Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1).

BACKGROUND: Patients with neurofibromatosis 1 (NF1) are shorter than expected and often have low bone mineral density (BMD), but the pathogenesis of these bony problems is poorly understood. METHODS: We performed an exploratory study of BMD, 18 laboratory measures of bone metabolism, and fracture history in 72 adult NF1 patients. RESULTS: Eight of the 18 clinical biochemical measures of bone health had at least 10% of NF1 patients outside the standard reference range. Serum 25-hydroxy-vitamin D concentrations were low in 56% of the NF1 patients, serum parathyroid hormone (PTH) concentrations were high in 34%, and urine deoxypyridinoline cross-link concentrations were high in 50%. Mean serum 25-hydroxy-vitamin D concentrations were significantly lower in people with NF1 than in season matched controls in both summer (p = 0.008) and winter (p<0.001). 36 (50%) of the 72 people with NF1 studied had BMD consistent with osteopenia, and 14 (19%) had BMD consistent with osteoporosis. High serum PTH concentration, high serum bone tartrate resistant acid phosphatase concentration, and high serum calcium concentration were associated with lower BMD among the NF1 patients. Males were more likely than females to have low BMD. The reported frequency of fractures in individuals with NF1 was much higher than in their unaffected siblings and spouses (p<0.001), and pathological fractures were reported only in NF1 patients. CONCLUSION: People with NF1 often have a generalised abnormality of bone metabolism. Further studies are needed to determine the biochemical and molecular basis of this abnormality.

Health-economic comparison of three recommended drugs for the treatment of osteoporosis.

Osteoporosis is a large and growing disease with significant health consequences. Based on an evaluation of clinical evidence, the German osteology umbrella organization DVO (Dachverband Osteologie deutschsprachiger wissenschaftlicher Fachgesellschaften) published guidelines in March 2003 for the diagnosis and treatment of osteoporosis. For prevention of fractures in women with postmenopausal and senile osteoporosis, these guidelines recommend three treatment options as first-line therapy: risedronate, alendronate and raloxifene. No evidence is currently available for the reduction of hip fractures by raloxifene. Only risedronate and alendronate, therefore, are recommended for prevention of hip fractures. Information on the cost-effectiveness of preventing and treating osteoporosis may support decision makers in more efficient allocation of resources. Accordingly, the objective of this study is the comparative assessment of the cost-effectiveness of risedronate, alendronate and raloxifene for patient populations in Germany at high risk of osteoporotic fracture due to low bone mineral density (BMD) (i.e., T-score < -2.5) and resulting from a history of at least one previous vertebral fracture, as compared to osteoporotic patients with no treatment. Target variables for the economic comparison are costs per hip fracture avoided and costs per quality-adjusted life year (QALY) gained. Hip fractures are the most costly and best-documented complication of osteoporosis. A cost-effectiveness analysis was therefore conducted, using as criteria for evaluating intervention the incremental cost per hip fracture avoided and the cost per QALY gained. We used a fracture-incidence-based Markov model of osteoporosis, with analysis of patients' transition across outcome states over time (e.g., fracture, healthy, dead). Base-case analysis was conducted on a cohort of 1,000 women aged 70 with low spine BMD and prevalent vertebral fracture, over 3 years of treatment with risedronate, alendronate or raloxifene, and with application of a 10-year analytic time horizon. Model inputs included hip and vertebral fracture incidence rates; relative risk of fracture given low BMD and prevalent vertebral fracture, fracture cost, treatment prices/day (risedronate: 35 mg, 1.76 euro; alendronate: 70 mg, 1.82 euro; raloxifene: 60 mg, 1.82 euro); health utility; and efficacy in terms of relative-risk reduction of fracture of the hip (60% risedronate; 51% alendronate; not significant raloxifene) and vertebrae (49% risedronate; 47% alendronate; 30% raloxifene). A 5% discount rate was applied to cost and outcomes. In the base case, treatment with risedronate reduces costs from the social insurance perspective with respect to both endpoints: i.e., costs per averted hip fracture and QALY. Over the 3-year treatment period and 10-year observation, furthermore, risedronate proved superior to alendronate and raloxifene (i.e., risedronate was less expensive and more effective). From the perspective of statutory health insurance, the cost per averted hip fracture is 37,348 euro for risedronate and 48,349 euro for alendronate (costs for raloxifene were not calculated due to a nonsignificant effect on prevention of hip fractures); and cost per QALY gained is 32,092 euro for risedronate, in comparison to patients in Germany with no therapy (alendronate 41,302 euro; raloxifene 1,247,119 euro). This cost-effectiveness analysis gives evidence that bisphosphonates are cost effective. Under consideration of current prices and the published clinical evidence, risedronate dominates the comparison of DVO-recommended drugs.

