Ana Monegal

Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.

OBJECTIVES:Osteopenia increases the morbidity of primary biliary cirrhosis (PBC). In this study, we have compared two bisphosphonates, alendronate and cyclical etidronate, that inhibit osteoclast-mediated bone resorption and have examined their effects on bone mass in patients with this disease.METHODS:A total of 32 women with PBC were randomly assigned to receive alendronate (10 mg/day) or etidronate (400 mg/day) for 14 days every 3 months. Bone mineral density of the lumbar spine and proximal femur were measured initially and every 6 months. Bone fractures and markers of bone mineral metabolism were also evaluated.RESULTS:Sixteen patients were allocated to each group, which were comparable with respect to the severity of PBC and osteopenia. Thirteen patients in each group completed the 2-yr trial. Both treatments increased bone mineral density after 2 yr, although the increase at the lumbar spine and at the proximal femur was significantly higher in patients receiving alendronate than in patients on etidronate. This higher effect of alendronate paralleled with changes in the biochemical markers of bone turnover. No patient developed new vertebral fractures, but new peripheral fractures were detected in two patients on alendronate and in one on etidronate. There were no serious adverse effects. Neither treatment impaired liver function or cholestasis.CONCLUSIONS:Alendronate effectively increases bone mass and has greater antiresorptive power than etidronate in patients with primary biliary cirrhosis, and is associated with minor or no side effects.

Effect of vertebroplasty on pain relief, quality of life, and the incidence of new vertebral fractures: A 12-month randomized follow-up, controlled trial

Uncertainty regarding the benefits of vertebroplasty (VP) for the treatment of acute osteoporotic vertebral fractures has recently arisen. A prospective, controlled, randomized single‐center trial (ClinicalTrials.gov registration number NCT00994032) was designed to compare the effects of VP versus conservative treatment on the quality of life and pain in patients with painful osteoporotic vertebral fractures, new fractures and secondary adverse effects were also analyzed during a 12‐month follow‐up period. A total of 125 patients were randomly assigned to receive conservative treatment or VP. The primary end point was to compare the evolution of the quality of life (Quality of Life Questionnaire of the European Foundation for Osteoporosis [Qualeffo‐41] and pain (Visual Analogue Scale [VAS]) during a 12 month follow‐up. Secondary outcomes included comparison of analgesic consumption, clinical complications, and radiological vertebral fractures at the same time points. Both arms showed significant improvement in VAS scores at all time points, with greater improvement (p = 0.035) in the VP group at the 2‐month follow‐up. Significant improvement in Qualeffo total score was seen in the VP group throughout the study, whereas this was not seen in the conservative treatment arm until the 6‐month follow‐up. VP treatment was associated with a significantly increased incidence of vertebral fractures (odds ratio [OR], 2 · 78; 95% confidence interval [CI], 1.02–7.62, p = 0.0462). VP and conservative treatment are both associated with significant improvement in pain and quality of life in patients with painful osteoporotic vertebral fractures over a 1‐year follow‐up period. VP achieved faster pain relief with significant improvement in the pain score at the 2‐month follow‐up but was associated with a higher incidence in vertebral fractures.

Collagen‐Related Markers of Bone Turnover Reflect the Severity of Liver Fibrosis in Patients with Primary Biliary Cirrhosis

The influence of a nonskeletal disease with increased connective tissue synthesis or degradation in the collagen‐related markers of bone turnover has been evaluated in 34 women with primary biliary cirrhosis (PBC; age range 41–81 years), a disease with increased hepatic fibrosis, often associated with osteoporosis. Serum osteocalcin (BGP), and carboxy‐terminal (PICP) and amino‐terminal (PINP) propeptides of type I collagen were assessed as indexes of bone formation, whereas serum tartrate‐resistant acid phosphatase (TRAP), and cross‐linked carboxy‐terminal telopeptide of type I collagen (ICTP), and urinary hydroxyproline (HYP), pyridinoline (PYR), deoxypyridinoline (DPYR), and type I collagen cross‐linked N‐ (NTX) and C‐telopeptide (CTX) were measured as markers of bone resorption. The histologic stage of the disease and serum amino‐terminal propeptide of type III collagen (PIIINP) as an index of liver fibrogenesis were also evaluated. BGP levels were significantly lower, whereas PICP and PINP levels were higher in patients than in controls. Among the bone resorption markers, serum ICTP and urinary PYR, DPYR, HYP, NTX, and CTX levels were significantly higher in patients than in controls. Serum PIIINP levels were also increased in PBC patients. BGP did not correlate with PICP and PINP, but these markers of bone formation as well as ICTP, PYR, DPYR, and NTX correlated with serum PIIINP levels. Serum TRAP did not correlate with collagen‐related markers of bone resorption. Moreover, patients with PIIINP and bilirubin above normal levels had higher PICP, PINP, ICTP PYR, DPYR, CTX, and NTX. These markers correlated with the histologic stage of the disease, but not with osteopenia measured by densitometric procedures in 22 patients. In conclusion, collagen‐related markers of bone turnover do not reflect bone remodeling in PBC. The close association of these markers with PIIINP and the clinical and histologic stage of the liver disease suggests that they are influenced by liver collagen metabolism.

