Artigos abordam a osteoporose na distrofia muscular de Duchenne

Reino Unido, Itália, Suécia e USA - 6 pesquisas publicadas na revista Bone analisam a osteoporose em portadores de distrofia muscular de Duchenne e Becker (os resumos em inglês estão abaixo). A primeira pesquisa relata que os pacientes com distrofia muscular de Becker tem menos osteoporse que os portadores de Duchenne. A segunda analisa as causas prováveis da osteoprose em Duchenne, provavelmente devido a citocinas inflamatórias. O terceira acompanha o descréscimo da densitometria óssea em Duchenne. A quarta pesquisa relata a redução da densitometria óssea em Duchenne, mesmo antes do uso de corticóides e relata que que após o uso de corticóides existe uma relação entre a piora da densidade óssea e a redução dos níveis de cortisol do sangue. A quinta relaciona a densitometria óssea e as fraturas de pacientes com Duchenne e em pacientes com paralisia cerebral. A sexta pesquisa fez um acompanhamento da densitometria óssea em pacientes com Duchenne e tratados com corticóides observando que as crianças que andam tem menor perda de massa óssea mesmo usando corticóides e que a perda da capacidade de andar associada ao uso de corticóides promove maior perda de massa óssea.

(Bone, 2009) Duchenne and Becker muscular dystrophies: A 4-year longitudinal follow-up study of bone mineral density

A.C. Söderpalma, A.K. Kroksmarka, P. Magnussonb, A.C. Åhlandera, J. Karlssona, M. Tuliniusa, D. Swolin-Eidea -Sweden

Duchenne muscular dystrophy (DMD) is an inherited X-linked recessive disorder that leads to reduced bone turnover and an increased risk of osteoporosis due to progressive muscular impairment. Becker muscular dystrophy is caused by a deletion in the same gene, but shows a relatively milder clinical course. Muscle mass and bone mass are closely related and it is known that inactivity and immobilisation lead to loss of mineral from the skeleton. Six boys with Becker (10.8–18.9 years at baseline) and 18 boys with DMD (2.3–19.7 years at baseline) were followed 4 years with respect to areal bone mineral density (BMD) in the hip and axial skeleton measured by DXA and calcaneal BMD measured by DXL Calscan BMD at all sites; total body (TB) (P=0.0002), TB head excluded (TBHE) (P<0.0001), spine (P=0.0001), hip (P=0.002) and calcaneal (P<0.0001), were significantly lower in the DMD group compared with Becker at baseline and follow-up for all sites, P<0.0001. Bone mineral accretion was significantly less in the DMD group at all sites after the study period in comparison with Becker; TB (P=0.002), TBHE (P<0.0001), spine (P=0.0001), hip (P=0.002) and calcaneal (P<0.05). BMD increased at all sites in Becker during the follow-up period, but only significantly for TB and spine, P<0.05. A smaller increase was found in the DMD group for TB, TBHE and spine, P<0.05; but decreased BMD in the hip (P<0.05) after 4 years. Summary: A greater bone mineral accretion was observed in the Becker group in comparison with DMD and we even observed a decreased hip BMD in the DMD group after the study period. We suggest that these findings could, in part, be explained by the better preserved muscle strength in Becker and the earlier appearing weakness in DMD of the lower extremities compared with the upper body.

(Bone, 2009) Mechanisms underlying low bone density in muscular dystrophy

A. Rufoa, A.Del Fattorea,M.L.Bianchib, L.Morandif, E. Bertinic, A.Musaròd, S. Ferrarie, D. Pierroze, M. Capullia, N. Ruccia, F. De Benedettic, A. Tetia - Italy

