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In the past decades, the expansion policy of hard discounters is receiving increasing scientific attention. One of the main reasons of their success is location choices, which needs geographical thinking and knowledge of socio-economic environment. Although it has key importance to gain high purchase power territories in this competition, each company have to implement their own geo-strategy. While discount stores are operating in the town, national franchise small stores have an extensive network in the rural area. This paper is a case study which deals with competition of hard discounters and Coop in Northern Hungary.

The age structure of the society in the individual countries belonging to the Visegrád Group has changed significantly since 1989. In Hungary, changes in the age structure have had a great impact on the whole economy. The process of aging in society has been going on in Western Europe and will probably continue. Unlike in the Western European countries, in our region the significance of the purchasing power of the elderly has not yet been fully recognized. There is no best practice or strategy to attract the ever-growing age group; applying marketing to seniors is a novelty in the business sector. Shopping centres and e-business face great challenges in the near future, and the change incorporates the risk of failure or renewal. Although the processes apply to all shopping centres, due to the number and the purchasing power of the seniors, malls in Budapest are more affected. Their situation is not the same even in different areas of the capital, as the composition of the buyers in their gravity zone is different. It is up to their own features, and decision-making abilities whether they will be able to adjust to the new circumstances, who will “win” and who will “lose”.

During pregnancy and lactation, mothers require significant amounts of calcium to pass on to the developing fetus and suckling neonate, respectively. Given the dependence of adult calcium concentrations and bone metabolism on vitamin D, one might anticipate that vitamin D sufficiency would be even more critical during pregnancy and lactation. However, maternal adaptations during pregnancy and lactation and fetal adaptations provide the necessary calcium relatively independently of vitamin D status. It is the vitamin D -- deficient or insufficient neonate who is at risk of problems, including hypocalcemia and rickets. Due to poor penetrance of vitamin D and 25-hydroxyvitamin D [25(OH)D] into milk, exclusively breastfed infants are at higher risk of vitamin D deficiency than are formula-fed infants. Dosing recommendations for women during pregnancy and lactation might be best directed toward ensuring that the neonate is vitamin D -- sufficient and that this sufficiency is maintained during infancy and beyond. A dose of vitamin D that provides 25(OH)D sufficiency in the mother during pregnancy should provide normal cord blood concentrations of 25(OH)D. Research has shown that during lactation, supplements administered directly to the infant can easily achieve vitamin D sufficiency; the mother needs much higher doses (100 [micro]g or 4000 IU per day) to achieve adult-normal 25(OH)D concentrations in her exclusively breastfed infant. In addition, the relation (if any) of vitamin D insufficiency in the fetus or neonate to long-term nonskeletal outcomes such as type 1 diabetes and other chronic diseases needs to be investigated. © 2008 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Inactivation of 24-hydroxylase (CYP24A1) causes mild hypercalcemia in humans that becomes severe and life-threatening during pregnancy through unclear mechanisms. We studied Cyp24a1 null mice during pregnancy, lactation, and post-weaning. We hypothesized that Cyp24a1 nulls have a much greater increase in calcitriol during pregnancy and lactation, leading to markedly increased intestinal calcium absorption and reduced lactational bone loss. WT and Cyp24a1 null sisters were mated to Cyp24a1+/- males. Timepoints included baseline (BL), late pregnancy (LP), mid-lactation (ML), late lactation (LL), and weekly x4 weeks of post-weaning recovery (R1-4). Assessments included intestinal calcium absorption (IntCaAbs) by gavage of 45Ca, bone mineral content (BMC) by DXA, microCT of femurs, 3-point bending tests of tibias, serum hormones, serum and urine minerals, milk analysis, and intestinal gene expression. At LP, whole body BMC increased equally by ~12% in null and WT. Calcitriol was 2.5-fold higher in nulls vs WT, accompanied by 3-fold increased IntCaAbs, hypercalcemia, hypercalciuria, and 6.5-fold higher FGF23. PTH was suppressed in both. Twenty percent of null dams died during delivery but their serum calcium at LP did not differ from Cyp24a1 nulls that survived. At ML, calcitriol, IntCaAbs, and FGF23 declined in both genotypes but remained higher than BL values in Cyp24a1 nulls. By LL, nulls were still hypercalcemic vs WT, and had lost less mean whole body BMC (11% vs. 21%, P<.02), but by micro-CT there were no differences from WT in cortical or trabecular bone mass. Lactational losses in BMC, cortical thickness, and trabecular number were restored by R4 in both genotypes. In summary, ablation of Cyp24a1 increased IntCaAbs and caused hypercalcemia during pregnancy and lactation, late gestational mortality in some nulls, and reduced lactational BMC loss. Treating women with gestational hypercalcemia from CYP24A1 mutations should focus on reducing calcitriol or IntCaAbs, since increased bone resorption is not the cause., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Ablation of Cyp27b1 eliminates calcitriol but does not disturb fetal mineral homeostasis or skeletal development. However, independent of fetal genotypes, maternal loss of Cyp27b1 altered fetal mineral and hormonal levels compared to offspring of WT dams. We hypothesized that these maternal influences would alter postnatal skeletal development. Cyp27b1 null and WT females were mated to bear only Cyp27b1+/- offspring. Forty-eight hours after birth, pups were cross-fostered to dams of the same or opposite genotype that bore them. Maternal and offspring samples were collected on days 21 (weaning) and 42. Offspring measurements included minerals and hormones, BMC by DXA, ash weight and mineral content, gene expression, 3-point bending tests, and microCT. Maternal lactational behavior was evaluated. Milk was analyzed for nutritional content. At day 21, offspring fostered by nulls, independent of birth dam, had ~20% lower weight, BMC, ash weight, and ash calcium than pups fostered by WT dams. Adjustment for body weight accounted for the lower BMC but not the lower ash weight and ash calcium. Hormones