Development of a Wearable Device for Osteoporosis Prevention and Fracture Risk Reduction in Women

CURRENT STATUS AND JUSTIFICATION OF THE PROPOSAL Osteoporosis is an important public health problem and it is characterized by the deterioration of the microarchitecture of bone tissue and a low bone mineral density (BMD) that leads to a reduction in bone strength and the consequent increased risk of skeletal fractures 1. One in three women will suffer an osteoporotic fracture in their lifetime 2. In fact, it is estimated that more than 200 million people suffer from osteoporosis and these figures are increasing due to the aging of the population and the change in lifestyles 3. A recent systematic review gathered epidemiological information on selected musculoskeletal injuries and provided pooled injury-specific incidence rates. Authors reported that the most common fractures in the whole adult population based on the pooled incidence rates were distal radius fractures (212 per 100,000 person-years)4. Distal radius fractures account for one in five bony injuries in both primary and secondary care5. According to data from the International Osteoporosis Foundation (IOF), in Spain there would be more than 2.8 million women over the age of 50 with osteoporosis, with more than 330,000 fragility fractures per year and projections suggest that by 2030 these figures will increase 28.8%1. Consequently, there is a significant economic burden on the healthcare system for patients who experience an osteoporosis-related fracture. Direct costs for osteoporosis, such as medications, occupational therapies, and inpatient and outpatient visits, are expected to increase to $25 billion by 2025 as the population ages 6. Together with the indirect costs, such as loss of productivity, are expected to rise to more than $95 billion in 2040 6. Osteoporosis, and the 4.3 million fragility fractures that it causes, cost the health care systems of Europe over €56 billion each year based on data for 2019 7. Only in our country it is estimated that the cost associated with sick days due to fragility fractures amounts to €355,000 each year. Only the direct and indirect costs associated with these fractures would exceed €4.2 billion, with a projected increase of 30.6% by 2030 1. It should not surprise us, therefore, that in postmenopausal women, osteoporotic fracture costs exceed the annual costs for breast cancer, myocardial infarction (MI), and stroke 6.

The loss of the protective effect of estrogens on the skeletal structure after menopause intensifies the decrease in bone density as a result of a sudden imbalance between bone formation and bone resorption. This decrease in estrogens (e.g., estradiol) leads to an increase in the rate of bone remodeling due to an increase in the number of osteoblasts and osteoclasts; although osteoclast-mediated removal of bone matrix is much greater than osteoblast bone formation8. Therefore, the loss of BMD is very evident, especially in the 3-5 years following the last menstrual period 9, in a 2% loss rate per year 10. Parallel to this decrease in BMD, it is common to find a decrease in muscle mass and strength, probably derived from the decrease during menopause of certain precursors (e.g., insulin-like growth factor type 1, -IGF-1-) 11. It is important to note that bone strength is determined not only by bone mass, but also by the size, shape, structure, or properties of collagen 12. Since densitometry (DEXA) captures only bone mass, there is growing interest in the use of other three-dimensional imaging modalities, such as quantitative computed tomography (QCT) to assess bone strength. QCT can help differentiate between the cortical and trabecular compartments of bone and their relative contribution to bone strength in vivo. Similarly, various biomarkers have been identified to detect the dynamics of bone remodeling 13,14. The National Bone Health Alliance and the American Association for Clinical Chemistry have suggested that the most widely accepted biomarkers for the evaluation of interventions in osteoporosis are the C-terminal telopeptide of collagen type 1 -CTX-1- (bone resorption) and the amino-terminal propeptide of procollagen type 1 -P1NP- (bone formation) 13,14.

There are well-known modifiable and non-modifiable risk factors for osteoporosis. Non-modifiable items would include age, family history of fragility fractures, type 1 diabetes, rheumatoid arthritis, or cancer treatment (e.g., aromatase inhibitors or chemotherapy). In the first group, smoking, excessive alcohol consumption, the use of corticosteroids, insufficient calcium or vitamin D, low body mass index (BMI), sedentary lifestyle15, or the lack of physical activity, which would be another of the main risk factors can be included. However, bone loss can remain clinically silent. A recent retrospective healthcare study found that 79.4% of patients did not have a diagnosis or treatment on-board for osteoporosis 12 months before the fracture 6. It surprises that less than half of women at high risk of fracture are treated despite the high cost of fractures and the availability of affordable medications 2. Consequently, according to the IOF, there is a large unmet need as it relates to the prevention of postmenopausal osteoporosis because many women are not undergoing the recommended diagnostic screenings or assessing baseline osteoporosis risk 15.

