Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats.

Osteocyte apoptosis is the first reaction to estrogen depletion, thereby stimulating osteoclastic bone resorption resulting in bone loss. We investigated the effects of two different risedronate (RIS) doses (high and low) on osteocyte apoptosis, osteoclast activity and bone loss in ovariectomized rats. Forty rats with ovariectomy (OVX) and sham ovariectomy (SHAM) were divided into 4 groups: 1) SHAM rats treated with saline (SHAM); 2) OVX rats treated with saline (OVX); 3) OVX rats treated with low-dose RIS (OVX-LR, 0.08 µg/kg/day); 4) OVX rats treated with high-dose RIS (OVX-HR, 0.8 µg/kg/day). All animals were sacrificed 90 days after surgery for the examinations of osteocyte apoptosis by caspase-3 staining, osteoclast activity by TRAP staining and bone volume by micro-CT scanning in lumbar vertebral cancellous bone. Both low and high dose RIS significantly reduced caspase-3 positive osteocytes, empty lacunae and TRAP positive osteoclasts in OVX rats. Although the difference in caspase-3 positive osteocytes was not significant between the OVX-LR and OVX-HR groups, numerically these cells were significantly more prevalent in OVX-HR (not OVX-LR) group than in SHAM group. TRAP positive osteoclasts were significantly higher in OVX-LR group than in SHAM or OVX-HR group. There was no significant difference in bone volume among the OVX-LR, OVX-HR and SHAM groups, but lower in OVX group alone. However, significant increase in trabecular thickness only occurred in OVX-LR group. We conclude that both low and high dose RIS significantly inhibit osteocyte apoptosis and osteoclast activity in OVX rats, but the low-dose RIS has weaker effect on osteoclast activity. However, low-dose RIS preserves cancellous bone mass and microarchitecture as well as high-dose RIS after estrogen depletion.

Measles virus nucleocapsid protein modulates the Signal Regulatory Protein-ß1 (SIRPß1) to enhance osteoclast differentiation in Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic localized bone disorder in an elderly population. Environmental factors such as paramyxovirus are implicated in PDB and measles virus nucleocapsid protein (MVNP) has been shown to induce pagetic osteoclasts (OCLs). However, the molecular mechanisms underlying MVNP stimulation of OCL differentiation in the PDB are unclear. We therefore determined the MVNP regulated gene expression profiling during OCL differentiation. Agilent microarray analysis of gene expression identified high levels of SIRPß1 (353-fold) expression in MVNP transduced human bone marrow mononuclear cells stimulated with RANKL. Real-time PCR analysis further confirmed that MVNP alone upregulates SIRPß1 mRNA expression in these cells. Also, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPß1 mRNA expression compared to normal subjects. We further show that MVNP increases SIRPß1 interaction with DAP12 adaptor protein in the presence and absence of RANKL stimulation. shRNA knockdown of SIRPß1 expression in normal human bone marrow monocytes decreased the levels of MVNP enhanced p-Syk and c-Fos expression. In addition, SIRPß1 knockdown significantly decreased MVNP stimulated dendritic cell-specific transmembrane protein (DC-STAMP) and connective tissue growth factor (CTGF) mRNA expression during OCL differentiation. Furthermore, we demonstrated the contribution of SIRPß1 in MVNP induced OCL formation and bone resorption. Thus, our results suggest that MVNP modulation of SIRPß1 provides new insights into the molecular mechanisms which control high bone turnover in PDB.

Atrial Fibrillation and Its Association with Endocrine Disorders.

