Download effect of type 2 diabetes on bone mineral density and markers of

Effect of type 2 diabetes on bone mineral density and markers of bone turnover in
women with osteoporosis
‫ على الكثافة المعدنية للعظام وعلى عالمات تجدد وتهدم (ايض) العظام عند النساء‬2 ‫تأثير داء السكري من النوع‬
Raluca Nan, MD, Mădălina Muşat, MD, PhD, Daniel Grigorie, MD, PhD, Alina Şucaliuc,
MD, PhD, Emilia Rusu, MD, PhD, Ramona Drăguţ, MD, Adrian Cursaru, MD, Gabriela
Radulian, Prof, PhD.
,‫ الينا شوكاليوك‬. ‫دكتوراه‬,‫ طبيبة‬,‫ دانييل كريكوريه‬. ‫دكتوراه‬,‫ طبيبة‬,‫ مادالينا موشات‬. ‫دكتوراه‬,‫ طبيبة‬,‫رالوكا نان‬
‫ علم‬,‫ كابريليا رادوليان‬. ‫ طبيب‬,‫ ادريان كورسارو‬. ‫ طبيبة‬,‫ رامونا دراكوت‬. ‫دكتوراه‬,‫ طبيبة‬,‫ ايميليا روسو‬. ‫دكتوراه‬,‫طبيبة‬
. ‫دكتوراه‬, ‫االحياء الطبي‬
Disclosure. Authors have no conflict of interests, and the work was not supported or funded
by any drug company.
Type 2 diabetes and osteoporosis
1
From the Department of Hygiene and Diabetes (Nan, Drăguţ, Rusu), Dental Medicine,
University of Medicine and Pharmacy Carol Davila, Calea Plevnei 17-23, Bucharest,
Romania, formerly of Department of Endocrinology (Nan, Muşat, Şucaliuc, Grigorie),
National Institute of Endocrinology C.I. Parhon, Aviatorilor, no. 34-36, Bucharest, Romania,
Department of Diabetes II (Drăguţ, Rusu, Radulian), National Institute of Diabetes, Nutrition
and Metabolic Diseases Prof. Dr. N. Paulescu, Ion Movila, no.5-7, Bucharest, Romania,
Department of Orthopaedic and Traumatology (Cursaru), Bucharest Emergency University
Hospital, Splaiul Independentei no. 169, Bucharest, Romania.
-17 ‫رقم‬, ‫ شارع بليفنا‬,‫كارول دافيال‬, ‫جامعة الطب والصيدلية‬,‫ طب االسنان‬,)‫روسو‬,‫دراكوت‬,‫قسم الصحة والسكري (نان‬
‫ رومانيا‬, ‫ بوخارست‬,23
‫شارع كونستانتين يون‬,‫شوكاليوك) المعهد الوطني للغدد الصماء‬,‫كريكورية‬,‫موشات‬,‫ سابقا قسم الغدد الصماء (نان‬,
,‫ رومانيا‬,‫ بوخارست‬,36-34 ‫رقم‬,‫بارهون‬
‫المعهد الوطني للسكري و التغذية واالمراض االيضية بروفسور دكتور‬,)‫ رادوليان‬,‫ روسو‬,‫(دراكوت‬,2 ‫قسم داء السكر‬
,‫ رومانيا‬, ‫بوخارست‬,7-5 ‫ رقم‬,‫شارع يون موفيال‬, ‫باوليسكو‬
, ‫بوخارست‬,169 ‫شارع اندبنتتي رقم‬,‫ مستشفى بوخارست الجامعي للطواريء‬,)‫ق سم الكسور و جراحة العظام (كورسارو‬.
.‫رومانيا‬
Corresponding author: Nan R, Medical Doctor, Department of Hygiene and Diabetes, Dental
Medicine, University of Medicine and Pharmacy Carol Davila, Calea Plevnei 17-23,
Bucharest, Romania, 0745151500, E-mail: [email protected].
,23-17 ‫رقم‬, ‫ شارع بليفنا‬,‫كارول دافيال‬, ‫جامعة الطب والصيدلية‬,‫ طب االسنان‬, ‫طبيبة‬, ‫ رالوكا نان‬: ‫ال مؤل ف ال م قاب لة‬
[email protected] :‫ البريد االلكتروني‬,0040745151500 ‫رقم الهاتف‬,‫ رومانيا‬, ‫بوخارست‬
2
ABSTRACT
Objectives: The effect of type 2 diabetes on bone tissue is still under debate. This study was
designed to assess the effects of type 2 diabetes on bone mineral density (BMD) and markers
of bone turnover in women with recently diagnosed postmenopausal osteoporosis and a year
later.
