Proceedings of the 2023 Santa Fe Bone Symposium: Progress and Controversies in the Management of Patients with Skeletal Diseases.

The Santa Fe Bone Symposium (SFBS) held its 23rd annual event on August 5-6, 2023, in Santa Fe, New Mexico, USA. Attendees participated in-person and remotely, representing many states and countries. The program included plenary presentations, panel discussions, satellite symposia, a Project ECHO workshop, and a session on healthcare policy and reimbursement for fracture liaison programs. A broad range of topics were addressed, including transitions of osteoporosis treatments over a lifetime; controversies in vitamin D; update on Official Positions of the International Society for Clinical Densitometry; spine surgery and bone health; clinical applications of bone turnover markers; basic bone biology for clinicians; premenopausal-, pregnancy-, and lactation-associated osteoporosis; cancer treatment induced bone loss in patients with breast cancer and prostate cancer; genetic testing for skeletal diseases; and an update on nutrition and bone health. There were also sessions on rare bone diseases, including managing patients with hypophosphatasia; treatment of X-linked hypophosphatemia; and assessment and treatment of patients with hypoparathyroidism. There were oral presentations of abstracts by endocrinology fellows selected from those who participated in the Santa Fe Fellows Workshop on Metabolic Bone Diseases, held the 2 days prior to the SFBS. These proceedings of the 2023 SFBS present the clinical highlights and insights generated from many formal and informal discussions in Santa Fe.

Special Issue: Metabolic Bone Diseases: Molecular Biology, Pathophysiology and Therapy.

Bone is a vital tissue as it carries out various metabolic functions: support of the body, protection of the internal organs, mineral deposit and hematopoietic functions [...].

Extracellular vesicles rejuvenate the microenvironmental modulating function of recipient tissue-specific mesenchymal stem cells in osteopenia treatment.

Systemic transplantation of mesenchymal stem cells (MSCs), such as bone marrow MSCs (BMMSCs) and stem cells from human exfoliated deciduous teeth (SHED), is considered a prominent treatment for osteopenia. However, the mechanism of action of the transplanted MSCs has been poorly elucidated. In the recipient target tissue, including bone and bone marrow, only a few donor MSCs can be detected, suggesting that the direct contribution of donor MSCs may not be expected for osteopenia treatment. Meanwhile, secretomes, especially contents within extracellular vesicles (EVs) released from donor MSCs (MSC-EVs), play key roles in the treatment of several diseases. In this context, administrated donor MSC-EVs may affect bone-forming function of recipient cells. In this review, we discuss how MSC-EVs contribute to bone recovery recipient tissue in osteopenia. We also summarize a novel mechanism of action of systemic administration of SHED-derived EVs (SHED-EVs) in osteopenia. We found that reduced telomerase activity in recipient BMMSCs caused the deficiency of microenvironmental modulating function, including bone and bone marrow-like niche formation and immunomodulation in estrogen-deficient osteopenia model mice. Systemic administration of SHED-EVs could exert therapeutic effects on bone reduction via recovering the telomerase activity, leading to the rejuvenation of the microenvironmental modulating function in recipient BMMSCs, as seen in systemic transplantation of SHED. RNase-preconditioned donor SHED-EVs diminished the therapeutic benefits of administrated SHED-EVs in the recipient osteopenia model mice. These facts suggest that MSC-EV therapy targets the recipient BMMSCs to rejuvenate the microenvironmental modulating function via telomerase activity, recovering bone density. We then introduce future challenges to develop the reproducible MSC-EV therapy in osteopenia.

Transition of young adults with metabolic bone diseases to adult care.

As more accurate diagnostic tools and targeted therapies become increasingly available for pediatric metabolic bone diseases, affected children have a better prognosis and significantly longer lifespan. With this potential for fulfilling lives as adults comes the need for dedicated transition and intentional care of these patients as adults. Much work has gone into improving the transitions of medically fragile children into adulthood, encompassing endocrinologic conditions like type 1 diabetes mellitus and congenital adrenal hyperplasia. However, there are gaps in the literature regarding similar guidance concerning metabolic bone conditions. This article intends to provide a brief review of research and guidelines for transitions of care more generally, followed by a more detailed treatment of bone disorders specifically. Considerations for such transitions include final adult height, fertility, fetal risk, heritability, and access to appropriately identified specialists. A nutrient-dense diet, optimal mobility, and adequate vitamin D stores are protective factors for these conditions. Primary bone disorders include hypophosphatasia, X-linked hypophosphatemic rickets, and osteogenesis imperfecta. Metabolic bone disease can also develop secondarily as a sequela of such diverse exposures as hypogonadism, a history of eating disorder, and cancer treatment. This article synthesizes research by experts of these specific disorders to describe what is known in this field of transition medicine for metabolic bone diseases as well as unanswered questions. The long-term objective is to develop and implement strategies for successful transitions for all patients affected by these various conditions.

