Vertebral fractures are increased in rheumatoid arthritis despite recent therapeutic advances: a case-control study.

Prevalence and risk factors of vertebral fractures in postmenopausal RA women were assessed in 323 patients and compared with 660 age-matched women. Of patients, 24.15% had at least one vertebral fracture vs.16.06% of controls. Age, glucocorticoids and falls were the main fracture risks. Vertebral fractures were associated with disease severity. INTRODUCTION: There is little quality data on the updated prevalence of fractures in rheumatoid arthritis (RA) that may have changed due to advances in the therapeutic strategy in recent years. This study was aimed at analysing the prevalence and risk factors of vertebral fractures in postmenopausal women with RA and comparing it with that of the general population. METHODS: We included 323 postmenopausal women diagnosed with RA from 19 Spanish Rheumatology Departments, randomly selected and recruited in 2018. Lateral radiographs of the thoracic and lumbar spine were obtained to evaluate morphometric vertebral fractures and the spinal deformity index. We analysed subject characteristics, factors related to RA, and fracture risk factors. The control group consisted of 660 age-matched Spanish postmenopausal women from the population-based Camargo cohort. RESULTS: Seventy-eight (24.15%) RA patients had at least one vertebral fracture. RA patients had increased fracture risk compared with controls (106 of 660, 16.06%) (p = 0.02). Logistic regression analysis showed that age (OR 2.17; 95% CI 1.27-4.00), glucocorticoids (OR 3.83; 95% CI 1.32-14.09) and falls (OR 3.57; 95% CI 1.91-6.86) were the independent predictors of vertebral fractures in RA patients. The subgroup with vertebral fractures had higher disease activity (DAS28: 3.15 vs. 2.78, p = 0.038) and disability (HAQ: 0.96 vs. 0.63, p = 0.049), as compared with those without vertebral fractures. CONCLUSION: The risk of vertebral fracture in RA is still high in recent years, when compared with the general population. The key determinants of fracture risk are age, glucocorticoids and falls. Patients with vertebral fractures have a more severe RA.

Osteoporotic patients treated with bisphosphonates do not show the increased mortality observed in those untreated.

INTRODUCTION: Osteoporosis has been said to be associated with increased mortality. On the other hand, it is debated whether treatment with bisphosphonates may reduce mortality in osteoporotic patients. To contribute to the clarification of these issues, we have studied in a prospective cohort the mortality in people without osteoporosis and in patients with osteoporosis, untreated or treated with bisphosphonates MATERIAL AND METHODS: At their inclusion in the cohort, four groups of participants were identified: (a) people without osteoporosis (group 1); (b) osteoporotic patients treated with bisphosphonates (group 2); (c) osteoporotic patients who refused to be treated (group 3); and (d) patients who met osteoporosis diagnostic criteria but were not treated because their risk of fracture was considered to be low (group 4). To compare all four groups, unadjusted Kaplan-Meier estimates of survivorship were obtained and they were compared using log-rank test. Hazard ratios were then estimated via Cox regression adjusting for the main confounders. A comparison among the osteoporotic groups was made by means of a Cox regression analysis performed using only these three groups, adjusting for propensity scores. RESULTS: Two thousand six hundred and sixty-five people were included. In the unadjusted analysis, mortality in group 3 was higher than in the other groups (p < 0.001). Taking group 1 as a reference, Cox regression analysis showed the following mortality HRs for groups 2, 3, and 4 after adjusting for confounding factors: 0.82 (0.41-1.63), 1.37 (0.90-2.10), and 0.69 (0.46-1.02). In the analysis of the osteoporotic groups with the PS generated for them, and taking group 2 as a reference, the HRs were as follows: group 3, 2.38 (1.34-4.22); group 4, 1.45 (0.61-3.43). CONCLUSION: Mortality in osteoporotic patients who refused treatment is higher than in osteoporotic patients treated with bisphosphonates. In unadjusted analysis, it was also higher than in non-osteoporotic people; however, this difference disappeared after adjustment for confounding factors.

Profile of patients who visit medical internists for an osteoporosis assessment: The OSTEOMED registry. / Perfil de los pacientes que acuden al médico internista para valoración de osteoporosis: registro OSTEOMED.