Prevention should be the priority when pursuing the reduction of the burden caused by osteoporosis16. In addition to prevention, the optimization of the management, from first aid to rehabilitation, should be well considered to reduce excess costs. The approach in this population group is usually multimodal and includes both pharmacological and non-pharmacological interventions. In Europe, the most commonly used drugs for osteoporosis are bisphosphonates, raloxifene, parathyroid hormone drugs, and denosumab 17. However, the widespread and long-term use of these drugs is limited due to possible side effects 18. Therefore, diet and physical exercise, together with other environmental and lifestyle factors, would constitute the main non-pharmacological strategies for the management of this pathology 19. However, although physical activity is a modifiable factor that contributes to the improvement of bone mass and strength, our understanding of how to quantify the dimensions of physical activity that are osteogenic (including frequency, intensity, time, and type) is incomplete. There is no doubt that to initiate an osteogenic response, the bone must be subjected to a stimulus that exceeds a threshold determined by the usual range of deformation in the predominant load direction19. Precisely, the mechanical stress to which exercise (impacts and muscle contraction) subjects the bone (e.g. tension, compression, hydrostatic pressure) can promote osteogenic differentiation of mesenchymal stem cells, increasing osteoblastic regulation through different mechanisms 20. To increase effectiveness, the exercise must: (i) be dynamic, not static; (ii) exceeding an intensity threshold; (iii) exceeding a strain frequency threshold; (iv) be relatively short but intermittent; (v) imposing an unusual load pattern on the bones; (vi) include adequate availability of calcium and vitamin D 21. However, the optimum loading patterns of bone that produce clinically significant benefits have not been clearly defined to date, since it has not been possible to easily quantify exercise intensity in terms of bone-loading forces in clinical settings22. Q1

Recent guidelines for the prevention and management of osteoporosis through physical exercise suggest interventions that last longer than 8 months and that combine high impacts and high-intensity strength training. Interventions in which fast walking (e.g., \> 6 km/h) is combined with activities that incorporate a relatively short number of impacts (e.g., 10-50 jumps per day), at intensities exceeding 2-4 times body weight (\~ 3.9 G), at least 4 sessions a week and using multiaxial exercises to generate an unusual load on the hip, can help postmenopausal women to compensate for age-related bone loss 23. These would be effective strategies to preserve BMD in postmenopausal women with a level of evidence 1a24. However, there is no evidence of its effectiveness in preventing distal radius fractures Q2 and also dropout rates in these types of programs are high25 and, despite the evidence, participants are often reluctant to exercise, citing barriers as poor health, lack of time due to family responsibilities, lack of companionship or encouragement, lack of access to adequate facilities or opportunities, or cost. Patients with osteoporosis often report a lack of time and transportation limitations as the main barriers that would limit their participation in supervised training programs 26. For these reasons, it has been suggested that intervention trials should use settings that are easily accessible to participants and provide flexible exercise schedules 25.

In the literature, it is suggested that in interventions aimed at bone health in young adult women, it is crucial to minimize the perceived demands of time (e.g., short and flexible intervals) and environmental barriers related to the convenience and accessibility of physical activity 25. Therefore, to increase adherence in this population group, regular contact with study personnel, personalization of progression, and adequate exercise monitoring (avoid safety concerns and lack of confidence) are suggested. In a recent study from our group, evidence showing that non-supervised exercise programs could be effective to improve BMD in adult women was found. However, only five studies were available in postmenopausal women and overall registered a substantial dropout rate (above 40%) due to unwillingness to continue and illness among the main reasons. Therefore, the necessity to investigate the efficacy of remote/assistive technologies for delivering and monitoring non-supervised exercise interventions was highlighted. The question that should be asked is, in what way all these issues can be managed, facilitating the monitoring of the program and solving the barriers outlined?

Mobile and digital technologies (mHealth) allow complementing exercise programming for the management of osteoporosis by providing information on skeletal mechanics during locomotion23. However, and even though wearable activity trackers offer potential as a multifaceted intervention to help people become more active, no study has examined the usefulness of these wearable devices in postmenopausal women nor in the upper extremities Q3. The importance of reaching a minimum threshold of stimulation to obtain bone adaptations has been justified, since insufficient loads would not have the desired effect, for this reason, precise quantification of the mechanical loads to which the musculoskeletal system is subjected is necessary, what could be achieved with certain biosensors28. However, interventions based on this type of technology aimed at preventing osteoporosis are very scarce29, even though authors agree on their potential, not only for increase the benefits of the interventions, but mainly to improve adherence to them.

In summary, the scientific community face a group of women with a high risk of suffering from osteoporosis (potential incidence of fragility fracture), with the subsequent incidence for their functionality and quality of life, on the one hand, and for the health system, on the other. The strategies for managing this group suggest the incorporation of activities that require impact and strength training; however, direct measurement of bone strains requires invasive surgical procedures and indirect measurement of ground reaction forces are limited to a fixed place and time, being thus impracticable in long-term clinical measurements. Assessing the effects of this type of intervention could help to record variables that, after proper analysis (e.g., machine learning), facilitate decision-making

• Body composition [Срок оценки: Pre (week 0) and post (week 36).]
• Quality of life [Срок оценки: Pre (week 0) and post (week 36).]
• Symptoms of menopause [Срок оценки: Pre (week 0) and post (week 36).]
• Mobility and dynamic balance [Срок оценки: Pre (week 0) and post (week 36).]
• Strength [Срок оценки: Pre (week 0) and post (week 36).]
• Jump ability [Срок оценки: Pre (week 0) and post (week 36).]
• Physical activity and sedentary behavior [Срок оценки: Pre (week 0) and post (week 36).]
• Eating patterns [Срок оценки: Pre (week 0) and post (week 36).]
• Adherence to the program and adverse effects [Срок оценки: Pre (week 0), week 20 and post (week 36).]
• Health gain and costs [Срок оценки: Pre (week 0) and post (week 36).]
• Waist circumference (cm) [Срок оценки: Pre (week 0) and post (week 36).]
• Height [Срок оценки: Pre (week 0) and post (week 36).]