Early elevated alkaline phosphatase as a surrogate biomarker of ongoing metabolic bone disease of prematurity.

Very low birth weight (VLBW) neonates present a high risk of metabolic bone disease (MBD). Our main objective was to determine the easiest way to make an early diagnosis of this disease by identifying surrogate biomarkers before any radiological signs occurred. We conducted in our NICU a 6-month observational prospective study, with inclusion of all singleton VLBW neonates. We collected clinical and biological data, and nutritional intakes during hospitalization. We defined biological MBD (bMBD) as alkaline phosphatase (ALP) levels superior to 600 UI/L at day of life 30 (DOL30) and performed a case-control analysis. Nine out of 30 patients (30%) exhibited bMBD. All have extremely low birth weight and were significantly younger in gestational age (GA) and smaller at birth. There was no statistically significant difference in nutritional intake between bMBD and control groups. In the bMBD group, phosphatemia was lower since DOL3. ALP was already significantly higher at DOL15, and way beyond normal range. CONCLUSIONS: Our results showed that even the strict respect of nutritional guidelines cannot completely prevent bMBD in high-risk patients and suggest that an early screening from DOL15, with ALP levels greater than 500 UI/L, could be sufficient for detection of upcoming MBD. WHAT IS KNOWN: • Metabolic bone disease of prematurity (MBD) definition is not consensual, but biological changes appear earlier than radiological signs of rickets. • MBD management relies on biological evidence. Treatment is based on phosphate and/or calcium and calcitriol supplementation. WHAT IS NEW: • Studying phosphocalcic biological assessment in very low birth weight neonates, we showed respect of nutritional guidelines could not protect from biological MBD. • Increase in alkaline phosphatase (ALP), about 500 UI/l at day of life 15, could be a biomarker of MBD with no need of X-ray evaluation and sufficient to begin a treatment to prevent osteopenia.

Bone loss in chronic liver diseases: Could healthy liver be a requirement for good bone health?

Given that the liver is involved in many metabolic mechanisms, it is not surprising that chronic liver disease (CLD) could have numerous complications. Secondary osteoporosis and increased bone fragility are frequently overlooked complications in CLD patients. Previous studies implied that up to one-third of these individuals meet diagnostic criteria for osteopenia or osteoporosis. Recent publications indicated that CLD-induced bone fragility depends on the etiology, duration, and stage of liver disease. Therefore, the increased fracture risk in CLD patients puts a severe socioeconomic burden on the health system and urgently requires more effective prevention, diagnosis, and treatment measures. The pathogenesis of CLD-induced bone loss is multifactorial and still insufficiently understood, especially considering the relative impact of increased bone resorption and reduced bone formation in these individuals. It is essential to note that inconsistent findings regarding bone mineral density measurement were previously reported in these individuals. Bone mineral density is widely used as the "golden standard" in the clinical assessment of bone fragility although it is not adequate to predict individual fracture risk. Therefore, microscale bone alterations (bone microstructure, mechanical properties, and cellular indices) were analyzed in CLD individuals. These studies further support the thesis that bone strength could be compromised in CLD individuals, implying that an individualized approach to fracture risk assessment and subsequent therapy is necessary for CLD patients. However, more well-designed studies are required to solve the bone fragility puzzle in CLD patients.

Proceedings of the 2022 Santa Fe Bone Symposium: Current Concepts in the Care of Patients with Osteoporosis and Metabolic Bone Diseases.

