No genetic causal association between iron status and osteoporosis: A two-sample Mendelian randomization.

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.

Significance of ß-catenin expression for the incidence of pathological fractures in giant cell tumors of bone.

Aim of the study is to determine the possible roles of p53, cyclin D1, ß-catenin and Ki-67 in the increase in risk of fractures in patients with giant cell tumor of bone. The study included a total of 164 patients with giant cell tumor of bone (GCTB), 21 (12.8%) with and 143 (87.2%) without fracture. The samples were analyzed immunohistochemically for expression of Ki-67, p53, cyclin D1 and ß-catenin. According to the immunohistochemical expression of p53 and Ki 67 in mononuclear stromal cells, as well as of cyclin D1 in multinuclear giant cells, there was no significant association with immunopositivity and risk of fractures. However, our research revealed that patients with cytoplasmic expression of b-catenin in stromal cells had three times more frequent occurrence of pathological fractures, which was highly statistically significant (χ2 = 7.065; p = 0.008). Moreover, a highly statistically significant correlation between the nuclear expression of ß-catenin in giant cells and the incidence of pathological fractures was also found (χ2 = 8.824; p = 0.003). The study showed that ß-catenin expression highly correlates with the incidence of pathological fractures in patients with GCTB. Taking into account that ß-catenin is closely linked to activation of the Wnt signaling pathway in GCTB pathogenesis, one could postulate that activation of the Wnt pathway is one of the contributing factors to locally destructive behavior of this tumor, as well as to the incidence of pathological fractures.

Mesenchymal phosphaturic tumour: early detection of recurrence.

The case of a recurrent phosphaturic mesenchymal tumour of the maxillary sinus 10 years after the first surgical excision is reported. The neoplasm first presented with paraneoplastic osteomalacia causing a pathological femur fracture. A right maxillary sinus tumour was identified and treated thereafter. The patient had no local symptoms and serum electrolytes returned to normal after surgical removal of the tumour. However, 10 years later, the patient's urine Ca and P levels increased and an octreoscan detected a new tumour in the right maxillary sinus. Early diagnosis prevented the effects of the paraneoplastic activity of the neoplasm. This case emphasises the importance of specific, close follow-up, because the neoplasm rarely produces local signs indicating its position. To our knowledge, this is the first reported case of a late relapse presenting without relevant symptoms (local pain or swelling or pathological fractures).

Strontium ranelate decreases the incidence of new caudal vertebral fractures in a growing mouse model with spontaneous fractures by improving bone microarchitecture.

UNLABELLED: Young mice over-expressing Runx2 fail to gain bone relative to wild type mice with growth and present spontaneous fractures. It allows, for the first time in rodents, direct assessment of anti-fracture efficacy of strontium ranelate which was able to decrease caudal vertebrae fracture incidence through an improvement of trabecular and cortical architecture. INTRODUCTION: The aim was to investigate whether strontium ranelate was able to decrease fracture incidence in mice over-expressing Runx2, model of severe developmental osteopenia associated with spontaneous vertebral fractures. METHODS: Transgenic mice and their wild type littermates were treated by oral route with strontium ranelate or vehicle for 9 weeks. Caudal fracture incidence was assessed by repeated X-rays, resistance to compressive loading by biochemical tests, and bone microarchitecture by histomorphometry. RESULTS: Transgenic mice receiving strontium ranelate had significantly fewer new fractures occurring during the 9 weeks of the study (-60%, p < 0.05). In lumbar vertebrae, strontium ranelate improves resistance to compressive loading (higher ultimate force to failure, +120%, p < 0.05) and trabecular microarchitecture (higher bone volume and trabecular number, lower trabecular separation, +60%, +50%, -39%, p < 0.05) as well as cortical thickness (+17%, p < 0.05). In tibiae, marrow cavity cross-section area and equivalent diameter were lower (-39%, -21%, p < 0.05). The strontium level in plasma and bone was in the same range as the values measured in treated postmenopausal women. CONCLUSIONS: This model allows, for the first time, direct assessment of anti-fracture efficacy of strontium ranelate treatment in rodents. In these transgenic mice, strontium ranelate was able to decrease caudal vertebral fracture incidence through an improvement of trabecular and cortical architecture.

[Secondary osteoporosis UPDATE. Pathophysiology and management of cancer treatment-induced bone loss/fractures].

Patients with cancers such as breast or prostate cancer who have been treated with hormone deprivation therapies or anti-cancer agents for certain periods of time frequently manifest reduced bone mass or pathological fractures during their clinical course. These are likely due to an imbalance between osteoblastic bone formation and osteoclastic bone resorption resulting from hypogonadism. Bone should be carefully monitored in cancer patients who are going to continually receive adjuvant hormonal or anti-cancer therapies. Administration of anti-bone resorption agents such as bisphosphonates may be necessary to maintain bone mineral density and protect pathological fractures in these cancer patients.

