Epidemiology of Tumor-Induced Osteomalacia in Germany Based on Real World Data.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused mostly by benign tumors that secrete fibroblast growth factor-23. Because of nonspecific symptoms, the diagnostic delay is long, and therapy can be challenging. Moreover, epidemiological data on TIO are scarce owing to its rarity. Therefore, this study aimed to quantify TIO's incidence rates and prevalence in Germany. Retrospective longitudinal and cross-sectional analyses were conducted using anonymized German claims data from the statutory health insurance (SHI) database. This database, which comprises the data of approximately 5 million insurants, is a representative sample of the German population and supports national projections. As there is no unique International Statistical Classification of Diseases and Related Health Problems (ICD) code for TIO, operational categories based on different surrogates were defined to determine the prevalence and incidence rates of TIO among probable patients. This study showed that TIO has a prevalence of (documented code, advanced imaging, medication, or tumor removal) 0.187 per 100,000 persons and an incidence rate of ≤ 0.094 per 100,000 person years. This analysis provides the first epidemiological insight into German patients with TIO. Despite the general limitations associated with the analysis of SHI claims data of ultra-rare diseases, we believe that this analysis provides a sound basis for further analysis, particularly with regard to the care situation of patients with TIO.

Osteomalacia Prevalence, Biochemical Profile, and Histology in Patients with Low-Energy Hip Fractures Over the Age of 45.

Our objective was to determine the prevalence of osteomalacia in low-energy hip fracture patients over the age of 45, based on biochemical and histological measures. This cross-sectional study included 72 patients over 45 with low-energy mechanism hip fractures. Samples of fasting venous blood were taken for hemograms and serum biochemistry analyses. Bicortical biopsies of the iliac crest were obtained, processed, and evaluated by an expert pathologist for osteomalacia. Biochemical osteomalacia (b-OM) is defined according to a distinct criterion. A low level of serum calcium, phosphorus, albumin, and 25OHD was found in 43.1, 16.7, 73.6, and 59.7% of patients, respectively. 50.0% of patients had high serum alkaline phosphatase (ALP) levels. b-OM was found in 30 (41.7%), and no significant association was found with PTH, Cr, Alb, age, sex, fracture type, side of the trauma, and season were not associated with osteomalacia. Osteomalacia was diagnosed on histopathological analysis in 19/72 (26.7%), and 54/72 (75.0%) of all cases fulfilled b-OM criteria. In the histologic evaluation, osteoid seam width, osteoid surface, and osteoid volume were 28.5 µm, 25.6, and 12.1%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the biochemical test for detecting osteomalacia were 73.6, 64.2, 42.4, 87.2, and 66.7%, respectively. Up to 30% of elderly patients with low-energy hip fractures are affected by osteomalacia. A biochemical screening along with a bone biopsy and histopathologic evaluation may be logical in a high-risk population for osteomalacia diagnosis.

Prevalence of biochemical osteomalacia in adults undergoing vitamin D testing.