Methods: In this retrospective study data was collected using the patients database of the
National Institute of Endocrinology C.I. Parhon, Bucharest, Romania, from September 2014
to May 2015. Two groups of women have been evaluated at baseline and at one year after
initiation bisphosphonates: a group of 35 women diagnosed with type 2 diabetes and newly
postmenopausal osteoporosis (diabetic group) and a group of 35 women only with
postmenopausal osteoporosis (control group).
Results: Body mass index and glycemia were significally higher in the diabetic women
throughout the study period. There was not significant statistical difference regarding the
BMD at hip between the two groups during the study. BMD at lumbar spine was significantly
higher in diabetic group than control group throughout the study. Osteocalcin and crosslaps
have been significantly lower compared to the control group at baseline. After a year of
bisphosphonate treatment, osteocalcin did not change in the diabetic group and crosslaps was
decreased in both groups.
Conclusion: In diabetic women bone mineral density at lumbar spine and crosslaps are
improved within one year of treatment with bisphosphonates.
‫الملخص‬
‫ تم تصميم وانجاز هذه‬.‫ على نسيج العظام ال يزال تحت الدراسة و النقاش‬2 ‫ ان تأثير داء السكري من النوع‬:‫فادهألا‬
‫ على الكثافة المعدنية للعظام وعلى عالمات تجدد وتهدم (ايض) العظام‬2 ‫الدراسة لغرض تقييم تاثيرات داء السكري نوع‬
.‫عند النساء المشخصات حديثا بهشاشة العظام بعد انقطاع الطمث وبعد فترة سنة‬
‫ تم تجميع البيانات عن طريق استخدام قاعدة بيانات المرضى التابعة للمعهد الوطني‬,‫ في هذه الدراسة االستعادية‬:‫الطريقة‬
‫ تم دراسة مجموعتين من النساء قبل وبعد‬.2015 ‫ الى مايو‬2014 ‫رومانيا خالل الفتره من ايلول‬, ‫ بوخارست‬,‫للغدد الصماء‬
2 ‫ امرأة تشخيص مرض السكري نوع‬35 ‫ المجموعه االولى مكونه من‬:‫سنة من بداية العالج باستخدام البايفوسفونيت‬
‫ أمرأة مشخصة‬35 ‫ و المجموعة الثانية مكونة أيضا من‬,‫وكذلك مشخصة حديثا بهشاشة العظام بعد انقطاع الطمث‬
.)‫فقط بهشاشة العظام بعد انقطاع الطمث (المجموعة الضابطة‬
‫ تبين ان نسب مؤشر كتلة الجسم و معدل سكر الدم كانت اعلى بشكل ملحوظ لدى النساء‬,‫ حسب نتائج هذة الدراسة‬:‫النتائج‬
‫ لم يكن هناك فروق ذات داللة إحصائية فيما الكثافة المعدنية للعظام عظم الورك‬.‫المصابات بالسكري خالل فترة الدراسة‬
‫ خالل فترة الدراسة لوحظ الكثافة المعدنية للعظام العمود الفقري القطني أع لى بكثير‬.‫بين المجموعتين خالل فترة الدراسة‬
‫ اضافة الى ذلك فقد‬.)‫في مجموعة المريضات المصابات بالسكري مقارنة بالمجموعة االخرى (الغير المصابات بالسكري‬
.‫لوحظ ان األوستيوكالسين و الكروسالبس كان اقل بكثير بالمقارنة مع مجموعة الغير مصابين بالسكري عند خط االساس‬
‫بعد فترة سنة من العالج بالبايفوسفونيت لوحظ ان مستوى االوستيوكالسين لم يتغير عند المريضات المصابات بداء السكري‬
.‫ولكن مستوى الكروسالبس هبط لدى المجموعتين‬
3
‫ لوحظ تحسن في الكثافة المعدنية للعظام من الفقرات القطنية والكرورسالبس عند النساء المصابات بداء السكر‬:‫الخاتمة‬
.‫بعد فترة سنة عالج البايفوسفونيت‬
Diabetes and osteoporosis are two very common diseases with a great socio-economic
impact. The westernization of lifestyle characterized by decreased physical activity and
increased consumption of high calorie foods contributes to accelerated growth of diabetes and
osteoporosis.1 The prevalence of diabetes is 9.28% in Romania2 and the prevalence of
osteoporosis in women and men over the age of 50 years in Romania is 20.5% and 6.2%3
respectively. The relationship between diabetes and bone tissue has been investigated for a
long time. The mechanisms by which diabetes affects bone differ in type 1 from type 2
diabetes. Type 1 diabetes mellitus is characterized by insulin deficiency since the diagnosis,
while type 2 diabetes mellitus is characterized by hyperinsulinemia in the early stages of the
