Study to Weigh the Effect of Exercise Training on BONE (SWEET-BONE) Quality and Strength in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is associated with increased fracture risk despite normal to increased bone mass, thus suggesting poor bone quality. This study is aimed at weighing the effect of an exercise intervention program on parameters of bone quality in patients with type 2 diabetes mellitus. Two hundred patients with T2DM will be randomized to supervised exercise training on top of standard care (exercise, EXE, group; n=100) versus standard care (control, CON, group; n=100) for 24 months.

Type 2 diabetes mellitus (T2DM) is associated with increased fracture risk despite normal to increased bone mass, as assessed as bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). Increased fracture risk remains after adjustment for BMD, and also falls, which are more frequent in these individuals than in their non-diabetic counterparts, due to chronic complications and treatments, and for body mass index, which seems to be protective through an increase in BMD. This suggests that patients with T2DM have poor bone quality, i.e. altered bone geometry and microarchitecture, which results in reduced strength. Based on the mechanostat therapy, physical activity (PA)/exercise would be beneficial for preventing fractures in T2DM individuals through greater mechanical loading on the skeleton, which causes favorable bone adaptations, and also by increasing muscle mass, strength, and performance, which reduces the risk of falls by improving gait and balance.

The aim of this study is to assess the effects of a specific exercise training intervention program on parameters of bone quality in patients with type 2 diabetes.

Two hundred patients with T2DM will be randomized to supervised exercise training on top of standard care (exercise, EXE, group; n=100) versus standard care (control, CON, group; n=100) for 24 months.

Sample size calculation is based on a recent report showing that TBS is lower in diabetic vs. control subjects (1.228 vs. 1.298) with a standard deviation of 0.140. To observe a normalization of TBS in EXE participants with a statistical power of 90% (α=0.05) by unpaired t-test, 85 patients per arm are needed (170 total). A sample size of 200 patients will allow to support a dropout rate up to 15%.

A sample of 100 non-diabetic subjects matched 1:2 by age, gender, and BMI will be used as controls for baseline measures.

EXE participants will attend two weekly sessions of 75 min each, supervised by an exercise specialist in a dedicated gym facility. Each session will include: 5 min of warm up; 20 min of aerobic training using treadmill; 15 min of resistance training of muscle groups of skeletal sites of fragility fractures; 15 min of "weight bearing" exercises using weighted vests; 8 min of core stability training; 8 min of balance training; and 4 min of flexibility training. Weighted vest worn also during aerobic training and any occupational, home and leisure-time PA.

CON subjects will receive advises to maintain a physically active lifestyle, according to current guidelines, by performing any type of commuting, occupational, home and leisure-time PA.

All patients will be subjected to a treatment regimen aimed at achieving optimal glycemic, lipid, BP and body weight targets, as established by current guidelines and including glucose-, lipid- and BP-lowering agents as needed. For ethical reasons, drugs will be also adjusted throughout the study to attain target levels and to account for reduced needs. Since all patients are overweight or obese, caloric intake (55% complex carbohydrates, 30% fat, and 15% protein) will be reduced to obtain a negative balance of 500 kcal/day. Requirements will be calculated by adding the estimated energy expenditure from PA to basal metabolism. Adherence to diet will be verified by the use of food diaries and dietary prescriptions will be adjusted at each intermediate visit. Patients with vitamin D levels ranging from 10 to 20 ng/dl will be treated with cholecalciferol 25.000 IU every 2 weeks for 2 months, then with cholecalciferol 25.000 IU every months, whereas those with vitamin D levels ranging from 20 to 30 ng/dl will be given cholecalciferol 25.000 IU every month. At 6 months participants, will be re-evaluated and treatment will be discontinued in case of vitamin D values \>30 ng/dl or continued for additional 6 months at the doses indicated above, and so on until the end of the study.

Randomization will be stratified by gender (males versus females), age (65-70 versus 71-75) and type of diabetes treatment (non-insulin versus insulin), using a permuted-block randomization software. Physicians and patients will not be blinded to group assignment, at variance with operators executing instrumental procedures, whereas sample blinding at central laboratory will be achieved using bar codes.