BACKGROUND AND OBJECTIVES: Osteoporosis is considered a generalised skeletal disorder in which there is impaired bone resistance, which predisposes the individual to a greater risk of fracture. The aim of this cross-sectional study was to collect and present data on the main clinical characteristics of patients who consult medical internists in Spain. Understanding these characteristics can help in implementing action plans to improve these patients' care more effectively and efficiently. MATERIAL AND METHODS: Through an analysis of the Osteoporosis in Internal Medicine (OSTEOMED) registry, this study presents the main clinical characteristics of patients with osteoporosis who attended internal medicine consultations in 23 Spanish hospital centres between 2012 and 2017. We analysed the reasons for the consultations, the densitometric values, the presence of comorbidities, the prescribed treatment and other lifestyle-related factors. RESULTS: In total, 2024 patients with osteoporosis were assessed (89.87% women, 10.13% men). The patients' mean age was 64.1±12.1 years (women, 64.7±11.5 years; men, 61.2±14.2 years). There was no significant difference between the sexes in their history of recent falls (9.1% and 6.7%); however, there were significant differences in the daily intake of calcium from milk products (553.8±332.6mg for women vs. 450.2±303.3mg for men; P<.001) and in the secondary causes of osteoporosis (13% of men vs. 6.5% of women; P<.001). In the sample, there were 404 fractures (20%), with a notable number of confirmed vertebral fractures (17.2%, 35.6% in men vs. 15.2% in women; P<.001). A large portion of the patients did not undergo the indicated treatment and presented low levels of physical activity and sun exposure. A significant percentage of the patients presented associated comorbidities, the most common of which were hypertension (32%) and dyslipidaemia (28%). CONCLUSIONS: These results define the profile of patients with osteoporosis who attend internal medicine consultations in Spain. The results also show the multisystemic character of this condition, which, along with its high prevalence, determine that the specific internal medicine consultations dedicated to managing the condition are the appropriate place for caring for these patients.

Serum 25-hydroxyvitamin D, parathyroid hormone, calcium intake, and bone mineral density in Spanish adults.

UNLABELLED: Vitamin D insufficiency is very common among Spanish community-dwelling adult subjects. A threshold of serum 25(OH)D around 30 ng/ml would be necessary for the prevention of secondary hyperparathyroidism and hip bone loss in our population, regardless of the dairy calcium ingestion. INTRODUCTION: This study aims to assess 25-hydroxyvitamin D-25(OH)D-status in Spanish adult subjects and to analyze its relationships with serum PTH levels, calcium intake, and bone mineral density (BMD). METHODS: A total of 1811 individuals (1154 postmenopausal women and 657 men) aged 44-93 years participated in the study. Serum 25(OH)D, intact parathyroid hormone (PTH), aminoterminal propeptide of type I collagen (P1NP), and C-terminal telopeptide of type I collagen (ß-CTX) levels were measured by electrochemiluminescence. BMD was determined by dual x-ray absorptiometry (DXA) at lumbar spine, femoral neck, and total hip. RESULTS: Serum 25(OH)D levels were below 10, 20, and 30 ng/ml in 5, 40, and 83 % of participants, respectively. There was a significant seasonal difference in mean serum 25(OH)D, with higher levels in summer-autumn. In multivariate analysis, 25(OH)D levels were negatively correlated with age, serum PTH and creatinine, body mass index, smoking, alcohol intake, and a number of chronic diseases, but positively with dairy calcium intake. The magnitude of the difference in serum PTH according to 25(OH)D quartiles was not influenced by calcium intake. A threshold of serum 25(OH)D around 30 ng/ml was observed for serum PTH and hip BMD. CONCLUSIONS: Vitamin D insufficiency is very common among Spanish community-dwelling adult subjects. A threshold of serum 25(OH)D around 30 ng/ml would be necessary for the prevention of secondary hyperparathyroidism and hip bone loss in our population, regardless of the dairy calcium ingestion. Programs to improve vitamin D status may be required in our country.

Serum uric acid is associated with quantitative ultrasound parameters in men: data from the Camargo cohort.

