Low-Intensity Vibration Protects the Weight-Bearing Skeleton and Suppresses Fracture Incidence in Boys With Duchenne Muscular Dystrophy: A Prospective, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

The ability of low-intensity vibration (LIV) to combat skeletal decline in Duchenne Muscular Dystrophy (DMD) was evaluated in a randomized controlled trial. Twenty DMD boys were enrolled, all ambulant and treated with glucocorticoids (mean age 7.6, height-adjusted Z-scores [HAZ] of hip bone mineral density [BMD] -2.3). Ten DMD boys were assigned to stand for 10 min/d on an active LIV platform (0.4 g at 30 Hz), while 10 stood on a placebo device. Baseline and 14-month bone mineral content (BMC) and BMD of spine, hip, and total body were measured with DXA, and trabecular bone density (TBD) of tibia with quantitative computed tomography (QCT). All children tolerated the LIV intervention well, with daily compliance averaging 78%. At 14 months, TBD in the proximal and distal tibia remained unchanged in placebo subjects (-1.0% and -0.2%), while rising 3.5% and 4.6% in LIV subjects. HAZ for hip BMD and BMC in the placebo group declined 22% and 13%, respectively, contrasting with no change from baseline (0.9% and 1.4%) in the LIV group. Fat mass in the leg increased 32% in the placebo group, contrasting with 21% in LIV subjects. Across the 14-month study, there were four incident fractures in three placebo patients (30%), with no new fractures identified in LIV subjects. Despite these encouraging results, a major limitation of the study is-despite randomized enrollment-that there was a significant difference in age between the two cohorts, with the LIV group being 2.8y older, and thus at greater severity of disease. In sum, these data suggest that noninvasive LIV can help protect the skeleton of DMD children against the disease progression, the consequences of diminished load bearing, and the complications of chronic steroid use. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A Novel Germline Mutation of ADA2 Gene in Two "Discordant" Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype.

Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up.

Alkaline Phosphatase Replacement Therapy.

Hypophosphatasia (HPP) is a rare genetic disease, characterized by the defective production of tissue-non-specific alkaline phosphatase (TNSALP). Six subtypes of the disease - affecting neonates (beginning in utero), infants, children, or adults - are recognized: perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia. The clinical presentation of these subtypes is very different and the severity ranges from mild to lethal. This chapter, after an overview of the genetics, epidemiology, classification, and clinical presentation of the different forms of HPP, will review the current experience with enzyme replacement therapy (ERT).

Evolution of bone mineral density, bone metabolism and fragility fractures in Spinal Muscular Atrophy (SMA) types 2 and 3.

With recent advances in the treatment of Spinal Muscular Atrophy (SMA), there is a strong need to increase knowledge on the involvement of organs and systems outside the central nervous system. We investigated bone metabolism, bone mineral density (BMD) and fractures, and their possible correlation with age and motor capacities. Thirty-two children with SMA (27 type 2, 5 type 3), mean age 40 ±â€¯32.3 months, underwent two evaluations at an 18-month interval (V1 and V2). Twelve of these children also underwent a third evaluation at month 36 (V3). Diet, bone metabolism, BMD, X-rays, and motor function (by the Hammersmith Functional Motor Scale Expanded - HFMSE - and the Upper Limb Module - ULM) were assessed. At V1, 25-OH vitamin D3 (25OH D) therapy was started, and dietary calcium intake adjusted according to the recommended dietary allowance. Low 25OH D levels and asymptomatic vertebral fractures were mainly observed at V1. At all visits, bone resorption markers were higher than normal. At V2 and V3, decreased BMD was observed. Higher spine BMD values at follow-up were associated with HFMSE score >12 at baseline (p<0.03). This study suggests that even young children with SMA are at risk of severe bone fragility. Further investigations of the molecular mechanisms leading to altered bone metabolism in SMA could help identify novel therapeutic targets and establish better guidelines for bone fragility management.

Bone and Spinal Muscular Atrophy.

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease, leading to progressive denervation atrophy in the involved skeletal muscles. Bone status has been poorly studied. We assessed bone metabolism, bone mineral density (BMD) and fractures in 30 children (age range 15-171 months) affected by SMA types 2 and 3. Eighteen children (60%) had higher than normal levels of CTx (bone resorption marker); 25-OH vitamin D was in the lower range of normal (below 20 ng/ml in 9 children and below 12 ng/ml in 2). Lumbar spine BMAD (bone mineral apparent density) Z-score was below -1.5 in 50% of children. According to clinical records, four children had sustained four peripheral fractures; on spine X-rays, we observed 9 previously undiagnosed vertebral fractures in 7 children. There was a significant inverse regression between PTH and 25-OH D levels, and a significant regression between BMC and BMAD values and the scores of motor-functional tests. Even if this study could not establish the pathogenesis of bone derangements in SMA, its main findings - reduced bone density, low 25OH vitamin D levels, increased bone resorption markers and asymptomatic vertebral fractures also in very young patients - strongly suggest that even young subjects affected by SMA should be considered at risk of osteopenia and even osteoporosis and fractures.

Strontium ranelate: an increased bone quality leading to vertebral antifracture efficacy at all stages.

Strontium ranelate is a new antiosteoporotic treatment with a dual mode of action, both increasing bone formation and decreasing bone resorption, which rebalances bone turnover in favor of bone formation and increases bone strength. The antifracture efficacy of strontium ranelate, 2 g per day orally, in the treatment of postmenopausal osteoporosis has been investigated in a large-scale, international, multicenter, phase 3 program in which more than 7000 patients were recruited. This article deals with the vertebral antifracture efficacy of strontium ranelate in postmenopausal women with osteoporosis. A significant early (after 1 year) and sustained (over 3 years) antifracture efficacy of strontium ranelate, compared with placebo, was demonstrated in patients with prevalent vertebral fracture with reductions in risk of new vertebral fracture of 49% after 1 year (P < 0.001) and 41% over 3 years (P < 0.001). In addition, the relative risk of clinical vertebral fracture was significantly reduced by 52% (P = 0.003) after 1 year and by 38% (P < 0.001) over 3 years in the strontium ranelate group compared with placebo. Strontium ranelate was also demonstrated to significantly decrease the relative risk of vertebral fractures by 45% (P < 0.001) in patients without prevalent vertebral fracture over 3 years, vs. placebo. Bone mineral density was linearly increased during 3 years of treatment with strontium ranelate in comparison with placebo. Strontium ranelate was well tolerated throughout the entire duration of the clinical trials. Thus, strontium ranelate, 2 g per day orally, is a new, effective, and safe treatment for postmenopausal patients with osteoporosis, to reduce the vertebral fracture risk in patients with or without a history of vertebral fracture.