Atrial Fibrillation (AF) is the most common arrhythmia affecting millions of people and the number is rising, it is therefore important to understand the risk factors causing AF. Risk factors such as hypertension, heart failure, coronary heart disease, and type 2 diabetes mellitus increase the risk of AF, however, the underlying etiology in a majority of patients remains elusive. Many of the endocrine disorders have been implicated in causing AF and an in depth knowledge of these disorders helps in early diagnosis and treatment. Due to the high prevalence of AF and its complications, it is therefore important to recognize these risk factors and have a low threshold for suspicion while other common causes are being excluded. In this review we summarize the issues related to AF and endocrine disorders. A better understanding of the relationship may lead to the development of the primary preventive strategies, fostering a more preventive and predictive approach that may result in decreased incidence of AF and its associated complications and provide personalized treatment options. For this review we carried out a search of Pubmed, the words or combination of words we used for our search include Endocrine disorders, metabolic disorders, Dyslipidemia, Diabetes mellitus type 2, Vitamin D, Hyperthyroidism, Primary aldosteronism, Pheochromocytoma, Obesity, Hypercalcemia, Hypogonadism, Medications, and Atrial fibrillation. We also retrieved articles from the references of retrieved articles.

The effect of endogenous parathyroid hormone in iliac bone structure and turnover in healthy postmenopausal women.

Little is known about the effect of endogenous parathyroid hormone (PTH) on the skeleton in postmenopausal women without hyperparathyroidism. In this study, the effects of PTH on bone were investigated in iliac crest biopsies obtained from 37 healthy white postmenopausal women aged 50-73 years. The results showed that neither cancellous nor cortical bone structure changed with serum PTH levels. In cancellous bone, bone formation (wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and mineral apposition rate) and turnover (bone formation rate at the surface, volume levels, and activation frequency) variables increased with increasing serum PTH levels (all p < 0.05) in univariate analysis. Multiple linear regressions, adjusted for serum 25-OHD, calcium, alkaline phosphatase, age, and BMI, showed that serum PTH level was independently associated with wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and bone formation rate (all p < 0.05). In cortical bone, no histomorphometric variable was correlated with PTH levels. On the endosteal surface, some of the bone formation (osteoid surface, osteoblast surface, mineralizing surface) and turnover (bone formation rate at the bone surface levels and activation frequency) variables were positively correlated with PTH levels (all p < 0.05). None of these variables could be independently predicted by PTH status. We conclude that in healthy postmenopausal women endogenous PTH has a positive effect on bone formation on the cancellous surface. The effects of PTH on the endosteal surface are probably confounded by other factors.

A retrospective analysis of vertebral body fractures following epidural steroid injections.

BACKGROUND: Lumbar epidural steroid injections (LESIs) are frequently prescribed for the treatment of radiculopathy or neurogenic claudication arising from compression of spinal nerves. However, there is evidence suggesting that corticosteroids adversely affect bone strength by diminishing new bone formation and increasing bone resorption. Our study sought to assess whether LESIs increase the risk of subsequent vertebral body fracture. METHODS: A retrospective cohort study was conducted to compare patients receiving LESIs with a control group. A total of 50,345 patients with ICD-9 (International Classification of Diseases, Ninth Revision) diagnosis codes involving the spine were identified by searching a corporate database, and 3415 of these were found to have received at least one LESI. We randomly selected a study population of 3000 patients from the injected population, and we selected a matched cohort of 3000 patients from the non-injected group with use of propensity matching. The incidence of vertebral body fractures in each group was assessed with use of survival analysis. RESULTS: There was no significant difference between the injected and non-injected groups with respect to age, predicted propensity score, sex, race, hyperthyroidism, or steroid use. In the survival analysis, an increasing number of injections was associated with an increasing likelihood of fractures. Each successive injection increased the risk of fracture by a factor of 1.21 (95% confidence interval, 1.08 to 1.30) after adjustment for covariates (p = 0.003). CONCLUSIONS: The findings suggest that LESIs, like other forms of exogenous steroid administration, may lead to increased bone fragility. The added exposure to glucocorticoids resulting from LESI use may carry a greater risk than previously thought, suggesting that use of LESIs should be approached cautiously in patients at risk for osteoporotic fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project.