UNLABELLED: This study analyzes the association between serum uric acid levels and heel quantitative ultrasound (QUS) parameters in men aged 50 or more from the Camargo cohort. We found that higher serum uric acid levels are positively associated with all QUS measurements, suggesting a better bone quality in men with elevated serum uric acid values. INTRODUCTION: Higher serum uric acid concentrations have been associated with higher bone mineral density and lower prevalence of fractures. However, there are no studies that have assessed the bone quality properties in Caucasians. Therefore, we have analyzed the association between quantitative ultrasound (QUS) and serum uric acid levels in adult men from a population-based cohort. METHODS: A total of 868 men older than 50 were recruited from a larger cohort (Camargo Cohort) after excluding those with any known condition or drug treatment with a possible influence on bone metabolism, or those with a previous diagnosis of gout or taking hipouricemic agents. Bone turnover markers (PINP and CTX), 25OH-vitamin D and PTH levels were measured by electrochemiluminiscence. BMD was determined by DXA, and heel QUS with a gel-coupled device. RESULTS: Lumbar, femoral neck and total hip BMD was significantly higher in men with higher serum uric acid levels. QUS parameters were also significantly higher in men with high uric acid levels than those with lower values, and increased continuously across quartiles after adjustment for confounding variables. In multiple regression analysis, serum uric acid was significantly associated with all QUS parameters. Finally, men with serum acid levels above median showed higher values in all the QUS parameters than men with lower values. CONCLUSIONS: Higher serum uric acid levels in men older than 50 years are positively associated with QUS parameters. These data might suggest a better bone quality in men with elevated serum uric acid values.

Bone mass and vitamin D levels in women with a diagnosis of fibromyalgia.

UNLABELLED: No differences in either bone mineral density or serum 25OHD levels have been found between 205 women with fibromyalgia (both pre- and postmenopausal) and their controls. However, a lack of the expected 25OHD summer rise was observed in patients. INTRODUCTION: Contradictory data have been published regarding a possible association between fibromyalgia and osteoporosis or hypovitaminosis D. Most studies, however, have been performed in small size samples and have excluded postmenopausal women. We decided to study this association in a larger sample of fibromyalgia patients including both pre- and postmenopausal women. METHODS: Two hundred five patients were recruited from a clinic specializing in fibromyalgia and 205 healthy controls were enrolled from the census of a Primary Care Center. Controls were matched with patients by age and the time of the year they were included in the study. Bone mineral density (BMD) was measured by DXA. Serum 25OHD, iPTH, P1NP, and CTX were also determined. RESULTS: BMD was similar in both groups (lumbar spine, 0.971 ± 0.146 g/cm(2) in patients and 0.970 ± 0.132 g/cm(2) in controls; femoral neck, 0.780 ± 0.122 g/cm(2) and 0.785 ± 0.117 g/cm(2), respectively). 25OHD levels were also similar: 23.0 ± 9.5 ng/ml and 24.1 ± 9.6 ng/ml. However, while controls showed the usual summer rise in 25OHD, fibromyalgia patients did not. PTH did not show seasonal changes, but on average was higher in patients (51 pg/ml vs. 48 pg/ml; p = 0.034). P1NP or CTX were similar in both groups. CONCLUSIONS: No differences in BMD were found between patients and controls. As for 25OHD, a lack of its expected summer rise was observed. It is doubtful whether this has any homeostatic consequence. We consider that the association reported in other studies is merely circumstantial, and not due to the intrinsic characteristics of these disorders.

Missense polymorphisms of the WNT16 gene are associated with bone mass, hip geometry and fractures.

UNLABELLED: Two missense polymorphisms of WNT16 were associated with hip bone mineral density (BMD), the buckling ratio of the femoral neck, calcaneal ultrasound and hip fractures in individuals under 80 years of age. These results confirm the association of the WNT16 gene with bone mass and osteoporotic fractures. INTRODUCTION: Osteoporosis has a strong genetic component. Wnt ligands stimulate the differentiation of osteoblast precursors and play a major role in skeletal homeostasis. Therefore, the aim of this study was to explore the association of allelic variants of the WNT16 gene with BMD, other structural parameters of bone and osteoporotic hip fractures. METHODS: Six single nucleotide polymorphisms were analysed in 1,083 Caucasian individuals over 49 years of age. RESULTS: Two missense polymorphisms (rs2908004 and rs2707466) were associated with femoral neck BMD, with average differences across genotypes of 35 mg/cm(2) (p = 0.00037 and 0.0015, respectively). Likewise, the polymorphisms were associated with calcaneal quantitative ultrasound parameters (p = 0.00004 and 0.0014, respectively) and the buckling ratio, an index of cortical instability of the femoral neck (p = 0.0007 and 0.0029, respectively). Although there were no significant differences in the genotype frequency distributions between 294 patients with hip fractures and 670 controls, among the subgroup under 80 years of age, TT genotypes were underrepresented in patients with fractures (odds ratio 0.50; CI 0.27-0.94). CONCLUSION: Common missense polymorphisms of the WNT16 gene are associated with BMD at the hip, calcaneal ultrasound and the buckling ratio of the femoral neck, as well as with hip fractures in individuals under 80 years of age. Overall, these results confirm the association of the WNT16 locus with BMD identified in genome-wide association studies and support its role in determining the risk of osteoporotic fractures.

