Snyder-Robinson syndrome: differential diagnosis of osteogenesis imperfecta.

Snyder-Robinson syndrome is an extremely rare genetic disorder, caused by mutations of the spermine synthase gene. We report a novel case of Snyder-Robinson syndrome, caused by a de novo mutation and first misdiagnosed with osteogenesis imperfecta. Clinical features, course, and genetic analysis are presented. The patient was treated with bisphosphonates for a decade, until developing an atypical femoral fracture. Teriparatide was then administered for 2 years and then changed to denosumab every 6 months, improving his bone density mass and preventing further fractures.

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

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

Patients with cirrhosis and ascites have false values of bone density: implications for the diagnosis of osteoporosis.

UNLABELLED: The effect of ascites on bone densitometry has been assessed in 25 patients with advanced cirrhosis, and it was concluded that ascites over 4 l causes inaccuracy of BMD measurements, particularly at the lumbar spine. This fact must be considered when assessing bone mass in patients with decompensated cirrhosis. INTRODUCTION: Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DXA) is the best procedure for assessment of osteoporosis and fracture risk, but BMD values at the central skeleton may be influenced by changes in soft tissues. Therefore, we have studied the effect of ascites on BMD. METHODS: BMD was measured by DXA at the lumbar spine, femoral neck and total hip, just before and shortly after therapeutic paracentesis in 25 patients with advanced liver cirrhosis. Changes in BMD, lean and fat mass, abdominal diameter and weight, as well as the amount of removed ascites were measured. RESULTS: The amount of drained ascites was 6.6 ± 0.5 l (range: 3.0 to 12.7 l). After paracentesis, BMD increased at the lumbar spine (from 0.944 ± 0.035 to 0.997 ± 0.038 g/cm(2), p < 0.001) and at the total hip (from 0.913 ± 0.036 to 0.926 ± 0.036 g/cm(2), p < 0.01). Patients with a volume of drained ascites higher than 4 l showed a significant increase in lumbar BMD (7.0%), compared with patients with a lower amount (1.5%) (p < 0.03). The decrease in total soft tissue mass correlated with the amount of removed ascites (r = 0.951, p < 0.001). Diagnosis of osteoporosis or osteopenia changed after paracentesis in 12% of patients. CONCLUSION: Ascites over 4 l causes inaccuracy of BMD measurements, particularly at the lumbar spine. This fact must be considered when assessing bone mass in patients with advanced cirrhosis.

Prolonged bisphosphonate release after treatment in women with osteoporosis. Relationship with bone turnover.

Bisphosphonates (BP), especially alendronate and risedronate, are the drugs most commonly used for osteoporosis treatment, being incorporated into the skeleton where they inhibit bone resorption and are thereafter slowly released during bone turnover. However, there are few data on the release of BP in patients who have received treatment with these drugs for osteoporosis. This information is essential for evaluating the possibility of BP cyclic therapy in these patients and for controlling their long-term presence in bone tissue. This study evaluated the urinary excretion of alendronate and risedronate in patients treated with these drugs for osteoporosis and analysed its relationship with bone turnover, time of previous drug exposure and time of treatment discontinuation. We included 43 women (aged 65±9.4 years) previously treated with alendronate (36) or risedronate (7) during a mean of 51±3 and 53±3 months, respectively, who had not been treated with other antiosteoporotic treatment and with a median time of discontinuation of 13.5 and 14 months, respectively. Both BP were detected in 24-hour urine by HPLC. In addition, bone formation (PINP) and resorption (NTx) markers were analysed. Both BP were also determined in a control group of women during treatment. Alendronate was detected in 41% of women previously treated with this drug whereas no patient previously treated with risedronate showed detectable urinary values. All control patients showed detectable values of both BP. In patients with detectable alendronate levels, the time of drug cessation was shorter than in patients with undetectable values (12 [6-19] versus 31 [7-72] months, p<0.001). Alendronate was not detected in any patient 19 months after treatment cessation. Alendronate levels were inversely related to time of treatment discontinuation (r=-0.403, p=0.01) and the latter was directly related to NTx (r=0.394, p=0.02). No relationship was observed with age, length of drug exposure, renal function or weight. In conclusion, contrary to risedronate, which was not detected in patients after cessation of treatment, alendronate was frequently detected in women previously treated with this agent up to 19 months after discontinuation of therapy. The relationship between alendronate levels and both bone resorption and time of treatment cessation further indicates a residual effect of this drug in bone, despite treatment discontinuation.

Lithocholic acid downregulates vitamin D effects in human osteoblasts.

