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Background Primary hyperparathyroidism (PHPT) is one of the known causes of secondary osteoporosis. PHPT is associated with increased bone turnover, low bone density and quality; but there have been conflicting results on the risk of fractures. There is limited information on the effects of age, gender, and ethnicity on fracture risk in PHPT. Objective To determine the prevalence of vertebral fractures (VFx) and associated risk factors in patients with PHPT Design: Retrospective cross-sectional study Setting: Academic medical center in a community setting Main outcome measured: 1) Bone mineral density (BMD), and T- and Z-scores of the lumbar spine (LS). 2) Vertebral morphometry was assessed using the Genant method to identify asymptomatic vertebral fractures (VFx) on CT spine images. 3) Biochemical measurements included serum PTH, Creatinine (Cr) and Calcium (Ca). Results In this retrospective study of consecutive 560 PHPT patients verified by surgery [447 women with a median age of 62y; 362 Caucasians (65%), 142 African Americans (AA, 25%) and 22 unspecified race (10%)] were included. Prevalence of VFx was 13% (n=75), other sites 15% (n=84), wrist fractures 3% (n=16) and hip fractures 1% (n=6). Fracture prevalence at all sites was higher in women, but significant only for VFx (71% vs 29%, p=0.04). In subgroup analysis by age (above or below 50y) and gender, there was no significant difference in LS BMD, T- or Z-score values, serum PTH, Ca and Cr in patients with and without VFx. In subgroup analysis by ethnicity: i) prevalence of all fractures was higher in Caucasians compared to AA and others ii) mean serum PTH (±SD) level was significantly higher in AA vs Caucasian patients with VFx (190 ± 124 vs 121 ± 57 pg/mL, p=0.03) and iii) no significant differences were noted in LS BMD, T-or Z-scores, serum Ca and Cr in patients with VFx. In multivariate analysis (age, serum Ca, PTH >100, and LS BMD) to predict risk of VFx in all patients, only age [OR 1.07, CI 1.03-1.11) and serum Ca [OR 1.7, CI 1.03–2.79] were significant factors. In women, multivariate analysis identified increasing age to be the only significant risk factor to predict risk of VFx. [OR 1.107, CI 1.03-1.12]. Conclusion Vertebral fractures (VFx) is more prevalent in comparison to wrist and hip fractures in patients with PHPT. Serum PTH is significantly higher in African American PHPT patients with VFx. Increasing age and serum calcium ≥11.1 mg/dL are significant predictors of VFx in PHPT patients. Presentation: Saturday, June 11, 2022 12:42 p.m. - 12:47 p.m., Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

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.

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

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.

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/cm2 (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/cm2, 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.

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 SIRPβ1 (353-fold) expression in MVNP transduced human bone marrow mononuclear cells stimulated with RANKL. Real-time PCR analysis further confirmed that MVNP alone upregulates SIRPβ1 mRNA expression in these cells. Also, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. We further show that MVNP increases SIRPβ1 interaction with DAP12 adaptor protein in the presence and absence of RANKL stimulation. shRNA knockdown of SIRPβ1 expression in normal human bone marrow monocytes decreased the levels of MVNP enhanced p-Syk and c-Fos expression. In addition, SIRPβ1 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 SIRPβ1 in MVNP induced OCL formation and bone resorption. Thus, our results suggest that MVNP modulation of SIRPβ1 provides new insights into the molecular mechanisms which control high bone turnover in PDB., Highlights • We identified elevated levels of signal regulatory protein-β1 (SIRPβ1) expression in Paget's disease of bone (PDB). • Measles virus nucleocapsid protein (MVNP) enhances SIRPβ1 expression. • MVNP enhances SIRPβ1 interaction with DAP12 essential for osteoclast differentiation. • Suppression of SIRPβ1 inhibits MVNP enhanced osteoclast differentiation and bone resorption activity.

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.We compared the effects of an established anabolic agent, teriparatide (TPTD), with those of a prototypical antiresorptive agent, zoledronic acid (ZOL).This was a 12-month, randomized, double-blind, active-comparator controlled, cross-sectional biopsy study.The study was conducted at 12 U.S. and Canadian centers.Healthy postmenopausal women with osteoporosis participated in the study.Subjects received TPTD 20 μg once daily by sc injection (n = 34) or ZOL 5 mg by iv infusion at baseline (n = 35).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.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%, P0.001). Other bone formation indices, including MAR, were also higher in the TPTD group (P0.05). 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.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.

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.

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.

We measured indices of bone volume (cancellous, cortical) and bone surface (cancellous, endocortical, and intracortical) in intact full-thickness transiliac bone biopsies obtained from 144 healthy women aged 20-74 (35 black and 109 white, 62 premenopausal and 82 postmenopausal). The data were analyzed by two-way analysis of variance of the four groups defined by age/menopause and ethnicity and by linear regression of major variables on age. None of the interaction terms was significant, and none of the regression slopes on age differed between blacks and whites, indicating that the effects of ethnicity and of age/menopause were independent. Accordingly, the data were also analyzed separately for the effects of ethnicity (pre- and postmenopausal combined) and age/menopause (blacks and whites combined). The analyses led to the following conclusions. (1) Blacks have more cancellous and cortical bone than whites in the ilium; the difference was due to thicker trabeculae and thicker cortices with no difference in trabecular number or cortical porosity. (2) The magnitude of the black/white differences was the same throughout the age range covered by the study, indicating differences in peak adult values, not in rates of loss with age. (3) As the result of age/menopause, there were significant reductions in all indices of the amount and structure of bone except for trabecular thickness; the magnitude of the reductions was the same in blacks and whites. (4) Cancellous bone loss was mainly the result of the complete removal of some trabecular elements with increased separation between remaining elements. Cortical bone loss was due to thinning from the endocortical surface with a small but significant contribution from increased cortical porosity, due to an increased number of intracortical canals. These patterns of bone loss were the same in blacks and whites. (5) Although the percentage losses of bone with age/menopause were higher for cancellous than for cortical bone, the absolute amounts of bone lost were about the same for cortical as for cancellous bone. (6) The ratio of surface to tissue volume decreased with age/menopause in cancellous bone but increased in cortical bone; rates of bone loss would change in the same manner if the loss per unit of surface remained constant. (7) The total extent of bone surface in the ilium did not change with age/menopause, so that the surface/volume ratio for the entire bone increased; volumetric bone turnover would increase and bone age decrease if remodeling activity per unit of surface remained constant.

