Interventions to prevent steroid-induced osteoporosis and osteoporotic fractures in Duchenne muscular dystrophy

  • Protocol
  • Intervention

Authors

  • Jennifer M Bell,

    Corresponding author
    1. Queen's University Belfast, Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Belfast, Northern Ireland, UK
    • Jennifer M Bell, Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Room 02.041, 2nd Floor, Mulhouse, Grosvenor Road, Belfast, Northern Ireland, BT12 6BJ, UK. j.m.bell@qub.ac.uk.

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  • Bronagh Blackwood,

    1. Queen's University Belfast, Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Belfast, Northern Ireland, UK
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  • Michael D Shields,

    1. Queen's University Belfast, Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Belfast, Northern Ireland, UK
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  • Janet Watters,

    1. Belfast Health and Social Care Trust, GP Out of Hours Service, Belfast, Northern Ireland, UK
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  • Alistair Hamilton,

    1. Belfast Health and Social Care Trust, Withers Orthopaedic Centre, Belfast, Northern Ireland, UK
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  • Timothy Beringer,

    1. Belfast Health and Social Care Trust, Department of Care for the Eldery, Belfast, Northern Ireland, UK
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  • Mark Elliott,

    1. Musgrave Park Hospital, Belfast Health and Social Care Trust, Belfast, UK
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  • Rosaline Quinlivan,

    1. UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery and Great Ormond Street, MRC Centre for Neuromuscular Diseases and Dubowitz Neuromuscular Centre, London, UK
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  • Sandya Tirupathi

    1. Royal Belfast Hospital for Sick Children, Paediatric Neurology, Belfast, UK
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

Primary objective

To assess the effects of interventions to delay or treat osteoporosis in DMD patients treated with glucocorticoid steroids.

Secondary objectives

To assess the effects of interventions to delay or treat osteoporosis in DMD on the frequency of vertebral fragility fractures and long bone fractures in DMD patients treated with glucocorticoid steroids.

Background

Description of the condition

Duchenne muscular dystrophy (DMD) is a progressive disorder affecting skeletal, cardiac and smooth muscle (Emery 1998; Voisin 2004). Inheritance is sex-linked recessive and the condition has an incidence of 1 in 3500 to 6000 male live births (Emery 2003; Emery 1991). The condition is caused by deletions, duplications or mutations in the dystrophin gene located at Xp21, resulting in absence or low levels of the protein (Chaturvedi 2001; Flanigan 2009; Lee 2012; Muntoni 2003; Soltanzadeh 2010). Dystrophin is a large protein located on the sarcolemmal membrane. It forms part of the dystrophin-associated protein complex and is involved in membrane integrity. Absence of dystrophin leads to membrane damage and progressive dystrophic changes within the muscle (Blake 2002). Affected boys appear normal at birth and start to show signs of muscle weakness in early childhood. Without glucocorticoid steroid treatment they become wheelchair dependent by 13 years of age and without respiratory support, death occurs in the late teens or early twenties. However, in recent years prognosis has improved substantially with the introduction of non-invasive ventilation and co-ordinated multidisciplinary care (Bushby 2010; Passamano 2012).

Glucocorticoid steroids have been shown to slow the decline in muscle function and may protect cardiac and respiratory function. Corticosteroid-treated boys lose the ability to walk at around 12 to 14 years of age, compared with 7 to 13 years for non-treated boys (Ricotti 2012). Physicians usually start treatment during the 'plateau phase' of the condition (usually between four and six years of age) (Bushby 2010). The optimum maintenance doses are 0.75 mg/kg of prednisone or prednisolone or 0.9 mg/kg of deflazacort, taken daily (Biggar 2004; Fenichel 1991; Griggs 1991; Mesa 1991), or intermittently (Dubowitz 2002; Kinali 2002). Treatment continued after the loss of ambulation may preserve upper body strength, respiratory and cardiac function, and delay onset of scoliosis (spinal deformity) (Biggar 2004; King 2007; Manzur 2008). Glucocorticoid steroids have significant side-effects, which require pro-active management (Angelini 2007; Balaban 2005; Biggar 2006; Bonifati 2000; Bushby 2004; Bushby 2010; Houde 2008; King 2007; Manzur 2008; Merlini 2012; Moxley 2010). One of the major side-effects is the development of vertebral fragility fractures caused by steroid-induced osteoporosis, where there is reduced bone mineral density, mainly of trabecular bone (Angelini 2012; Balaban 2005; Bothwell 2003; Canalis 2004; Houde 2008; King 2007; Mayo 2012; Quinlivan 2010; Soderpalm 2007; Weldon 2009). Glucocorticoid steroid treatment is now considered as 'gold standard' in DMD and so steroid-induced osteoporosis is an important problem(Bushby 2010).