Common allelic variants of the farnesyl diphosphate synthase gene influence the response of osteoporotic women to bisphosphonates.

Farnesyl diphosphate synthase (FDPS) is necessary for osteoclast survival and activity and is considered as a major molecular target of aminobisphosphonates. Our objective was to analyze the influence of FDPS polymorphisms on bone mineral density (BMD) and the response to antiresortive drugs. Three single-nucleotide polymorphisms of FDPS were analyzed in 1186 postmenopausal women. There was only a marginally significant association of baseline hip BMD with rs11264359 alleles (P=0.043). However, among 191 women receiving antiresortive therapy, there was a very significant association between rs2297480 or rs11264359 alleles and the BMD changes after aminobisphosphonate therapy for an average period of 2.5 years (P=0.001). The genotype explained 7.2% of the variance in the BMD response. On the other hand, there was no association between the BMD changes after raloxifene therapy and any of the polymorphisms studied. These results suggest that common polymorphisms of the FDPS gene influence the response to aminobisphosphonates.

Future care for long-term cancer survivors: towards a new model.

PURPOSE: The increase in the prevalence "long-term cancer survivor" (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care. METHODS: This qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report. RESULTS: 232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions. CONCLUSION: The role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologies.

Association of ACACB polymorphisms with obesity and diabetes.

Acetyl-CoA carboxylase beta, encoded by the ACAB gene, plays an important role in the oxidation of fatty acids. The aim of this study was to check the hypothesis that allelic variants of ACACB influence the risk of obesity and type 2 diabetes mellitus. Twenty five tagging single nucleotide polymorphisms (SNPs) capturing common variants of the ACACB gene were selected and analyzed in two cohorts including 1695 postmenopausal women of the general population and in 161 women with severe obesity (BMI>35). In vitro binding of transcription factors was explored by electrophoretic mobility shift assays (EMSA). T alleles at the rs2268388 locus were overrepresented in women with severe obesity (18% vs. 10% in controls; OR 1.74 [95% confidence interval 1.30-2.47]), which was statistically significant after multiple-test adjustment (p=0.0004). Likewise, T alleles at the rs2268388 locus and C alleles at the rs2239607 locus were associated with diabetes, in the discovery as well as in the replication cohorts, even after women with severe obesity were excluded (OR 3.6 and 2.8, for TT and CC homozygotes, respectively). Allelic differences in the binding affinity for nuclear proteins were revealed in vitro by EMSA and competition experiments were consistent with the binding of glucorticoid receptor and serum response factor. In conclusion, common polymorphisms of ACACB gene are associated with obesity and, independently, with type 2 diabetes in postmenopausal women, suggesting that the activity of acetyl-CoA carboxylase beta plays an important role in these disorders related to energy metabolism.

Profile of patients who consult with internists for an osteoporosis assessment: The OSTEOMED registry.

BACKGROUND AND OBJECTIVES: Osteoporosis is considered a generalised skeletal disorder in which there is impaired bone resistance, which predisposes the individual to a greater risk of fracture. The aim of this cross-sectional study was to collect and present data on the main clinical characteristics of patients who consult medical internists in Spain. Understanding these characteristics can help in implementing action plans to improve these patients' care more effectively and efficiently. MATERIAL AND METHODS: Through an analysis of the Osteoporosis in Internal Medicine (OSTEOMED) registry, this study presents the main clinical characteristics of patients with osteoporosis who attended internal medicine consultations in 23 Spanish hospital centres between 2012 and 2017. We analysed the reasons for the consultations, the densitometric values, the presence of comorbidities, the prescribed treatment and other lifestyle-related factors. RESULTS: In total, 2024 patients with osteoporosis were assessed (89.87% women, 10.13% men). The patients' mean age was 64.1±12.1 years (women, 64.7±11.5 years; men, 61.2±14.2 years). There was no significant difference between the sexes in their history of recent falls (9.1% and 6.7%); however, there were significant differences in the daily intake of calcium from milk products (553.8±332.6mg for women vs. 450.2±303.3mg for men; p<.001) and in the secondary causes of osteoporosis (13% of men vs. 6.5% of women; p<.001). In the sample, there were 404 fractures (20%), with a notable number of confirmed vertebral fractures (17.2%, 35.6% in men vs. 15.2% in women; p<.001). A large portion of the patients did not undergo the indicated treatment and presented low levels of physical activity and sun exposure. A significant percentage of the patients presented associated comorbidities, the most common of which were hypertension (32%) and dyslipidaemia (28%). CONCLUSIONS: These results define the profile of patients with osteoporosis who attend internal medicine consultations in Spain. The results also show the multisystemic character of this condition, which, along with its high prevalence, determine that the specific internal medicine consultations dedicated to managing the condition are the appropriate place for caring for these patients.