Pharmacoeconomic analysis of osteoporosis treatment with risedronate.

Hip fracture is an important and costly problem. Therapy with the bisphosphonate risedronate effectively prevents hip and other fractures among women with established osteoporosis. Risedronate is a first-choice therapy option in the German Guidelines of the Dachverband Osteologie for Osteoporosis according to evidence-based medicine criteria for the treatment of postmenopausal osteoporosis, osteoporosis of the elderly (women aged > 75 years) and glucocorticoid-induced osteoporosis. There are few published economic evaluations of bisphosphonates in Germany. Therefore, an assessment of the cost-effectiveness of risedronate utilizing a state transition Markov model of established postmenopausal osteoporosis based on randomized clinical trial data was developed. Uncertainty underlying model parameters and outcomes was dealt with using traditional sensitivity analysis and stochastic sensitivity analysis to produce quasi-95% Cls. We focused on patients aged 70 years, since this population most closely matches the randomized controlled trial and is typical of osteoporosis patients in Germany. The baseline model was a cohort of 1,000 70-year-old women, who received risedronate for 3 years and were followed up for an overall observation period of 10 years, modelling transitions through estimated health states and evaluating outcomes. Over the 3-year treatment period and 10-year observation period, risedronate dominated the current average basic treatment in Germany. In the risedronate group 33 hip fractures were averted and 32 quality-adjusted life years (QALYs) were gained (discounted values). Risedronate treatment saves costs for German social insurance: the present net value of the associated costs from the perspective of German social insurance is [symbol: see text]10.66 million if risedronate treatment is used versus [symbol: see text]11 million if basic treatment is used. Thus, net savings of [symbol: see text]340,000 for the treatment group per 1,000 treated women were calculated. Furthermore, risedronate treatment is cost effective from the perspective of the statutory health insurance with costs per averted hip fracture in the analyzed population of [symbol: see text]33,856 and cost per QALY gained of [symbol: see text]35,690. Both results demonstrate cost-effectiveness and are far below the accepted threshold level of [symbol: see text]50,000. Based on this analysis, risedronate is a cost-effective treatment for postmenopausal osteoporosis within the German health care system, offering benefits for osteoporotic patients and for budget decision-makers.

Bone mineral density in children with primary hyperoxaluria type I.

BACKGROUND: In primary hyperoxaluria type I (PH 1), hepatic overproduction of oxalate leads to its deposition in various organ systems including bone (oxalosis). To evaluate skeletal status non-invasively in PH 1 we measured bone mineral density (BMD). METHODS: Peripheral quantitative computed tomography of the distal radius was performed in 10 children with PH 1 (mean chronological age 9+/-3.1, mean skeletal age 8.3+/-3.0 years): seven were on conservative treatment (CT) including one patient after pre-emptive liver transplantation (PH1-CT) and three were studied with end-stage renal disease on peritoneal dialysis (PH1-ESRD). RESULTS: Mean trabecular bone density (TBD) was significantly increased in PH1-ESRD compared with both age-matched healthy and uraemic controls (65227 vs. 168+/-63 and 256+/-80 mg/cm(3); P<0.002 and P<0.007, respectively), while cortical bone density (CBD) was elevated to a lesser degree (517+/-23 vs. 348+/-81 vs. 385+/-113 mg/cm(3); P<0.02 and P<0.04, respectively). In PH 1, CBD and, even more so, TBD were significantly correlated with serum creatinine (r=0.91 and r=0.96, P<0.0001, respectively) and plasma oxalate levels (r=0.86 and r=0.94, P<0.001 and P<0.0001, respectively). In children with PH 1 and normal glomerular function, both CBD and TBD were comparable with healthy controls. CONCLUSION: These preliminary data suggest that in PH 1 BMD is significantly increased in ESRD, probably due to oxalate disposal. Measurement of BMD may be a valuable and non-invasive tool in determining and monitoring oxalate burden in this disorder.