Muscular dystrophies are characterized by inflammation, osteoporosis and increased risk of fractures other than myofiber necrosis and reduced muscular strength. We observed muscular atrophy and bone loss in mice overexpressing the pro-inflammatory cytokine IL-6 and propose that IL-6 may link the muscular and the bone phenotype in muscular dystrophies. Duchenne Muscular Dystrophy (DMD) is an X-linked disease due to mutations of the dystrophin gene. In DMD patients, we observed increased IL-6 in muscle biopsies and in sera. Similar to osteoblasts from IL-6 overexpressing mice and to osteoblasts treated with IL-6, human osteoblasts exposed to DMD sera failed to mineralize the extracellular matrix and showed reduced Osterix and Osteocalcin mRNA expression, despite normal alkalinephosphatase activity and Runx2 mRNA. The circulating RANKL/OPG protein ratio was low in DMD patients and inversely correlated with bone density. Transcriptional analysis revealed a similar reduction in RANKL/OPG ratio and increased IL-6 in osteoblasts exposed to DMD sera, along with up-regulation of further 26 genes and downregulation of further 90 genes associated with osteoblast function and osteoblast–osteoclast cross-talk. Despite low RANKL/OPG ratio, peripheral blood monocytes from patients and those from healthy donors exposed to DMD sera exhibited increased osteoclastogenesis similar to that observed in IL-6 overexpressing mice. In addition, mature osteoclasts expressed dystrophin, co-localized with F-actin in podosomes and actin rings, suggesting a role in cytoskeletal remodelling and bone resorption. Dystrophin-deficient mice (MDX) showed reduced tibial trabecular and cortical bone compared to WT, due to decreased osteoblast and increased osteoclast activity. Similar increase of osteoclast activity was observed in MDX calvariae. These latter bones are not subjected to muscular traction, suggesting systemic induction of osteoclastogenesis. We therefore propose that, besides mechanical failure, additional factors induce low bone density in DMD, among which we hypothesize relevant roles for systemic IL-6 and osteoclast dystrophin.

(Bone, 2009) Trends in bone mineral density in children with Duchenne Muscular Dystrophy before and after glucocorticoid therapy

A. Peacock, B. Oldroyd, A. Shaw, A.M. Childs, T Mushtaq - UK

Background: Duchenne Muscular Dystrophy (DMD) is characterised by progressive muscle wasting. Glucocorticoids (GCs) are used to slow the progression of the disease and prolong ambulation, but they also suppress growth and bone metabolism. Aim: A retrospective study that assessed serial changes in body composition and bone mineral density (BMD) as measured by dualenergy absorptiometry (DXA) in boys with DMD before and after GC treatment. Method: 11 boys were treated with prednisolone (0.75 mg/kg/ day: 10 days on/10 days off). Standard deviation scores (SDS) were calculated from local reference data for total body BMD (TBBMD), Total Body Less Head BMD (TBLH), Lumbar Spine (LS) BMD (LSBMD) and LS Bone Mineral Apparent Density (LSBMAD). Serial scans were repeated if symptomatic or initial low BMD. Results:

By scan 3 there was a trend for decreasing BMD at all sites. The TBLH is lower than the TBBMD indicating the influence of the skull in the growing child. The LSBMAD is lower than the TBBMD which could reflect the detrimental GC effects on trabecular bone. Due to the limited number of scans there were no significant differences in the DXA BMD results. As there is no control group it is not possible to compare the effects of GC to those with reducing mobilisation. Conclusion: Serial BMD measurements in boyswith DMD may show a progressive reduction in bone density with time. (⁎Pre-steroids.)

(Bone, 2009) Bone density and bone metabolism in Duchenne Muscular Dystrophy

S. Vaia, L. Morandib, M.L. Bianchia - Italy

A frequent complication of Duchenne Muscular Dystrophy (DMD) is an increased susceptibility to fractures, causing immobilization and worsening of muscle hypotrophy and weakness. There are very few data on bone density (BMD) and bone metabolism in DMD patients and it is unknown if DMD per se – independently of glucocorticosteroid (GC) treatment – causes bone metabolism derangements and osteoporosis. In a group of 15 DMD children (aged 3–6 years), we evaluated BMD (with DXA) and bone metabolism before starting GCs, at baseline and after 6 and 12 months. In most children, BMD (spine and total body) was lower than normal for age, and in 8 (53.3%) it was significantly reduced (spine BMAD Z-score −2.4±0.6). Low BMD was present in 2 (28.5%) of the 7 children aged 3– 4 years, but in 6 of 8 (75%) of those aged 5–6 years. We also measured the pituitary-adrenal response with a 1 mg dexamethasone overnight suppression test, to evaluate whether the acute response to GCs could predict the long-term GCs impact on bone. The suppressed morning serum cortisol and the increased insulin levels were correlated with changes in BMD and in bone turnover markers during the 12-month follow-up. Upon multiple regression analysis, cortisol suppression and insulin increase were correlated with spine BMD Z-score (p=0.03), BMD loss rate (p=0.02), and bone marker changes (NTx: p=0.02; BSAP: p=0.03). In children with suppressed cortisol levels below 50th percentile, spine BMD Z-score decreased (−0.7±0.5) after 12 months. These findings indicate that: BMD is often decreased in DMD even before GCs; Reduced BMD might be more prevalent in older than in younger boys; Cortisol suppression test may be used to evaluate the sensitivity to exogenous GCs and their ability to induce bone side effects.