It is both a necessary and a sufficient condition for bone to be lost with age at any surface location that during remodeling the replacement of resorbed bone is incomplete. In both the ilium and the rib, the degree of such focal imbalance is smaller on the intracortical than on the endocortical or cancellous surfaces that are adjacent to bone marrow. The reason for this difference is unknown. To further examine this question, we measured various geometric variables in 1263 osteons in rib cross sections from 65 persons, including both sexes and age ranges 20 to 30 years and 60 to 70 years (four groups). Haversian canal (HC) area did not differ significantly between sexes or age groups. Percent osteonal refilling was close to 95% in all groups and did not differ between sexes but fell slightly with age. There was a very highly significant linear relationship between osteon bone area and (osteon area + HC area) in all groups, with coefficients of determination (r2) greater than 0.98. The regression slopes declined slightly with age in women but not in men. There was a very highly significant quadratic relationship between osteon bone area and osteon perimeter in all groups, with r2 values greater than 0.97. The ratio osteon bone area:osteon perimeter, an index of bone yield—the volume of bone deposited on each unit area of cement surface—was strongly related to osteon area and did not differ between sexes but was slightly less in the older groups. We conclude the following: (1) The high efficiency of intracortical remodeling in the rib is confirmed, with only trivial effects of age. (2) For HC area to be maintained within narrow limits and bone balance preserved, either initial osteoblast density or osteoblast capacity (the two determinants of bone yield) or, most likely, both must increase progressively with the size of the resorption cavity, suggesting that osteoblast recruitment (relative to available surface) and osteoblast lifespan increase with the volume of bone resorbed. (3) Intracortical remodeling in the rib is more efficient than marrow-adjacent remodeling at any site, possibly because of the different relationships to the circulation. In osteonal remodeling, all molecules released from resorbed bone must travel past the sites of osteoblast recruitment and operation, but in hemiosteonal remodeling, some molecules may not be subject to this constraint. (4) If marrow-adjacent remodeling became as efficient as rib intracortical remodeling, age-related bone loss would cease to be an important medical problem. © 2010 American Society for Bone and Mineral Research

Wall thickness, a major determinant of trabecular thickness, falls with age and falls further in osteoporosis. To estimate the importance of defective osteoblast recruitment in the pathogenesis of this defect, we compared various histologic indices of bone formation in iliac bone biopsies in three groups of subjects--healthy premenopausal women, healthy postmenopausal women, and patients with postmenopausal osteoporosis and at least one non-traumatic vertebral compression fracture. Indices that reflect the frequency of activation of bone remodeling and consequent birth rate of new teams of osteoblasts (osteoid surface, mineralizing surface, osteoblast surface, and bone formation rate, all expressed per unit of bone surface) were each higher in healthy subjects who were postmenopausal than in those who were premenopausal, but lower in osteoporotic than in normal postmenopausal women. In each group, the primary surface measurements were significantly correlated with each other, but the correlation was less close in those with osteoporosis. Indices that reflect the average collective performance of individual teams of osteoblasts (mineralizing surface and osteoblast surface per unit of osteoid surface, mineral apposition rate, adjusted apposition rate, and wall thickness) were all lower in postmenopausal than in premenopausal normal subjects, and even lower in those with postmenopausal osteoporosis. The parameters of the regression lines relating bone formation rate to osteoblast surface were essentially the same in each group, indicating that bone formation rate per unit of osteoblast surface was unaffected by age or menopause, and was the same in osteoporosis as in healthy subjects of similar age.(ABSTRACT TRUNCATED AT 250 WORDS)

The sustained effects of biochemical screening to increase both apparent incidence and age at diagnosis indicate that, without screening, most patients with primary hyperparathyroidism would would never be diagnosed. This suggests that asymptomatic patients discovered as a result of screening have a nonprogressive form of the disease, with adverse health effects that are few or nontraditional, for which treatment policies validated only in symptomatic patients may be inappropriate. Accordingly, in 1975 we formulated criteria for withholding surgical treatment from such patients. Of 174 who were eligible for study over a 10 year period, clinical, biochemical, and densitometric assessment was repeated after at least 1 year (mean 52 months) in 106 patients who did not differ in any initial characteristic from 68 patients in whom follow-up was inadequate. There was no change in symptoms, no disease complications, and no change in any index of hormone secretion or disease severity. In 30 patients, individual regression slopes against time were not significant for any serum measurement. In these patients the disease appeared to have stopped progressing by the time the diagnosis was made, most likely because of cessation of tumor growth. There was a significant deficit in appendicular cortical bone at the time of diagnosis but no further acceleration of bone loss thereafter. In an earlier study, surgical cure was followed by a modest increase in forearm bone density for the first 6 months, but even after 3 years only about 20% of the deficit was corrected. The deficit in bone density is smaller in the spine than in the forearm and is not accompanied by any increase in vertebral fracture risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Receptor activator for nuclear factor-κB ligand (RANKL), a critical osteoclastogenic factor expressed in marrow stromal/preosteoblast cells is up-regulated in Paget’s disease of bone (PDB). We previously demonstrated that heat-shock factor-2 (HSF-2) is a downstream target of fibroblast growth factor-2 (FGF-2) signaling to induce RANKL expression in bone marrow stromal/preosteoblast cells. In this study, we identified a 2.5-fold increase in serum FGF-2 levels in patients (n = 8) with PDB compared with normal subjects (n = 10). We showed that HSF-2 co-immunoprecipitates with heat-shock protein-27 (HSP-27) and that FGF-2 stimulation significantly increased phospho-HSP-27 levels in marrow stromal cells. Confocal microscopy revealed HSF-2 colocalization with HSP-27 in unstimulated cells and HSF-2 nuclear translocation upon FGF-2 stimulation. We further show that FGF-2 stimulation significantly increased the levels of phosphorylated signal transducers and activators of the transcription (p-STAT-1) in these cells. Western blot analysis confirmed that small interfering RNA suppression of STAT-1 significantly decreased (3.2-fold) RANKL expression and promoter activity in FGF-2-stimulated cells. Chromatin immunoprecipitation assay revealed STAT-1 binding to a putative motif located far upstream (−8 kb) in the hRANKL gene promoter region. These results suggest STAT-1 is a downstream effector of FGF-2 signaling and that elevated levels of FGF-2 stimulates RANKL expression in PDB.

