Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows.

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Reply to Wimalawansa, S.J. Comment on "Bertoldo et al. Definition, Assessment, and Management of Vitamin D Inadequacy: Suggestions, Recommendations, and Warnings from the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Nutrients 2022, 14, 4148".

With regard to Dr. Wimalawansa's comment [...].

Definition, Assessment, and Management of Vitamin D Inadequacy: Suggestions, Recommendations, and Warnings from the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS).

In the recent years, both the prescriptions of serum 25(OH)D levels assay, and vitamin D supplementation are constantly increasing, as well as the costs to be incurred relating to these specific aspects. As in many other countries, the risk of vitamin D deficiency is particularly high in Italy, as recently confirmed by cohort studies in the general population as well as in patients with metabolic bone disorder. Results confirmed the North-South gradient of vitamin D levels described among European countries, despite the wide use of supplements. Although vitamin D supplementation is also recommended by the Italian Medicine Agency for patients at risk for fragility fracture or for initiating osteoporotic medication, the therapeutic gap for osteoporosis in Italy is very high. There is a consistent proportion of osteoporotic patients not receiving specific therapy for osteoporosis following a fragility fracture, with a poor adherence to the recommendations provided by national guidelines and position paper documents. The failure or inadequate supplementation with vitamin D in patients on antiresorptive or anabolic treatment for osteoporosis is thought to further amplify the problem and exposes patients to a high risk of re-fracture and mortality. Therefore, it is important that attention to its possible clinical consequences must be given. Thus, in light of new evidence from the literature, the SIOMMMS board felt the need to revise and update, by a GRADE/PICO system approach, its previous original recommendations about the definition, prevention, and treatment of vitamin D deficiency in adults, released in 2011. Several key points have been here addressed, such as the definition of the vitamin D status: normality values and optimal values; who are the subjects considered at risk of hypovitaminosis D; opportunity or not of performing the biochemical assessment of serum 25(OH)D levels in general population and in subjects at risk of hypovitaminosis D; the need or not to evaluate baseline serum 25(OH)D in candidate subjects for pharmacological treatment for osteoporosis; how and whether to supplement vitamin D subjects with hypovitaminosis D or candidates for pharmacological treatment with bone active agents, and the general population; how and whether to supplement vitamin D in chronic kidney disease and/or chronic liver diseases or under treatment with drugs interfering with hepatic metabolism; and finally, if vitamin D may have toxic effects in the subject in need of supplementation.

A literature review to understand the burden of disease in people living with tumour-induced osteomalacia.

This study reviews publications to describe the signs, symptoms and impact of tumour-induced osteomalacia (TIO) on patients' burden of disease. TIO is associated with a spectrum of signs and symptoms imposing a significant clinical burden, but the psychosocial impact of this rare disease has been poorly researched so far. INTRODUCTION: To describe the signs, symptoms and impacts of tumour-induced osteomalacia (TIO) and summarise the state of research on the burden of disease of this ultra-rare condition. METHODS: A targeted literature review was conducted in PubMed using pre-defined search terms. Relevant articles published between 1980 and 2021 were screened for inclusion. Seventy records were selected for analysis. Data were extracted and grouped into categories and sub-categories to identify recurrent signs, symptoms and impacts of TIO and describe the burden on patients. Chord diagrams were created to analyse the relationships between different TIO outcomes and characterise the presentation of TIO. RESULTS: Although the number of articles on TIO published have been increasing over the past 20 years, most studies were case reports and case series (n = 65/70) and only few were studies with higher quality of evidence (n = 5/70). Most articles were based on data reported by clinicians (n = 67/70). Patients with TIO experienced a combination of outcomes including chronic pain, weakness, skeletal-related manifestations and limitations in mobility. Only a few studies (n = 2/70) analysed the burden of TIO on the emotional wellbeing and on the work life of the patient. CONCLUSION: Patients with TIO present with a spectrum of signs and symptoms that impose a significant burden. The impact on the psychosocial wellbeing of patients should be further investigated, as this has been poorly researched so far. Studies with high quality of evidence should be designed to further the understanding of the burden of disease of TIO from the patient's perspective.

Vertebral Fracture Assessment in Postmenopausal Women With Postsurgical Hypoparathyroidism.

