Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice.

UNLABELLED: Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates. INTRODUCTION: Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass. METHODS: To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity. RESULTS: +/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling. CONCLUSIONS: Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.

Sequential bone mineral content in small preterm infants with and without fractures and rickets.

Seventy-four infants with birth weights 1009 +/- 28 grams and gestational age 28.6 +/- 0.3 weeks (M +/- SEM) were studied prospectively to test the hypotheses that bone mineral content (BMC) measured by photon absorptiometry, would be: (1) lower in very low birth weight (VLBW) infants with radiographic evidence of fractures and/or rickets (F/R), and (2) will continue to be lower over the first year when compared to VLBW infants without F/R. BMC and bone width (BW) of the distal one-third of left radius and ulna were measured at 5 weeks (n = 8), 14 weeks (n = 61), 26 weeks (n = 58), 40 weeks (n = 59), and 1 year (n = 52). Standardized radiographs of both forearms, and weight, length, and head circumference were also determined at each study age. Investigators and technicians involved in the photon absorptiometry measurements were unaware of the radiographic findings and vice versa. Twenty-three of 74 infants were found to have F/R. BMC of studied infants remained markedly below our previously determined range of "intrauterine bone mineralization," even at 26 weeks after birth. There was no significant difference in BMC or BW between infants with and without F/R, either at the time of confirmation of F/R or during early follow-up; however, BMC was lower at greater than or equal to 6 months and BW was lower at greater than or equal to 9 months in infants with F/R. We suggest that the extremely low BMC measurements in early infancy predispose all VLBW infants to fractures and rickets.

Arthropathy of Down syndrome.

A juvenile rheumatoid arthritis-like arthropathy has previously been documented in 12 patients with Down syndrome. An additional 9 patients are described and the literature is reviewed. It is unknown whether these patients have juvenile rheumatoid arthritis or a unique arthropathy in light of the genetic and immunologic abnormalities associated with Down syndrome. Most of the patients had a progressive course with polyarticular disease complicated by subluxations and a long lag time to diagnosis. The purpose of reporting these children is to increase awareness of this association and facilitate more appropriate and timely diagnosis of arthritis in Down syndrome patients.

Pleural effusion: the thorn sign. Not a rare finding.

Eleven percent of an unselected series of 157 patients with pleural effusion showed a thorn-like protrusion of fluid at the lateral end of the minor fissure at some time during their illnesses. None of a series of 146 normal x-ray films of young patients showed this "thorn sign." The thorn sign is a useful radiographic finding of right-sided pleural effusion.

Vitamin D requirement in infants receiving parenteral nutrition.

The adequacy of low dose vitamin D (25 IU/dl) parenteral nutrition (PN) solution was studied in 18 infants. All infants had surgical indications for PN. The birth weights were 2810 +/- 135 g and gestational ages 37.4 +/- 0.5 wk (mean +/- SEM). Duration of study ranged from 5 to 175 days. Thirteen infants were studied for up to 6 weeks and five infants for 71 to 175 days. Results showed that studied infants maintained growth along normal percentiles for weight, length, and head circumference. Vitamin D status as indicated by serum 25 hydroxyvitamin D (25 OHD) rose from 15 +/- 1.9 ng/ml to 26 +/- 2.8 ng/ml, mean +/- SEM (p less than 0.001) after 9 days, and remained normal up to 6 months. Five infants with biochemical liver dysfunction also had normal serum 25 OHD concentrations, indicating the hepatic 25 hydroxylation process was not severely impaired. Serum total and ionized calcium, phosphorus, and vitamin D-binding protein concentrations were normal. Serum magnesium was mildly elevated in five infants (2.6 to 3 mg/dl) on one occasion and resolved spontaneously. Serum alkaline phosphatase (AP) concentrations rose above baseline values in 12 of 17 infants, but remained within normal range (less than 400 IU/liter at 30 degrees C). Another infant with markedly elevated AP values died from liver dysfunction. Radiographs of the forearms were normal except for marked demineralization in one infant in spite of normal 25 OHD concentrations. We conclude that 25 IU vitamin D/dl of nutrient infusate is adequate to maintain normal vitamin D status, as indicated by normal serum 25 OHD concentrations in infants receiving PN for as long as 6 months.

Radiology pitfalls in the use of barium enema in pediatric appendicitis.

Barium enema (BE) is usefull and safe in diagnosis of pediatric appendicitis, but pitfalls must be avoided. Reasons for false negative BE include failing to or inability to obtain good compression local views of the cecum and accepting a partially filled appendix as normal. In addition to right ovarian lesions in girls, there are less common causes of false positives, including mucocele, intussuscepted appendix, and recurrent inflammation of appendiceal stump. Non-filing of the appendix is not in itself abnormal. Abdominal ultrasound may be complementary, and increasingly is becoming the primary imaging modality for uncertain appendicitis.

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.

H. Binga Dismond, MD--pioneer Harlem physician and much more.

All physicians hopefully have some interests beyond their specialty. Dismond exemplified a broad range of activities, including athletics, military service, poetry, multiple marriages, and socializing, as well as two specialties in medicine.

Pleural effusion in sickle cell disease.

Pneumococcal and mycoplasma infection of the lung or pleura, infarction of lung or pleura, local abscess below the diaphragm, and heart, kidney, or pancreas involvement are among the many causes of pleural effusion. Several of these have an increased likelihood of occurrence in sickle cell disease as a direct consequence of sicklemia or of the functional asplenia which develops. A patient is presented in whom many of these considerations arose.

A helpful hint for chest radiology: "look behind the heart".

Pathologic abnormalities on frontal chest radiographs are often located solely or partially in the retrocardiac region. It is essential to include a look behind the heart when viewing the frontal x-ray. Cases of pneumonia, metastases, and posterior mediastinal mass, all of which would have been missed without a look behind the heart, are used to illustrate this precept.

Rickets as an unexpected x-ray finding.

Rickets, whether due to lack of proper nutrition or secondary to disease or medication, may be unexpectedly detected on radiographs obtained for other reasons. Several recent examples are reported here. It is important to be aware of the manifestations of rickets so that appropriate treatment is not delayed. Physicians should be alert for signs of rickets in the x-ray examination of any child.

Transient loss of femoral head Tc-99m diphosphonate uptake with prolonged maintenance of femoral head architecture.

Nine pediatric patients presented with synovitis and suspected Legg-Perthes disease, hemarthrosis, acute slipped capital femoral epiphysis, prolonged traumatic hip dislocation, or transcervical femoral fracture. All had hip scintigraphs that showed loss of Tc-99m diphosphonate uptake in the affected femoral head. Radiographic changes associated with aseptic necrosis failed to appear during the initial follow-up period of three to 14 months. Repeat scintigraphy showed complete revascularization in six cases and partial revascularization in two. Reambulation at 1.5 to eight months after presentation was accomplished without recurrence of pain in seven cases, without development of x-ray changes in 5 cases. Three children developed x-ray changes associated with avascular necrosis after reambulation, while one child had minimal x-ray changes. Some children with loss of uptake in the femoral head do not develop x-ray changes associated with aseptic necrosis.