and serum/urine minerals did not differ across offspring groups. Offspring fostered by nulls had shorter femurs and lower cortical thickness, mean polar moment of inertia, cortical area, trabecular bone volume, and trabecular number. Dam lactational behaviors and milk nutritional content did not differ between groups. At day 42, body weight, ash weight, lengths, BMC, and tibial bone strength were no longer different between pups fostered by null vs WT dams. In summary, pups fostered by Cyp27b1 nulls, regardless of birth dam, have proportionately smaller skeletons at 21 d, impaired microstructure, but normal mineral homeostasis. The skeletal effects are largely recovered by day 42 (3 wk after weaning). In conclusion, maternal loss of calcitriol impairs early postnatal cortical bone growth and trabecular bone mass, but affected offspring catch up after weaning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Sedentary behavior (SB) or sitting is associated with multiple unfavorable health outcomes. Bone tissue responds to imposed gravitational and muscular strain with there being some evidence suggesting a causal link between SB and poor bone health. However, there are no population-based data on the longitudinal relationship between SB, bone change, and incidence of fragility fractures. This study aimed to examine the associations of sitting/SB (defined as daily sitting time), areal BMD (by DXA), and incident low trauma (fragility) osteoporotic fractures (excluding hands, feet, face, and head). We measured baseline (1995-7) and 10-yr self-reported SB, femoral neck (FN), total hip (TH), and lumbar spine (L1-L4) BMD in 5708 women and 2564 men aged 25 to 80+ yr from the population-based, nationwide, 9-center Canadian Multicentre Osteoporosis Study. Incident 10-yr fragility fracture data were obtained from 4624 participants; >80% of fractures were objectively confirmed by medical records or radiology reports. Vertebral fractures were confirmed by qualitative morphological methods. All analyses were stratified by sex. Multivariable regression models assessed SB-BMD relationships; Cox proportional models were fit for fracture risk. Models were adjusted for age, height, BMI, physical activity, and sex-specific covariates. Women in third/fourth quartiles had lower adjusted FN BMD versus women with the least SB (first quartile); women in the SB third quartile had lower adjusted TH BMD. Men in the SB third quartile had lower adjusted FN BMD than those in SB first quartile. Neither baseline nor stable 10-yr SB was related to BMD change nor to incident fragility fractures. Increased sitting (SB) in this large, population-based cohort was associated with lower baseline FN BMD. Stable SB was not associated with 10-yr BMD loss nor increased fragility fracture. In conclusion, habitual adult SB was not associated with subsequent loss of BMD nor increased risk of fracture., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Two months after her first pregnancy, a 35-yr-old exclusively breastfeeding woman bent to move her baby in the car seat and experienced sudden, severe pain from 5 spontaneous vertebral compression fractures. Genomic screen was negative but she had mild ankylosing spondylitis previously well controlled on etanercept. She was vegetarian with a high phytate intake. A lactation consultant had advised her to pump and discard milk between feeds, leading her to believe she produced twice as much milk as her baby ingested. She presented with a LS Z score of -3.6 and a TH Z score of -1.6. After 6 mo postweaning, she was treated with teriparatide (14 mo intermittently over 18 mo) and ultimately achieved a 50% increase in LS bone density and an 8% increase in TH bone density. Her fragility is explained by normal lactational bone loss amplified by excessive milk production and phytate-induced impairment of intestinal calcium absorption, ankylosing spondylitis, and the bend-and-lift maneuver. The marked increase in bone density resulted from the combined effects of spontaneous recovery and pharmacotherapy. Spontaneous recovery of bone mass and strength should occur during 12 mo after weaning in all women, including those who have fractured., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by the loss of CYP24A1 is unknown. We hypothesized that loss of Cyp24a1 in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. The Cyp24a1 +/- mice were mated to create pregnancies with wildtype, Cyp24a1 +/- , and Cyp24a1 null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to Cyp24a1 +/- fetuses only), with 3.5-fold increased calcitriol, 4-fold increased fibroblast growth factor 23 (FGF23), and unchanged parathyroid hormone. The quantitative RT-PCR confirmed the absence of Cyp24a1 and 2-fold increases in S100g , sodium-calcium exchanger type 1, and calcium-sensing receptor in null placentas but not in fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental 45 Ca and 32 P transport were unchanged in null fetuses. Fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology did not differ among the genotypes. Serum procollagen 1 intact N-terminal propeptide and bone expression of sclerostin and Blgap were reduced while calcitonin receptor was increased in nulls. In conclusion, loss of Cyp24a1 in fetal mice causes hypercalcemia, modest hypophosphatemia, and increased FGF23, but no alteration in skeletal development. Reduced incorporation of calcium into bone may contribute to the hypercalcemia without causing a detectable decrease in the skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of CYP24A1 will also be hypercalcemic in utero but with normal skeletal development., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Aim: Assessing the visual accuracy of two large language models (LLMs) in microbial classification. Materials & methods: GPT-4o and Gemini 1.5 Pro were evaluated in distinguishing Gram-positive from Gram-negative bacteria and classifying them as cocci or bacilli using 80 Gram stain images from a labeled database. Results: GPT-4o achieved 100% accuracy in identifying simultaneously Gram stain and shape for Clostridium perfringens , Pseudomonas aeruginosa and Staphylococcus aureus . Gemini 1.5 Pro showed more variability for similar bacteria (45, 100 and 95%, respectively). Both LLMs failed to identify both Gram stain and bacterial shape for Neisseria gonorrhoeae . Cumulative accuracy plots indicated that GPT-4o consistently performed equally or better in every identification, except for Neisseria gonorrhoeae's shape. Conclusion: These results suggest that these LLMs in their unprimed state are not ready to be implemented in clinical practice and highlight the need for more research with larger datasets to improve LLMs' effectiveness in clinical microbiology.