A high prevalence (60%) of vitamin D (VitD) depletion, defined as a serum 25-hydroxyvitamin D level ofor =20 ng/mL, is present in preoperative morbidly obese patients. Despite daily supplementation with 800 IU VitD and 1500 mg calcium after Roux-en-Y gastric bypass (RYGB), VitD depletion persists in almost one half (44%) of patients. However, the optimal management of VitD depletion after RYGB and the potential benefits of such treatment are currently unknown.A total of 60 VitD-depleted morbidly obese women were randomly assigned to receive 50,000 IU of VitD weekly after RYGB (group 1; n = 30) or no additional VitD after RYGB (group 2; n = 30). All patients received a daily supplement of 800 IU VitD and 1500 mg calcium. The serum calcium, parathyroid hormone, 25-hydroxyvitamin D, bone-specific alkaline phosphatase, urinary N-telopeptide, and bone mineral density were measured preoperatively and 1 year after RYGB. Questionnaires were used to assess other potential sources of VitD, including sunlight exposure and ingestion of VitD-containing foods/liquids.At 1 year after RYGB, VitD depletion and mean 25-hydroxyvitamin D level had improved significantly in group 1 (14% and 37.8 ng/mL, respectively) compared with the values in group 2 (85% and 15.2 ng/mL, respectively; P.001 for both). A significant 33% retardation in hip bone mineral density decline (P = .043) and a significantly greater resolution of hypertension was seen in group 1 (75% versus 32%; P = .029). No significant adverse effects were encountered from pharmacologic VitD therapy.The results of our study have shown that 50,000 IU of VitD weekly after RYGB safely corrects VitD depletion in most women, attenuates cortical bone loss, and improves resolution of hypertension.

Background: At the Third International Workshop on Asymptomatic Primary Hyperparathyroidism (PHPT) in May 2008, recent data on the disease were reviewed. We present the results of a literature review on issues arising from the clinical presentation and natural history of PHPT. Methods: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was reviewed, and the questions of the International Task Force were addressed by the Consensus Panel. Conclusions: 1) Data on the extent and nature of cardiovascular involvement in those with mild disease are too limited to provide a complete picture. 2) Patients with mild PHPT have neuropsychological complaints. Although some symptoms may improve with surgery, available data remain inconsistent on their precise nature and reversibility. 3) Surgery leads to long-term gains in spine, hip, and radius bone mineral density (BMD). Because some patients have early disease progression and others lose BMD after 8–10 yr, regular monitoring (serum calcium and three-site BMD) is essential in those followed without surgery. Patients may present with normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism). Data on the incidence and natural history of this phenotype are limited. 4) In the absence of kidney stones, data do not support the use of marked hypercalciuria (>10 mmol/d or 400 mg/d) as an indication for surgery for patients. 5) Patients with bone density T-score −2.5 or less at the lumbar spine, hip, or distal one third radius should have surgery.

Summary Objectives To report and explore potential reasons for undetectable or low-normal serum intact PTH levels in patients with surgically verified primary hyperparathyroidism with parathyroid adenomas, review the relevant literature, and offer suggestions for management of such patients occasionally encountered in clinical practice. For future research, to help understand mechanisms underlying ‘undetectable’ or inappropriately low serum intact PTH levels. Methods Serum intact PTH levels were measured pre- and postoperatively by immunochemiluminescent assay (ICMA) and the results were confirmed by at least two repeated measurements on different occasions in each patient. Patients We encountered two unusual patients with primary hyperparathyroidism who had suggestive biochemical and/or clinical features of primary hyperparathyroidism. However, serum intact PTH levels were either very low or undetectable in the context of hypercalcaemia, with no other obvious cause. A 99mTc sestamibi scan showed increased uptake in one of the parathyroid glands, suggesting a single adenoma in each case that was confirmed at surgery. Results In the first patient, from India, mean ± SD serum calcium was 2·6 ± 0·32 mmol/l (reference range 2·12–2·74 mmol/l) with intact PTH of 0·11 pmol/l (reference range 1·1–7·59 pmol/l). In the second patient, from the USA, mean ± SD serum calcium and intact PTH were 2·9 ± 0·07 mmol/l (reference range 2·17–2·51 mmol/l) and 1·35 pmol/l (reference range 1·1–7·59 pmol/l), respectively. Following curative parathyroidectomy, serum calcium levels normalized in both patients. By contrast, serum intact PTH levels, which were either suppressed or very low before surgery, rose into the low-normal reference range in all patients. Conclusions When the clinical suspicion is high, the diagnosis of primary hyperparathyroidism should be pursued despite suppressed or low-normal serum intact PTH levels after carefully excluding other causes of hypercalcaemia. Further research on various intact PTH molecular species secreted by parathyroid adenomas or post-translational changes in the intact PTH molecule that might interfere with in vitro measurements should be undertaken to understand the precise reason(s) for such anomalous findings.

Paget's disease (PD) of bone is characterized by increased activity of large abnormal osteoclasts (OCLs) which contain paramyxoviral nuclear and cytoplasmic inclusions. MVNP gene expression has been shown to induce pagetic phenotype in OCLs. We previously characterized the osteoclast inhibitory peptide-1 (OIP-1/hSca) which inhibits OCL formation/bone resorption. OIP-1 is a glycophosphatidylinositol (GPI)-linked membrane protein containing a 79 amino acid extra cellular peptide and a 32 amino acid carboxy terminal GPI-linked peptide (c-peptide) which is critical for OCL inhibition. In this study, we demonstrate that OIP-1 c-peptide significantly decreased (43%) osteoclast differentiation of peripheral blood mononuclear cells from patients with PD. Also, OIP-1 treatment to normal human bone marrow mononuclear cells transduced with the MVNP inhibited (41%) osteoclast precursor (CFU-GM) growth in methyl-cellulose cultures. We further tested if OIP-1 overexpression in the OCL lineage in transgenic mice inhibits MVNP stimulated OCL formation. MVNP transduction and RANKL stimulation of OIP-1 mouse bone marrow cells showed a significant decrease (43%) in OCL formation and inhibition (38%) of bone resorption area compared to wild-type mice. Western blot analysis identified that OIP-1 decreased (3.5-fold) MVNP induced TRAF2 expression during OCL differentiation. MVNP or OIP-1 expression did not affect TRAF6 levels. Furthermore, OIP-1 expression resulted in a significant inhibition of MVNP stimulated ASK1, Rac1, c-Fos, p-JNK, and NFATc1 expression during OCL differentiation. These results suggest that OIP-1 inhibits MVNP induced pagetic OCL formation/activity through suppression of RANK signaling. Thus, OIP-1 may have therapeutic utility against excess bone resorption in patients with PD.