CONTEXT: Hypoparathyroidism is a rare endocrine disorder whose skeletal features include suppression of bone turnover and greater volume and width of the trabecular compartment. Few and inconsistent data are available on the prevalence of vertebral fractures (VF). OBJECTIVE: To evaluate the prevalence of VF assessed by vertebral fracture assessment (VFA) in postmenopausal women with chronic postsurgical hypoparathyroidism. DESIGN: Cross-sectional study. SETTING: Ambulatory referral center. PATIENTS OR OTHER PARTICIPANTS: Fifty postmenopausal women (mean age 65.4 ± 9 years) with chronic postsurgical hypoparathyroidism and 40 age-matched healthy postmenopausal women (mean age 64.2 ± 8.6). MAIN OUTCOME MEASURES: Lumbar spine, femoral neck, and total hip bone mineral density were measured by dual X-ray absorptiometry (Hologic Inc., USA) in all subjects. Site-matched spine trabecular bone score was calculated by TBS iNsight (Medimaps, Switzerland). Assessment of VF was made by VFA (iDXA, Lunar GE, USA) using the semiquantitative method and the algorithm-based qualitative assessment. RESULTS: All-site BMD values were higher in the hypoparathyroid vs the control group. By VFA, we observed a 16% prevalence of VF in hypoparathyroid women vs 7.5% in control subjects. Among those with hypoparathyroidism who fractured, 5 (62.5%) had grade 1 wedge, 2 (25%) had grade 2 wedge, and 1 (12.5%) had grade 2 wedge and grade 2 biconcave VF. In the hypoparathyroid group, 57% with VFs and 32% without VFs had symptoms of hypoparathyroidism. CONCLUSION: We demonstrate for the first time that in postmenopausal women with chronic postsurgical hypoparathyroidism, VFs are demonstrable by VFA despite normal BMD.

Algorithm for the Use of Biochemical Markers of Bone Turnover in the Diagnosis, Assessment and Follow-Up of Treatment for Osteoporosis.

INTRODUCTION: Increased biochemical bone turnover markers (BTMs) measured in serum are associated with bone loss, increased fracture risk and poor treatment adherence, but their role in clinical practice is presently unclear. The aim of this consensus group report is to provide guidance to clinicians on how to use BTMs in patient evaluation in postmenopausal osteoporosis, in fracture risk prediction and in the monitoring of treatment efficacy and adherence to osteoporosis medication. METHODS: A working group with clinical scientists and osteoporosis specialists was invited by the Scientific Advisory Board of European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). RESULTS: Serum bone formation marker PINP and resorption marker ßCTX-I are the preferred markers for evaluating bone turnover in the clinical setting due to their specificity to bone, performance in clinical studies, wide use and relatively low analytical variability. BTMs cannot be used to diagnose osteoporosis because of low sensitivity and specificity, but can be of value in patient evaluation where high values may indicate the need to investigate some causes of secondary osteoporosis. Assessing serum levels of ßCTX-I and PINP can improve fracture prediction slightly, with a gradient of risk of about 1.2 per SD increase in the bone marker in addition to clinical risk factors and bone mineral density. For an individual patient, BTMs are not useful in projecting bone loss or treatment efficacy, but it is recommended that serum PINP and ßCTX-I be used to monitor adherence to oral bisphosphonate treatment. Suppression of the BTMs greater than the least significant change or to levels in the lower half of the reference interval in young and healthy premenopausal women is closely related to treatment adherence. CONCLUSION: In conclusion, the currently available evidence indicates that the principal clinical utility of BTMs is for monitoring oral bisphosphonate therapy.

Screening for hypovitaminosis D: cost-effective or not?

Few topics have elicited more emotion than the issue of screening for vitamin D status and the discussion on the need for global supplementation with vitamin D metabolites. The importance of the problem is highlighted by the USPSTF posted draft research plan with the aim of making an update recommendations statement, possibly next year. Here, we discuss two different viewpoints on screening for vitamin D status: for and against. In the literature there are scientifically sound opinions supporting pro and cons positions. However, we believe that the best way to definitively elucidate this issue is the implementation of a randomized controlled trial evaluating clinical outcomes or harms in persons screened versus those not screened for vitamin D deficiency. The feasibility of such a trial is probably questionable owing to uncertainties still present concerning threshold for vitamin D sufficiency and end points (that is, for example, improved bone mineral density, reduced risk of falls and so on) to be reached.

Imaging of the parathyroid glands in primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is one of the most frequent endocrine diseases worldwide. Surgery is the only potentially curable option for patients with this disorder, even though in asymptomatic patients 50 years of age or older without end organ complications, a conservative treatment may be a possible alternative. Bilateral neck exploration under general anaesthesia has been the standard for the definitive treatment. However, significant improvements in preoperative imaging, together with the implementation of rapid parathyroid hormone determination, have determined an increased implementation of focused, minimally invasive surgical approach. Surgeons prefer to have a localization study before an operation (both in the classical scenario and in the minimally invasive procedure). They are not satisfied by having been referred a patient with just a biochemical diagnosis of PHPT. Imaging studies must not be utilized to make the diagnosis of PHPT. They should be obtained to both assist in determining disease etiology and to guide operative procedures together with the nuclear medicine doctor and, most importantly, with the surgeon. On the contrary, apart from minimally invasive procedures in which localization procedures are an obligate choice, some surgeons believe that literature on parathyroidectomy over the past two decades reveals a bias towards localization. Therefore, surgical expertise is more important than the search for abnormal parathyroid glands.