Radium-223 in the therapeutic sequence of metastatic castration-resistant prostate cancer. / Radio-223 en la secuencia terapéutica del cáncer de próstata resistente a la castración metastásico.

CONTEXT: Radium-223 is an □ -particle transmitter with specific action on bone metastases. The Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study showed that radium-223 extended overall survival and delayed the onset of bone events in patients with symptomatic castration-resistant prostate cancer with bone metastases (mCRPC) and without visceral metastases, with a good safety profile. OBJECTIVE: To review the new scientific evidence on radium-223 based on prespecified and post-hoc analyses of the ALSYMPCA study and on early-access programs after the publication of the ALSYMPCA study, thereby providing new data on the management of patients with mCRPC. ACQUISITION OF EVIDENCE: We searched for evidence on PubMed and in the abstracts of international urology and oncology congresses, as well as ongoing clinical trials (ClinicalTrials.gov). SYNTHESIS OF THE EVIDENCE: The results of the reviewed studies offer promising results that will broaden the therapeutic benefits of radium-223 to patients with mild symptoms and those with no symptoms. The results also provide preliminary evidence on the benefit of radium-223 treatment after the failure of docetaxel, enzalutamide or abiraterone or the combination of radium-223 with these agents or other therapeutic agents such as bone-targeted agents and immunotherapy. CONCLUSION: Radium-223 can be a treatment option for patients with mild symptoms and can provide a therapeutic benefit after failure of currently available treatments or in combination with these treatments. This evidence should be corroborated in clinical trials before being added to clinical practice.

Review of the evidence on handling drugs and hazardous products in Urology Departments. Consensus document between the Spanish Urological Association and the Spanish Society of Hospital Pharmacy. / Revisión de la evidencia sobre el manejo de medicamentos y productos peligrosos en los servicios de Urología. Documento de consenso entre la Asociación Española de Urología y la Sociedad Española de Farmacia Hospitalaria.

BACKGROUND: The intravesical administration of hazardous drug products is a standard practice in the urology setting, which potentially exposing medical personnel to these drug products. It was deemed necessary to have a consensus document among the scientific societies involved (the Spanish Urological Association and the Spanish Society of Hospital Pharmacy) that collects the best available evidence on the safest handling possible of dangerous drug products in the setting of urology departments. METHODS: We reviewed the legislation and recommendations on the handling of dangerous drug products, both at the national and international level. RESULTS: There is national legislation and regulations for protecting workers who handle dangerous drugs and products, as well as recommendations for handling to protect both the product and workers. DISCUSSION: Following the strategic lines of the European Parliament for 2014-2020 in the chapter on occupational safety and health, the Spanish Urological Association and the Spanish Society of Hospital Pharmacy proposed a series of actions that decrease the risks of exposure for practitioners and caregivers involved in the handling of these products. CONCLUSIONS: After this review, 19 recommendations were established for handling dangerous drug products, which can be summarised as the need to train all individuals involved (from management teams to patients and caregivers), adopt systems that prevent contaminating leaks, implement exposure surveillance programmes and optimise available resources.

Safety and efficacy of various strains of bacille Calmette-Guérin in the treatment of bladder tumours in standard clinical practice. / Eficacia y seguridad de distintas cepas de BCG en el tratamiento del tumor vesical en práctica clínica habitual.

