Boneloss following immobilization in diabetes mellitus, an inventory using an ultrasound method (BINDEX).

Diabetes mellitus leads to an increased risk of bone fractures for a not
completely known reason, which is not reflected in bone density measurement. On
average, a patient with diabetes mellitus has a normal to increased bone
density. Presumably, the cause of the increased fracture risk is multifactorial
and is based on a greater chance of falling through vaso-lability and
neuropathy and adverse effects of high blood sugar on the bone mineral
properties of the bone mineral. It is known that diabetes mellitus gives a
decrease in bone turnover and an accumulation of AGEs: Advances Glycation End
products. This results in reduced bone strength. Also, diabetic neuropathy is
thought to lead to a decrease in bone strength.

Bone loss by immobilization is a known clinical phenomenon presumably partly
caused by a decreased load on the osteocytes . This cell type is an osteogenic
cell derived from osteoblasts. In fact they are differentiated osteoblasts
which are arranged in a network in the bone. Applied pressure on this network
causes an osteocytic fluid flow, which causes less sclerostin to be produced.
This is a bone producing-inhibiting peptide. This reduction of sclerostine
results in more bone production. Conversely, bone breakdown occurs if there is
no pressure. From previous studies in space, a decrease in BMD was found to be
1 to 2 percent per month. The tibia cortex thickness decreased by 4% in 4-6
months. [6-7] However, in a case report on a patient with diabetic neuropathy,
a 20% decrease in bone density was found after 6 weeks immobilization using
calcaneal ultrasound.

Diabetes mellitus results in neurogenic and vascular complications. Known
complications are the diabetic footulcers and the charcot-foot. Both
complications are, among other things, treated by total cast immobilization of
the lower leg. This immobilization may last for many months and several periods
of immobilization may be necessary. Based on current literature one would
expect that this extensive immobilization would result in a decrease in bone
strength. Considering the already increased fracture risk, this is a very
undesirable effect. To our knowledge there are no studies on this phenomenon
and the extent of this effect is still unknown.

Research regarding the effect of bone loss on bone strength has shown that the
cortex contributes significantly to bone strength. A decreased cortex thickness
is a predictor for decreased bone strength. Evaluation of the cortex can be
done by ultrasound assessment (Speed **of Sound (SOS) and Broadband Attenuation
(BUA)). The Reinier de Graaf Gasthuis has gained considerable experience with
ultrasound of the lower leg using Bindex®. Bindex® is a Class I medical device
with a CE mark. The system used has been developed in Finland and is well
applicable in acute situations, either directly after a trauma or immediately
prior to the application of plaster. This method measures the cortex thickness
in millimeters and estimates the femoral neck density index in g / cm2 based on
patient characteristics and the measured cortex thickness of the tibia.

References:

1. Epstein et al. Diabetes and disordered bone metabolism (diabetic
osteodystrophy): time for recognition. Osteoporos Int (2016) 27:1931-1951
2. Yamamoto M., Sugimoto T. Advanced Glycation End Products, Diabetes, and Bone
Strength. Curr Osteoporos Rep (2016) 14:320*326
3. Joshua N. Farrm Sundeep Khosla. Determinants of bone strength and quality
in diabetes mellitus in humans. Bone 82 (2016) 28*34
4. De Waard et al. Increased fracture risk in patients with type 2 diabetes
mellitus: An overview of the underlying mechanisms and the usefulness of
imaging modalities and fracture risk assessment tools. Maturitas 79 (2014) 265*
274
5. Barwick, A. L., Janse de Jonge, X. A. K., Tessier, J. W., Ho, A., & Chuter,
V. H. (2014). The effect of diabetic neuropathy on foot bones: A systematic
review and meta-analysis. Diabetic Medicine, 31, 136*147
6. Holick MF. Perspective on the impact of weightlessness on calcium and bone
metabolism. Bone. 1998; 22:105S*111S.
7. Vico et al. Cortical and trabecular bone microstructure did not recover at
weightbearing skeletal sites and progressively deteriorated at
non-weight-bearing sites during the year following International Space Station
missions. Journal of Bone and Mineral research. doi: [10.1002/jbmr.3188]
8. Hastings M., Sinacore D., Fielder F., Johnsen J. Bone Mineral Density
During Total Contact Cast Immobilization for a Patient With Neuropathic
(Charcot) Arthropathy. Phys Ther. 2005 March ; 85(3) 249-256
9. Augat P., Schorlemmer S., The role of cortical bone and its microstructure
in bone strength. Age and Ageing 2006; 35-S2: ii27*ii31
10. Karjalainen et al. Multi-site bone ultrasound measurements in elderly women
with and without previous hip fractures. Osteoporos Int (2012) 23:1287*1295
11. Karjalainen et al. New method for point-of-care osteoporosis screening and
diagnostics. Osteoporos Int (2016) 27:971*977
12. Schousboe J. T., Riekkinen O., Karjalainen J. Prediction of hip
osteoporosis by DXA using a novel pulse-echo ultrasound device. Osteoporos Int
(2017) 28:85*93

The purpose of the study is to investigate the effect of (repeated) cast
immobilization on the bone strength of the lower leg in patients with diabetes
mellitus. In this study, bone strength is examined by cortex thickness in
millimeters and density index in grams per cm 2. The following questions will
be answered:

1. What is the effect of cast immobilization of the lower leg on the difference
in cortex thickness between both legs of diabetes mellitus patients, measured
with Bindex?

2. What is the effect of cast immobilization of the lower leg on the difference
in density index between both legs of diabetes mellitus patients, measured with
Bindex?

3. What is the difference in effect of cast immobilization between patients
with diabetes studied in a tertial care institute, HGC, compared to patients
with diabetes at the Reinier de Graaf Hospital?

4. What is an average difference in density index and cortex thickness between
both legs, measured in healthy subjects with Bindex?

Secondarily, the impact of the following factors will be assessed by analysis:

- Number of cast treatments
- Duration of cast treatments
- Number of years known with diabetes mellitus
- Average HbA1c

It is an inventory study.

During their already planned visit to the plaster room for assessment by the
special multidisciplinary 'feettteam', the plaster will first be removed. Then,
patients are waiting for their physicians to come to them. At the time they are
usually waiting, both lower legs will be measured by using ultrasound to
measure the cortex thickness and the estimated bone density. This takes about 5
minutes, the measurment is not painful and patients do not have to change their
position. It does not affect normal treatment. This happens every time they
visit the plaster room again during the study period.

There are no changes in treatment due to participation in the research. There
are no risks known for ultrasound.
Both the pressure on the patient and the risk are therefore very minimal.