Bone is a living tissue which is constantly remodelled by bone formation and bone resorption (Joyce 2012). Factors which affect bone mass include: genetics, nutrition, physical activity (loading), age, and hormones. Glucocorticoid steroid treatment affects endocrine function, suppressing growth, delaying puberty, reducing bone mineral density and increasing body weight (Bianchi 2011a; Dooley 2013). Glucocorticoid steroids reduce bone mass by both hindering bone formation through osteoblastic apoptosis (the death of cells that make bone) and by stimulating bone mineral resorption through an increase in the number of osteoclasts (cells which break down bone). The reduction in bone mineral density from changes in bone metabolism is not fully understood (Bianchi 2011a). Deficiencies in testosterone (delayed puberty) and growth hormone, or resistance to an insulin-like growth hormone, and limited mobility with excessive weight gain contribute (Allen 1998; Bianchi 2011a; Dooley 2013). Because peak bone mass does not occur until early adulthood, it can be difficult to evaluate bone mass in prepubertal children, in whom glucocorticoid steroid treatment may not reduce bone mass to the same extent as in adults. Soderpalm 2008 commented that lower bone mineral density in children with DMD is likely to be the combined result of glucocorticoid steroid treatment, muscle loss from disease, and reduced mobility. Low bone mineral density increases the risk of bone fragility fractures (Bachrach 2005; Douvillez 2005; Joyce 2012; Quinlivan 2005; Talim 2002). There are some data to suggest that children with DMD who are steroid naïve (that is, those who have not previously been exposed to glucocorticoid steroids) are at increased risk of long bone fractures (Biggar 2006; Granata 1991; Houde 2008; Hsu 1979; Larson 2000; McDonald 2002; Vestergaard 2001).

Vertebral fragility fractures are recognised as the most common manifestation of corticosteroid-induced osteoporosis (Al-Osail 2010; Rodd 2012; Sugiyama 2011; Van Staa 2000; Van Staa 2001; Van Staa 2003; Varonos 1987). In steroid naïve DMD patients, there have not been reports of vertebral fragility fractures (Alman 2004; Houde 2008; King 2007). In those taking glucocorticoid steroids, the occurrence of vertebral fractures ranges from 15% to 75% for a mean duration of 6.3 years on treatment (ranging from 4.5 to 8.0 years) (Bothwell 2003; Houde 2008; King 2007; Mayo 2012). The incidence of long bone fractures was similar in treated and untreated patients (Houde 2008; McDonald 2002) (24% and 26%, respectively in Houde 2008).

The body fat composition in a patient with DMD may be important to bone health. Body fat percentage is significantly higher in patients with vertebral fractures (47.8% ± 12%) than in those with long-bone fractures (33% ± 14.2%) (P < 0.05) (Mayo 2012). The mobility status of the patient with DMD is also important. Steroid treated patients are walking longer. Patients who are walking are more likely to fall and sustain a long bone fracture and in nonambulatory patients there appears to be an increased risk of vertebral fractures (Larson 2000; Mayo 2012). Previous surgical intervention for scoliosis may also prevent vertebral fragility fractures (Mayo 2012).

Vertebral fractures can be symptomatic or asymptomatic. Acute back pain is closely associated with symptomatic vertebral fragility fractures (odds ratio (OR) 10.6, 95% CI 2.1 to 53.8, P = 0.004) and requires radiological investigation to confirm the diagnosis (Huber 2010; Talim 2002), but it has been estimated that 20% of vertebral fractures are asymptomatic (Manzur 2010). Asymptomatic fractures are thought to be precursors of painful symptomatic fragility fractures (Leung 2011). Asymptomatic fractures may be undetected because radiological or densitometric monitoring is not conducted routinely (Quinlivan 2010). Diagnosis and confirmation of a vertebral fracture requires the visual examination of lateral X-ray or magnetic resonance imaging (MRI) images to assess the change in shape of the vertebrae as biconcave, wedge or crush, and the degree of deformity (Genant 1993; Lenchik 2004; Quinlivan 2010).