OBJECTIVE: Prolonged severe vitamin D deficiency can cause osteomalacia, but the 25-hydroxyvitamin D (25OHD) concentration below which this occurs is unknown. We investigated the prevalence of biochemical osteomalacia in adults with a measurement of 25OHD. DESIGN, MEASUREMENT, AND PATIENTS: 25OHD results between 1/1/2009 and 15/6/2020 were obtained from the regional laboratory database, together with measurements of serum calcium, parathyroid hormone (PTH) and alkaline phosphatase (ALP) within 6 months of the index 25OHD. We defined biochemical osteomalacia as all 3 of: albumin-adjusted serum calcium (aCa)<2.0 mmol/L, PTH>7.3 pmol/L and ALP>150 IU/L. Possible osteomalacia was 2/3 criteria with the other test not done. 25OHD measurements associated with significant renal impairment, elevated hepatic transaminases or hypercalcaemia were excluded. RESULTS: 110,046 25OHD measurements were identified over the 11.5 years period. After removal of ineligible measurements, 42,171 25OHD measurements from 32,386 individuals with at least 2 of aCa, PTH and ALP were included in analyses. Median 25OHD was 63 nmol/L; 8% were <25 nmol/L, and 33% were <50 nmol/L. Five index 25OHD measurements met the definition of biochemical osteomalacia, and another 11 were possible osteomalacia. After reviewing available clinical records for these 16 episodes, we classified 9 cases as osteomalacia and 7 as other diagnoses. Thus, the prevalence of biochemical osteomalacia was 0.02% (9/42,171) for 25OHD measurements and 0.23% (8/3432) for 25OHD<25 nmol/L. All cases of osteomalacia with 25OHD measurements prior to supplementation had 25OHD≤18 nmol/L. CONCLUSION: The prevalence of biochemical osteomalacia is very low, even in individuals with 25OHD<25 nmol/L.

Epidemiology of Tumor-Induced Osteomalacia in Denmark.

Tumor-induced osteomalacia (TIO) is a rare, acquired condition of phosphate wasting due to phosphaturic mesenchymal tumors. Because the incidence and prevalence of TIO is unknown, we conducted an observational cohort study using national Danish health registers for the period 2008 to 2018 to obtain such information. The study also aimed to describe the demographics of the TIO population and the prognosis. The operational definition was based on hypophosphatemia or adult osteomalacia diagnoses, combined with prescriptions used in the initial management and procedures consistent with advanced imaging used for locating tumors. The incidence of TIO in Denmark was found to be below 0.13 per 100,000 person years for the total population of the country and 0.10 per 100,000 in adult-onset disease. The prevalence of TIO was estimated to be no more than 0.70 per 100,000 persons for the total population and 0.43 per 100,000 in adults. In 2018, there were a maximum of nine new cases of TIO in Danish adults. Mortality was low but few patients fulfilled the protocol cure criterion during the observation period. TIO has no ICD-10 code and limitations to the study include lack of information on serum biochemistry and on the use of phosphate supplements. Strengths include the use of long-term longitudinal, national hospital and prescription data from a country with universal healthcare. Given the very small patient population with TIO and the known delay to diagnosis and cure, management of patients with suspected TIO should be centralized.

The genetic polymorphisms of XPR1 and SCL34A3 are associated with Fanconi syndrome in Chinese patients of tumor-induced osteomalacia.

PURPOSE: Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia caused by tumors with excess production of fibroblast growth factor 23 (FGF23). Some reports showed that TIO patients had renal Fanconi syndrome (FS) with unidentified mechanism. In this study, we investigated the association between genetic polymorphisms of phosphate transporters in renal proximal tubules and TIO with FS. METHODS: We recruited 30 TIO patients with FS (TIO-FS) as well as 30 TIO patients (TIO-nonFS) without any urine abnormalities matched by age and gender. We collected clinical manifestations and conducted targeted sequencing of SLC34A1, SLC34A3 and XPR1 genes and the association analysis between variants in TIO with FS and phenotypes. RESULTS: TIO-FS group had lower levels of serum phosphate (0.44 ± 0.12 vs. 0.51 ± 0.07 mmol/L, p < 0.05) than TIO-nonFS group. Among the 16 SNPs in SLC34A1, SLC34A3 and XPR1 genes, GG/GC genotypes of rs148196667 in XPR1 and AA/TA genotypes of rs35535797 in SLC34A3 were associated with a reduced susceptibility to have FS. The G allele of rs148196667 in XPR1 decreased the risk of FS. The GGAA haplotype in SLC34A3 and GCT haplotype in XPR1 were associated with a decreased risk for FS. CONCLUSIONS: The polymorphisms of XPR1 and SCL34A3 are associated with TIO patients with Fanconi syndrome. It provides novel insight to the relationship of phosphate transportation and general functions of renal proximal tubules.