Can satiety be measured?

An energy-controlled study on a Western diet composed of 45% fat, 40% carbohydrate and 15% protein by energy was carried out. The study consisted of four test phases having a length of 9 days in each case, where 8 healthy free-living subjects were adjusted to individual energy requirements at maintenance level. Between the tests, wash-out phases of 4-5 months were inserted to avoid adaptation effects. By using a standard breakfast of constant composition, satiety was evaluated by applying the concept of categorical comparison, which was based on the common fact, that the perception between two meals is changed and usually a set of sensations can be discriminated. These were termed very full and full (just after finishing a meal), appetite and hungry (just before the next meal). These sensations were used as categories on a categorical scale. The evaluation of satiety was performed such that on each day of the four test phases the subjects had to select over a period of 4 h every 30 min one category out of the four, what corresponded to the individual sensation at that time. This procedure was followed by a mathematical treatment of data such that the individual judgements were transformed into a numerical system. As a result, the time course of satiety was available characterizing the time-dependent change of the interoception after consuming the test meal. Using this concept highly reliable results were obtained as demonstrated by the comparison of the four test series.

[Osteoporosis in the male]. / Die Osteoporose des Mannes.

BACKGROUND: Osteoporotic fractures occur frequently also in men. Epidemiologic data from Germany indicate that more than 900,000 men are affected by osteoporotic fractures. Diagnosis and therapy of male osteoporosis are hampered by a lack of clinical studies. DIAGNOSIS: Risk factor analysis, conventional spine X-rays, bone densitometry and a limited number of serum and urine analyses contribute to the diagnosis of osteoporosis and the assessment of future fracture risk. Bone densitometry at the femoral neck is superior to measurements at the lumbar spine because of the high prevalence of degenerative changes at the lumbar spine in elderly men. Major risk factors for osteoporosis are hypogonadism, glucocorticoid therapy, hypercalciuria, gastrointestinal disease, and high alcohol consumption. In individual cases, bone histology or additional biochemical studies are needed to establish the cause of osteoporosis. THERAPY: Calcium and vitamin D deficits should be substituted both in prevention and treatment of male osteoporosis. Testosterone replacement therapy is effective in hypogonadism. In primary osteoporosis and in corticosteroid-induced osteoporosis, bisphosphonates (cyclical etidronate, alendronate) and fluorides are therapeutic options. CONCLUSION: Important principles in the care of men with osteoporosis are the transfer of knowledge established for postmenopausal osteoporosis and the rigorous search for secondary osteoporosis aiming at treatment of the underlying cause. Large prospective randomized trials aiming at the reduction of fracture rate in male osteoporosis are missing. They are urgently needed.

Effects of inulin on faecal bifidobacteria in human subjects.