BACKGROUND: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. METHODS: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). RESULTS: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. CONCLUSIONS: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

CXCL5 stimulation of RANK ligand expression in Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over 55 years of age. PDB is marked by highly localized areas of bone turnover with increased osteoclast activity. Evidence suggests a functional role for measles virus nucleocapsid protein (MVNP) in the pathogenesis of PDB. In the present study, we identified elevated levels (≈ 180-fold) of CXCL5 mRNA expression in bone marrow cells from patients with PDB compared with that in normal subjects. In addition, CXCL5 levels are increased (five-fold) in serum samples from patients with PDB. Furthermore, MVNP transduction in human bone marrow monocytes significantly increased CXCL5 mRNA expression. Real-time PCR analysis showed that CXCL5 stimulation increased (6.8-fold) RANKL mRNA expression in normal human bone marrow-derived stromal (SAKA-T) cells. Moreover, CXCL5 increased (5.2-fold) CXCR1 receptor expression in these cells. We further showed that CXCL5 treatment elevated the expression levels of phospho-ERK1/2 and phospho-p38. CXCL5 also significantly increased phosphorylation of CREB (cAMP response element-binding) in bone marrow stromal/preosteoblast cells. Chromatin immuneprecipitation (ChIP) assay confirmed phospho-CREB binding to RANKL gene promoter region. Further, the suppression of p-CREB expression by the inhibitors of ERK1/2, p38 and PKA significantly decreased CXCL5 stimulation of hRANKL gene promoter activity. Thus, our results suggest that CREB is a downstream effector of CXCL5 signaling and that increased levels of CXCL5 contribute to enhanced levels of RANKL expression in PDB.

Effect of epidural steroid injection on bone mineral density and markers of bone turnover in postmenopausal women.

STUDY DESIGN: A prospective, observational study. OBJECTIVE: To evaluate the effect of epidural steroid injection (ESI) on bone mineral density (BMD) in postmenopausal women. SUMMARY OF BACKGROUND DATA: ESIs are used to treat the pain associated with radiculopathy. Although it is known that exogenous steroid use can disrupt skeletal architecture, it is less clear whether ESIs result in a decrease of BMD. METHODS: Twenty-eight postmenopausal women experiencing radiculopathy elected L4-L5 ESI treatment. We had a 50% dropout rate due to noncompliance with study requirements. BMD of the hip, femoral neck, and spine along with markers of bone turnover, bone specific-alkaline phosphatase and serum C-telopeptide of collagen I (CTX), was evaluated at baseline preinjection and 3 and 6 months postinjection. RESULTS: There was a significant decline in the hip BMD of 0.018 g/cm (0.028 ± 0.007, P = 0.002) at 6 months compared with baseline. We compared this decline with an age-matched control population that exhibited a decline of 0.003 g/cm(2), significantly less than our study population (P = 0.007). Bone-specific alkaline phosphatase increased significantly by 2.33 U/L from 3 to 6 months (P = 0.012), but the rise of CTX was not significant. CONCLUSION: A single ESI in postmenopausal women adversely affects BMD of the hip. This is in conjunction with a rise in bone remodeling activity, as evidenced by an increase in bone-specific alkaline phosphatase and CTX. In addition, when compared with an age-matched control population, our study population exhibited a greater decline in BMD. Our findings show that epidural administration of corticosteroids has a deleterious effect on bone, which should be considered when contemplating treatment options for radiculopathy. The resulting decrease in BMD, while slight, suggests that ESIs should be used with caution in those at a risk for fracture.

Vitamin D nutritional status and antenatal depressive symptoms in African American women.

BACKGROUND: Vitamin D deficiency is associated with depression; however, no studies have examined the relationship of vitamin D and antenatal depression. Antenatal depression increases the risk of adverse birth outcomes and poorer postpartum maternal and infant health. African American women are at increased risk for vitamin D deficiency and antenatal depression. Thus, we examined if early pregnancy vitamin D nutrition (VDN) was associated with antenatal depressive symptoms among African American women in the second trimester of pregnancy. METHODS: Women (n=178) were recruited from obstetrics clinics of a large health system. VDN was assessed by serum 25-hydroxyvitamin D (25-OHD). Depression symptoms were measured with the Center for Epidemiological Studies Depression (CES-D) scale; CES-D≥16 equates with criteria for clinical depression. Logistic regression was used to examine the association of log-transformed 25-OHD and elevated depression symptoms (CES-D≥16). RESULTS: Mean 25-OHD was 13.4±8.4 ng/mL; most women (82.6%, n=147) were vitamin D inadequate or deficient (25-OHD<20 ng/mL). Mean CES-D was 15.2±10.7, and 74 (41.6%) women had a CES-D≥16, suggestive of clinical depression. A significant inverse relationship was found between log (25-OHD) and CES-D≥16 (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.29-0.99, p=0.046). For every 1-unit increase in log (25-OHD) (corresponding to ~2.72 ng/mL increase in 25-OHD), the odds of CES-D≥16 decreased by 46%. CONCLUSIONS: African American women with lower VDN exhibit increased depressive symptoms. Research on vitamin D supplementation for reducing antenatal depressive symptoms is needed.