Vitamin D and Cardiovascular Disease: An Updated Narrative Review.

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.

Association of asthma with osteopenia, osteoporosis, osteomalacia, and fractures.

Background: Previous studies that examined the relationship between asthma, osteoporosis, and pathologic fractures found conflicting results. Objective: To determine whether asthma is associated with osteopenia, osteoporosis, osteomalacia, and fractures in U.S. adults. Methods: A cross-sectional study of 198,102,435 children and adults, including 10,129,307 with asthma, from the 2006-2012 National Emergency Department Sample, which includes a representative 20% sample of emergency department (ED) visits throughout the United States. Results: ED visits of patients with versus without asthma were associated with higher odds of osteopenia (7 of 7 years: multivariable logistic regression of all years pooled; adjusted odds ratio [aOR] 1.45 [95% confidence interval {CI}, 1.41-1.50]), osteoporosis (7 of 7 years: aOR 1.85 [95% CI, 1.82-1.88]), osteomalacia (7 of 7 years: aOR 2.00 [95% CI, 1.61-2.49]), and pathologic fractures (7 of 7 years: OR 1.24 [95% CI, 1.20-1.27]). Patients with asthma and with long-term glucocorticoid use had higher odds of osteoporosis, osteopenia, osteomalacia, and fractures compared with patients with asthma and without long-term glucocorticoid use. Patients with asthma and with fractures incurred significantly more inpatient admissions, and higher costs of ED and inpatient care. Conclusion: ED visits with asthma were associated with osteopenia, osteoporosis, osteomalacia, and pathologic fractures.

Drug-induced osteoporosis/osteomalacia: analysis in the French and Spanish pharmacovigilance databases.

INTRODUCTION: Osteomalacia and osteoporosis are two metabolic bone disorders that increase the risk of fracture due to several causes. In terms of drugs, apart from corticosteroids, which are known to induce bone disorders, several other drugs used in chronic disease management have also been linked with an increased risk of osteoporosis and osteomalacia. PURPOSE: The aim of this study was to describe spontaneous reports of drug-induced osteoporosis and osteomalacia in the French (FPVDB) and Spanish (SPVDB) pharmacovigilance databases. METHODS: Data were provided by the FPVDB and SPVDB. All reports of osteoporosis and osteomalacia recorded from 1985 up to 31 December 2015 inclusive were selected. Taking the time to onset of bone loss into account, all cases occurring in less than 1 month were excluded. RESULTS: A total of 369 reports (44 cases of osteomalacia, 325 cases of osteoporosis) were registered in the FPVDB and 64 (22 cases of osteomalacia, 42 cases of osteoporosis) in the SPVDB. In France, the top 5 drugs involved in the onset of osteoporosis were corticosteroids accounting for approximately half of the reports (n = 170) followed by systemic antiviral (n = 87), antacid (n = 29), antiepileptic (n = 27) and antithrombotic (n = 24) drugs. The 2 main classes of drugs implicated in osteomalacia were systemic antiretroviral drugs for half of the reports (n = 21) and antiepileptic drugs (n = 15). In Spain, corticosteroids were involved in 35.7% of reported cases of osteoporosis (n = 15) followed by systemic antiviral drugs (n = 12). There was no spontaneous report for antacid drugs. For osteomalacia, the 2 main drug classes were systemic antiretroviral drugs (n = 18, 81.8%) followed by antiepileptics (n = 2, 9.0%). In both countries, concomitant administration of systemic corticosteroids with other suspected drugs did not significantly modify the time to onset of drug-induced osteoporosis. CONCLUSION: Despite some differences between the French and Spanish PVDBs, our data consistently show that bone loss is not only restricted to glucocorticoids but also involves antivirals, antiepileptic drugs, antacid drugs or antidepressants. Further analysis might prove useful in exploring the characteristics of drug-induced bone loss on a larger scale.