Is there a role for bone morphogenetic proteins in osteoporotic fractures?

The central role of bone morphogenetic proteins (BMPs) in the remodelling process of the human skeleton has been identified in numerous experimental and clinical studies. BMPs appear to be key agents in the osteoblastic differentiation of mesenchymal stem cells, and more recent evidence implicates them with the cells of the osteoclastic lineage. BMP-2, BMP-4, BMP-6 and BMP-7 have been studied in the context of osteoporosis and have been associated with its pathophysiological pathways. The theoretical advantages of local or systemic treatment of osteoporotic fractures with BMPs include the potential of inducing a rapid increase in bone strength locally at the fractured area and systemically in the entire skeleton, as well as accelerating the bone-healing period. Animal models of osteoporotic fractures suggested that the induction of new bone by local or systemic use of BMP-7 should be investigated as potential bone augmentation therapy to improve bone quality in symptomatic spinal osteoporosis. As our knowledge expands, new innovations may provide clinicians with advanced biologically-based therapies for the successful treatment of osteoporotic fractures.

[Fractures and chronic renal insufficiency]. / La patologia fratturativa nei diversi gradi di insufficienza renale cronica.

Chronic renal insufficiency (CRI) causes important modifications in the metabolism of phosphorus and calcium, to which frequently resulting in serious disorders of the skeleton, including demineralization, reduction of the bone resistance and a higher risk of fractures. Renal osteodystrophy is the term used to describe these disorders; they are generally heterogeneous and are classified according to the state of bone turnover into secondary hyperparathyroidism, adynamic bone, and osteomalacia. The incidence of hip fractures in the patients with CRI is higher than in the general population. Hip fractures are an important cause of morbidity and mortality. The evaluation of the fracture risk in the patients with different degrees of CRI is problematic, in particular because of the difficulty in identifying fractures, especially vertebral ones. The instrumental index that best expresses the fracture risk in the general population is bone mineral density (BMD); however, the relationship between low BMD and CRI is disputed. Bone disorders in patients with CRI have in fact a multifactorial pathogenesis and low BMD is not the only risk factor for fractures. Besides densitometric evaluation, also that vertebral morphometric evaluation would be desirable in patients with CRI. The fracture risk increases progressively with the severity of chronic renal disease and it is especially high in patients with renal insufficiency in more advanced-stages CRI (creatinine clearance<15-20 mL/min). However, not only in patients with severe CRI undergoing dialysis, but also in those with milder renal disease is the risk of bone fractures high.

Change of cross-linked telopeptide of type I collagen (ICTP) and other bone resorption markers in patients with bone fragility fractures.

BACKGROUND: The serum concentration of cross-linked telopeptide of type I collagen (ICTP) has been reported to be a useful marker and for both diagnosis and monitoring of bone metastasis. This study was performed to clarify the changes in various bone turnover markers, including ICTP, after bone fragility fracture. METHODS: Seventy-six bone fragility fracture patients (14 men and 62 postmenopausal women; mean age, 77.0 years) were evaluated for bone resorption markers, including serum ICTP. We measured urinary N-terminal telopeptides of type I collagen (NTX) several times after fracture. Furthermore, serum ICTP, serum NTX, urinary deoxypyridinoline (DPD), and urinary C-telopeptide-cross-linked type I collagen (CTX) were measured at the times of both minimum and maximum urinary NTX. RESULTS: Urinary NTX was increased significantly from 86.4 +/- 57.9 to 214.3 +/- 137.2 nmol BCE/mmol Cr following fracture. Serum ICTP showed a similar significant increase from 7.6 +/- 4.7 to 10.4 +/- 5.5 ng/ml in bone fragility fracture patients. Furthermore, other markers also showed similar increases. The level of increase in urinary NTX (148.0%) was especially high compared with other bone resorption markers. On the other hand, the level of increase in serum ICTP (36.8%) was similar to that in serum NTX (39.8%). Serum ICTP levels were significantly correlated with other bone resorption markers, with an especially strong correlation between serum ICTP and serum NTX (r = 0.647, P < 0.001). The percentage of cases in which ICTP exceeded the cutoff value for suspected bone metastasis in postmenopausal women was 73.6%. CONCLUSIONS: The value of ICTP increases with bone fragility fracture and is correlated with other bone resorption markers, and ICTP obviously exceeded the reference value as compared with other bone resorption markers.

Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis.

CONTEXT: Osteoporosis has a significant genetic component. The aromatase-dependent conversion of androgenic precursors is the main source of estrogens in postmenopausal women. OBJECTIVE: The objective of the investigation was to study the relationship of a set of single nucleotide polymorphisms (SNPs) of the aromatase gene with osteoporosis and determine their functional influence on gene transcription. DESIGN, PARTICIPANTS, AND METHODS: This was a case-control study including 135 women with vertebral fractures due to postmenopausal osteoporosis and 312 controls. Alleles at four SNPs situated between exons I.2 and 3 were determined by Taqman assays. Total aromatase RNA and differential allelic-specific expression were studied by RT-real time PCR in adipose tissue samples taken from 50 individuals. RESULTS: The SNPs studied were in strong linkage disequilibrium. A common haplotype, present in about half of the population, was identified as being associated with an increased risk of fractures (odds ratio 1.8, 95% confidence interval 1.2-2.8, P = 0.006). There was evidence of differential allelic expression. In heterozygous individuals, transcripts bearing T alleles at rs700518 SNP (which were included in the risk haplotype) were less abundant than those with the alternative C alleles (P < 0.001). Total aromatase expression was four times lower in fat samples from individuals who were homozygotes for the unfavorable alleles than in the opposite homozygotes (P = 0.007). CONCLUSIONS: A common haplotype of aromatase associated with gene expression is also associated with the risk of osteoporotic vertebral fractures in postmenopausal women. These data are in line with the hypothesis that the aromatase-dependent synthesis of estrogens plays an important role in bone homeostasis in postmenopausal women.

A method for determining the grade of osteoporosis based on risk factors in postmenopausal women.

The aim of this study was to determine whether the probability of osteoporosis and osteopenia was affected by the risk factors, physical examination findings, or radiological investigations such as spinal X-rays in postmenopausal women. We assessed risk factors such as use of hormone replacement therapy, physical activity level, calcium intake, smoking, caffeine consumption, long-term immobilization, previous history of fracture, family history of fracture, presence of certain systemic diseases (hyperthyroidism or hyperparathyroidism), or use of medications (corticosteroids or others), physical examinations, and presence of vertebral fractures on spinal X-rays. Patients' bone mineral density (BMD) was evaluated using dual energy X-ray absorptiometry (DXA) in the lumbar spine, and we compared the risk factors between osteopenic and osteoporotic women according to DXA. We evaluated 235 postmenopausal women who attended our osteoporosis outpatient clinic. Those patients were divided into two groups as either osteopenic (n = 67, mean age: 63.1 years) or osteoporotic (n = 168, mean age: 66.2 years) according to WHO criteria. The lumbar spinal (L1-L2) T-score values were -1.5 +/- 0.6 and -3.1 +/- 0.6 in osteopenic and osteoporotic groups, respectively. There were significant differences between the two groups in terms of mean age and lumbar BMD (p = 0.009 and p < 0.001, respectively). We also observed that vertebral tenderness on palpation, back pain, and existing vertebral fracture (fx) were significantly different between the osteopenic and osteoporotic groups (p < 0.05). As a result of the statistical analysis, we found an equation to determine osteopenic and osteoporotic women by using those four factors (age, vertebral tenderness on palpation, back pain, and existing vertebral fx) in multivariate stepwise logistic regression. The equation is as follows: Y (DXA) = -2.9024 + 0.044 (age in year) + 0.819 (vertebral fx) + 0.877 (pain) + 1.136 (vertebral tenderness). We can estimate whether a postmenopausal woman is osteopenic or osteoporotic based on these risk factors by using the stepwise logistic regression equation.

The use of bisphosphonates in the treatment of osteoporosis.

PURPOSE OF REVIEW: The bisphosphonates alendronate and risedronate, given orally once weekly, are the cornerstone of treatment of postmenopausal osteoporosis, as well as of male and secondary osteoporosis. They reduce significantly the risk of vertebral and nonvertebral fractures; their effects appear early, within 6-12 months, and appear to be sustained. Several questions remain unanswered, however. In addition, data on a new bisphosphonate became available in 2004. RECENT FINDINGS: The optimal duration of treatment has not been clearly established. Long-term data with alendronate are now available, indicating a persistence of alendronate effects on bone mineral density and bone turnover markers several years after stopping treatment given for 5 years. Whether these effects translate into sustained reduction of fractures needs to be further analyzed. Because of their efficacy, bisphosphonate use has been explored in other forms of osteoporosis, such as after androgen deprivation therapy for prostatic cancer. The challenge of long-term compliance with treatment of osteoporosis has triggered the use of intermittent bisphosphonate. The effects of intermittent oral and intravenous ibandronate on bone mineral density, bone turnover, and fractures have been recently reported. SUMMARY: The mechanism by which bisphosphonates improve bone strength is not yet fully understood but probably involves complex effects on different components of bone strength, such as microarchitecture.