The 22nd Annual Santa Fe Bone Symposium (SFBS) was a hybrid meeting held August 5-6, 2022, with in-person and virtual attendees. Altogether, over 400 individuals registered, a majority of whom attended in-person, representing many states in the USA plus 7 other countries. The SFBS included 10 plenary presentations, 2 faculty panel discussions, satellite symposia, Bone Health & Osteoporosis Foundation Fracture Liaison Service Boot Camp, and a Project ECHO workshop, with lively interactive discussions for all events. Topics of interest included fracture prevention at different stages of life; how to treat and when to change therapy; skeletal health in cancer patients; advanced imaging to assess bone strength; the state of healthcare in the USA; osteosarcopenia; vitamin D update; perioperative bone health care; new guidelines for managing primary hyperparathyroidism; new concepts on bone modeling and remodeling; and an overview on the care of rare bone diseases, including hypophosphatasia, X-linked hypophosphatemia, tumor induced osteomalacia, osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and osteopetrosis. The SFBS was preceded by the Santa Fe Fellows Workshop on Osteoporosis and Metabolic Bone Diseases, a collaboration of the Endocrine Fellows Foundation and the Osteoporosis Foundation of New Mexico. From the Workshop, 4 participating fellows were selected to give oral presentations at the bone symposium. These proceedings represent the clinical highlights of 2022 SFBS presentations and the discussions that followed, all with the aim of optimizing skeletal health and minimizing the consequences of fragile bones.

Hereditary Metabolic Bone Diseases: A Review of Pathogenesis, Diagnosis and Management.

Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases. In this review, we examine 25 selected hereditary metabolic bone diseases and recognized genetic variations of 78 genes that represent each of the three groups, including sclerosing bone disorders, disorders of defective bone mineralization and disorder of bone matrix and cartilage formation. We also review pathophysiology, manifestation and treatment for each disease. Advances in molecular genetics and basic sciences has led to accurate genetic diagnosis and novel effective therapeutic strategies for some diseases. For other diseases, the genetic basis and pathophysiology remain unclear. Further researches are therefore crucial to innovate ways to overcome diagnostic challenges and develop effective treatment options for these orphan diseases.

Effects of Three Interventions Combining Impact or Walking at Intense Pace Training, with or without Calcium and Vitamin Supplements, to Manage Postmenopausal Women with Osteopenia and Osteoporosis.

The purpose was to assess the effects of three interventions on bone mineral density (BMD) to prevent the onset or progression of osteoporosis in postmenopausal women. Specifically, thirty-nine postmenopausal women, diagnosed with osteopenia or osteoporosis, implemented either high-impact training (G1), the same training + calcium and vitamin D intake (G2), or walked at an intense pace + calcium and vitamin D (G3). Baseline change (BC) in BMD was estimated using the femoral neck and lumbar spine T-scores. Participants were classified as having suffered fractures and/or falls before (24-month) and during the 2-year intervention. The participants-aged 61.8 years-were allocated into G1 (n = 9), G2 (n = 16), and G3 (n = 14). The groups evolved similarly over time; however, participants in G2 exhibited the largest T-score improvements with BC over 20%. G1 and G3 maintained BMD levels (BC = -7 to 13.3%; p > 0.05). Falls occurred similarly across the interventions, while the participants in G2 had the lowest percentage of fracture events (p = 0.037). Overall, the findings suggest that regular physical exercise may be effective in maintaining or improving BMD in postmenopausal women presenting with osteopenia or osteoporosis. Due to the limited sample size, the results are preliminary and warrant future randomized trials to validate the findings.

Effect of physiotherapy on the promotion of bone mineralization in preterm infants: a randomized controlled trial.

Preterm infants have a low level of bone mineralization compared to those born at term. The purpose of the present study was to investigate the effect of reflex locomotion therapy (RLT) on bone mineralization and growth in preterm infants and compare its effect to other physiotherapy procedures. Forty-six preterm infants born at 29-34 weeks were randomized into three groups: one group received RLT (n = 17); the other group received passive movements with gentle joint compression (n = 14); and the control group received massages (n = 15). All the treatments were performed at the neonatal unit for one month. The main outcome measure was bone mineralization, which was measured using the tibial speed of sound (Tibial-SOS). All the groups were similar in terms of gestational age (31.8 ± 1.18), birth weight (1,583.41 ± 311.9), and Tibia-SOS (1,604.7 ± 27.9) at the beginning of the intervention. At the end of the study, significant differences were found among the groups in the Tibial-SOS [F(4,86) = 2.77, p = 0.049, ηp2 = 0.114] in terms of the benefit to the RLT group. In conclusion, RLT has been effective at improving Tibial-SOS levels and has been more effective than other physical therapy modalities; therefore, it could be considered an effective physiotherapeutic modality for the prevention and treatment of osteopenia from prematurity.