disease. The hyperinsulinemia might contribute to the increased bone mass and
hyperglycemia might accelerate bone resorption.4,5 Patients with type 2 diabetes have higher
bone mineral density at the femoral neck and lumbar spine and a 69% higher risk of nonvertebral fractures than those without diabetes.6,7,8 The efficacy of osteoporosis treatment in
patients with diabetes is low.9
Early studies, which investigated markers of bone turnover, used urinary calcium and
hydroxyproline.10 In more recent studies, new markers of bone formation (osteocalcin, bone
specific alkaline phosphatase, alkaline phosphatase (ALP)) and markers of bone resorbtion
(type 1 cross-linked C-telopeptide (CTX), serum beta CTX (crosslaps), cross-linked Nterminal telopeptide of type 1 collagen (NTX)) are used.11 Osteocalcin is synthesized and
secreted by osteoblasts12 and has additional functions that improve glucose metabolism and
reduce fat mass.13
The aim of this study was to assess the effects of type 2 diabetes on bone mineral density
and markers of bone turnover in women with recently diagnosed postmenopausal
osteoporosis and a year later, after initiation osteoporosis therapy.
Methods. Study design. We performed a retrospective study using the patients database of the
National Institute of Endocrinology C.I. Parhon, Bucharest, Romania, from September 2014
to May 2015. We included in the study 70 women with newly diagnosed postmenopausal
osteoporosis, split in two groups: 35 women with postmenopausal osteoporosis and type 2
diabetes (diabetic group) and 35 non-diabetic women with postmenopausal osteoporosis
(control group) who were assesssed at baseline and one year, after beginning the osteoporosis
treatment. The study has been approved by the Institute of Endocrinology C.I. Parhon, Ethical
Committee.
Inclusion criteria were newly diagnosed women with postmenopausal osteoporosis, aged
between 50 and 80 years. Women were matched in terms of age. Postmenopausal status of
participants was confirmed by interview.
Exclusion criteria were early onset hypogonadism, growth hormone deficiency, thyroid
gland disease, primary hyperparathyroidism, cirrhosis, reduced glomerular filtration rate
(GFR <60 ml/min/1,73 m²), corticosteroid therapy, neoplasms, total or partial hysterectomy,
systemic lupus erythematosus, rheumathoid artritis, malabsorbtion or any bone-active
medication, menopause hormone replacement therapy at the time of bone assessment.
Treatments for osteoporosis were bisphosphonates, vitamin D and calcium and treatment for
diabetes was diet or oral agents (other than thiazolidinediones). Body mass index (BMI) was
calculated according to Centers for Disease Control and Prevention (CDC).14
4
Biochemical parameters. Bone turnover markers (osteocalcin and crosslaps), 25hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) were measured by
electrochemiluminescence immunoassay (ECLIA) on a Roche Cobas e 601 ((Roche
Diagnostics, North America). The measurements of fasting blood glucose (FPG), alkaline
phosphatase (ALP), total calcium, magnesium (photometric method) and glycosylated
hemoglobin (HbA1c) (imunoturbidimetric method) concentrations were performed using the
standard laboratory methods applied on Cobas 6000 analyzer (Roche Diagnostics, North
America). All these parameters were assessed at baseline and after one year.
Bone mineral density. All women studied underwent measurement of body mass density
(BMD) at lumbar and femoral neck using GE Lunar iDXA (USA) machine at baseline and
one year later. Postmenopausal osteoporosis was assessed based on T-score from BMD
measurements as defined by the World Health Organization (WHO): T-score < -2.5.15 For
statistical analysis we used T-score.