Research Grant UILDM - TELETHON (GUP 0300537).

(Bone, 2009) Fracture history and bone mineral density (BMD) in children with Duchenne Muscular Dystrophy (DMD) and cerebral palsy (CP)

H.H. Kecskemethy, H.T. Harckea,, S.J. Bachracha, - USA

This study examines the history of fracture in relation to BMD and ambulation as measured by group mean Z-scores for lateral distal femur (LDF) and lumbar spine (LS) in three cohorts of children: non-ambulatory DMD and CP and ambulatory DMD. Fracture history of 49 children with DMD (23 ambulatory, 26 nonambulatory) and 47 non-ambulatory children with CP was obtained at time of first BMD assessment. Mean LS and LDF Zscores (3 regions) were calculated for positive or negative fracture history.

Positive fracture history in ambulatory DMD was 4/23 with half occurring in the lower extremity. Non-ambulatory DMD fracture history was positive in 13/26 (with 69% in the lower extremity). Fracture history was positive in 19/47 of the CP group (lower extremity 89%). Both non-ambulatory groups had mean LDF Z-scores well below normal regardless of fracture history, whereas ambulatory DMD subjects had LDF values in normal/low-normal range. Ambulatory status did not influence LS Z-scores of DMD patients compared to LDF Z-scores. Differences in LDF Z-scores were noted in fracture and nonfracture groups except for the non-ambulatory DMD group. LDF BMD is easily obtained on disabled children and provides another DXA parameter for use in evaluating fracture risk.

(Bone, 2009) Bone strength in boys with Duchenne Muscular Dystrophy (DMD): A longitudinal study

N.J. Crabtreea,b, K.A. Wardc, H. Roperd, J.E. Adamsc, M.Z. Mughale, N.J. Shawb - UK

DMD is the most common childhood neuromuscular disorder causing loss of ambulation in early life. Steroids are currently used to improve muscle strength and prolong ambulation although the effect on bone health in this group of children is still unclear. The aim of this study was to compare the longitudinal changes in bone strength in healthy children with those observed in children with DMD, who either remained ambulant or who lost independent ambulation during the period of follow-up. Forty children were studied, 17 healthy boys (9.1±1.5 years) and 23 boys with DMD (8.6±2.1 years), taking intermittent steroids. PQCT was used to measure bone geometry, density and strength of the non-dominant tibia. Measurements were made at the distal metaphysis and mid-diaphysis sites. Data were adjusted for age, height and duration of steroids. After 15.0±3.1 months, 7 DMD boys lost independent ambulation. Longitudinal growth between the groups remained constant. In DMD boys, who remained ambulant, there was a slowing down in periosteal bone growth at the mid diaphysis (0.8 vs. 2.6 mm2/month; p<0.05). Whereas for DMD boys who lost ambulation, there was a significant reduction in the rate of bone growth at the mid-diaphysis (0.4 mm2/month; p<0.05) and at the distal metaphysis (2.8 vs. 6.2 mm2/month; p<0.05). In contrast, the rate of change in bone density at the distal metaphysis (−2.8 vs. 0.3 mg/cm3/month; p<0.001) and cortical bone mass (−0.2 vs. 1.3 mg/mm/month; p<0.001) and stress-strain index (2.0 vs. 9.9 mm3/month; p<0.05) at the mid diaphysis was only significantly different from the healthy boys in the 7 boys who lost independent ambulation. These data suggest that ambulation and hence muscle function and gravitational load have the greatest effect on bone strength and density in boys with DMD. Whilst they remain ambulant the effect of the relatively high dose steroids appears to be negligible. However, when they eventually lose independent ambulation significant losses in bone strength occur as a direct result of diminished periosteal bone growth and bone mineral accrual.

Fonte: http://distrofiamuscular.net/noticias.htm