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., Competing Interests: Disclosure E. Michael Lewiecki: Amgen investigator, consultant, and speaker, Radius investigator and consultant, Kyowa Kirin consultant and speaker. Teresita Bellido: nothing to disclose. John P. Bilezikian: Amgen consultant and speaker, Amolyt consultant and speaker, Radius consultant, Ascendis consultant and speaker, Abiogen consultant. Jacques P. Brown: Amgen consultant and speaker, Mereo researcher, Radius researcher, Ultragenyx data monitoring committee, Gilead consultant, Pfizer consultant. Azeez Farooki: Novartis consultant, Johnson and Johnson stock ownership. Christopher S. Kovacs: Novo Nordisk consultant and speaker, Ipsen consultant and speaker. Brendan Lee: Biomarin data safety monitoring board, Pacira, Sanofi, Acer royalties. William D. Leslie: nothing to disclose. Michael R. McClung: AbbVie consultant, Alexion consultant, Amgen consultant and speaker, Myovant consultant, Theramax speaker. Mark L. Prasarn: Stryker speaker. Deborah E. Sellmeyer: nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Recovery from lactation-induced bone loss appears to be calcitriol-independent, since mice lacking 1-alpha-hydroxylase or vitamin D receptor (VDR) exhibit full skeletal recovery. However, in those studies mice consumed a calcium-, phosphorus-, and lactose-enriched "rescue" diet. Here we assessed whether postweaning skeletal recovery of Vdr null mice required that rescue diet. Wild type (WT) and Vdr null mice were raised on the rescue diet and switched to a normal (1% calcium) diet at Day 21 of lactation until 28 days after weaning. Unmated mice received the same regimen. In WT mice, cortical thickness was significantly reduced by 25% at 21 days of lactation and was completely restored by 28 days after weaning. Three-point bending tests similarly showed a significant reduction during lactation and full recovery of ultimate load and energy absorbed. Although Vdr null mice exhibited a similar lactational reduction in cortical thickness and mechanical strength, neither was even partially restored after weaning. Unmated mice showed no significant changes. In micro-computed tomography scans, diaphyses of Vdr null femora at 28 days after weaning were highly porous and exhibited abundant low-density bone extending into the marrow space from the endocortical surface. To quantify, we segregated bone into low-, mid-, and high-density components. In WT diaphyses, high-density bone was lost during lactation and restored after weaning. Vdr null mice also lost high-density bone during lactation but did not replace it; instead, they demonstrated a threefold increase in low-density bone mass. Histology revealed that intracortical and endocortical surfaces of Vdr null bones after weaning contained very thick (up to 20 micron) osteoid seams, covered with multiple layers of osteoblasts and precursors. We conclude that during the postweaning period, osteoblasts are potently stimulated to produce osteoid despite lacking VDRs, and that either calcitriol or a calcium-enriched diet are needed for this immature bone to become mineralized. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Bone diseases such as otosclerosis (conductive hearing loss) and osteoporosis (low bone mineral density) can result from the abnormal expression of genes that regulate cartilage and bone development. The forkhead box transcription factor FOXL1 has been identified as the causative gene in a family with autosomal dominant otosclerosis and has been reported as a candidate gene in GWAS meta-analyses for osteoporosis. This potentially indicates a novel role for foxl1 in chondrogenesis, osteogenesis, and bone remodelling. We created a foxl1 mutant zebrafish strain as a model for otosclerosis and osteoporosis and examined jaw bones that are homologous to the mammalian middle ear bones, and mineralization of the axial skeleton. We demonstrate that foxl1 regulates the expression of collagen genes such as collagen type 1 alpha 1a and collagen type 11 alpha 2 , and results in a delay in jawbone mineralization, while the axial skeleton remains unchanged. foxl1 may also act with other forkhead genes such as foxc1a , as loss of foxl1 in a foxc1a mutant background increases the severity of jaw calcification phenotypes when compared to each mutant alone. Our zebrafish model demonstrates atypical cartilage formation and mineralization in the zebrafish craniofacial skeleton in foxl1 mutants and demonstrates that aberrant collagen expression may underlie the development of otosclerosis.

Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (≥3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE ≥ 24). The annual % change in MMSE was similar for both genders (women -0.33, interquartile range [IQR] -0.70 to +0.00; and men -0.34, IQR: -0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Parathyroid hormone-related protein (PTHrP, gene name Pthlh) is a pleiotropic regulator of tissue homeostasis. In bone, Dmp1Cre-targeted PTHrP deletion in osteocytes causes osteopenia and impaired cortical strength. We report here that this outcome depends on parental genotype. In contrast to our previous report using mice bred from heterozygous (flox/wild type) Dmp1Cre.Pthlh f/w parents, adult (16-week-old and 26-week-old) flox/flox (f/f) Dmp1Cre.Pthlh f/f mice from homozygous parents (Dmp1Cre.Pthlh f/f(hom) ) have stronger bones, with 40% more trabecular bone mass and 30% greater femoral width than controls. This greater bone size was observed in Dmp1Cre.Pthlh f/f(hom) mice as early as 12 days of age, when greater bone width was also found in male and female Dmp1Cre.Pthlh f/f(hom) mice compared to controls, but not in gene-matched mice from heterozygous parents. This suggested a maternal influence on skeletal size prior to weaning. Although Dmp1Cre has previously been reported to cause gene recombination in mammary gland, milk PTHrP protein levels were normal. The wide-bone phenotype was also noted in utero: Dmp1Cre.Pthlh f/f(hom) embryonic femurs were more mineralized and wider than controls. Closer examination revealed that Dmp1Cre caused PTHrP recombination in placenta, and in the maternal-derived decidual layer that resides between the placenta and the uterus. Decidua from mothers of Dmp1Cre.Pthlh f/f(hom) mice also exhibited lower PTHrP levels by immunohistochemistry and were smaller than controls. We conclude that Dmp1Cre leads to gene recombination in decidua, and that decidual PTHrP might, through an influence on decidual cells, limit embryonic bone radial growth. This suggests a maternal-derived developmental origin of adult bone strength. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Prevention of early menopausal bone loss may reduce the future burden of osteoporosis. In this modelling exercise, an osteoporosis prevention strategy involving 5-year infusions of zoledronic acid, beginning early in menopause, reduced long-term fracture risk and the proportion of aging women with femoral neck densitometric osteoporosis. This strategy warrants further evaluation., Introduction: Preventing early menopausal bone loss may substantially reduce the future burden of osteoporosis. We modelled the effects of infrequent zoledronic acid infusions on long-term fracture risk., Methods: Data from the Canadian Multicentre Osteoporosis Study (CaMos) were used to determine the expected natural history of femoral neck areal bone mineral density (BMD) and fracture risk (using FRAX®) from ages 50-80 for women with no antiresorptive drug exposures. We modelled the effects of three infusions of zoledronic acid (at ages 50, 55, 60) on long-term fracture risk, assuming this intervention would preserve BMD until age 65 years, followed by losses mirroring early menopausal BMD loss., Results: At age 65, untreated women and zoledronic acid recipients had expected mean (SD) femoral neck T-scores of - 1.5(1.0) and - 0.8(1.0), 10-year major osteoporotic fracture (MOF) risks of 9.8%(5.0) and 8.0%(3.7) and hip fracture risks of 1.7%(2.4) and 0.8%(1.2), respectively. At age 80, untreated women and zoledronic acid recipients had expected femoral neck T-scores of - 1.9(0.9) and - 1.4(0.9), MOF risks of 17.9%(8.2) and 14.9%(6.4) and hip fracture risks of 6.3%(6.2) and 4.4%(4.5), respectively. The expected proportion of women with femoral neck T-score ≤ - 2.5 was 14.9% for untreated women and 3.8% for zoledronic acid recipients at age 65, increasing to 28.1% and 12.0%, respectively, at age 80. Numbers-needed-to-treat to prevent one case of densitometric osteoporosis were 9 at age 65 and 5 at age 80., Conclusion: Infrequent infusions of zoledronic acid, initiated early in menopause, are expected to reduce long-term fracture risk and result in a substantial reduction in the proportion of women with densitometric osteoporosis after age 65.