Skeletal histomorphometry in subjects on teriparatide or zoledronic acid therapy (SHOTZ) study: a randomized controlled trial.

CONTEXT: Recent studies on the mechanism of action (MOA) of bone-active drugs have rekindled interest in how to present and interpret dynamic histomorphometric parameters of bone remodeling. OBJECTIVE: We compared the effects of an established anabolic agent, teriparatide (TPTD), with those of a prototypical antiresorptive agent, zoledronic acid (ZOL). DESIGN: This was a 12-month, randomized, double-blind, active-comparator controlled, cross-sectional biopsy study. SETTING: The study was conducted at 12 U.S. and Canadian centers. SUBJECTS: Healthy postmenopausal women with osteoporosis participated in the study. INTERVENTIONS: Subjects received TPTD 20 µg once daily by sc injection (n = 34) or ZOL 5 mg by iv infusion at baseline (n = 35). MAIN OUTCOME MEASURES: The primary end point was mineralizing surface/bone surface (MS/BS), a dynamic measure of bone formation, at month 6. A standard panel of dynamic and static histomorphometric indices was also assessed. When specimens with missing labels were encountered, several methods were used to calculate mineral apposition rate (MAR). Serum markers of bone turnover were also measured. RESULTS: Among 58 subjects with evaluable biopsies (TPTD = 28; ZOL = 30), MS/BS was significantly higher in the TPTD group (median: 5.60 vs. 0.16%, P < 0.001). Other bone formation indices, including MAR, were also higher in the TPTD group (P < 0.05). TPTD significantly increased procollagen type 1 N-terminal propeptide (PINP) at months 1, 3, 6, and 12 and carboxyterminal cross-linking telopeptide of collagen type 1 (CTX) from months 3 to 12. ZOL significantly decreased PINP and CTX below baseline at all time points. CONCLUSIONS: TPTD and ZOL possess fundamentally different mechanisms of action with opposite effects on bone formation based on this analysis of both histomorphometric data and serum markers of bone formation and resorption. An important mechanistic difference was a substantially higher MS/BS in the TPTD group. Overall, these results define the dynamic histomorphometric characteristics of anabolic activity relative to antiresorptive activity after treatment with these two drugs.

Relating micromechanical properties and mineral densities in severely suppressed bone turnover patients, osteoporotic patients, and normal subjects.