The primary endpoint is the trabecular bone score (TBS), which is derived from the antero-posterior spine raw DXA image(s) from the same region of interest as the BMD measurement by the use of a specific software and correlates with three-dimensional bone micro-architecture parameters. Among the numerous potential measures of bone quality, TBS is the only one that has been consistently shown to be lower in T2DM vs. control subjects.

Secondary endpoints include:

1. other potential measures of bone quality as assessed by peripheral quantitative computed tomography (pQCT) and quantitative ultrasound (QUS);
2. bone mass (BMD as assessed by DXA);
3. bone metabolism (sclerostin and other biochemical markers of bone formation and resorption);
4. body composition (total body lean and fat mass by total body DXA);
5. muscle strength (by dynamometer);
6. muscle mass/density (by pQCT);
7. balance, gait and power (by Short Battery Performance Test);
8. musculoskeletal (MS) symptoms (by questionnaire);

h. number of falls (by questionnaire); i. symptomatic and asymptomatic fractures (by history or medical records and vertebral morphometry, respectively).

Other measures include:

* quality of life (QoL);
* cardiorespiratory fitness;
* flexibility;
* volume of PA;
* coronary heart disease 10-year risk score.

Dietary intake and adverse events will be also recorded. Participants from both groups will be followed for additional 5 years in order to record the number of falls and eventual fractures during this time period. PA and MS symptoms will be also monitored throughout this 5-year interval. To this end, patients will be seen yearly (or every 6 months according to the degree of glycemic control and the overall cardiovascular risk profile) in order to collect self-report data on number of falls and type and amount of PA from a daily diary, clinical documentation on eventual fractures, and MS questionnaire.

Eligibility Criteria:
Inclusion Criteria:

* diabetes duration \>5-year
* sedentary lifestyle (i.e. more than 8 hours/day spent in any waking behavior characterized by an energy expenditure ≤1.5 metabolic equivalents \[METs\] while in a sitting or reclining posture) from at least 6 months;
* physically inactivity (i.e. insufficient amounts of physical activity \[PA\] according to current guidelines) from at least 6 months;
* body mass index (BMI) 27-40 kg/m2;
* ability to walk 1.6 Km without assistance;
* a Short Battery Performance Test score ranging from 4 to 9;
* eligibility after cardiologic evaluation.

Exclusion Criteria:

* any condition limiting participation in a clinical trial, including psychiatric disorders or hospitalization for depression in the past 6 months;
* any condition limiting PA/exercise, including musculoskeletal disorders or deformities, central nervous system dysfunction such as hemiparesis, myelopathies, cerebral ataxia, vestibular dysfunction, and postural hypotension (i.e. a fall of \>20 mmHg of systolic or \>10 mmHg of diastolic blood pressure when changing position);
* cancer and other life-expectancy limiting conditions;
* recent major acute cardiovascular event, including heart attack, stroke/transient ischemic attack(s), revascularization procedure, or participation in a cardiac rehabilitation program within the past three months, or documented history of pulmonary embolism in the past six months;
* pre-proliferative and proliferative retinopathy;
* macroalbuminuria and/or estimated glomerular filtration rate (eGFR) \<45 ml/min/1.73 m2;
* ankle/brachial index (ABI) \<0.9;
* severe motor and sensory neuropathy;
* diabetic foot with history of ulcer;
* hemoglobin (Hb) A1c \>9.0%;
* blood pressure (BP) \>150/90 mmHg;
* vitamin D \<10 ng/ml;
* treatment with anti-fracturative agents, estrogens, aromatase inhibitors, testosterone, corticosteroids and/or glitazon;
* previous documented non-traumatic fractures,
* total spine deformity index (SDI) \>3 (and \>1 in a single vertebra);
* a T score \<-2.5 at spine/hip at dual-energy X-ray absorptiometry (DXA). Subjects with HbA1c or blood pressure above the indicated threshold will be receive appropriate treatment and will be re-evaluated after 3 months. Patients with vitamin D levels \< 10 ng/dl will be treated with cholecalciferol 25.000 IU/week for 6 weeks and will be re-evaluated for eligibility 2 weeks after the last