Low Bone Mass and Severity of Cholestasis Affect Fracture Risk in Patients With Primary Biliary Cirrhosis

BACKGROUND & AIMS The influence of osteoporosis and liver disease on fracture risk is not well characterized in patients with primary biliary cirrhosis (PBC). We studied a large series of women with PBC to assess the prevalence and risk factors for fractures and the fracture threshold. METHODS In female patients with PBC (n = 185; age, 55.7 +/- 0.7 years; range 28-79 years), age, duration of PBC, menopausal status, and histologic stage and severity of liver disease were assessed. Vertebral and non-vertebral fractures were recorded in 170 and 172 patients, respectively. Osteoporosis and osteopenia were diagnosed based on densitometry analysis. RESULTS The prevalences of vertebral, non-vertebral, and overall fractures were 11.2%, 12.2%, 20.8%, respectively. Osteoporosis was significantly more frequent in patients with PBC than in normal women. Osteoporosis was associated with age, weight, height, histologic stage, severity, and duration of liver damage; fractures were associated with osteoporosis, menopause, age, and height but not with severity of PBC. Osteoporosis was a risk factor for vertebral fracture (odds ratio [OR], 8.48; 95% confidence interval [CI]: 2.67-26.95). Lumbar T score <-1.5 (OR, 8.27; 95% CI: 1.84-37.08) and femoral neck T score <-1.5 (OR, 6.83; 95% CI: 1.48-31.63) were significant risk factors for vertebral fractures. CONCLUSIONS Fractures, particularly vertebral fractures, are associated with osteoporosis, osteopenia, and T scores less than -1.5, whereas osteoporosis and osteopenia are associated with the severity of liver damage. Patients with T scores less than -1.5 might require additional monitoring and be considered for therapy to prevent fractures.

Septic arthritis in heroin addicts

Over a 6-year period (1982 to 1988), 36 episodes of septic arthritis were diagnosed in 35 heroin addicts from Barcelona, Spain. Thirty (86%) were men and five (14%) were women, with a mean age of 24 years (range, 14 to 39). Twenty-nine episodes (80%) were monoarticular and seven (20%) were oligoarticular. The sacroiliac (16 cases), sternoclavicular (8), hip (5), and shoulder (4) joints were most frequently infected. Staphylococcus aureus and Pseudomonas aeruginosa were the etiological agents in 75% and 11% of episodes, respectively. Response to antibiotic treatment was good in 32 cases (90%), eight patients needed surgical drainage, and none died. We conclude that septic arthritis in heroin addicts localizes predominantly in axial joints. In our geographic area, infection with S aureus is more frequent than with gram-negative rods such as P aeruginosa or Serratia marcescens, which are most frequently found in reports from the United States.