A controlled study with eight healthy free-living subjects was carried out, in which energy intake was adjusted to the individual energy requirements. On administration of inulin, blood lipids, the faecal microflora, short-chain fatty acids and accompanying gastrointestinal symptoms were characterized in order to investigate the long-term effect of inulin. During the run-in phase (8 d), subjects received a typical Western diet providing 45% energy as fat and 40% energy as carbohydrate. Subsequently, the subjects consumed a fat-reduced diet which provided 30% energy as fat and 55% energy as carbohydrate for a period of 64 d using inulin as a fat replacer. The amounts of inulin consumed by the subjects (up to 34 g/d) were based on individual energy requirements with the aim to keep the diet isoenergetic with that used in the run-in period. To assess the effects of inulin administration, a control study (run-in and intervention) was carried out in which subjects consumed the same diet but devoid of inulin during the whole course of the study. To investigate the effect of inulin on faecal flora composition total bacteria and bifidobacteria in the faeces were enumerated by in situ hybridization with 16S rRNA targeted oligonucleotide probes. Inulin significantly increased bifidobacteria from 9.8 to 11.0 log10/g dry faeces and caused a moderate increase in gastrointestinal symptoms such as flatulence and bloatedness, whereas blood lipids and short-chain fatty acids remained essentially unaffected.

[Phosphate deficiency as a rare cause of osteomalacia--case report of several years of enteral feeding and antacid therapy]. / Phosphatmangel als seltene Ursache einer Osteomalazie--Fallbericht einer mehrjährigen enteralen Sondenernährung und Antazidatherapie.

HISTORY AND CLINICAL FINDINGS: Floor-of-the-mouth cancer had been diagnosed and surgically treated in a 55-year-old man 4 years before the latest admission. For the last 3 years he had been fed through a percutaneous endoscopic gastrostomy (PEG). Since then he had experienced reflux oesophagitis which was being treated with aluminium-containing antacids. He was hospitalized for the surgical treatment of bilateral fractures of the neck of the femur. A surgical biopsy revealed osteomalacia but no metastasis. INVESTIGATIONS: The serum phosphate level was significantly reduced (0.21 mmol/l) and there was no detectable phosphate excretion in the 24-hour urine. Serum calcium concentration was unremarkable, but there was hypercalciuria (34.4 mmol/d). Alkaline phosphate activity was significantly raised (393 U/l) and parathormone level reduced (7 ng/l). Vitamin D concentration was unremarkable. TREATMENT AND COURSE: The phosphate content in the parenteral feed was at first increased and additional phosphate was given by mouth. The calcium and phosphate levels slowly became normal only after medication had been changed from antacids to H2-blockers. CONCLUSIONS: In this case osteomalacia was caused not by vitamin D deficiency but by a lack of phosphate. The reduced intestinal phosphate absorption by the antacids only partially explains the pronounced clinical signs. If antacids are taken over long periods the phosphate balance should be carefully monitored to avoid osteomalacia.

Bone alkaline phosphatase in children with chronic renal failure.

BACKGROUND: With the introduction of a new immunoradiometric assay based on two monoclonal antibodies (Tandem-Ostase, Hybritech) the determination of bone alkaline phosphatase (BAP) to evaluate bone metabolism in chronic renal failure has become easier and more valid. SUBJECTS AND METHODS: Using this test we investigated BAP in a total of 90 paediatric patients, 42 (9.2+/-5.5 years) with chronic renal failure on conservative treatment, 22 (9.5+/-5.4 years) under chronic dialysis, and 26 (16.2+/-5.9 years) after renal transplantation, compared to 203 controls (10.1+/-5.7 years). RESULTS: The physiological age dependency found in controls including two peaks during infancy and puberty was distinctly disturbed in chronic renal failure. However, in patients BAP significantly correlated with height velocity rather reflecting the last 6 (r=0.56 P<0.001) than the last 12 months. Although BAP correlated well with total alkaline phosphatase (TAP; r=0.95 P<0.001), a significant correlation with the serum level of the intact parathyroid hormone could only be detected for BAP (r=0.45 P<0.001) but not for TAP (r=0.19 n.s.). Furthermore, BAP positively correlated with trabecular (n=40; r=0.40 P<0.05) and inversely with cortical bone density (n=19; r=-0.58 P<0.01) but no relationship was found with conventional X-ray. CONCLUSION: BAP determined by the new radioimmunoassay seems to represent an additional diagnostic tool to assess growth and bone turnover in paediatric patients with chronic renal failure that is complementary to the information provided by X-ray and total alkaline phosphatase.