Occult metabolic bone disease in chronic pancreatitis.

BACKGROUND: Chronic pancreatitis (CP) leads to malabsorption and metabolic bone disease (MBD). Alcoholic CP (ACP) and tropical CP (TCP) are the two common types of CP. OBJECTIVE: We investigated the presence of occult MBD in patients with CP and compared the same between ACP and TCP. MATERIALS AND METHODS: In this cross-sectional, observational study, we included serial patients of CP in different stages and are grouped as ACP (Group 1; n = 67) and TCP (Group 2; n = 35). We determined serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D (25OHD), and intact parathyroid hormone (PTH) levels. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in the neck of the left femur. MBD was defined by the presence of either low bone mass (Z-score Results: The study participants (85 males; 17 females) had a mean age of 40.8 ± 12.6 years, CP duration of 3.7 ± 4.7 years, and Body Mass Index of 22.5 ± 3.2 kg/m2. A total of 37 (36%) patients had MBD (osteomalacia in 31 and low bone mass in 6). The frequency of MBD was same in the TCP (16/35) and ACP (21/65) groups (P = 0.1940). Elevated PTH (>70 pg/mL) was seen in 14 patients with 25OHD deficiency and low calcium (<8.5 mg/dL) in 29 patients. BMD did not show a significant correlation with the duration of CP. CONCLUSION: Occult MBD is seen in a third of patients with CP and is similar irrespective of the etiology. The disease is silent and mandates active screening in all susceptible individuals.

Vitamin D Status in South Asian Populations - Risks and Opportunities.

Human body acquires a significant amount of vitamin D by cutaneous synthesis under the action of sunlight and less is supplied through nutritional sources. Diversified sociocultural and economic determinants have been identified that limit the dietary intake of vitamin D and enough distribution of sunlight to maintain optimal levels of 25-hydroxyvitamin D (25(OH)D). Consequently, the world has witnessed a high prevalence of hypovitaminosis D in resource-limited South Asian countries. The purpose of this review is to provide a South Asian perspective of vitamin D status, critically examining India, Pakistan, Bangladesh, and Sri Lanka, and to shed light on potential determinants (latitude and season, sunshine exposure habits, age, gender, and genetic factors) leading to hypovitaminosis D among a variety of population groups. Literature search was carried out using bibliographic databases "PubMed," "Google Scholar," and "ScienceDirect.com." Serum 25(OH)D level, 20-50 nmol/L, was mainly taken as vitamin D deficiency, and determinants of low serum 25(OH)D concentration of the population under study were also considered. The review concludes that vitamin D deficiency is highly prevalent among South Asian populations and global efforts are needed to overcome hypovitaminosis in the region. In addition, dietary diversification, supplementation and fortification of foods with vitamin D, adequate exposure to sunlight, and consumption of animal foods were suggested as viable approaches to maintain 25(OH)D levels for optimal health.

Serum concentrations of 25-hydroxyvitamin D and its association with bone mineral density and serum parathyroid hormone levels during winter in urban males from Guiyang, Southwest China.

Serum vitamin D (25-hydroxyvitamin D (25OHD)) may influence serum parathyroid hormone (PTH) levels and bone mineral density (BMD). In the present study, we assessed serum 25OHD concentration and its association with PTH and BMD in urban males from Guiyang (N26.57°), the capital city of Guizhou province, Southwest China. We recruited 634 males aged >20 years from the Guiyang Health Measures Survey, and stratified them into three groups according to age: young (20-39 years), middle aged (40-59 years) and older (60-79 years). We measured serum concentrations of 25OHD, PTH levels and BMD of the lumbar spine (L1-L4), femoral neck and total hip. In addition, we also explored the relationship between 25OHD and lifestyle, socio-economic characteristics and medical history by applying covariance analysis and locally weighted regression plots. The results showed that serum 25OHD was 75 nmol/l in 12·6 % of the subjects. Higher level of serum PTH was detected in relation to lower concentrations of serum 25OHD up to 50 nmol/l. A negative correlation between serum 25OHD and PTH concentrations was observed (r -0·207, P=0·003). Mean concentration of serum PTH increased gradually and plateaued while concentrations of serum 25OHD decreased to 50 nmol/l. Gradual increase in serum PTH was observed as 25OHD concentration was <25 nmol/l (P=0·004). BMD values at all sites were greater in the higher serum 25OHD concentration group. This study shows that low concentrations of serum 25OHD were common in males, and bone health was likely to be improved when serum 25OHD values were between 30 and 50 nmol/l.