Osteosarcopenia: A Narrative Review on Clinical Studies.

Osteosarcopenia (OS) is defined by the concurrent presence of osteopenia/osteoporosis and sarcopenia. The pathogenesis and etiology of OS involve genetic, biochemical, mechanical, and lifestyle factors. Moreover, an inadequate nutritional status, such as low intake of protein, vitamin D, and calcium, and a reduction in physical activity are key risk factors for OS. This review aims to increase knowledge about diagnosis, incidence, etiology, and treatment of OS through clinical studies that treat OS as a single disease. Clinical studies show the relationship between OS and the risk of frailty, falls, and fractures and some association with Non-communicable diseases (NCDs) pathologies such as diabetes, obesity, and cardiovascular disease. In some cases, the importance of deepening the related mechanisms is emphasized. Physical exercise with adequate nutrition and nutritional supplementations such as proteins, Vitamin D, or calcium, represent a significant strategy for breaking OS. In addition, pharmacological interventions may confer benefits on muscle and bone health. Both non-pharmacological and pharmacological interventions require additional randomized controlled trials (RCT) in humans to deepen the synergistic effect of exercise, nutritional interventions, and drug compounds in osteosarcopenia.

In osteoporosis or osteopenia, exercise interventions improve BMD; effects vary by exercise type and BMD site.

SOURCE CITATION: Zhang S, Huang X, Zhao X, et al. Effect of exercise on bone mineral density among patients with osteoporosis and osteopenia: a systematic review and network meta-analysis. J Clin Nurs. 2021. [Epub ahead of print]. 34725872.

The effect of whole-body vibration in osteopenic patients after total knee arthroplasty: a randomized controlled trial.

BACKGROUND: Total knee arthroplasty (TKA) is an important treatment for knee osteoarthritis, but the result of whole-body vibration (WBV) in knee function rehabilitation and bone loss with osteopenia was unknown. Therefore, the purpose of this study is to study whether low-frequency, low-amplitude WBV can improve the clinical outcome of knee osteoarthritis. METHODS: This study was randomized and included 67 osteopenic patients (55-90 years, 85% women) for TKA surgery (control group N = 32, WBV group N = 35). All selected patients after TKA surgery tested clinical results, such as knee function and bone mass in baseline, 3 months after surgery, and 6 months after surgery. RESULTS: Compared to the control group, the WBV group improved pain scores, thigh circumference, lower limb muscle strength, joint activity, and joint function in 6 months after surgery. WBV intervention also improves bone density in the spine, the microstructure of the radius and tibia, and the bone turnover marker. At 3 months after TKA surgery, the WBV group had no significant effect on knee function and bone loss. CONCLUSIONS: Whole-body vibration for osteopenic patients with knee arthroplasty showed good therapeutic results in 6 months after TKA surgery, but the long-term therapeutic effect still needs to be further observed.

Effects of teriparatide and low-intensity aerobic exercise on osteopenia in type 2 diabetes mellitus rats.

INTRODUCTION: In patients with type 2 diabetes mellitus (T2DM), bone fragility increases fracture risk. Teriparatide (TPTD) improves bone strength, and exercise therapy suppresses blood glucose levels in T2DM. In this study, the combined effects of TPTD and exercise therapy on trabecular and cortical bone were examined in advanced T2DM model rats. MATERIALS AND METHODS: Thirty-week-old Otsuka Long-Evans Tokushima Fatty rats were divided into four groups (n = 9-10 in each group at two time points): Cont group (vehicle-treated control), TPTD group (TPTD 30 µg/kg injected subcutaneously, 3 times/week), Exe group (treadmill exercise, 10 m/min, 60 min/day, 5 times/week), and Comb group (TPTD-treated and treadmill exercise combined). Five and 10 weeks after treatment, bone mineral density (BMD), bone strength, and bone micro-architecture were measured. RESULTS: TPTD and combined treatment significantly increased BMDs of the lumbar spine and femur compared to the Cont group (p < 0.05 to p < 0.01). In the three-point bending test of the femur, only combined treatment increased the maximum load at 5 weeks compared with the Cont and Exe groups (p < 0.01). In the compression test of the distal femoral metaphysis, both TPTD and combined treatment increased the trabecular bone strength compared with the Cont and Exe groups (p < 0.05 to p < 0.01). Although TPTD and combined treatment improved the micro-architecture of trabecular bone (p < 0.05 to p < 0.01), only combined treatment improved the micro-structures of cortical bone from 5 weeks of treatment (p < 0.05 to p < 0.01). CONCLUSION: The combination of TPTD and treadmill exercise increased BMD and trabecular and cortical bone strength of the femur with improved micro-architecture in T2DM model rats.