BACKGROUND: Osteoporosis is a common complication in chronic cholestasis. It has been proposed that retained substances such as bile acids may produce a damaging effect on bone cells. This study analyses the effects of lithocholic acid (LCA) on cell survival and vitamin D metabolism in human osteoblasts (hOB). MATERIALS AND METHODS: Human osteoblasts cultures were performed with or without foetal bovine serum (FBS) or human albumin (HA) at different LCA concentrations and times with or without vitamin D. RESULTS: Lithocholic acid at concentrations higher than 10(-5 )M decreased cell survival. This effect was partially prevented by the presence of FBS or HA. Vitamin D stimulated CYP24A, BGLAP and TNFSF11 expression in hOB and these effects were modified by nontoxic LCA concentrations. LCA significantly decreased vitamin D stimulation of CYP24A, BGLAP and TNFSF11 gene expression at 72%, 79% and 56% (respectively). LCA alone has an agonistic effect, as has vitamin D, thus partially increasing CYP24A and BGLAP expression, but with no changes on TNFRSF11B expression. Equivalent effects of the LCA were observed by performing gene reporter assays using MG-63 cells transfected with constructs containing CYP24A1 promoter regions. CONCLUSIONS: Lithocholic acid decreases the stimulatory effect of vitamin D on CYP24A, BGLAP and TNFSF11 expression in hOB. This effect is produced through vitamin D response elements (VDREs), located in the promoter regions of these genes, suggesting that LCA acts as a mild analogous of vitamin D, interacting with the vitamin D receptor. These results may explain the potential deleterious effects of retained bile acids on hOB.

Prostaglandin E2 and bone turnover markers in the evaluation of primary hypertrophic osteoarthropathy (pachydermoperiostosis): a case report.

Primary hypertrophic osteoarthropathy, or pachydermoperiostosis (PDP), is an infrequent genetic condition characterized by digital clubbing, periostosis, and pachydermia and is distinct from a more common form, secondary hypertrophic osteoarthropathy, which always associates with an underlying cause (frequently pulmonary or cardiac disease). The diagnosis of this disorder as well as its clinical evaluation can be difficult. We report a 15-year-old boy presenting with intermittent arthralgias and clubbing of fingers and toes for the previous 2 years. The ankles and knees were enlarged, and X-rays showed periosteal apposition. The search for a secondary cause was negative. The skin appearance was normal, but a skin biopsy was indicative of pachydermia, further confirming the diagnosis of PDP. Bone turnover markers were increased at diagnosis and progressively decreased during follow-up; prostaglandin E(2), a recently implicated mediator of this disorder, was markedly elevated. In the present case, carrying out a skin biopsy helped us to diagnose this condition. In addition, bone turnover markers were useful for monitoring the disease activity; whereas, increased prostaglandin E(2) levels seems to confirm the role of this mediator in the etiopathogenesis of this disorder.

Aetiology and clinical characteristics of male osteoporosis. Have they changed in the last few years?

OBJECTIVE: The aim of this study was to analyse the clinical characteristics and etiological factors related to male osteoporosis in patients attending an out-patient rheumatology department during an 11-year period (1995-2006), as well as to compare them with the observed characteristics in a previous study performed 12 years ago. METHODS: 232 males aged 21-88 (mean 56.1+/-14) with osteoporosis were included in the study. Previous skeletal fractures and family history of osteoporosis were recorded. Bone mass assessment, automated biochemical profile and hormonal measurements (including PTH, 25-OH vitamin D, cortisol, thyroid and sexual hormones) were performed on most patients as well as 24 h urinary calcium, and bone markers. In patients with idiopathic osteoporosis 1-25-OH2 vitamin D was also determined. In addition, x-rays of the spine were obtained for all patients. RESULTS: 67% of the patients had previous skeletal fractures and 51% had vertebral fractures. 57% of the patients had idiopathic and 43% had secondary osteoporosis whereas in the previous series only 22% of the patients had idiopathic disease. The most frequent causes of secondary osteoporosis were corticosteroid therapy, hypogonodism and alcoholism. 38% of the patients with idiopathic osteoporosis had associated hypercalciuria. Patients with secondary osteoporosis were older, shorter, had lower femoral neck T-score and lower serum values of 25-OH vitamin D and testosterone, as well as higher gonadotrophin and PTH values than the patients with idiopathic osteoporosis, whereas patients with idiopathic osteoporosis had higher urinary calcium and more frequent family history of osteoporosis. Hypercalciuric patients were younger, had lower lumbar BMD, higher urinary calcium and greater incidence of lithiasis than normocalciuric patients with idiopathic osteoporosis. Back pain, frequently associated with vertebral fractures, was the most common cause of referral in all groups of patients. CONCLUSION: Idiopathic osteoporosis is the most frequent cause of male osteoporosis in this study. In these patients, family history of osteoporosis and associated hypercalciuria are frequent. The most frequent causes of secondary osteoporosis in males include corticosteroid therapy, hypogonadism and alcoholism. Although clinical characteristics of male osteoporosis are similar to that previously reported, in this study the percentage of patients with idiopathic osteoporosis was higher than previously observed.