When the government actively faces the burden of osteoporosis: the Italian experience.

EPIDEMIOLOGY AND COSTS OF FRAGILITY FRACTURES IN ITALY: The problem of osteoporosis is emerging as growing phenomenon, with an enormous impact on quality of life and on health expenses. As a consequence, a reduction in the social and health impact of bone fragility would be associated with an improved quality of life of all elderly citizens and with valuable cost savings at the health system level. OSTEOPOROSIS: EVOLUTION OF THE CONCEPT IN ITALY: In the last 20 years, there have been enormous advances in the knowledge of diagnostic and therapeutic options and thus we would be in the position of starting effective therapies in at risk populations. However, this not always happens. NEW APPROACHES TO THE FRAGILITY FRACTURES BY THE ITALIAN GOVERNMENT: In this paper we offer to the reader the possibility to know the history of osteoporosis, its diagnosis and its therapy in Italy, a country where life expectancy is one of the highest in the world. THE FUTURE OF OSTEOPOROSIS IN ITALY: We hope that the example of Italy would serve as an inspiration to those countries where the history of osteoporosis only recently began.

Diagnostic performance of vertebral fracture assessment by the lunar iDXA scanner compared to conventional radiography.

The purpose of this study was to evaluate the diagnostic performance of vertebral fracture assessment (VFA) using the Lunar iDXA scanner. Conventional spinal radiographs and images acquired by dual-energy X-ray absorptiometry (DXA) of 350 subjects (269 females, 81 males) were evaluated by two different readers. We visualized 4,476/4,550 (98.4 %) vertebrae from T4 to L4 on VFA images compared to 4,535/4,550 (99.7 %) on radiographs. Among the visualized vertebrae, 205/4,535 (4.5 %) and 190/4,476 (4.2 %) were identified as nonfracture deformities by reading of radiographs and VFA, respectively. Vertebral fractures (VFs) were 231 in 126 patients and 228 in 125 patients by semiquantitative assessment of radiographs (SQ-Rx) and by VFA, respectively. There was excellent agreement between the two techniques and high diagnostic performance of VFA both on a per-vertebra basis (k score = 0.984, 95 % CI 0.972-0.996, sensitivity 98.68 %, specificity 99.91 %, PPV 98.25 %, NPV 99.93 %) and on a per-patient basis (k score = 0.957, 95 % CI 0.925-0.988, sensitivity 96.83 %, specificity 98.66 %, PPV 97.60 %, NPV 98.22 %). In older patients (≥65 years) affected by moderate or severe osteoarthritis, SQ-Rx and VFA identified 96 VFs and 95 versus 90 vertebral deformities, respectively. This study demonstrates that most vertebrae are evaluable using the iDXA scanner, with improved VFA diagnostic performance even in discriminating mild VFs from vertebral deformities. Therefore, VFA may be appropriate as an alternative to conventional radiography in patients at high risk of VF who are undergoing DXA bone densitometry and in the follow-up of osteoporotic patients on treatment.

Impact of fractures on health care in a major university hospital in Rome.

BACKGROUND AND AIMS: The aim of the study was to investigate the impact of fractures (i.e., hip, Colles, humeral and vertebral fractures), compared with that of other common diseases requiring hospitalization, on health care in the main hospital in Rome (Italy). METHODS: Hospital discharge forms, filled in according to the 9th International Classification of Diseases, were examined from 1996 to 1999. Data on fractures were compared with those related to other diseases which occupy a considerable proportion of hospital operating time in Italy: coronary heart disease (CHD), cerebrovascular disorders (CVD), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD) and breast cancer (BC). RESULTS: In all groups of patients, the mean age of females was significantly higher (p<0.0001) than that of males. Male patients with hip fractures had hospital stays significantly longer than females (p<0.0001), whereas women with Colles fractures had significantly (p<0.02) longer stays. When patients were divided according to age (i.e., over or under 60 years), mean hospital stays did not differ between younger and older patients in all groups except Colles fractures (p<0.001). Hip fractures in older patients showed striking in-hospital mortality. Throughout the study period, hip fractures accounted for the highest overall and per-patient costs. The number of female patients with fractures (and, obviously, breast cancer) was higher, while the opposite applied to the other disorders. Male patients with fractures, CHD and CVD were significantly younger than females (p<0.0001). When the percentage of deaths was added to that of patients discharged to other institutions, fractures showed the poorest outcome of any hospitalization event. Per-patient costs were remarkably higher for CHD, followed by fractures. CONCLUSIONS: Fractures represent a growing but often underestimated burden for hospital care in Italy; further studies are needed on this issue.