The major mineralized tissues are bone and teeth, which share several mechanisms governing their development and mineralization. This crossover includes the hormones that regulate circulating calcium and phosphate concentrations, and the genes that regulate the differentiation and transdifferentiation of cells. In developing endochondral bone and in developing teeth, parathyroid hormone-related protein (PTHrP) acts in chondrocytes to delay terminal differentiation, thereby increasing the pool of precursor cells. Chondrocytes and (in specific circumstances) pre-odontoblasts can also transdifferentiate into osteoblasts. Moreover, bone and teeth share outcomes when affected by systemic disorders of mineral homeostasis or of the extracellular matrix, and by adverse effects of treatments such as bisphosphonates and fluoride. Unlike bone, teeth have more permanent effects from systemic disorders because they are not remodelled after they are formed. This Review discusses the normal processes of bone and tooth development, followed by disorders that have effects on both bone and teeth, versus disorders that have effects in one without affecting the other. The takeaway message is that bone specialists should know when to screen for dental disorders, just as dental specialists should recognize when a tooth disorder should raise suspicions about a possible underlying bone disorder.

Biomineralization is the process by which organisms produce mineralized tissues. This crucial process makes possible the rigidity and flexibility that the skeleton needs for ambulation and protection of vital organs, and the hardness that teeth require to tear and grind food. The skeleton also serves as a source of mineral in times of short supply, and the intestines absorb and the kidneys reclaim or excrete minerals as needed. This Review focuses on physiological and pathological aspects of the hormonal regulation of biomineralization. We discuss the roles of calcium and inorganic phosphate, dietary intake of minerals and the delicate balance between activators and inhibitors of mineralization. We also highlight the importance of tight regulation of serum concentrations of calcium and phosphate, and the major regulators of biomineralization: parathyroid hormone (PTH), the vitamin D system, vitamin K, fibroblast growth factor 23 (FGF23) and phosphatase enzymes. Finally, we summarize how developmental stresses in the fetus and neonate, and in the mother during pregnancy and lactation, invoke alternative hormonal regulatory pathways to control mineral delivery, skeletal metabolism and biomineralization.