Biomechanical stereology is proposed as a two-dimensional (2D) finite element (FE) method to estimate the ability of bone tissue to sustain damage and to separate patients with osteoporotic fracture from normal controls. Briefly, 2D nonlinear compact tension FE models were created from quantitative back scattered electron images taken of iliac crest bone specimens collected from the individuals with or without osteoporotic fracture history. The effects of bone mineral microstructure on predicted bone fracture toughness and microcrack propagation were examined. The 2D FE models were used as surrogates for the real bone tissues. The calculated microcrack propagation results and bone mechanical properties were examined as surrogates for measurements from mechanical testing of actual specimens. The results for the 2D FE simulation separated patients with osteoporotic fracture from normal controls even though only the variability in tissue mineral microstructure was used to build the models. The models were deliberately created to ignore all differences in mean mineralization. Hence, the current results support the following hypotheses: (1) that material heterogeneity is important to the separation of patients with osteoporotic fracture from normal controls and; and (2) that 2D nonlinear finite element modeling can produce surrogate mechanical parameters that separate patients with fracture from normal controls.

INTRODUCTION To determine the prevalence of type 2 diabetes mellitus (DM) in patients with primary hyperparathyroidism. METHODS Prevalence of type 2 DM in 609 patients with surgically verified primary hyperparathyroidism presenting between 1992 and 2003 in a tertiary care hospital setting was assessed retrospectively and compared with published data of type 2 DM prevalence in Michigan's general population. Diagnosis of type 2 DM was made on the basis of documentation in the medical record of fasting or random blood glucose level thresholds according to the 1997 American Diabetes Association criteria, history of diabetes mellitus, or therapy with antidiabetic medications. RESULTS The crude prevalence rate of type 2 DM in patients with primary hyperparathyroidism was significantly higher than the prevalence in the Michigan general population (15.9% vs 7.8%, respectively; P

Using iliac bone histomorphometry on 78 patients with vertebral fracture and 66 healthy postmenopausal women, cortical thickness discriminated at least as well as any cancellous bone structural index between the two groups. Subjects with a deficit in both cortical and cancellous bone had much greater likelihood of fracture. Introduction: Vertebral fracture is often attributed to disproportional loss of cancellous bone, but fracture patients may have deficits in cortical and cancellous bone. Accordingly, we examined the contribution of cortical and cancellous bone deficits, separately and together, to the likelihood of vertebral fracture. Materials and Methods: Iliac bone histomorphometry was performed in 78 white woman with clinically apparent vertebral fracture, 66 healthy postmenopausal women, and 38 healthy premenopausal women. We measured cancellous bone volume (Cn.BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), cortical bone volume (Ct.BV/TV), and cortical thickness (Ct.Th). For each variable, a value of >1 SD below the mean in premenopausal women was treated as a putative risk factor, and its association with the presence or absence of fracture was determined by OR calculated by logistic regression and by receiver operating characteristic (ROC) curve analysis. Subsets of fracture and control subjects were separately matched for Cn.BV/TV and Ct.Th. Results: All structural indices differed between fracture patients and controls except Ct.BV/TV. There was a weak but highly significant correlation between Cn.BV/TV and Ct.Th in the entire group (r = 0.389, r2 = 0.151 p < 0.001). Many control subjects had a high value for one of these variables and a low value for the other. Ct.Th., Cn.BV/TV, and Tb.N were all significantly associated with vertebral fracture (ORs, 4.4–5.8; ROC area under the curve [AUC], 0.74–0.85). In subjects matched for Cn.BV/TV, Ct.Th was reduced by 29% (OR, 5.0), and in subjects matched for Ct.Th, Cn.BV/TV was reduced by 27% (OR, 5.0). In patients with deficits in both cortical and cancellous bone, the ORs (28–35) were much higher. Conclusions: Deficits in cortical bone (reduced value for Ct.Th) and in cancellous bone (reduced values for Cn.BV/TV or Tb.N) were equally effective in discriminating between subjects with and without vertebral fracture. With a deficit in both cortical and cancellous bone, the association with vertebral fracture was much stronger. Vertebral fracture is not the result of disproportionate loss of cancellous bone in the patients as a whole, although individual patients may have relatively greater deficits in either cancellous or cortical bone.

Abnormalities in calcium and vitamin D metabolism have been reported after bariatric surgery. The purpose of this study was to evaluate vitamin D nutritional status among morbidly obese patients before gastric bypass surgery.We prospectively studied 279 morbidly obese patients seeking gastric bypass surgery for vitamin D nutritional status as assessed by serum 25-hydroxyvitamin D level. In addition, serum samples were analyzed for calcium, alkaline phosphatase (AP), intact parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D.Mean patient age was 43 +/- 9 years; 87% of the study patients were women, and 72% were white. Serum calcium and AP levels were normal in 88% and 89% of the patients, respectively. Vitamin D depletion, defined as serum 25-hydroxyvitamin D levelor= 20 ng/mL, was found in 166 patients (60%). An elevated PTH level was found in 48% of the patients. A significant inverse correlation was found between serum 25-hydroxyvitamin D level and both body mass index (r = .15; P = .012) and serum PTH level (r = .45; P.001). Vitamin D depletion was significantly more prevalent in the African-American patients than in the white patients (91% vs 48%; P.001).Before gastric bypass surgery, a majority of morbidly obese patients have vitamin D depletion and secondary hyperparathyroidism. Studies evaluating the effects of gastric bypass on vitamin D metabolism must consider preoperative vitamin D nutritional status.