Association between endogenous hormones and sex hormone-binding globulin and bone turnover in older women: study of osteoporotic fractures.

Estrogen therapy decreases bone remodeling, but the association between endogenous estradiol (E2), estrone (E1), testosterone (T), and bone turnover in older women is not clear. To test the association of serum E2, E1, free T, and sex hormone-binding globulin (SHBG) with bone turnover, we analyzed cross-sectional relationships among E2, E1, T, SHBG, and biochemical markers of bone turnover serum osteocalcin [OC], serum bone-specific alkaline phosphatase [bAP], and serum breakdown products of C telopeptide of type I collagen [CTx] in 704 women enrolled in the Study of Osteoporotic Fractures. Women with lower estradiol levels tended to have higher levels of bone turnover, but the association was weak (R(2) = 0.01 for the association E2-OC, p = 0.03; and R(2) = 0.024 for E2-CTx, p = 0.001). Relationships between SHBG and turnover were also weak (R(2) for the association SHBG-OC was 0.07, p < 0.001, and 0.03 for SHBG-sCTx, p = 0.03), or not significant (R(2) < 0.01 for the association SHBG-bAP). Associations of E1 and T with these markers were of the same magnitude. These results were not modified after adjustment for age, weight, and smoking status. We conclude that older women with low endogenous hormones have somewhat higher bone turnover, but these associations are weak. Bone turnover is determined mainly by factors other than endogenous concentrations of sex hormones.

Evidence of continuing bone recovery at a mean of 7 years after liver transplantation.

Patients with end-stage liver disease have low bone-turnover osteoporosis, and there is often further bone loss of 20% to 30% after orthotopic liver transplantation (OLT). Bone recovery after OLT has been reported, but data are limited. We undertook studies to determine whether bone recovery continues in the long term. Twenty-eight adult patients alive at least 5 years after OLT were studied (14 men, 14 women). Bone mineral density (BMD), serum parathyroid hormone (PTH), osteocalcin, and vitamin D levels were measured pretransplantation, at 3 months, 12 months, a mean of 46 months, and a mean of 85 months (range, 63 to 117 months) after transplantation. When BMD is expressed as a z score, the results were as follows: x0.82 +/- 0.22 pre-OLT; -2.04 +/- 0.27 at 3 months; -1.68 +/- 0.24 at 12 months; -1.23 +/- 0.24 at a mean of 46 months; and -1.0 +/- 0.26 at a mean of 85 months after OLT. The results at 46 and 85 months were significantly greater than the measurement at 3 months after OLT (P <.05). Furthermore, mean BMD (expressed as a z score) returns to the pre-OLT level at a mean of 85 months. At final follow-up, 9 of 28 patients had elevated PTH levels, and 14 of 27 patients had elevated osteocalcin levels. Five patients had spontaneous fractures in the first 12 months after transplantation, and 5 more patients had fractures by final follow-up. Even at 7 years after OLT, there was a significant increase in BMD (expressed as a z score) compared with 3 months after transplantation. Elevation of serum PTH and osteocalcin levels in some patients suggests continuing bone remodeling.

Intravenous bisphosphonate prevents symptomatic osteoporotic vertebral collapse in patients after liver transplantation.

Osteoporosis is common in patients with chronic cholestatic liver disease, and atraumatic spinal fracture is a recognized complication after orthotopic liver transplantation. Bisphosphonates are potent inhibitors of osteoclast bone resorption and have been successfully used to treat postmenopausal osteoporosis. We examined whether preoperative bone mineral density can predict the risk of fracture after orthotopic liver transplantation and whether intravenous bisphosphonate can prevent fractures in high-risk patients. Beginning in February 1993, standard bone mineral density measurements of the lumbar spine were performed as part of routine pretransplantation assessment. On the basis of a preliminary analysis from January 1995, patients with a lumbar spine bone mineral density of <0.84 g/cm2, or <84% of the predicted value (age/sex), were treated with intravenous bisphosphonate (pamidronate disodium) every 3 months before and for 9 months after liver transplantation. Bone mineral density measurements were available in 90 of 136 consecutive first transplants performed in our unit from February 1993 to September 1996. Before the use of pamidronate, 7 patients sustained symptomatic vertebral fractures. Their mean spine bone mineral density was lower than in the 38 patients with no clinical evidence of fracture (81.8% +/- 12.3% v 94.2% +/- 10.2%; P = .006). Since the introduction of pamidronate, no symptomatic vertebral fractures have occurred. Of 29 surviving patients with bone mineral density <0.84 g/cm2 before transplantation, 38% who did not receive treatment with pamidronate suffered spontaneous fracture, whereas 0 of 13 who received treatment suffered such a complication. A low lumbar spine bone mineral density is associated with a high risk of symptomatic vertebral fracture after liver transplantation. These results suggest that this risk is considerably reduced by the administration of intravenous bisphosphonate before and after transplantation.