Statistical analysis. The Statistical Package version 17 was used for collection, analysis and
interpretation of the results. Variables in control and study groups are shown as elements of
descriptive statistics (mean±standard deviation). Comparisons between groups were
performed using ANOVA for quantitative variables and independence chi square test for
categorical variables. Correlation analysis was performed using Spearman’s correlation
coefficient. Two-tailed, p<0.05 was considered statistically significant.
Results. Mean age of the women included in the study was 63.9±8.5 years (Tabel 1). BMI
and FPG were significantly greater in women with type 2 diabetes (T2D) than in non-diabetic
women (Tabel 1) throughout the study period.
Serum levels of osteocalcin and crosslaps in women with T2D were significantly lower than
in women without diabetes, but these differences were not encountered one year after
beginning of the osteoporosis treatment (Tabel 2). The level of ALP was decreased in both
study groups after one year osteoporosis treatment, but without statistical significance.
5
Table 1: Anthropometric and biochemical parameters of the study populations at baseline and
at one year later.
Variables
Diabetic
Non-
group
(n=35)
p-value
Diabetic
Non-
diabetic
group
diabetic
group
(n=35)
group
(n=35)
(n=35)
At baseline
At one year
p-value
Age (years)
64.2±8.1
63.6±9.1
0.761†
65.2±8.1
64.6±9.1
0.761†
BMI (kg/m²)
29.85±4.1
25.0±3.9
0.001*
29.8±3.8
25.2±3.7
0.001*
Ca (mg/dl)
9.6±0.45
9.5±0.4
0.674†
9.7±0.5
9.6±0.4
0.241†
Mg (mg/dl)
1.9±0.2
2.05±0.2
0.001*
1.85±0.25
2.0±0.2
0.007*
FPG (mg/dl)
135.9±52.7
88.05±8.9
0.001*
132.1±36.4
88.9±15.5
0.001*
HbA1c (%)
7.1±0.85
-
-
7.0±0.8
-
-
*
statistically significant (p<0.05), † not statistically significant
BMI - body mass index, Ca - calcium, Mg - magnesium, FPG - fasting plasma glucose,
HbA1c - glycosylated hemoglobin
6
Tabel 2. Bone mineral density, markers of bone turnover and 25(OH)D in the populations
study at baseline and at one year later.
Parameters
Osteocalcin
Diabetic
Non-
group
(n=35)
p-value
Diabetic
Non-
diabetic
group
diabetic
group
(n=35)
group
(n=35)
(n=35)
At baseline
At one year
p-value
18.8±10.1
30.9±15.6
0.001*
19.5±20.4
20.65±11.5
0.778†
0.3±0.2
0.55±0.3
0.001*
0.25±0.1
0.3±0.2
0.181†
73.9±20.6
90.5±59.8
0.125†
69.4±15.5
72.6±30.2
0.578†
17.1±9.6
18.2±7.7
0.585†
23.9±9.4
24.4±7.9
0.837†
50.5±15.9
44.1±13.6
0.077†
46.1±14.9
47.5±16.6
0.714†
-2.3±0.75
-2.35±0.7
0.859†
-2.1±0.9
-2.3±0.7
0.377†
-2.9±0.4
-3.35±0.8
0.014*
-2.5±0.45
-3.0±0.8
0.003*
(ng/ml)
Crosslaps
(ng/ml)
ALP
(UI/l)
25(OH)D
(ng/ml)
PTH
(pg/ml)
BMD hip
(T-score)
BMD lumbar
(T-score)
*
statistically significant (p<0.05), † not statistically significant
7
ALP - alkaline phosphatase, 25(OH)D - 25-hydroxyvitamin D, PTH - parathyroid hormone,
BMD - bone mineral density
In diabetic group, 25(OH)D was lower than in control group throughout the study period,
however not reaching statistical significance. After osteoporosis treatment the level of vitamin
D has increased (Tabel 2). There were no significant differences in serum PTH between
women with type 2 diabetes and women without diabetes.
Serum magnesium levels were significantly lower in the diabetic women compared with
non-diabetic women throghout the study period. In diabetic group, magnesium correlates
negatively with FPG (r=-0.395, p<0.019).