BACKGROUND: The natural progression of bladder tumours (nonmuscle-invasive bladder cancer [NMIBC]) is recurrence with a high rate of progression. Bacille Calmette-Guérin (BCG) has been shown effective in reducing these rates, but there are few comparative studies between strains. MATERIAL AND METHODS: An observational, prospective and multicentre registry studied 433 patients with a 12-month follow-up visit from 961 registered patients, assessing disease-free survival (DFS), progression-free survival (PFS) cancer-specific survival (CSS) and adverse effects. We studied the Tice, Russian, Tokyo, Connaught and RIVM strains. RESULTS: The sociodemographic data, NMIBC history, comorbidities, size, number, stage, grade, associated carcinoma in situ and transurethral resection were well balanced. DFS: There were 85 relapses (19.6%). The median DFS time was 20months. When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.93). LPS: There were 33 cases of progression (7.62%). When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.69). CSS: Seven patients died (1.68%). When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.93). In terms of safety, 33.3% of the patients presented some type of adverse effect, mostly lower urinary symptoms (no urinary tract infections) <48h, >48h and haematuria. According to the Common Toxicity Criteria of the European Organisation for Research and Treatment of Cancer, 92.7% of the patients were grade1. There were no statistically significant differences between the strains. CONCLUSIONS: In this intermediate analysis, the risk of recurrence, progression, specific death and safety were independent of the BCG strain employed.

Clinical practice guidelines for posmenopausal, glucocorticoid-induced and male osteoporosis. Spanish Society for Research on Bone and Mineral Metabolism (3rd updated version 2014).

These guidelines update issues covered in previous versions and introduce new ones that have arisen in recent years. The former refer mainly to the therapeutic developments that have been made during this time (zoledronate, denosumab, bazedoxifene), which have led to a change in the drug selection algorithm. The latter deal with therapeutic management, the description of new adverse effects (which have led to changes in therapeutic behaviour patterns, as is the case with atypical fracture of the femur), treatment duration (with consideration for the so-called "therapeutic holidays"), the so-called sequential treatment and changes in treatment imposed by certain circumstances. A new algorithm has been introduced for sequential treatment. Attention has also been paid to vertebroplasty and kyphoplasty.

Seasonal deficiency of vitamin D in children: a potential target for osteoporosis-preventing strategies?

Peak bone mass attained after skeletal growth is a major determinant of the risk of developing osteoporosis later in life, hence the importance of nutritional factors that contribute to bone mass gain during infancy and adolescence. An adequate supply of vitamin D is essential for normal bone homeostasis. This study was undertaken to determine what the levels are of 25-hydroxyvitamin D (25(OH)D) that may be considered desirable in children and to assess if normal children maintain these levels throughout the year. Vitamin D metabolites and parathyroid hormone (PTH) serum levels were measured in 21 children in March and October, prior to and after the administration of a daily supplement of 25(OH)D (40 microg for 7 consecutive days). There were inverse correlations between basal 25(OH)D levels and supplementation-induced changes in serum 1,25(OH)2D (r = 0.57, p < 0.05) and PTH (r = 0.41, p < 0.05). When basal levels of 25(OH)D were below 20 ng/ml, the supplement induced an increase in serum 1,25(OH)2D; with basal 25(OH)D under 10-12 ng/ml, the supplement also decreased serum PTH. The lowest serum level of 25(OH)D in 43 normal children studied in summer was 13 ng/ml. Those results suggested that the lowest limit for desirable levels of 25(OH)D in children was somewhere between 12 and 20 ng/ml. However, 31% of 51 normal children studied in winter had levels below 12 ng/ml, and 80% had levels lower than 20 ng/ml. Those children are likely to have suboptimal bioavailability of vitamin D, which might hamper their achievement of an adequate peak bone mass. Since cutaneous synthesis of vitamin D is rather limited in winter, oral vitamin D supplementation should be considered.

Expression and functional role of nitric oxide synthase in osteoblast-like cells.

Nitric oxide synthases (NOS) are enzymes that produce nitric oxide (NO) from L-arginine in a reaction yielding citrulline as a coproduct. Nitric oxide modulates the activity of a wide variety of cells, but little is known about its effects on bone cells. In the present study we report that the NOS inhibitor NG-monomethyl-L-arginine (NMMA) induced a dose-dependent inhibitory effect on the proliferation of the osteoblast-like cell lines MG63 and ROS 17/2.8. The inhibitory effect was prevented by increasing L-arginine concentrations in the medium and by the NO donor sodium nitroprusside. Likewise, NMMA inhibited interleukin-6 secretion, independently of its effect on cell number. NOS expression by MG63 cells was confirmed by measuring their ability to metabolize radiolabeled L-arginine to citrulline. NOS bioactivity was detected in unstimulated cells, but was markedly increased by stimulating the cells with cytokines, lipopolysaccharide, or 1,25-dihydroxyvitamin D3. NOS activity was partially dependent upon the presence of calcium in the medium. Furthermore, constitutive-type NOS (c-NOS) and inducible-type NOS (i-NOS) mRNA expression was detected in ROS 17/2.8 cells after reverse transcription and polymerase chain reaction amplification. In conclusion, osteoblast-like cells express c-NOS and i-NOS, and NOS activity seems to play an important role in the regulation of cell proliferation and function.