Global Health Disparities in Childhood Rickets.

Nutritional rickets is a global health problem reflecting both historical and contemporary health disparities arising from racial, ethnic, environmental, and geopolitical circumstances. It primarily affects marginalized populations and can contribute to long-term morbidity. Deficits in bone health in childhood may also contribute to osteomalacia/osteoporosis. Solutions require a global public health approach.

Hyperparathyroidism in a Large Cohort of Chinese Patients With Tumor-induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Hyperparathyroidism (HPT) including secondary HPT (SHPT) and tertiary HPT (THPT) in TIO patients, which is believed to be associated with phosphate supplementation, has not been well documented. OBJECTIVES: To clarify the prevalence, clinical characteristics, and risk factors for HPT in a large cohort of Chinese patients with TIO in our hospital. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study enrolled 202 patients with TIO. MAIN OUTCOME MEASUREMENTS: Occurrence of HPT in patients with TIO. RESULTS: HPT was observed in 91 patients (91/202, 45.1%): 84 patients (41.6%) with SHPT and 7 patients (3.5%) with THPT. All patients with THPT underwent parathyroidectomy and only 1 patient experienced recurrence. Compared with patients without HPT, patients with SHPT had longer disease duration, higher rate of phosphate and calcitriol supplementation, lower serum calcium, lower urine calcium excretion, and higher urine phosphate excretion. Compared with patients with SHPT, patients with THPT had even longer disease duration and a higher rate of phosphate and calcitriol supplementation. PTH levels showed positive correlation with intact FGF23 and 1,25-dihydroxyvitamin D levels, but not 25-hydroxy vitamin D level in patients with TIO. Multivariate logistic regression analysis showed that long disease duration and phosphate supplementation were independently associated with occurrence of HPT in patients with TIO. Further logistic regression analysis and restricted cubic spline model revealed dose-response relationship between cumulative dose of phosphate supplementation and PTH levels. CONCLUSIONS: HPT is common in patients with TIO. To avoid the occurrence of HPT in patients with TIO, timely diagnosis and tumor resection is necessary and an excessive dose of phosphate supplementation is not suggested before surgery.

Should 25-hydroxyvitamin D and bone density using DXA be tested in adolescents with lumbar stress fractures of the pars interarticularis?