During pregnancy, female physiology adapts to meet the additional mineral demands of the developing fetus. Meanwhile, the fetus actively transports minerals across the placenta and maintains high circulating levels to mineralize the rapidly developing skeleton. Most of this mineral is accreted during the last trimester, including 30 g of calcium, 20 g of phosphate and 0.8 g of magnesium. Given the dependence of calcium homeostasis on vitamin D and calcitriol in the adult and child, it may be expected that vitamin D sufficiency would be even more critical during pregnancy and fetal development. However, the pregnant mother and fetus appear to meet their mineral needs independent of vitamin D. Adaptations in maternal mineral and bone metabolism during pregnancy appear to be invoked independent of maternal vitamin D, while fetal mineral metabolism and skeletal development appear to be protected from vitamin D deficiency and genetic disorders of vitamin D physiology. This review discusses key data from both animal models and human studies to address our current knowledge on the role of vitamin D and calcitriol during pregnancy and fetal development.

Study Purpose: Morphometric methods categorize potential osteoporotic vertebral fractures (OVF) on the basis of loss of vertebral height. A particular example is the widely used semiquantitative morphometric tool proposed by Genant (GSQ). A newer morphologic algorithm-based qualitative (mABQ) tool focuses on vertebral end-plate damage in recognizing OVF. We used data from both sexes in the Canadian Multicentre Osteoporosis Study (CaMos) to compare the 2 methods in identifying OVF at baseline and during 10 years of follow-up., Materials and Methods: We obtained lateral thoracic and lumbar spinal radiographs (T4-L4) 3 times, at 5-year intervals, in 828 participants of the population-based CaMos. Logistic regressions were used to study the association of 10-year changes in bone mineral density (BMD) with incident fractures., Results: At baseline, 161 participants had grade 1 and 32 had grade 2 GSQ OVF; over the next 10 years, only 9 of these participants had sustained incident GSQ OVF. Contrastingly, 21 participants at baseline had grade 1 and 48 grade 2 mABQ events; over the next 10 years, 79 subjects experienced incident grade 1 or grade 2 mABQ events. Thus, incident grades 1 and 2 morphologic fractures were 8 times more common than morphometric deformities alone. Each 10-year decrease of 0.01 g/cm 2 in total hip BMD was associated with a 4.1% (95% CI: 0.7-7.3) higher odds of having an incident vertebral fracture., Conclusions: This analysis further suggests that morphometric deformities and morphologic fractures constitute distinct entities; morphologic fractures conform more closely to the expected epidemiology of OVF.

The scorecard evaluates the burden and management of osteoporosis in Canada and how care pathways differ across Canadian provinces. The results showed there are inequities in patients' access to diagnosis, treatment, and post-fracture care programs in Canada. Interventions are needed to close the osteoporosis treatment gap and minimize these inequities., Introduction: The purpose of this study was to develop a visual scorecard that assesses the burden of osteoporosis and its management within Canada and seven Canadian provinces., Methods: We adapted the Scorecard for Osteoporosis in Europe (SCOPE) to score osteoporosis indicators for Canada and seven provinces (British Columbia, Alberta, Saskatchewan, Ontario, Quebec, New Brunswick, and Newfoundland). We obtained data from a comprehensive literature review and interviews with osteoporosis experts. We scored 20 elements across four domains: burden of disease, policy framework, service provision, and service uptake. Each element was scored as red, yellow, or green, indicating high, intermediate, or low risk, respectively. Elements with insufficient data were scored black., Results: Canada performed well on several elements of osteoporosis care, including high uptake of risk assessment algorithms and minimal wait times for hip fracture surgery. However, there were no established fracture registries, and reporting on individuals with high fracture risk who remain untreated was limited. Furthermore, osteoporosis was not an official health priority in most provinces. Government-backed action plans and other osteoporosis initiatives were primarily confined to Ontario and Alberta. Several provinces (Saskatchewan, New Brunswick, Newfoundland) did not have any registered fracture liaison service (FLS) programs. Access to diagnosis and treatment was also inconsistent and reimbursement policies did not align with clinical guidelines., Conclusion: Government-backed action plans are needed to address provincial inequities in patients' access to diagnosis, treatment, and FLS programs in Canada. Further characterization of the treatment gap and the establishment of fracture registries are critical next steps in providing high-quality osteoporosis care.