Mineralization of bone, from the tissue level to whole bones, is associated with mechanical properties. The relationship between bone tissue mineralization and micromechanical properties may be affected by age, disease, and drug treatment. Patients with severely suppressed bone turnover (SSBT) suffered atypical fractures while on bisphosphonate treatment. The role of tissue level mineralization in predicting material level properties of SSBT bone may be different from that of other osteoporotic patients and of normal subjects. The aim of this study was to compare the relationships between mineralization and micromechanical properties of bone biopsies from patients with SSBT, bisphosphonate-naive osteoporotic patients with typical vertebral fracture, and normal young and age-matched subjects. We used nanoindentation and quantitative backscattered electron microscopy to characterize the elastic modulus, contact hardness, plastic deformation resistance, and tissue mineralization of the biopsies at site-matched locations within each biopsy. The linear mineralization-mechanical property relationships were different among the groups with respect to the intercepts for only cortical bone tissue but not the slopes for cortical and trabecular bone tissues. For a given mineral density, there was a trend of greater plastic deformation resistance in SSBT cortical bone compared to young normal bone. Similarly, there was a trend of greater plastic deformation resistance in osteoporotic trabecular bone compared to young normal bone for a given mineral density. The age-matched normal group had higher elastic modulus and a trend of higher contact hardness compared to the young normal group for a given mineral density. However, the mechanical property-mineralization relationships within an individual were weak, and only 21 of 53 biopsies that were analyzed had at least one significant association between mineralization and a mechanical property measurement for either cortical or trabecular bone tissues. The average properties of microstructural regions (deep and superficial remodeling packets in trabecular bone; osteonal and interstitial regions in cortical bone) were consistent with mineral accumulation with tissue age, with the exception of the SSBT group. SSBT trabecular bone deep packets had higher hardness and plastic deformation resistance than superficial packets, but mineralization levels and tissue modulus were not different between packet types. We conclude that relationships between mineral and mechanical properties were different between fracture and normal groups and between young and old normal groups, and that atypical fracture may be associated with changed microstructural material properties and tissue level mineralization compared to osteoporotic patients with vertebral fracture and normal subjects. We hypothesize that tissue level bone quality may be an important determinant in fracture risk, such that tissue mineral density may predict different material properties in different patient groups.

Osteomalacia as a result of vitamin D deficiency.

Osteomalacia is an end-stage bone disease of chronic and severe vitamin D or phosphate depletion of any cause. Its importance has increased because of the rising incidence of vitamin D deficiency. Yet, not all cases of osteomalacia are cured by vitamin D replacement, and furthermore, not all individuals with vitamin D deficiency develop osteomalacia. Although in the past osteomalacia was commonly caused by malabsorption, nutritional deficiency now is more common. In addition, recent literature suggests that nutritional vitamin D deficiency osteomalacia follows various bariatric surgeries for morbid obesity. Bone pain, tenderness, muscle weakness, and difficulty walking are all common clinical manifestations of osteomalacia. Diagnostic work-up involves biochemical assessment of vitamin D status and may also include a transiliac bone biopsy. Treatment is based on aggressive vitamin D repletion in most cases with follow-up biopsies if patients are started on antiresorptive or anabolic agents.

Mechanical property and tissue mineral density differences among severely suppressed bone turnover (SSBT) patients, osteoporotic patients, and normal subjects.

Pathogenesis of atypical fractures in patients on long term bisphosphonate therapy is poorly understood, and the type, the manner in which they occur and the fracture sites are quite different from the usual osteoporotic fractures. We hypothesized that the tissue-level mechanical properties and mean degree of mineralization of the iliac bone would differ among 1) patients with atypical fractures and severely suppressed bone turnover (SSBT) associated with long-term bisphosphonate therapy, 2) age-matched, treatment-naïve osteoporotic patients with vertebral fracture, 3) age-matched normals and 4) young normals. Large differences in tissue-level mechanical properties and/or mineralization among these groups could help explain the underlying mechanism(s) for the occurrence of typical osteoporotic and the atypical femoral shaft fractures. Elastic modulus, contact hardness, plastic deformation resistance, and tissue mineral densities of cortical and trabecular bone regions of 55 iliac bone biopsies--12 SSBT patients (SSBT; aged 49-77), 11 age-matched untreated osteoporotic patients with vertebral fracture (Osteoporotic), 12 age-matched subjects without bone fracture (Age-Matched Normal), and 20 younger subjects without bone fracture (Young Normal)--were measured using nanoindentation and quantitative backscattered electron microscopy. For cortical bone nanoindentation properties, only plastic deformation resistance was different among the groups (p<0.05), with greater resistance to plastic deformation in the SSBT group compared to all other groups. For trabecular bone, all nanoindentation properties and mineral density of the trabecular bone were different among the groups (p<0.05). The SSBT group had greater plastic deformation resistance and harder trabecular bone compared to the other three groups, stiffer bone compared to the Osteoporotic and Young Normal groups, and a trend of higher mineral density compared to the Age-Matched Normal and Osteoporotic groups. Lower heterogeneity of modulus and contact hardness for cortical bone of the SSBT and trabecular bone of the Osteoporotic fracture groups, respectively, compared to the non-fractured groups, may contribute to fracture susceptibility due to lowered ability to prevent crack propagation. We tentatively conclude that, in addition to extremely low bone formation rate, atypical fractures in SSBT and/or long-term bisphosphonate treatment may be associated with greater mean plastic deformation resistance properties and less heterogeneous elastic properties of the bone.