BMD at the lumbar spine (T-score) was significantly higher in diabetic group than nondiabetic group and this difference was maintained throughout the study period. BMD at the
hip (T-score) did not differ between two groups at baseline and one year later (Tabel 2).
Discussion. During the menopause women often gain weight likely due to reduced physical
activity, change of hormonal levels and decrease in basal metabolism.16 Obesity seems to be a
protective factor for osteoporosis because it increases estradiol levels, stimulates of bone
formation by leptin and increases load on the cortical skeleton.17 It is classically thought that
overweight women are protected from osteoporosis, but there is an increasing evidence in
conflict with this observation, suggesting that obesity interferes with bone health.18,19 All
women included in our study were overweight, but women with type 2 diabetes had a
significantly higher BMI than women without diabetes throughout the study. Also fasting
plasma glucose levels were higher in diabetic group than non-diabetic group. Levels of
HbA1c suggest a poor glycemic control. There was no improvement in glycemic values at
one year after starting osteoporosis treatment.
The effect of hyperglycemia on the BMD is controversial and is still debated. Some studies
shown that people with T2D have reduced12,20, unchanged21,22 or increased7,23 bone mass in
comparison to healthy control. In our study, lumbar BMD (T-score) was significantly higher
in diabetic women than non-diabetic women. This is in accordance with meta-analysis
conducted by Ma et al24 who analyzed the association between bone mineral density and type
2 diabetes. They found a significantly higher BMD in diabetic population.
After a year of bisphosphonate treatment, there was not observed an increase hip BMD (Tscore), but there was found an increase lumbar BMD (T-score) in both groups. On the
contrary, study conducted by Sachmechi et al9 mainly on African American, South Asian and
Hispanic women has shown a significant increase in BMD at the spine and hip in alendronate
treated late postmenopausal osteoporotic women with T2D. Another study conducted by
Keegan et al25 mainly on Caucasian women demonstrated that alendronate increases BMD in
older women with low BMD and T2D.
According to the results obtained in our study, we observed that in T2D both the formation
and resorption of bone are altered. The diabetic women had a significantly decrease in
osteocalcin level, reflecting a reduction in bone formation. This difference was also observed
in study conducted by Oz et al.26 Another marker of bone formation used in this study was
ALP. It’s level was lower in diabetic group, but without statistical significance and reflects
different stages of osteoblastic differentiation. Bone alkaline phosphatase is currently
8
considered a more sensitive marker to assess bone formation than ALP, but in this study bone
ALP was not done. Serum level of crosslaps was significantly decreased in women with T2D
which suggests a decrease of bone resorption in this group. This results are consistent with
those reported by Malecha-Jędraszek et al.5 On contrary, other study suggests that the process
of bone resorption in T2D is slightly increased.26 After one year of bisphosphonate initiation,
osteocalcin level did not change in the diabetic group, but in non-diabetic group was observed
a decrease level of osteocalcin. Crosslaps was decreased in both diabetic and non-diabetic
groups, proving good therapy compliance. The study conducted by Ikeda et al27 which
investigated effect of alendronate on BMD in postmenopausal osteoporotic diabetic women
showed that alendronate treatment significantly decreased urinary NTX, a marker of bone
resorption.
The role of vitamin D in diabetes is still under investigation. Vitamin D seems to have an
influence on glucose metabolism by modulating inflammatory response and to control
calcium flux through the β-cells membrane and in peripheral tissue.28,29,30 In our study we
revealed an insufficiency of 25(OH)D31 with levels of vitamin D below 20 ng/ml in both
study groups at baseline. After one year from the initiation of osteoporosis treatment we
found a sufficiency of 25(OH)D31 in both study groups. Another study conducted by Farr et
al23 demonstrated that 25(OH)D did not differ between diabetic and non-diabetic women.
Magnesium is essential for all cells, including osteoblasts and osteoclasts.32 It seems to have
a regulatory role in energetic metabolism including the glycemic control. 33 In our study serum
level of magnesium did not differ within the same group throughout the study period, but
encountered a statistically significant difference between diabetic group and non-diabetic
group. The same results were observed in study conducted by Diwan et al34 on 40 type 2
diabetics and 40 age matched non-diabetic healthy subjects. Negatively correlation between
FPG and magnesium, which was observed in our diabetic group, suggests that a poor control
of diabetes is associated with decreased level of magnesium.