25 hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis

UNLABELLED It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis. METHODS We included 120 postmenopausal osteoporotic women (aged 68 ± 8 years) receiving BP (alendronate or risedronate) at their annual follow-up, performing complete anamnesis, including treatment adherence, use of vitamin D supplements, and previous falls and fractures during the last year. We analyzed the evolution of bone mineral density (BMD) during this period and serum PTH and 25 hydroxyvitamin D (25(OH)D) and urinary NTx levels. Patients were classified as inadequate responders to antiosteoporotic treatment based on BMD loss>2% and/or the presence of fragility fractures during the last year. RESULTS Thirty percent of patients showed inadequate response to BP treatment, with significantly lower levels of 25(OH)D (22.4 ± 1.3 vs. 26.6 ± 0.3 ng/ml, p=0.01), a higher frequency of 25(OH)D levels<30 ng/ml (91% vs. 69%, p=0.019) and higher urinary NTx values (42.2 ± 3.9 vs. 30.9 ± 2.3 nM/mM, p=0.01). Patients with 25(OH)D>30 ng/ml had a greater significant increase in lumbar BMD than women with values <30 ng/ml (3.6% vs. 0.8%, p<0.05). The probability of inadequate response was 4-fold higher in patients with 25(OH)D<30 (OR, 4.42; 95% CI, 1.22-15.97, p=0.02). CONCLUSIONS Inadequate response to BP treatment is frequent in postmenopausal women with osteoporosis as is vitamin D insufficiency, despite vitamin D supplementation. Maintenance of 25(OH)D levels >30 ng/ml is especially indicated for adequate response to BP treatment.

Pamidronate in the prevention of bone loss after liver transplantation: a randomized controlled trial

Rapid bone loss and high rates of fractures occur following liver transplantation. To analyze the effect of intravenous pamidronate on bone loss after liver transplantation. A randomized, double‐blind, placebo‐controlled study was performed. Seventy‐nine patients were randomized to two groups of treatment: the pamidronate group (n = 38) was treated with 90 mg/IV of pamidronate within the first 2 weeks and at 3 months after transplantation; the placebo group (n = 41) received glucose infusions at the same time points. All patients received calcium and vitamin D. Bone mineral density (BMD) at the lumbar spine (L2–L4) and proximal femur using dual energy X‐ray absorptiometry and also spinal X‐rays were performed before, and at 6 and 12 months after liver transplantation. Biochemical and hormonal determinations were performed previous to transplantation, at 24 h before and after treatment, as well as at 6 and 12 months after liver transplantation. At 12 months after transplantation, there were significant differences in lumbar BMD changes (6 months: pamidronate 1.6% vs. placebo 0.8%, P = NS; 12 months: pamidronate 2.9% vs. placebo 1%, P < 0.05). Femoral neck BMD decreased in the pamidronate‐ and placebo groups during the first 6 months (6 months: pamidronate −3.1% vs. placebo −2.9%, P = NS; 12 months: pamidronate −3.2% vs. placebo −3.1%, P = NS). BMD at the trochanter remained stable in the pamidronate group, whilst a reduction was observed in the placebo group at 6 months (6 months: pamidronate −0.7% vs. placebo −3.7%, P < 0.05; 12 months: pamidronate −0.5% vs. placebo −1.2%, P = NS). Moreover, no significant differences in the incidence of fractures, serum parathyroid hormone and serum 25‐hydroxyvitamin D values between both groups were found. Pamidronate did not increase the risk of serious adverse events. The results of this study show that 90 mg of intravenous pamidronate within the first 2 weeks and at 3 months following liver transplantation preserve lumbar bone mass during the first year, without significant adverse events. However, pamidronate does not reduce bone loss at the femoral neck and furthermore it does not reduce skeletal fractures.

Search for hidden secondary causes in postmenopausal women with osteoporosis.

Objective: The prevalence of secondary processes in women with postmenopausal osteoporosis (OP) is not well known. The aim of this study was to analyze the prevalence of conditions contributing to bone loss in postmenopausal women with OP and to evaluate the clinical characteristics and the impact of these disorders on the severity of the disease. Methods: A total of 204 postmenopausal women (mean ± SD age, 64.9 ± 10 y) with OP were prospectively included. None had an evident secondary cause of OP. Bone mineral density assessment, spine x-ray, and laboratory tests including parathormone (PTH), 25-hydroxyvitamin D (25OHD), thyroid hormones, urinary N-terminal cross-linked telopeptide of type I collagen (NTx), and 24-hour urinary calcium and cortisol were performed in all participants before treatment. Results: As a group, 82% had low 25OHD levels (<30 ng/mL), 35% had increased PTH levels (>65 pg/mL), and 20% had hypercalciuria (>250 mg/24 h). In addition, 41% had increased NTx urinary levels (>65 nmol/mmol). PTH levels were related to age and were higher in women with femoral Z score less than −2.0 (80.3 pg/mL vs 57.7 pg/mL; P = 0.03). Participants with increased urinary NTx showed lower lumbar T and Z scores, whereas women with low 25OHD levels had lower femoral neck bone mineral density and T score values. In addition, participants with vertebral fractures had higher prevalence of 25OHD levels less than 20 ng/mL (69.2% vs 53.4%; P < 0.05). Conclusions: Secondary processes that contribute to low bone mass in postmenopausal women with OP are frequent, especially vitamin D insufficiency, increased PTH values, and hypercalciuria. In addition, increased bone resorption is frequently observed in this group of women. Most of these processes contributed to the severity of the disease.