Mutant p62P392L stimulation of osteoclast differentiation in Paget's disease of bone.

Paget's disease of the bone (PDB) is an autosomal dominant trait with genetic heterogeneity, characterized by abnormal osteoclastogenesis. Sequestosome 1 (p62) is a scaffold protein that plays an important role in receptor activator of nuclear factor κB (RANK) signaling essential for osteoclast (OCL) differentiation. p62P392L mutation in the ubiquitin-associated (UBA) domain is widely associated with PDB; however, the mechanisms by which p62P392L stimulate OCL differentiation in PDB are not completely understood. Deubiquitinating enzyme cylindromatosis (CYLD) has been shown to negatively regulate RANK ligand-RANK signaling essential for OCL differentiation. Here, we report that CYLD binds with the p62 wild-type (p62WT), non-UBA mutant (p62A381V) but not with the UBA mutant (p62P392L) in OCL progenitor cells. Also, p62P392L induces expression of c-Fos (2.8-fold) and nuclear factor of activated T cells c1 (6.0-fold) transcription factors critical for OCL differentiation. Furthermore, p62P392L expression results in accumulation of polyubiquitinated TNF receptor-associated factor (TRAF)6 and elevated levels of phospho-IκB during OCL differentiation. Retroviral transduction of p62P392L/CYLD short hairpin RNA significantly increased TRAP positive multinucleated OCL formation/bone resorption activity in mouse bone marrow cultures. Thus, the p62P392L mutation abolished CYLD interaction and enhanced OCL development/bone resorption activity in PDB.

Vitamin D and nonmelanoma skin cancer in a health maintenance organization cohort.

OBJECTIVE: To examine the association of serum 25-hydroxyvitamin D (25-OHD) with the risk of nonmelanoma skin cancer (NMSC), defined as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). DESIGN: Cohort study. SETTING: Health maintenance organization. PATIENTS: The study included 3223 white health maintenance organization patients who sought osteoporosis- or low-bone-density-related advice from 1997 to 2001. INTERVENTIONS: Vitamin D levels were ascertained at the time of the initial appointment, and a sufficient vitamin D level was defined as a baseline serum 25-OHD level greater than or equal to 30 ng/mL (to convert to nanomoles per liter, multiply by 2.496) and as a deficient vitamin D level less than 15 ng/mL. MAIN OUTCOME MEASURES: The NMSC cases diagnosed between 1997 and 2009 were ascertained using claims data, considering first occurrence of specified disease outcome and complete person-years of follow-up since baseline. Charts were abstracted for histologic subtype and anatomical location. RESULTS: More patients were vitamin D insufficient (n = 2257) than sufficient (n = 966). There were 240 patients with NMSC: 49 had an SCC, 163 had a BCC, and 28 had both. Vitamin D levels greater than 15 ng/mL ("not deficient level") were positively associated with NMSC (unadjusted odds ratio [OR], 1.7; 95% confidence interval [CI], 1.04-2.7), and this association was sustained after additional risk factors were adjusted for (adjusted OR, 1.8; 95% CI, 1.1-2.9). The 25-OHD levels were similarly positively associated, though statistically insignificant, with NMSC occurring on less UV-exposed anatomical locations (adjusted OR, 2.2; 95% CI, 0.7-7.0), whether for SCC (adjusted OR, 3.2; 95% CI, 0.4-24.0) or for BCC, although the risk estimate for BCC was lower (adjusted OR, 1.7; 95% CI, 0.5-5.8). CONCLUSIONS: An increased baseline serum 25-OHD level was significantly associated with an increased NMSC risk. This association was positive, though nonsignificant on less UV-exposed body sites, and UV exposure remains a likely confounder. The complex and confounded relationship of vitamin D, UV, and NMSC makes classic epidemiological investigation difficult in the absence of carefully measured history of cumulative UV exposure.