STUDY DESIGN: Retrospective study. OBJECTIVE: To determine if 25-hydroxyvitamin D (25[OH]D) level measurement and bone mineral density (BMD) using dual-energy x-ray absorptiometry (DXA) are indicated in children with a history of stress fracture of the pars interarticularis. SUMMARY OF BACKGROUND DATA: Healing rates of 4%-25% for bilateral and unilateral pars fractures, respectively, have previously been reported. Factors that may contribute to osteomalacia, rickets, and poor bone healing include low (25[OH]D) and low BMD. METHODS: Patients were seen at the Nebraska Spine Center between 2008 and 2010. Selection criteria included a diagnosis of pars fracture with DXA Z-score values (lumbar and hip) and pretreatment serum (25[OH]D) level measurement. Twenty-four patients were included. Vitamin D was defined as sufficient when ≥ 32 ng/mL, insufficient when 20 to < 32 ng/mL, and deficient when < 20 ng/mL. BMD was interpreted from DXA Z-scores using reference intervals defined in the literature. A Z-score <-2.0 was considered low for chronological age. RESULTS: The mean (± SD) vitamin D level was 29.9 ng/mL ± 10.8 (range, 9-56 ng/mL). Values were ≤ 10 ng/mL in 1 patient (4%), 11-20 ng/mL in 4 patients (17%), 21-30 ng/mL in 8 patients (33%), 31-50 ng/mL in 10 patients (42%), and > 50 ng/mL in 1 patient (4%). This correlated to 3 (13%) patients with deficient vitamin D (≤ 15 ng/mL), 12 (50%) patients with insufficient levels, and 9 (38%) with sufficient levels of vitamin D. The mean Z-scores were 0.43 ± 0.93 (lumbar, range, -1.3 to 2.8) and 1.0 ± 1.11 (hip, range, -0.5 to 3.0). All scores were consistent with normal bony mineralization for age. CONCLUSIONS: On the basis of these data, we recommend routine vitamin D testing and do not recommend routine DXA in adolescents with lumbar stress fractures of the pars interarticularis.

Establishing the Prevalence of Osteomalacia in Arab Adolescents Using Biochemical Markers of Bone Health.

Nutrition-acquired osteomalacia is a bone mineralization disorder associated with dietary calcium and/or solar vitamin D deficiency, risk factors considered common in the Middle Eastern region. Establishing less invasive, cheap, and widely available diagnostic markers for this underdiagnosed entity is essential, in particular for screening in high-risk groups. This study assessed the prevalence of biochemical osteomalacia in Arab adolescents. In this cross-sectional study performed between September 2019 and March 2021, adolescents aged 12−17 years from 60 different secondary and preparatory year schools in Riyadh, Saudi Arabia were included. Anthropometrics and fasting blood samples were collected. Biochemical osteomalacia was defined as any two of the following four serum markers of hypomineralization, namely low 25 hydroxyvitamin D (25OHD < 30 nmol/L), high alkaline phosphatase (ALP), low calcium (Ca), and/or inorganic phosphorous (Pi). A total of 2938 Arab adolescents [1697 girls; mean age (years) 14.8 ± 1.8; 1241 boys; mean age 15.1 ± 1.6] were recruited. Vitamin D deficiency was noted in 56.2% (n = 953) of girls and 27.1% (n = 336) of boys (p < 0.001). The overall prevalence of biochemical osteomalacia was 10.0% (n = 295/2938) and was higher in girls than boys (14.7% vs. 3.6%, p < 0.001). The prevalence of low serum Ca and/or Pi was also higher in girls than in boys (24.2% vs. 12.5%, respectively, p < 0.001), as well as elevated ALP (5.1% vs. 1.5%, p < 0.001). Overall, girls were 4.6 times (95% CI 3.3−6.4) more likely to have biochemical osteomalacia than boys. Screening of apparently healthy Arab adolescents revealed a high prevalence of deranged mineralization markers suggestive of biochemical osteomalacia, which was significantly more common in girls than boys and was likely associated with Arab traditional clothing and diet. The proposed combination of typically altered mineralization markers for the diagnosis of osteomalacia is, at best, suggestive until further comparisons with established diagnostic tools (histological analysis of bone biopsies) are conducted.

Proceedings of the Rank Forum on Vitamin D.

The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations>75 nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.

Bone disorders in chronic liver diseases.

Bone disease is a major complication of chronic liver disease. Osteomalacia is quite uncommon despite low vitamin D levels in the majority of patients with cirrhosis. In contrast, osteoporosis is quite common, occurring in up to 50% of patients. Osteoporosis can result in spontaneous or low-impact fractures in patients with chronic liver diseases, adversely affecting morbidity, quality of life, and survival. The general biology of osteoporosis, including its pathogenesis, diagnostic tools, and rationale for treatment, have been determined largely empirically from studies of postmenopausal women with osteoporosis. Treatment regimens with modification of risk factors, use of vitamin D, and supplementation with calcium and bisphosphonates have been shown to be effective in select groups of patients with chronic liver diseases.