Fibroblast growth factor 23 (FGF23) appears to play no role until after birth, given unaltered phosphate and bone metabolism in Fgf23- and Klotho-null fetuses. However, in those studies maternal serum phosphorus was normal. We studied whether maternal phosphate loading alters fetal serum phosphorus and invokes a fetal FGF23 or parathyroid hormone (PTH) response. C57BL/6 wild-type (WT) female mice received low (0.3%), normal (0.7%), or high (1.65%) phosphate diets beginning 1 week prior to mating to WT males. Fgf23+/- female mice received the normal or high-phosphate diets 1 week before mating to Fgf23+/- males. One day before expected birth, we harvested maternal and fetal blood, intact fetuses, placentas, and fetal kidneys. Increasing phosphate intake in WT resulted in progressively higher maternal serum phosphorus and FGF23 during pregnancy, while PTH remained undetectable. Fetal serum phosphorus was independent of the maternal phosphorus and PTH remained low, but FGF23 showed a small nonsignificant increase with high maternal serum phosphorus. There were no differences in fetal ash weight and mineral content, or placental gene expression. High phosphate intake in Fgf23+/- mice also increased maternal serum phosphorus and FGF23, but there was no change in PTH. WT fetuses remained unaffected by maternal high-phosphate intake, while Fgf23-null fetuses became hyperphosphatemic but had no change in PTH, skeletal ash weight or mineral content. In conclusion, fetal phosphate metabolism is generally regulated independently of maternal serum phosphorus and fetal FGF23 or PTH. However, maternal phosphate loading reveals that fetal FGF23 can defend against the development of fetal hyperphosphatemia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10-13, 2019. The conference was held as a follow-up to previous meetings held in 2017 and 2018 to address topics of controversy in vitamin D research. The specific topics were selected by the steering committee of the conference and based upon areas that remain controversial from the preceding conferences. Other topics were selected anew that reflect specific topics that have surfaced since the last international conference. Consensus was achieved after formal presentations and open discussions among experts. As will be detailed in this article, consensus was achieved with regard to the following: the importance and prevalence of nutritional rickets, amounts of vitamin D that are typically generated by sun exposure, worldwide prevalence of vitamin D deficiency, the importance of circulating concentrations of 25OHD as the best index of vitamin D stores, definitions and thresholds of vitamin D deficiency, and efficacy of vitamin D analogues in the treatment of psoriasis. Areas of uncertainly and controversy include the following: daily doses of vitamin D needed to maintain a normal level of 25OHD in the general population, recommendations for supplementation in patients with metabolic bone diseases, cutaneous production of vitamin D by UVB exposure, hepatic regulation of 25OHD metabolites, definition of vitamin D excess, vitamin D deficiency in acute illness, vitamin D requirements during reproduction, potential for a broad spectrum of cellular and organ activities under the influence of the vitamin D receptor, and potential links between vitamin D and major human diseases. With specific regard to the latter area, the proceedings of the conference led to recommendations for areas in need of further investigation through appropriately designed intervention trials. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research., (© 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.)

Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged ≥60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7-15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with a T-score of -1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) cause significant inpatient morbidity and mortality. They are especially challenging to diagnose promptly in the intensive care unit because a plethora of other causes can contribute to clinical decline in complex, critically ill patients. The authors describe the diagnosis, management, and prevention of these diseases based on current guidelines and recent evidence., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health., Introduction: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk., Methods: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI)., Results: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ 2 (172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001)., Conclusions: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