Paget's disease (PD) of bone is a chronic focal skeletal disorder characterized by excessive bone resorption followed by abundant new bone formation. Enhanced levels of IL-6, RANKL, M-CSF, and endothelin-1 have been associated with PD. In the present study, we identified increased serum levels (2 to 5-fold) of inflammatory cytokine, kininogen (KNG) in patients with PD compared to normal subjects. Treatment of pagetic bone marrow derived stromal/preosteoblast cells with recombinant KNG (25 ng/ml) for 24 h period resulted in a 5-fold increase in the levels of phospho-HSP27 and a 3-fold increase in ERK1/2 phosphorylation in these cells. However, pagetic stromal cells stimulated with KNG in the presence of ERK activation inhibitor peptide did not significantly affect the levels of phospho-HSP27. KNG increased normal and pagetic marrow stromal cell proliferation at 1.4-fold and 2.5-fold, respectively. KNG in the presence of an ERK inhibitor peptide did not stimulate pagetic marrow stromal cell proliferation. Furthermore, siRNA suppression of HSP27 expression significantly decreased KNG inhibition of etoposide-induced caspase-3 activation and apoptosis in these cells. In summary, KNG modulate bone marrow derived stromal/preosteoblast cell proliferation and suppress etoposide-induced apoptosis through ERK and HSP27 activation, respectively. These results implicate a pathophysiologic role for KNG in patients with PD. J. Cell. Biochem. © 2006 Wiley-Liss, Inc.

We examined the differences in osteocyte and lacunar density between Black and White women, using previously obtained iliac bone biopsies from 34 healthy Black women, aged 21-70 years, and 94 White women, aged 20-73 years. For each subject, the density of osteocytes (Ot.N/B.Ar), empty lacunae (EL.N/B.Ar), and total lacunae (Tt.L.N/B.Ar) and the proportion of osteocyte-occupied lacunae (Ot.N/Tt.L.N) were separately measured in whole trabeculae, superficial bone (25 microm from the bone surface), and deep bone (45 microm from the bone surface). Compared with White women, Black women had higher values for osteocytes, empty lacunae, and total lacunae and lower values for percent occupied lacunae in superficial bone and whole trabeculae (P0.01 to0.001). In deep bone there were more osteocytes and total lacunae in Black women, but the other measurements did not differ significantly between the two groups. As in White women, there were fewer osteocytes and total lacunae and more empty lacunae in deep than in superficial bone. The regressions of osteocyte and total lacunar density on age were not significant in Black women, but postmenopausal Black women had fewer osteocytes than premenopausal Black women, and percent occupied lacunae declined significantly with age in whole trabeculae and deep bone, which could only have resulted from osteocyte death. In contrast to White women, there was no inverse relationship between bone formation rate and osteocyte density in superficial bone and the observed bone formation rate was lower than predicted by osteocyte density. We conclude the following: (1) Cancellous bone is made with more osteocytes in Black than in White women, most likely because of diminished apoptosis of osteoblasts; this could contribute to increased bone strength in Black women. (2) In Black women, as in White women, there are fewer osteocytes and total lacunae and more empty lacunae in deep than in superficial bone. (3) There was moderate age-related loss of osteocytes in deep bone in Black women, indicating that osteocyte density depends more on the age of the bone than on the age of the subject. (4) The higher osteocyte density in Black women was not responsible for their lower bone formation rate.

There is no detailed information available concerning the variations in bone, the Haversian canal, and osteocyte populations in different-sized osteons. In this study a total of 398 secondary osteons were measured in archived rib sections from nine white men (20-25 years old). The sections were stained with basic fuchsin. The parameters included the osteon area (On.Ar), Haversian canal area (HC.Ar) and perimeter (HC.Pm), bone area (B.Ar), and osteocyte lacunar number (Lc.N). From these primary measurements the following indices were deduced: 1) lacunar number per bone area (Lc.N/B.Ar) and per osteon (Lc.N/On); 2) the ratio between Haversian canal perimeter and bone area (HC.Pm/B.Ar); and 3) the fraction of Haversian canal area (HC.Ar/On.Ar) and its complement, the fraction of bone area (B.Ar/On.Ar). The results showed that the osteons varied greatly in size, but very little in the fraction of bone area. Regression analyses showed that HC.Ar, HC.Pm, and Lc.N/On were positively associated with On.Ar (P < 0.001 for all). A significant negative correlation was found between On.Ar and Lc.N/B.Ar (P < 0.05) and HC.Pm/B.Ar (P < 0.0001). HC.Ar and HC.Pm increased significantly with increasing Lc.N/On (both P < 0.0001) rather than Lc.N/B.Ar. Lc.N/B.Ar had a significant positive correlation with HC.Ar/On.Ar (P < 0.05) and HC.Pm/B.Ar (P < 0.01). We conclude that: 1) the size of the osteon is determined by the quantum of bone removed by osteoclasts, 2) the osteon is well designed for molecular exchange, and 3) a well designed osteon may be produced via the regulation of bone apposition by osteocytes during the process of osteon refilling.

Summary objective The long-term effects of primary hyperparathyroidism (PHPT), whether treated or untreated, on cortical bone are unclear, but the balance of evidence suggests that fracture risk is modestly increased in this patient group. We therefore compared changes in forearm cortical bone mineral density (BMD), at the site most relevant for PTH-mediated bone loss, in two groups of patients with PHPT; one with and one without surgery. design and patients We followed the course of forearm bone mineral/bone width (BM/BW, g/cm2) measured by single-energy photon absorptiometry at the standard proximal site, and Z-scores (deviations from the mean value expected for age, sex and race, calculated from a large local reference population) in 108 patients who underwent successful surgery (mean duration 47 months, range 12–120 months) and 108 who remained unoperated (mean duration 52 months, range 12–132 months). Criteria for recommending surgery had been formulated in 1975 and were generally similar to those of the NIH consensus conference published in 1991. At the time of diagnosis the Z-score was significantly reduced in both groups, indicating an earlier period of accelerated cortical bone loss. results In the entire operated population there was no difference between the initial and final BM/BW. As the age-expected mean value declined, the Z-score became significantly less negative, and if the rate of change remained constant the values would have reached zero, indicating recovery of all bone lost as a result of the disease, after about 20 years. In the unoperated patients BM/BW fell significantly but there was no change in Z-score, indicating that the rate of bone loss was the same as expected for normal ageing. conclusions It is reasonable to assume that cessation of further bone loss consequent on successful parathyroid surgery would eventually lead to abatement of the excess fracture risk, but the benefit to individual patients will depend mainly on their remaining life expectancy.