Effect of calcitriol on the secretion of prostaglandin E2, interleukin 1, and tumor necrosis factor alpha by human monocytes.

Cells of the monocyte/macrophage lineage express specific receptors for calcitriol (1,25-dihydroxyvitamin D3) and secrete prostaglandins and several cytokines with potent effects on bone metabolism. The aim of this study was to determine the effect of calcitriol on the secretion of prostaglandin E2 (PGE2), interleukin-1 (IL-1), and tumor necrosis factor (TNF alpha). Monocyte-enriched peripheral blood mononuclear cells (PBMC) from healthy subjects were cultured in the presence or absence of calcitriol (10(-11)-10(-7) M) and several stimulating agents. After 24 h, PGE2, IL-1, and TNF alpha were measured in the culture supernatants or lysates with specific immunoassays. Calcitriol induced a biphasic effect on PGE2 production by unstimulated cells and increased PGE2 synthesis by cells stimulated with either endotoxin or tau-interferon (IFN-tau). On the other hand, calcitriol inhibited the production of TNF alpha by monocytes stimulated with either IFN-tau or phorbol esters. This effect was not prevented by the addition of indomethacin, IL-1, or IL-2. Under the conditions used, we observed no effect of calcitriol on IL-1 alpha or IL-1 beta production. These results indicate that calcitriol induces in vitro marked changes in the secretion of monocyte products with known activity on bone cells. Further studies are needed to elucidate whether some effects of calcitriol on bone metabolism are mediated by the interaction of the sterol with cells of the immune system.

Sex and age distribution of 1,25(OH)2D3 receptors in peripheral blood mononuclear cells from normal human subjects.

Specific receptors for 1,25 Dihydroxyvitamin D3 have been described in human peripheral blood mononuclear cells (PBMC). We have tried to find out whether these receptors could show any difference in sex or age distribution. Twenty two healthy men aged 21-66 yr (mean +/- SD 41.0 +/- 13.6) and nineteen healthy women aged 22-60 yr (38.9 +/- 13.9) have been studied. The mean dissociation constant (Kd) was similar in both sexes (1.35 +/- 0.70 x 10(-10) M in males, 1.13 +/- 0.66 x 10(-10) M in females), but the concentration of binding sites (Nmax) was significantly lower in females (2.32 +/- 0.92 fmol/10(7) PBMC vs 4.43 +/- 1.38 fmol/10(7) PBMC in males; p = 0.0001). Neither Kd nor Nmax were significantly correlated with age. No difference was found between pre and postmenopausal women. Further studies are needed to elucidate if this sex difference in PBMC receptors for 1.25 Dihydroxyvitamin D3 is of any pathophysiological relevance.

Vitamin D metabolism and serum binding proteins in anorexia nervosa.

Serum vitamin D metabolites and other parameters of mineral metabolism were measured in 12 patients with anorexia nervosa. Serum concentrations of calcium, phosphate, albumin, alkaline phosphatase, parathyroid hormone, calcitonin, osteocalcin, and 24-hours calcium excretion were normal. Serum 25-hydroxyvitamin D (25OHD) concentration was similar in patients and normal subjects, whereas 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were significantly reduced in patients (62 +/- 17 vs 82 +/- 17 pmol/l); p less than 0.05). The concentration of vitamin D-binding protein (DBP) in patients was normal, but serum binding capacity (Nmax) was diminished in anorectic patients (2.05 +/- 0.50 vs 2.53 +/- 0.51 mumol/l; p less than 0.05). The diminished serum binding capacity, in spite of normal concentrations of albumin and DBP, reflects the presence of qualitative rather than quantitative defects in serum transport proteins. Since the reduction in 1,25(OH)2D and serum binding capacity was quantitatively similar, it is likely that free 1,25(OH)2D levels would be normal.