Effect of exercise on bone mineral density among patients with osteoporosis and osteopenia: A systematic review and network meta-analysis.

AIMS AND OBJECTIVES: To systematically review and compare the efficacy of different exercise interventions on bone mineral density (BMD, g/cm2 ) in patients with osteoporosis and osteopenia. BACKGROUND: It is vitally important to prevent and treat bone loss in patients with osteoporosis and osteopenia. Exercise can effectively increase bone density and slow down bone loss in middle-aged and older people. However, it is still unclear which type of exercise intervention is the most effective on bone mineral density. DESIGN: Systematic review and network meta-analysis (NMA) according to PRISMA. METHODS: Randomised controlled trials of different exercise treatments for osteopenia and primary osteoporosis were included. A Frequentist network meta-analysis was conducted to appraise the efficacy of different types of exercise. The outcome was bone mineral density of different parts of the body. RESULTS: Ninety-seven studies were included. The network meta-analysis showed that combined exercise, resistance exercise, aerobic exercise and mind-body exercise had a significant effect in improving the bone density of lumbar spine. The surface under the cumulative ranking area (SUCRA) values for mind-body exercise was 0.99 and ranked first. For BMD of the femoral neck, all kinds of exercise interventions increased the bone density significantly compared with no exercise and the optimal type was mind-body exercise (SUCRA = 0.99). In terms of the total hip bone mineral density, aerobic exercise and resistance exercise could improve hip bone density, with the resistance exercise (SUCRA = 0.95) ranking as first. CONCLUSIONS: This NMA demonstrated the mind-body exercise might be the optimal exercise type to increase the BMD of the lumbar spine and femoral neck and resistance exercise is the most promising type for total hip BMD.

Proceedings of the 2021 Santa Fe Bone Symposium: Advances in the Management of Osteoporosis and Metabolic Bone Diseases.

The 2021 Virtual Santa Fe Bone Symposium was held August 5-8, with over 300 registered attendees from throughout the USA, and at least 18 other countries. This annual meeting focuses on applying advances in basic science and clinical research to the care of patients with osteoporosis and those with inherited and acquired disorders of bone metabolism. Participants represented a broad range of medical disciplines with an interest in skeletal diseases. These included physicians of many specialties and practice settings, fellows, advanced practice providers, fracture liaison service (FLS) coordinators, clinical researchers, and bone density technologists. There were lectures, case presentations, and panel discussions, all followed by interactive discussions. Breakout sessions included an FLS workshop, Bone Health TeleECHO workshop, special interest groups, meet-and-greet the faculty, and satellite symposia. The agenda covered topics of interest such as strategies for the use of osteoanabolic therapy, prevention of periprosthetic fractures, management of atypical femur fractures, what we know and don't know about vitamin D, advances in the use of dual-energy X-ray absorptiometry in the assessment of skeletal health, controversies and conundrums in osteoporosis care, skeletal health in transgender patients, management of patients with hypophosphatasia and hypophosphatemia, and treat-to-target approaches for managing patients with osteoporosis. The Proceedings of the 2021 Virtual Santa Fe Bone Symposium consists of highlights of each presentation with current strategies for optimizing the care of patients with skeletal disorders.

Long-term effect of full-body pulsed electromagnetic field and exercise protocol in the treatment of men with osteopenia or osteoporosis: A randomized placebo-controlled trial.