Because of the known differences in bone mineral density (BMD) of the dominant and nondominant forearms, it has been customary to measure BMD of the nondominant forearm to reduce variance. However, it is less clear whether such systematic differences exist between BMD of the two hips. Accordingly, we measured BMD of both hips and the spine in 131 consecutive white women who presented to a community-based private practitioner for evaluation and advice on osteoporosis. There was a highly significant correlation between BMD of the two hips at the femoral neck, trochanter, and Ward's triangle ( r = 0.91, 0.93, and 0.89, respectively; p p p = 0.008 and 0.005, respectively). The left hip BMD was consistently higher than the right hip BMD at all measurement sites. Because of the small sample size of left-handed persons, we were unable to determine the influence of dominant handedness on hip BMD. We concluded the following: (1) BMDs of the two hips are highly correlated at relevant measurement sites; (2) there does not appear to be a dominant hip as there is dominant forearm; (3) because of strong agreement between BMD of the two hips, there is little justification to measure both hips in routine clinical practice.

Although routine fortification of milk and a few other dairy products has been successful in preventing rickets in children, its impact on preventing vitamin D depletion in adults is less than satisfactory. The prevalence of vitamin D depletion in the elderly is on the rise again and appears to be more common than is currently appreciated. Several groups of individuals are at an increased risk of developing vitamin D depletion, and a significant minority of otherwise healthy individuals is vitamin D deficient. Unrecognized vitamin D depletion leads to secondary hyperparathyroidism, accelerates cortical bone loss, and increases the risk of hip fractures. With the availability of techniques to assess vitamin D nutrition, it is probably cost-effective to routinely measure 25-hydroxyvitamin D levels in individuals at the greatest risk and in patients with various metabolic bone diseases to prevent vitamin D depletion. Early recognition and prompt treatment of vitamin D depletion improves functional well-being of the individual, reduces morbidity related to bone loss and fractures, and is associated with a highly favorable cost/benefit ratio.

We measured histologic indices of osteoblast function, bone mineralization, and osteoid accumulation separately on the cancellous, endocortical, and intracortical subdivisions of the endosteal envelope and on the combined total surface in transiliac biopsies obtained after double tetracycline labeling in 142 healthy women, aged 20-74 years, 34 who were black (19 pre- and 15 postmenopausal) and 108 white (42 pre- and 66 postmenopausal). The data were subjected to two-way analysis of variance of the four groups defined by age/menopause and ethnicity. Also, linear regressions of selected variables on age and between functionally related but independently measured variables were examined. None of the interaction terms was significant, and none of the regression slopes on age differed between blacks and whites, indicating that, as for the previously reported structural and remodeling indices, the effects of ethnicity and of age/menopause are independent. Accordingly, the data were analyzed separately for the effects of ethnicity (pre- and postmenopausal combined) and age/menopause (blacks and whites combined). The analyses led to the following conclusions (1) Osteoid surface and volume were higher and adjusted apposition rate and osteoid mineralization rate lower in postmenopausal than in premenopausal subjects, but none of the indices of osteoid accumulation differed between blacks and whites. (2) Each index of osteoid accumulation was significantly correlated with its primary independently measured kinetic determinant (osteoid thickness with adjusted apposition rate, osteoid surface/bone surface with activation frequency, and osteoid volume/bone volume with bone formation rate/bone volume). None of the regression parameters differed significantly between blacks and whites. (3) The ratio of mineralizing surface to osteoid surface (MS/OS) was substantially lower in all demographic groups than could be accounted for by the later onset of mineralization than of matrix apposition at individual bone forming sites. (4) The low values for MS/OS can be explained by terminal mineralization being too slow to trap enough tetracycline molecules to produce detectable fluorescence, and do not require that mineralization be interrupted. (5) MS/OS was about 25% lower in blacks than in whites on all surfaces with corresponding differences in derived indices based on MS/OS, including adjusted apposition rate, mineralization lag time, and formation period. (6) The lower values for MS/OS in blacks are most likely due to slower terminal mineralization. This could not be accounted for by a lower serum level of calcidiol, but is consistent with the reported effect of reduced bone blood flow. (7) All differences in bone cell function between blacks and whites that we have observed could be the result of the ethnic, and presumably genetic, difference in bone accumulation during growth. Higher bone mass would result in less fatigue microdamage, less need for repair by directed bone remodeling, lower bone turnover, lower bone blood flow, and slower terminal mineralization. (8) If this explanation is correct, there are no fundamental differences in the biology of bone remodeling between ethnic groups.

We measured histologic indices of bone remodeling and turnover separately on the cancellous, endocortical, and intracortical subdivisions of the endosteal envelope, and on the combined total surface, in transiliac bone biopsies obtained after double tetracycline labeling in 142 healthy women, aged 20-74 years, 34 black and 108 white, 61 premenopausal and 81 postmenopausal. The data were analyzed by two-way analysis of variance of the four groups defined by age/menopause and ethnicity and by linear regression of the major variables on age. None of the interaction terms was significant and none of the regression slopes on age differed between blacks and whites, indicating that, as for the previously reported structural indices, the effects of ethnicity and of age/menopause are independent. Accordingly, the data were also analyzed separately for the effect of ethnicity (pre- and postmenopausal combined) and age/menopause (blacks and whites combined). The analyses led to the following conclusions. (1) The geometric mean bone formation rate on the combined total surface was 25% lower in blacks than in whites; other histologic differences between ethnic groups were inconsistent between surfaces. (2) Serum osteocalcin (OC) but not bone-specific alkaline phosphatase (BSAP) was lower by about 15% in blacks than in whites. (3) The lower bone turnover in blacks is most likely in the directed rather than in the stochastic component because of a higher bone mass and consequent reduced susceptibility to fatigue damage. (4) All Class 1 bone formation variables and the three resorption indices were significantly higher in the postmenopausal compared with the premenopausal subjects, reflecting a 33% increase in activation frequency. (5) BSAP, but not OC, was increased relatively more (66%) than the bone formation rate (BFR). Consequently, BSAP is more sensitive to the effects of menopause than OC, but OC is more sensitive to the effects of ethnicity than BSAP. (6) There were highly significant differences between the three subdivisions of the endosteal envelope for every non-cell-related variable. All Class 1 formation variables were highest on the endocortical surface, but the magnitude and pattern of the differences otherwise was inconsistent between variables. The contributions of the different subdivisions to the total bone formation rate were cancellous 54%, endocortical 13%, and intracortical 33%. (7) The previously reported changes in bone surface location, together with the presently reported changes in activation frequency and wall thickness indicated that there was no significant effect of age/menopause on erosion depth on the cancellous and intracortical surfaces but a large increase in erosion depth on the endocortical surface. (8) The increase in bone turnover that results from hormonal changes is most likely in the stochastic rather than in the directed component because it serves no purpose but has harmful effects on skeletal integrity.