Protean manifestations of vitamin D deficiency, part 1: the epidemic of deficiency.

Just when vitamin deficiencies were thought to be a "thing of the past" a new vitamin deficiency-that of vitamin D has developed over the past 20 years. Vitamin D works like a hormone being produced primarily in one organ (the kidney) before circulating through the bloodstream to multiple organs where it has multiple effects. The increased prevalence of vitamin D deficiency is due to changes in modern lifestyle-mainly lack of exposure to sunlight and the increased prevalence of obesity that, results in sequestration of this fat-soluble vitamin in adipose tissue. Distance from the Equator and increasing age and skin pigmentation are additional risk factors. In pregnancy vitamin D deficiency can result in low birth weight, pre-term labor, pre-term birth, infections, and pre-eclamptic toxemia. While vitamin D deficiency is classically associated with rickets and osteomalacia, its effects are much more protean.

Upstream Regulators of Fibroblast Growth Factor 23.

Fibroblast growth factor 23 (FGF23) has been described as an important regulator of mineral homeostasis, but has lately also been linked to iron deficiency, inflammation, and erythropoiesis. FGF23 is essential for the maintenance of phosphate homeostasis in the body and activating mutations in the gene itself or inactivating mutations in its upstream regulators can result in severe chronic hypophosphatemia, where an unbalanced mineral homeostasis often leads to rickets in children and osteomalacia in adults. FGF23 can be regulated by changes in transcriptional activity or by changes at the post-translational level. The balance between O-glycosylation and phosphorylation is an important determinant of how much active intact or inactive cleaved FGF23 will be released in the circulation. In the past years, it has become evident that iron deficiency and inflammation regulate FGF23 in a way that is not associated with its classical role in mineral metabolism. These conditions will not only result in an upregulation of FGF23 transcription, but also in increased cleavage, leaving the levels of active intact FGF23 unchanged. The exact mechanisms behind and function of this process are still unclear. However, a deeper understanding of FGF23 regulation in both the classical and non-classical way is important to develop better treatment options for diseases associated with disturbed FGF23 biology. In this review, we describe how the currently known upstream regulators of FGF23 change FGF23 transcription and affect its post-translational modifications at the molecular level.

Vitamin D deficiency, supplementation and testing: have we got it right in New Zealand?

BACKGROUND: Severe prolonged vitamin D deficiency can cause rickets or osteomalacia. Both can be prevented by sunshine exposure or vitamin D supplementation. Although New Zealand guidance does not recommend vitamin D supplementation for the general population, it can be considered for individuals at risk of vitamin D deficiency. Routine measurement of 25-hydroxyvitamin D (25OHD) is also considered unnecessary. METHODS: We investigated the rates of vitamin D supplementation, rickets and osteomalacia in New Zealand, and of 25OHD results in Auckland, over the last two decades. RESULTS: Vitamin D prescriptions increased 14-fold, from 86,295/year to 1,215,507/year, between 2003 and 2019, with medication costs alone in 2019 being >$1 million. Despite these changes, the annual prevalence of hospital admissions for rickets, osteomalacia and unspecified vitamin D deficiency remained low and stable (10-20/year). 25OHD concentrations increased between 2002 and 2003 and between 2009 and 2019, and in the later time-period, 25OHD tests mainly identified individuals without vitamin D deficiency (40-50% >75nmol/L, 65-70% >50nmol/L and only 7-12.5% <25nmol/L). CONCLUSIONS: Osteomalacia and rickets persist at low rates despite widespread, increasingly costly vitamin D supplementation and testing, which largely identifies individuals without vitamin D deficiency. These results suggest that vitamin D guidance and practice in New Zealand should change.