It is recognized that the trabecular bone score (TBS) provides skeletal information, and frailty measurement is significantly associated with increased risks of adverse health outcomes. Given the suboptimal predictive power in fracture risk assessment tools, we aimed to evaluate the combination of frailty and TBS regarding predictive accuracy for risk of major osteoporotic fracture (MOF). Data from the prospective longitudinal study of CaMos (Canadian Multicentre Osteoporosis Study) were used for this study. TBS values were estimated using lumbar spine (L 1 to L 4 ) dual-energy X-ray absorptiometry (DXA) images; frailty was evaluated by a frailty index (FI) of deficit accumulation. Outcome was time to first incident MOF during the follow-up. We used the Harrell's C-index to compare the model predictive accuracy. The Akaike information criterion, likelihood ratio test, and net reclassification improvement (NRI) were used to compare model performances between the model combining frailty and TBS (subsequently called "FI + TBS"), FI-alone, and TBS-alone models. We included 2730 participants (mean age 69 years; 70% women) for analyses (mean follow-up 7.5 years). There were 243 (8.90%) MOFs observed during follow-up. Participants with MOF had significantly higher FI (0.24 versus 0.20) and lower TBS (1.231 versus 1.285) than those without MOF. FI and TBS were significantly related with MOF risk in the model adjusted for FRAX with bone mineral density (BMD) and other covariates: hazard ratio (HR) = 1.26 (95% confidence interval [CI] 1.11-1.43) for per-SD increase in FI; HR = 1.38 (95% CI 1.21-1.59) for per-SD decrease in TBS; and these associations showed negligible attenuation (HR = 1.24 for per-SD increase in FI, and 1.35 for per-SD decrease in TBS) when combined in the same model. Although the model FI + TBS was a better fit to the data than FI-alone and TBS-alone, only minimal and nonsignificant enhancement of discrimination and NRI were observed in FI + TBS. To conclude, frailty and TBS are significantly and independently related to MOF risk. Larger studies are warranted to determine whether combining frailty and TBS can yield improved predictive accuracy for MOF risk. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

Community-acquired pneumonia significantly contributes to patient morbidity and healthcare costs. As our understanding of this common infection grows, collaborative efforts among researchers and clinical societies provide new literature and updated guidelines informing its management. This review discusses diagnostic methods, empiric treatment, and infection prevention strategies for patients with suspected community-acquired pneumonia., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

There are remarkable differences in bone and mineral metabolism between the fetus and adult. The fetal mineral supply is from active transport across the placenta. Calcium, phosphorus, and magnesium circulate at higher levels in the fetus compared to the mother. These high concentrations enable the skeleton to accrete required minerals before birth. Known key regulators in the adult include parathyroid hormone (PTH), calcitriol, fibroblast growth factor-23, calcitonin, and the sex steroids. But during fetal life, PTH plays a lesser role while the others appear to be unimportant. Instead, PTH-related protein (PTHrP) plays a critical role. After birth, serum calcium falls and phosphorus rises, which trigger an increase in PTH and a subsequent rise in calcitriol. The intestines become the main source of mineral supply while the kidneys reabsorb filtered minerals. This striking developmental switch is triggered by loss of the placenta, onset of breathing, and the drop in serum calcium., (© 2019 Elsevier Ltd. All rights reserved.)

Background: Antibiotic allergy de-labeling using penicillin allergy skin testing (PAST) can reduce the use and cost of alternative, non-β-lactam antibiotics in general inpatient populations. This strategy's role in hematopoietic stem cell transplant (HSCT) recipients is unclear., Methods: This study aimed to determine the effect of a pre-transplant PAST protocol on antibiotic use, days of therapy (DOT), and cost in an immunocompromised population at a single center from 7/1/2010-2/1/2019. Patients who received chimeric antigen receptor (CAR) T-cell therapy and those who underwent transplantation in the outpatient setting were excluded., Results: Of 1560 patients who underwent inpatient HSCT during the study period, 208 reported β-lactam allergy (136/844 [16%] pre- and 72/716 [10%] post-implementation; P < .001). PAST was performed on 7% and 54% of HSCT recipients pre- and post-implementation, respectively. Only two positive PAST were noted. There were no adverse reactions to PAST. There were no significant differences in the disease and transplant characteristics between the two groups. Days of therapy and cost of alternative antibiotics significantly decreased post-implementation (mean 788 vs 627 days, P = .01; mean $24 425 vs $17 518, P = .009)., Conclusion: Penicillin allergy skin testing adjudicates reported β-lactam allergy in HSCT recipients, lowering use, DOT, and cost of alternative antibiotics and promoting effective formulary agents to treat immunocompromised HSCT recipients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39-0.96] and 1.35 [95% CI 0.86-2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%-84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)