ClinNutr. 2005;81(5):1232S–1239S
SUMMARY
 Globally, T2DM affects over 366 million adults and the number is expected to rise up to
552 million by 2030.
 T2DM is an independent risk factor for osteoporotic fractures as contributes to the
direct and indirect deleterious effects on osteoblast function and bone formation.
 Various studies have shown that vitamin D supplementation significantly increased
BMD, reduced fracture risk and normalized 25(OH)D levels.
 A comprehensive management that includes vitamin D and calcium along with a tight
metabolic control is most useful in diabetes patients with osteoporosis.