A human cadaver model for determination of pathologic fracture threshold resulting from tumorous destruction of the vertebral body.

STUDY DESIGN: Thoracic vertebrae were subjected to compressive loads after drilling of the centrum to simulate destruction from metastatic tumorous involvement. OBJECTIVE: To determine whether a threshold exists that is predictive of fractures to establish a correlation between significant variables and vertebral strength. SUMMARY OF BACKGROUND DATA: The mechanical effects of metastatic destruction of thoracic vertebral bodies and their correlation to pathologic fractures has been analyzed in few studies. In additional studies on intact vertebral strength, investigators have determined that bone mineral density and geometric factors are important. METHOD: Fifty-four cadaveric thoracic vertebrae were studied. All were examined by quantitative computed tomography. T4 and T10 served as mechanical controls to predict the intact strength of T7. The test vertebrae were drilled from the anterior cortex through to the posterior cortex before they were loaded. RESULTS: Linear correlation between the strength of T4 and T10 in each spine supported the predicted strengths of T7. Because of variation from other factors, no threshold defect size was noted beyond which failure consistently occurred. Results of linear correlation analyses showed that the best combination of parameters for predicting vertebral strength was the product of bone mineral density and the remaining intact vertebral body cross-sectional area. This vertebral strength index correlated linearly with the strength of intact and compromised T7 vertebrae (r2 = 0.52). CONCLUSIONS: The vertebral strength index can be used to predict the strength of any thoracic vertebra. When compared with an idealized vertebral strength index based on the intact vertebral cross-sectional area and normal bone mineral density, a patient's actual vertebral strength index can be used as one of the criteria for prophylactic stabilization.

Modulation of renal osteodystrophy by extrarenal production of calcitriol.

We report a patient with severe chronic renal failure who developed spontaneous bone fractures. He was found to have hypercalcemia, normal calcitriol levels (probably due to extrarenal production by noncaseating granulomas), and functional hypoparathyroidism. The bone biopsy showed low bone turn-over and the presence of noncaseating granulomas. Treatment with corticosteroids decreased the calcium and calcitriol levels and the parathyroid hormone levels rose. No further fractures occurred. A repeat bone biopsy revealed the presence of osteitis fibrosa. Renal osteodystrophy may be modulated by extrarenal production of calcitriol. In this case, excessive suppression of parathyroid hormone by endogenous calcitriol presumably caused an adynamic bone lesion and spontaneous fractures.

Sequential serum aluminum and urine aluminum: creatinine ratio and tissue aluminum loading in infants with fractures/rickets.

Aluminum toxicity is associated with the development of bone disorders, including fractures, osteopenia, and osteomalacia. Fifty-one infants with a mean (+/- SEM) birth weight of 1007 +/- 34 g, gestational age of 28.5 +/- 0.3 weeks, and serial radiographic documentation at 3, 6, 9, and 12 months for the presence (n = 16) or absence (n = 35) of fractures and/or rickets were studied at the same intervals to determine the serial changes in serum aluminum concentrations and urine aluminum-creatinine ratios. Autopsy bone samples were used to determine the presence of tissue aluminum. Serum aluminum concentrations from 46 infants were stable and similar between groups, with mean values between 15 and 22 micrograms/L. Urine aluminum-creatinine (micrograms per milligram) ratios from 14 infants were higher in infants with fractures and/or rickets (0.26 +/- 0.06 vs 0.12 +/- 0.04) at onset, and rate of decrease in aluminum-creatinine ratio was faster in infants without fractures and/or rickets. All but three infants were tolerating complete enteral feeding at all sampling points. One infant who received aluminum-containing antacid had marked increase in serum aluminum to 83 micrograms/L while urine aluminum-creatinine ratio increased from 0.09 to a peak of 8.53. Vertebrae from three infants at autopsy (full enteral feeding was tolerated for 37 and 41 days in two infants, respectively) showed aluminum deposition in the zone of provisional calcification and along the newly formed trabecula.(ABSTRACT TRUNCATED AT 250 WORDS)