Bone mineral density in pediatric patients after renal transplantation.

To evaluate the natural history of bone mineral density after successful renal transplantation (TPL) modulated by therapeutic strategies in pediatric patients we have studied peripheral and partially proximal quantitative computed radius tomography (XCT) differentiating between trabecular (TBD), cortical (CBD) and total bone density (BD) cross-sectionally in a group of 24 subjects (mean age 17.1 +/- 7.0 y, mean Scr 1.66 +/- 0.89), 66.1 months (5-260) post transplant and compared the results with 12 controls. After TPL median TBD was elevated (182.5 vs. 155.5 mg/cm3) whereas the opposite was true for CBD (361.8 vs. 437.8 mg/cm3). The physiologic age dependency of BD had got lost after TPL but could be reassumed by the measurement of proximal CBD. TBD correlated with the cumulative calcitriol dosage (r = 0.60, p < 0.05), bone alkaline phosphatase (r = 0.55, p < 0.01), the Ca x P product (r = 0.43, p < 0.05) and inversely with the time after TPL (r = -0.45, p < 0.05), but no significant correlation could be detected with the cumulative steroid dose. It was found to be higher in calcitriol treated than in vitamin D3 treated patients. Proximal CBD was inversely correlated with bone alkaline phosphatase (r = -0.71, p < 0.01) and intact PTH (r = -0.59, p < 0.05). In conclusion CBD in kidney grafted pediatric patients seems to be more or less reduced by secondary hyperparathyroidism whereas the increase of TBD appears to be induced by anticipated calcitriol treatment under dialysis regimen and gradually normalizes after TPL.

Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone.

OBJECTIVE: To compare the efficacy and safety of tiludronate and etidronate at the same dosage (400 mg/day) for the treatment of active Paget's disease of bone. METHODS: We studied 234 patients with radiologic lesions characteristic of Paget's disease of bone and serum alkaline phosphatase (AP) concentrations at least twice the upper limit of normal, in a prospective, randomized, double-blind, multicenter clinical trial lasting 6 months. Patients were randomly allocated into 1 of 3 treatment groups: tiludronate for 3 months followed by placebo for 3 months, tiludronate for 6 months, or etidronate for 6 months. Serum AP levels and urinary hydroxyproline excretion were measured at baseline and after 3 months and 6 months. Patients with a reduction of at least 50% in the serum AP concentration were considered to be responders. RESULTS: After 3 months, the proportion of responders was higher in the tiludronate group (57.4%) than in the etidronate group (13.9%) (P < 0.0001). In the etidronate group, this percentage was lower among patients who had received previous treatment with a bisphosphonate (2.3%) than among those who had not (28.6%) (P < 0.01). Previous bisphosphonate treatment was not associated with response in the tiludronate group. After 6 months, the proportion of responders did not differ between the 2 tiludronate groups (60.3% and 70.1%), but was lower in the etidronate group (25.3%) (P < 0.0001). There was a higher proportion of patients with treatment-resistant disease (< 25% reduction of serum AP) in the etidronate group (51.9%) than in the tiludronate 3-month group (17.9%) or the tiludronate 6-month group (19.5%) (P < 0.0001). Gastrointestinal disturbances were more common, and occurred earlier, with tiludronate, but they were mostly mild, requiring no treatment. CONCLUSION: Tiludronate at 400 mg/day for 3 months or 6 months is more effective than the same dosage of etidronate for 6 months in the treatment of Paget's disease.

Characterization of fat replacers.

Effects of commercial fat replacers on rheological properties of emulsions have been studied under a second-order design. The corresponding functions of regression have been calculated to describe the measured effects mathematically. On the basis of a figured three-dimensional plan of response, combinations of variables (fat, fat replacer, water) could be determined showing a similar consistency to the corresponding full-fat foodstuff.