Background: Osteoporosis is the most prevalent metabolic disease affecting bones. Objective: To investigate the long-term effect of pulsed electromagnetic field (PEMF) combined with exercise protocol on bone mineral density (BMD) and bone markers in men with osteopenia or osteoporosis. Methods: Ninety-five males with osteopenia or osteoporosis (mean age, 51.26 ± 2.41 years; mean height, 176 ± 2.02 cm; mean weight, 83.08 ± 2.60 kg; mean body-mass index (BMI), 26.08 ± 1.09 kg/m 2) participated in the study, and they were randomly assigned to one of three groups: Group 1 received a full-body PEMF and exercise protocol (PEMF +EX), Group 2 received a placebo full-body PEMF and exercise protocol (PPEMF +EX), and Group 3 received a full-body PEMF alone (PEMF). PEMF was applied for the whole body using a full-body mat three times per week for 12 weeks, with an exercise protocol that includes flexibility, aerobic exercise, strengthening, weight-bearing, and balance exercises followed by whole-body vibration (WBV) training. Outcome measures include BMD of total hip and lumbar spine and bone markers [serum osteocalcin (s-OC), Serum amino-terminal cross-linking telopeptide of type I collagen (s-NTX), Serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX), Parathyroid hormones (PTH), Bone-specific Alkaline Phosphatase (BSAP), and 25-hydroxy vitamin D (Vit D)]. Results: The BMD of total hip and lumbar spine was significantly increased post-treatment in all groups, and more so in Group 1 and Group 2 than Group 3. There was a significant difference in bone markers in all groups, more so in Group 1 and Group 2 than in Group 3. Conclusion: PEMF combined with exercise protocol exerts a potent role for treating OP, is more effective than exercise and PEMF alone for increasing BMD and enhancing bone formation, and suppresses bone-resorption markers after 12-weeks of treatment with the impact lasting up to 6 months.

Effect of Vitamin E Supplement on Bone Turnover Markers in Postmenopausal Osteopenic Women: A Double-Blind, Randomized, Placebo-Controlled Trial.

Vitamin E is a strong anti-oxidative stress agent that affects the bone remodeling process. This study evaluates the effect of mixed-tocopherol supplements on bone remodeling in postmenopausal osteopenic women. A double-blinded, randomized, placebo-controlled trial study was designed to measure the effect of mixed-tocopherol on the bone turnover marker after 12 weeks of supplementation. All 52 osteopenic postmenopausal women were enrolled and allocated into two groups. The intervention group received mixed-tocopherol 400 IU/day, while the control group received placebo tablets. Fifty-two participants completed 12 weeks of follow-up. Under an intention-to-treat analysis, vitamin E produced a significant difference in the mean bone resorption marker (serum C-terminal telopeptide of type I collagen (CTX)) compared with the placebo group (-0.003 ± 0.09 and 0.121 ± 0.15, respectively (p < 0.001)). In the placebo group, the CTX had increased by 35.3% at 12 weeks of supplementation versus baseline (p < 0.001), while, in the vitamin E group, there was no significant change of bone resorption marker (p < 0.898). In conclusion, vitamin E (mixed-tocopherol) supplementation in postmenopausal osteopenic women may have a preventive effect on bone loss through anti-resorptive activity.

Catch it before it breaks!: managing metabolic bone disease of prematurity.

PURPOSE OF REVIEW: Metabolic bone disease of prematurity, commonly referred to as osteopenia of prematurity, remains prevalent in the neonatal intensive care unit (NICU) despite recent medical advances. It is estimated that up to 60% of extreme low birth weight and 20% of very low-birth-weight infants have metabolic bone disease of prematurity. Often silent, it typically presents with poor growth, increased ventilator dependency and fractures. Clinical sequalae, such as short stature can extend into young adulthood. There is no universal consensus by neonatal intensive care unit clinicians on the screening, diagnosis, or treatment for metabolic bone disease of prematurity. The disease is often diagnosed late by radiographs or incidentally in this highly fragile population. RECENT FINDINGS: Suggest screening using DEXA (dual-energy X-ray absorptiometry) scans or ultrasound, in combination with serum markers like alkaline phosphatase, phosphorous levels, parathyroid hormone, and tubular reabsorption of phosphate, might identify at-risk babies earlier. The use of protocol-based screenings may aid in early diagnosis. SUMMARY: We present a review of the risk factors, recent screening methods, diagnosis and management of this prevalent, clinically relevant diagnosis, as well as propose a protocol for the early screening and management of this silent disease.