Effects of bilirubin and sera from jaundiced patients on osteoblasts: Contribution to the development of osteoporosis in liver diseases†

Low bone formation is considered to be the main feature in osteoporosis associated with cholestatic and end‐stage liver diseases, although the consequences of retained substances in chronic cholestasis on bone cells have scarcely been studied. Therefore, we analyzed the effects of bilirubin and serum from jaundiced patients on viability, differentiation, mineralization, and gene expression in the cells involved in bone formation. The experiments were performed in human primary osteoblasts and SAOS‐2 human osteosarcoma cells. Unconjugated bilirubin or serum from jaundiced patients resulted in a dose‐dependent decrease in osteoblast viability. Concentrations of bilirubin or jaundiced serum without effects on cell survival significantly diminished osteoblast differentiation. Mineralization was significantly reduced by exposure to 50 μM bilirubin at all time points (from −32% to −55%) and jaundiced sera resulted in a significant decrease on cell mineralization as well. Furthermore, bilirubin down‐regulated RUNX2 (runt‐related transcription factor 2) gene expression, a basic osteogenic factor involved in osteoblast differentiation, and serum from jaundiced patients significantly up‐regulated the RANKL/OPG (receptor activator of nuclear factor‐κB ligand/osteoprotegerin) gene expression ratio, a system closely involved in osteoblast‐induced osteoclastogenesis. Conclusion: Besides decreased cell viability, unconjugated bilirubin and serum from jaundiced patients led to defective consequences on osteoblasts. Moreover, jaundiced serum up‐regulates the system involved in osteoblast‐induced osteoclastogenesis. These results support the deleterious consequences of increased bilirubin in advanced chronic cholestasis and in end‐stage liver diseases, resulting in disturbed bone formation related to osteoblast dysfunction. (HEPATOLOGY 2011)

Incidence of skeletal fractures after traumatic spinal cord injury: a 10-year follow-up study:

Objective: To analyse the incidence and factors related to the development and clinical evolution of fractures in patients with traumatic spinal cord injury. Design: A retrospective 10-year follow-up study. Setting: Neurorehabilitation centre. Subjects: Sixty-three patients (50M/13F) with a mean age of 36 ± 20 years with recent traumatic spinal cord injury attended over a one-year period (January to December 2000). Main measures: Medical reports were reviewed, evaluating risk factors for osteoporosis, fracture incidence during the 10 years following spinal cord injury, severity (ASIA score) and level of spinal cord injury (paraplegia/tetraplegia), type of lesion (spastic/flaccid), weight-bearing standing activity, and the cause, location and evolution of the fracture. Results: Of the 129 patients attending during the study period, 75 had traumatic spinal cord injury (7 died and 5 had no follow-up). Finally, 63 patients were included. Fifty-four per cent had complete motor injury (ASIA A). Twenty-five per cent of these patients developed fractures, with 2.9 fractures per 100 patient-years. The femur was the most frequent location of the fractures. Fractures were observed 6.4 ± 2.4 years after spinal cord injury (range 2–10 years), all in males. Most fractures (70%) were related to low-impact injuries. Fifty per cent presented with associated clinical complications and only 20% of the patients had received anti-osteoporotic treatment. Spinal cord injury severity was the only risk factor for the development of fractures (complete spinal cord injury (ASIA A)) (RR 4.043; 95% confidence interval (CI) 1.081–23.846, P = 0.037). Conclusion: The incidence of fractures after spinal cord injury is high, with severity and time since spinal cord injury being the main determinants for their development. Fractures were frequently associated with clinical complications. However, the use of anti-osteoporotic treatment was uncommon.