Idiopathic osteoporosis in premenopausal women. Clinical characteristics and bone remodelling abnormalities.

OBJECTIVE: Osteoporosis is infrequent in young premenopausal women and is often associated with secondary disorders. However, idiopathic osteoporosis may be found in this setting and few data are known on this condition. Therefore, the aim of this study was to analyse the clinical characteristics and bone remodelling abnormalities in premenopausal women with idiopathic osteoporosis. METHODS: 28 premenopausal women with idiopathic osteoporosis (aged 38.3+/-7.6 years) were included. The patients had one or more fragility fractures and/or decreased bone mass (z-score <-2 in the lumbar spine or femur). In all patients, secondary causes of osteoporosis were excluded and previous skeletal fractures, family history and risk factors for osteoporosis were recorded. In addition, bone mineral density at the lumbar spine and hip, spinal x-rays, and laboratory tests including PTH, 25-hydroxyvitamin D, 1,25 (OH)2 vitamin D and urinary calcium excretion were measured. Bone markers such as serum bone alkaline phosphatase (bone AP) and P1NP, and urinary hydroxyproline (HYP), NTx and CTx were measured and results were compared with those observed in a control group of 28 healthy premenopausal women. RESULTS: 46% of the patients had previous fragility fractures, 53% had family history of osteoporosis, 36% had associated hypercalciuria and 30% had a BMI <20 Kg/m2. Patients with idiopathic osteoporosis had increased bone resorption markers (NTx and HYP) but normal bone formation markers when compared with healthy controls. No significant differences in the clinical and biochemical parameters were observed between patients with or without hypercalciuria. CONCLUSION: Young women with idiopathic osteoporosis have an increased bone resorption without changes in bone formation when assessed by biochemical markers.

Diazepam attenuation of somatostatin binding and effect of somatostatin on accumulation of inositol 1,4,5-trisphosphate in the rat frontoparietal cortex.

Numerous reports in both humans and animals have confirmed that benzodiazepines produce amnesia; however, mechanisms mediating this effect are not clear. In view of the important role of brain somatostatin (SRIF) in the cognitive function of rats, this study sought to determine if the benzodiazepine, diazepam, alters somatostatinergic system in the rat frontoparietal cortex. Intraperitoneal (i.p.) administration of diazepam (5 mg/kg/day) to male Wistar rats (200-250 g) for 3 or 7 days decreased the number of SRIF receptors (26 and 37%, respectively) in synaptosomes from the frontoparietal cortex, without influencing their apparent affinity. This decrease in the tracer binding was not attributable to a direct effect of diazepam on SRIF receptors, because no decrease of SRIF binding was induced by a large concentration of diazepam (10(-4) M) when the drug was added to a preparation of synaptosomes from frontoparietal cortex of untreated rats. To determine if the effect of diazepam on SRIF binding is related to the binding of diazepam to its recognition site on the GABA(A) receptor, a benzodiazepine antagonist, 2-phenylpyrazolo[3,4-c]quinolin-3(5H)-one (CGS 8216) was administered before the diazepam injection. Pretreatment with CGS 8216 (20 mg/kg/day, i.p.) blocked completely the diazepam-induced decrease in the number of SRIF receptors. CGS 8216 alone had no observable effect. The decrease in the number of 125I-Tyr11-SRIF receptor induced by diazepam was accompanied by a decrease in the effect of SRIF, after 15 seconds of stimulation, on inositol 1,4, 5-trisphosphate (IP3) mass accumulation in the rat frontoparietal cortex at 3 (64%) or 7 days (59%) after its administration. Diazepam alone had no observable effect on mass accumulation of IP3. After 14 days of daily diazepam injections, the levels of binding of 125I-Tyr11-SRIF in the frontoparietal cortex returned to control values, coinciding with the tolerance that develops to this benzodiazepine agonists when administered chronically. The decrease in IP3 levels was still observed after 14 days (57%) diazepam administration. Diazepam and CGS 8216 did not affect SRIF-like immunoreactivity levels in the frontoparietal cortex at the three time intervals studied (3, 7 or 14 days). The alteration of frontoparietal cortex SRIF receptor-effector system after 3 or 7 days of diazepam treatment suggests that somatostatinergic neurotransmission plays a role in the mechanism of diazepam action on memory.