Though this is a small retrospective study this is a valuable one as, there is a limited number
of studies assessing bone turnover markers and BMD (T-score) in women with recently
diagnosed postmenopausal osteoporosis and type 2 diabetes treated with bisphosphonates.
Future larger, prospective studies to analyze the present markers of bone turnover and also
newer ones as sclerostin and cathepsin K will bring more insight into the mechanisms of
diabetic bone osteoporosis.
In conclusion, women with type 2 diabetes and newly diagnosed postmenopausal
osteoporosis have significantly higher lumbar BMD and significantly lower serum levels of
osteocalcin and crosslaps than non-diabetic women, which are improved within one year of
treatment with bisphosphonates. Markers of bone turnover should be introduced in the
fracture risk assessment tool (FRAX), especially in diabetic patients.
Acknowledgements. ”This work received financial support through the project entitled
"CERO – Career profile: Romanian Researcher", grant number POSDRU/159/1.5/S/135760,
cofinanced by the European Social Fund for Sectoral Operational Programme Human
Resources Development 2007-2013”.
9
References
1
Brown SA, Sharpless JL. Osteoporosis: an under-appreciated complication of diabetes.
Clinical Diabetes 2004; 22: 10-20.
2
International Diabetes Federation. IDF Diabetes Atlas, Sixth Edition, 2014 UPDATE.
Available from: http://www.idf.org/diabetesatlas
3
Grigorie D, Sucaliuc A, Johansson H, Kanis JA, McCloskey E. FRAX-based intervention
and assessment thresholds for osteoporosis in Romania. Arch Osteoporos 2013; 8: 164.
4
Hamann C, Kirschner S, Günther KP, Hofbauer LC. Bone, sweet bone—osteoporotic
fractures in diabetes mellitus. Nat Rev Endocrinol 2012; 8: 297-305.
5
Malecha-Jędraszek A, Burska A, Donica H, Matuszek B, Korpysz M, Wojtysiak-Duma B, et
al. Selected markers of bone turnover in type 2 diabetic patients. Current Issues in Pharmacy
and Medical Sciences 2012; 25: 367-372.
6
Sultan E, Taha I, Saber LM. Altered bone metabolic markers in type 2 diabetes mellitus:
impact of glycemic control. Journal of Taibah University Medical Sciences 2008; 3: 104–
116.
7
Jackuliak P, Payer J. Osteoporosis, fractures, and diabetes. International Journal of
Endocrinology 2014; 820615, 2014.
8
de Liefde II, van der Klift M, de Laet CE, van Daele PL, Hofman A, Pols HA. Bone mineral
density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int
2005; 16: 1713–20.
9
Sachmechi I, Ahmed S, Joseph J, Reich D, Cardinal L, Kim P. Effect of alendronate on bone
mineral density in post menopausal women with type 2 diabetes mellitus. International
Journal of Endocrinology and Metabolism 2015; 1 (1): doi
http://dx.doi.org/10.16966/ijemd.103.
10
Gallacher SJ, Fenner JA, Fisher BM, Quin JD, Fraser WD, Logue FC, et al. An evaluation
of bone density and turnover in premenopausal women with type 1 diabetes mellitus. Diabet
Med 1993; 10: 129-133.
11
Talwar SA, Aloia JF, Talavera F, Griffing GT, Gambert SR. Bone markers in osteoporosis.
Medscape 2014.
12
Dutta MK, Pakhetra R, Garg MK. Evaluation of bone mineral density in type 2 diabetes
mellitus patients before and after treatment. Medical Journal Armed Forces India 2012; 68:
48–52.
13
Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of
energy metabolism by the skeleton. Cell 2007; 130: 456–469.
14
Centers for Disease Control and Prevention. Credible health information, 2009.
Available from: http://www.cdc.gov/healthyweight/assessing/bmi/adult_BMI/index.html
15
World Health Organisation. Assessment of fracture risk and its implication to screening for
postmenopausal osteoporosis. Technical report series 843. Geneva: WHO 1994.
16
Cagnacci A, Zanin R, Cannoletta M, Generali M, Caretto S, Volpe A. Menopause,
estrogens, progestin, or their combination on body weight and anthropometric measurements.
Fertil Steril 2007; 88: 1603–1608.