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.

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.

There have been conflicting reports about the effect of diabetes on bone density. In 1978, we studied 109 patients, 46 with type I and 63 with type II diabetes; ∼12 years later we restudied 35 of the 66 surviving patients. In the original study, radial bone density did not differ significantly between patients with either type of diabetes but was significantly lower than in nondiabetic control subjects. In eight osteopenic patients, bone formation rate and other histological indexes of osteoblast recruitment and function were markedly depressed compared with those in nondiabetic control subjects. In patients remeasured ∼2.5 years (41 patients) and ∼12.5 years (35 patients) after baseline, bone loss had continued at the expected rate in patients with type I diabetes, with maintenance of the same deficit, but was slower than expected in patients with type II diabetes, such that the initial deficit had been completely corrected. In six of the eight patients who had undergone bone biopsy, one with type I and five with type II diabetes, the mean bone mineral density z-score of the spine and femoral neck ∼12 years later was >0 and in one subject was significantly higher than normal at both sites. Based on these data and on previous studies, we propose that in patients with diabetes, low bone formation retards bone accumulation during growth, metabolic effects of poor glycemic control lead to increased bone resorption and bone loss in young adults, and low bone turnover retards agerelated bone loss. These effects account for low bone density in young patients with type I diabetes and normal or increased bone density in older patients with type II diabetes.

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.

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.

Hypersecretion of parathyroid hormone (PTH) occurs in three distinct nonfamilial forms. Sporadic primary hyperparathyroidism is the most common (see Chaps. 5 and 6). Tertiary hyperparathyroidism [1–3], the subject of this chapter, is the least common (Table 11.1). Secondary hyperparathyroidism caused by a pathologic process outside the parathyroid glands (e.g., kidney failure, phosphate wasting, and so forth) is discussed fully in Chap. 7 and is referred to in the current chapter in the context of “refractory” secondary hyperparathyroidism. Secondary hyperparathyroidism shares many pathogenic, clinical, biochemical, radiological, and bone histological features of tertiary hyperparathyroidism, except that with the development of hypercalcemia the classification changes from secondary to tertiary hyperparathyroidism [4].

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-naive 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

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.

It is unclear whether standard clinical doses of risedronate affect osteocyte viability. This study examined osteocyte viability and bone remodeling rate in early postmenopausal women (1-5 years after menopause) who were treated with a standard clinical dose of risedronate (5 mg/day, orally) for 1 year. Paired transiliac bone biopsies were obtained from 19 postmenopausal women at baseline and after 1-year treatment with placebo (n = 8, mean age 52.9 ± 3.4 years) or risedronate 5 mg/day (n = 11, mean age 52.5 ± 3.4 years). In these samples, we measured osteocyte- and bone remodeling-related variables in trabecular bone. In both the placebo and risedronate groups, empty lacunae were significantly decreased after 1-year treatment compared to baseline. There were no significant differences in osteocyte-related variables between placebo and risedronate. Risedronate significantly reduced bone-remodeling indices including mineralizing surface (MS/BS), bone formation rate (BFR/BS), and activation frequency (Ac.f). Risedronate treatment caused significantly lower MS/BS and Ac.f than placebo administration. In conclusion, risedronate 5 mg/day effectively inhibited bone remodeling but did not significantly reduce osteocyte viability in trabecular bone.

Abnormalities in bone and mineral metabolism occur frequently in chronic kidney disease (CKD) patients, leading to bone lesions. This disorder has more recently been termed chronic kidney disease-related mineral and bone disorder (CKD-MBD) by the Kidney Disease Improving Global Outcomes (KDIGO) foundation (1). Bone and mineral disorders in CKD patients have been associated with significant morbidity and mortality (2–5). The bone lesions, coined renal osteodystrophy (ROD), in this population can manifest symptoms such as intense pruritus, bone pain, myopathies, muscle tendon rupture, and increased incidence of fractures. Beyond symptoms, however, ROD manifests in derangements in bone histologic findings such as abnormalities in bone turnover, mineralization, and volume (6), a classification system that has been adopted by the KDIGO committee (1). Bone histology remains the “gold standard” for definitive diagnosis of the osteodystrophic lesion. However, in routine clinical practice nephrologists rely on noninvasive methods for assessment of bone turnover, such as intact parathyroid hormone (iPTH) levels. The Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines (CPG) for Bone Metabolism and Disease in Chronic Kidney Disease, released in 2003, provided the first integrated clinical action plan for the treatment of CKD-MBD (7). The treatment goals provided by these CPGs were developed through a systematic review of the literature to date (January 1, 2001) in addition to a broad-based review by experts, organizations, and the public. However, it is unclear if the recommended goals of therapy in the guidelines are also applicable to African-American (AA) hemodialysis patients. Differences in mineral metabolism between AA and non-AA individuals without CKD have been demonstrated previously in relation to calcium balance (8,9) and bone histomorphometry (10,11). These differences have been seen in the nondialysis CKD population as well, with AA CKD patients demonstrating differences in their levels of bone and mineral parameters that would suggest a more severe degree of secondary hyperparathyroidism (12). A recent study involving AA hemodialysis patients suggests that a higher serum iPTH threshold may be necessary in this ethnic group to avoid the development of adynamic bone disease (ABD) (13), which has been associated with adverse outcomes such as vascular calcifications, (14,15) fractures (16,17), and increased mortality (5,18). In particular, a iPTH of less than 200 pg/ml or a combination of a iPTH of less than 178 pg/ml with a higher serum phosphorus and calcium were associated with increased mortality in hemo- and peritoneal dialysis patients (5,18). African Americans constitute a significant proportion of patients on hemodialysis in the United States, approaching 32% in 2005 (19). Therefore, it is important to explore any potential differences in the assessment and treatment of bone and mineral disorders in this population. Although the work of Sawaya et al. and Gupta et al. has led to the recognition that there are differences between AA and non-AA hemodialysis subjects in relation to iPTH, the optimal serum levels of iPTH across the histologic spectrum of bone and mineral disorders have yet to be established in this population (13,20). The purpose of this study was to evaluate the relationship of bone histology across the spectrum of ROD to classical biochemical markers of bone and mineral metabolism in prevalent AA hemodialysis patients receiving the current standard of care for CKD-MBD.