Abnormal bone remodeling in patients with spontaneous painful vertebral fracture.

The application of tetracycline-based iliac bone histomorphometry to the study of the pathogenesis of osteoporosis has given conflicting results. Accordingly, we performed this procedure in 78 postmenopausal white women with one or more vertebral fractures identified according to rigorous criteria that excluded other causes of vertebral deformity and 66 healthy postmenopausal white women recruited from the same geographic region; the groups did not differ in age or weight. In each subject, measurements were made separately on the cancellous (Cn), endocortical (Ec), and intracortical (Ct) subdivisions of the endosteal envelope. In the fracture patients, osteoblast surface was reduced substantially on each subdivision, most markedly on the Cn surface, where about 25% of the deficit was in cuboidal (type II) osteoblasts, suggesting impaired recruitment; the remaining 75% of the deficit was in intermediate (type III) cells, suggesting earlier transition from type III to type IV (flat) cells. On the Ec and Ct surfaces, the deficit was exclusively in type III cells. Mean bone formation rate was reduced by about 18% on the Cn but not on the Ec or Ct surfaces. The deficit was more significant in subjects matched for Cn BV/TV when adjusted for the inverse regression on osteocyte density and after logarithmic transformation. The difference in bone formation rate resulted from a corresponding reduction in wall thickness without a change in activation frequency. The frequency distribution of bone formation rate was more skewed to the left in the fracture patients than in the controls. Osteoclast surface was significantly lower on each subdivision. The variation in osteoblast surface, bone formation rate, and osteoclast surface was significantly greater in the fracture patients than in the controls, with more abnormally low and abnormally high values. The data suggest the following conclusions: (1) The histologic heterogeneity of postmenopausal osteoporosis is reaffirmed; (2) the different subdivisions of the endosteal envelope, although in continuity, behave differently in health and disease; (3) a combination of defective osteoblast recruitment and premature osteoblast apoptosis would account for the deficit in type II and III cells and the reductions in wall thickness and bone formation rate on the Cn surface and the previously reported osteocyte deficiency in Cn bone; (4) premature disaggregation of multinuclear to mononuclear resorbing cells could account for the osteoclast deficit; and (5) some patients with vertebral fracture have one or another disorder of bone remodeling that at present cannot be identified by noninvasive means.

Calcium and vitamin D in sarcoidosis: how to assess and manage.

The synthesis of vitamin D is altered by the granulomatous inflammation of sarcoidosis leading to increased production of 1, 25-dihydroxyvitamin D. Mounting evidence suggests that vitamin D is an immunomodulating hormone that inhibits both antigen presentation by cells of the innate immune system, and the cytokine release and proliferation of Th1 cells. These and other extraskeletal health benefits have led to an increase in vitamin D assessment and pharmacological supplementation in the general population. This review highlights the altered synthesis and general immunomodulating properties of vitamin D with a special emphasis on known interactions with sarcoidosis. In addition, the assessment of vitamin D nutritional status, its pharmacological supplementation, and the management of bone health in patients with sarcoidosis are reviewed.

Osteomalacia as a result of vitamin D deficiency.

Osteomalacia is an end-stage bone disease of chronic and severe vitamin D or phosphate depletion of any cause. Its importance has increased because of the rising incidence of vitamin D deficiency. Yet, not all cases of osteomalacia are cured by vitamin D replacement, and furthermore, not all individuals with vitamin D deficiency develop osteomalacia. Although in the past osteomalacia was commonly caused by malabsorption, nutritional deficiency now is more common. In addition, recent literature suggests that nutritional vitamin D deficiency osteomalacia follows various bariatric surgeries for morbid obesity. Bone pain, tenderness, muscle weakness, and difficulty walking are all common clinical manifestations of osteomalacia. Diagnostic work-up involves biochemical assessment of vitamin D status and may also include a transiliac bone biopsy. Treatment is based on aggressive vitamin D repletion in most cases with follow-up biopsies if patients are started on antiresorptive or anabolic agents.