17
Rosen CJ, Bouxsein ML. Mechanisms of disease: Is osteoporosis the obesity of bone?
Nature Clinical Practice Rheumatology 2006; 2: 35–43.
18
Zhao LJ, Jiang H, Papasian CJ, Maulik D, Drees B, Hamilton J, et al. Correlation of obesity
and osteoporosis: effect of fat mass on the determination of osteoporosis. J Bone Miner Res
2008; 23: 17–29.
10
19
Migliaccio S, Greco EA, Fornari R, Donini LM, Lenzi A. Is obesity in women protective
against osteoporosis? Diabetes Metab Syndr Obes 2011; 4: 273–282.
20
Adil C, Aydin T, Taşpinar Ö, Kiziltan H, Eriş AH, Hocaoglu IT, et al. Bone mineral density
evaluation of patients with type 2 diabetes mellitus. Journal of Physical Therapy Science
2015; 27: 179–182.
21
Anaforoglu I, Nar-Demirer A, Bascil-Tutuncu N, Ertorer ME. Prevalence of osteoporosis
and factors affecting bone mineral density among postmenopausal Turkish women with type
2 diabetes. J Diabetes Complications 2009; 23: 12-7.
22
Caglayan EK, Engin-Ustun Y, Sari N, Karacavus S, Seckin L, Kara M. Evaluation of bone
density measurement in type 2 diabetic postmenopausal women with hypertension and
hyperlipidemia. J Menopausal Med 2015; 21: 36-40.
23
Farr JN, Drake MT, Amin S, Melton LJ 3rd, McCready LK, Khosla S. In vivo assessment
of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 2014; 29:
787–795.
24
Ma L, Oei L, Jiang L, Estrada K, Chen H, Wang Z, et al. Association between bone mineral
density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J
Epidemiol 2012; 27: 319–332.
25
Keegan TH, Schwartz AV, Bauer DC, Sellmeyer DE, Kelsey JL. Effect of alendronate on
bone mineral density and biochemical markers of bone turnover in type 2 diabetic women.
Diabetes Care 2004; 27: 1547-1553.
26
Oz SG, Guven GS, Kilicarslan A, Calik N, Beyazit Y, Sozen T. Evaluation of bone
metabolism and bone mass in patients with type-2 diabetes mellitus. J Natl Med Assoc 2006;
98: 1598–1604.
27
Ikeda T, Iwata K. Long-term effect of alendronate on bone mineral density in
postmenopausal type 2 diabetes mellitus. Journal of Diabetes & Metabolism 2011; S1: 002.
doi:10.4172/2155-6156.S1-002.
28
Chagas CEA, Borges MC, Martini LA, Rogero MM. Focus on vitamin D, inflammation
and type-Π diabetes. Nutrients 2012; 4: 52-67.
29
Alselami NM, Noureldeen AF, Al-Ghamdi MA, Khan JA, Moselhy SS. Bone turnover
biomarkers in obese postmenopausal Saudi women with type-II diabetes mellitus. Afr Health
Sci 2015; 15: 90-6.
30
Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol
Metab Clin North Am 2010; 39: 419–46.
31
Rizzoli R, Boonen S, Brandi ML, Bruyère O, Cooper C, Kanis JA, et al. Vitamin D
supplementation in elderly or postmenopausal women: a 2013 update of the 2008
recommendations from the European Society for Clinical and Economic Aspects of
Osteoporosis and Osteoarthritis (ESCEO). Curr Med Res Opin 2013; 29: 305-13.
32
Castiglioni S, Cazzaniga A, Albisetti W, Maier JA. Magnesium and osteoporosis: current
state of knowledge and future research directions. Nutrients 2013; 5: 3022–3033.
33
Mooren FC. Magnesium and disturbances in carbohydrate metabolism. Diabetes Obes
Metab 2015; 17: 813-23.
34
Diwan AG, Pradhan AB, Lingojwar D, Krishna KK, Singh P, Almekar SI. Serum zinc,
chromium and magnesium levels in type II diabetes. Int J Diabetes Dev Ctries 2006; 26: 122123.
11
I declare that any similar work has not been submitted to or published by another journal. I
declare that it has not been submitted/published elsewhere in the same form, in English or in
any other language, without the written consent of the Publisher.
We declare that the paper is our original work and not copied (in whole or in part) from any
other work.
12