Spatial patterns of mineralization for human iliac crest cancellous bone were measured from images obtained by quantitative backscattered electron microscopy. Biopsies collected from vertebral fracture patients and healthy individuals with high or low bone formation rate (BFR(s)) were examined (fracture/low BFR(s): N=12, fracture/high BFR(s): N=10, normal/low BFR(s): N=12, normal/high BFR(s): N=15). 20 by 20 pixel square areas or smaller were sampled from superficial and deep remodeling packets. Mean (Z(mean)) and standard deviation (SD) of mineralization were measured, and coefficients of variation (CV=SD/Z(mean)) were calculated. Fast Fourier transform analysis was used to quantify the distribution of the mineral in the packets. "FFT_ratio" was defined as the ratio magnitude of the principal spatial frequency to the average atomic number density. A higher FFT_ratio occurred in specimens with more pronounced alternating layers of light and dark as visible in the backscattered electron image, which was defined as lamellar patterning. Two-way ANOVA revealed that the coefficients of variation of mineralization for both superficial and deep packets were significantly lower in fracture patients than in normal individuals. However, the interaction between turnover rate and group (fracture/non-fracture) indicated that the difference in packet CV occurred among the low turnover individuals and not among those with high turnover. Mean mineralization levels and CV between deep and superficial packets were highly correlated. Regressions of packet CV of mineralization and FFT_ratio were highly significant (p

Udgivelsesdato: 2009-Feb OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostic tests for this condition in clinical practice. PARTICIPANTS: Interested professional societies selected a representative for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed. The conclusions were then circulated to the participating professional societies. EVIDENCE: Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting. CONSENSUS PROCESS: Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies. CONCLUSIONS: We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) DNA sequence testing can be useful in familial hyperparathyroidism or hypercalcemia; 4) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 5) serum 25-hydroxyvitamin D levels should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; and 6) the estimated glomerular filtration rate should be used to determine the level of kidney function in PHPT: an estimated glomerular filtration rate of less than 60 ml/min.1.73 m2 should be a benchmark for decisions about surgery in established asymptomatic PHPT.

Background Morbid obesity is a risk factor for hypertension (HTN) and vitamin D (VitD) depletion. Gastric bypass (GBP) resolves HTN in many patients. The goal of this study was to evaluate the potential role of VitD nutritional status on HTN resolution in patients undergoing GBP. Methods A retrospective review of morbidly obese patients taking antihypertensive medications and undergoing GBP from September 1, 2002, through February 28, 2006 was performed. Results At 1 year postoperatively HTN resolved in 53%, improved in 36%, and was unchanged in 11%. Sex, race, body mass index, and percentage of excess weight loss did not impact HTN resolution. Younger patients experienced a greater rate of HTN resolution. Patients with VitD depletion had significantly lower rates of HTN resolution compared to those with adequate levels of VitD (42% vs 61%; P = .008). Conclusions VitD nutritional status impacts the resolution rate of HTN after GBP. All morbidly obese patients undergoing GBP should be monitored and treated for VitD depletion.

The goals of this study were to measure tissue-level elastic moduli and hardness of human cancellous bone using nanoindentation, and determine the relationship between nanoindentation results and previously measured bone histomorphometric variables and bone mineralization. Forty iliac crest biopsies were used in this study, which were collected from Caucasian females with vertebral fracture or from a normal healthy female Caucasian population. They were also categorized into two groups according to high or low bone formation rate per bone surface (BFR/BS). Thirty-two sites were randomly selected on each specimen for nanoindentation with a Berkovich diamond indenter. Two sets of elastic moduli and hardness were calculated using the continuous stiffness measurement method and the Oliver-Pharr method, respectively. Relationships between nanoindentation results and donor age, bone mineralization, and histomorphometric variables were examined. No difference in elastic moduli or hardness was observed between the normal and fracture groups. Significantly lower elastic moduli were observed in the high BFR/BS group. The elastic moduli and hardness measurements were not significantly correlated with the bone mineralization measured independently in a previous study. Linear correlation between elastic modulus and hardness calculated using the Oliver-Pharr method was not different between the normal and fracture groups or between the high and low BFR/BS groups. Nanoindentation hardness was a very good predictor of bone tissue elastic modulus for both normal and osteoporotic bone tissues. Osteoporosis may not change the relationship between bone tissue elastic modulus, bone hardness, and bone mineralization.

We assessed vitamin D nutritional status in unselected consecutive patients seeking advice on osteoporosis. The prevalence of vitamin D depletion ranged from 15–72% depending upon the cut-off levels used for serum 25-hydroxyvitamin D, and the prevalence did not change over the 5 years of the study. Vitamin D depletion is a significant public health problem and has been studied in different populations using different cut-off levels, but the optimal level is yet to be established. In a cross-sectional study of 2924 patients seen for osteoporosis advice we determined the prevalence of vitamin D depletion, as assessed by 25-hydroxyvitamin D (25-OHD), using three different cut-off levels stratified by gender, race and the year of the study over 5 years. Mean age was 68.3 ± 10.0 years; 90% women and 88% white. Mean 25-OHD level was 24.6 ± 10 ng/ml and mean PTH was 48.4 ± 32 pg/ml. The prevalence of vitamin D depletion was 15% with a cut-off level of