The occurrence of fractures is significantly related to low bone mass in DMD (Aparicio 2002; Khatri 2008; Larson 2000). The bone mineral density is often lower than normal for the age of the patient (Bianchi 2003; Crabtree 2010; Mayo 2012; Soderpalm 2012). That is, the bone age is lowered (Bianchi 2011a). While some studies have shown no reduction in spinal bone mineral density after 30 months of steroid therapy for DMD (Crabtree 2010), or only a marginal reduction (Cohran 2008), others reported a substantially lowered bone mineral density in boys taking glucocorticoid steroids, particularly those with reduced mobility (Bianchi 2003; Hawker 2005; Mayo 2012).

Bone mineral content and bone mineral density are assessed in children by dual-energy X-ray absorptiometry (DXA) (Bianchi 2010). Quantitative computed tomography, peripheral quantitative computed tomography, quantitative ultrasonography or MRI are also used (Bachrach 2011). To avoid incorrect estimations, conventional DXA measurements are adjusted according to size for use in children, those with deteriorating bone, and people of shorter stature. Bone mineral density is measured as age-based and height-adjusted Z-scores (Bachrach 2011; Baim 2008; Bianchi 2010). DXA can also predict the risk of fractures before they occur. Its use is based on a relationship between low bone mineral density and risk of fracture in adults, which also exists in children (Clark 2006; Goulding 1998). This is an important application of DXA in patients with DMD, as part of bone health evaluation (Bianchi 2011a).

International consensus workshops have taken place, to prioritise poor bone health in DMD patients and to improve clinical outcomes through education (Biggar 2005; Leung 2011; Muntoni 2006; Quinlivan 2005; Quinlivan 2010). Bone health in patients with DMD is an important issue because long bone fractures seriously harm mobility: approximately 20% to 50% of independently mobile patients lose the ability to walk unaided following a long bone fracture (Larson 2000; Manzur 2010; Mayo 2012; McDonald 2002; Vestergaard 2001). Identifying treatment strategies to prevent steroid-induced osteoporosis and prevent often painful, osteoporotic fractures in DMD may have a significant effect in improving quality of life for these patients.

Description of the intervention

We describe here the pharmacological and non-pharmacological interventions that have the potential to prevent or treat steroid-induced osteoporosis by increasing bone mineral density and reduce the risk of fractures in patients with DMD.

Bisphosphonates

Bisphosphonates are a group of drugs that inhibit bone resorption by causing apoptosis of osteoclasts (Fleisch 2003; Poole 2012; Rogers 2011; Russell 2008). They are inorganic analogues of naturally occurring pyrophosphates, which prevent calcification by binding to hydroxyapatite salt in bone (Nancollas 2006; Russell 2011; Sebestyen 2012). This enables bisphosphonates to accumulate at bone resorption sites in the skeleton and stop osteoclast-mediated activity (Dominguez 2011; Drake 2008; Fleisch 2003; Hughes 1989; Hughes 1995; Sato 1991; Sebestyen 2012; Somalo 2007). There are two groups of bisphosphonates: non-nitrogen-containing bisphosphonates (etidronate, clodronate, and tiludronate), and nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, pamidronate, and zoledronate). The presence of a nitrogen or amino group in the chemical structure of bisphosphonates increases the potency of the drugs for osteoclastic activity (Drake 2008; Ebetino 2011; Reszka 2004). These more potent nitrogen-containing bisphosphonates are often used to treat children with corticosteroid-induced osteoporosis and osteopenia (low bone density) (Allington 2005; Black 2012; Brumsen 1997; Hawker 2005; Poole 2012; Rudge 2005; Schwartz 2010; Sholas 2005).

Calcium

Bones and teeth contain 99% of all body calcium. Calcium is essential to enable normal bone growth and development in children and adolescents (Flynn 2003; Peacock 2010). When combined with phosphate, calcium has a structural role in bone health as a component of hydroxyapatite within the bone matrix, which provides compressional strength in bone (Bonjour 2011; Peacock 2010). During remodelling, bone loses and replaces calcium. These metabolic processes determine the amount of calcium required to maintain bone health, and vary throughout life (Mesias 2011). Calcium requirements are greater during adolescence as growth peaks and approximately 40% of total skeletal bone mass is acquired (Flynn 2003; Greer 2006; Mesias 2011; Weaver 2006). A calcium deficiency can contribute to the development of osteoporosis. Not only is there inadequate calcium for bone mineralisation but also low calcium intake can cause increased bone resorption so as to release calcium and maintain homeostasis in the blood. Lower than normal blood calcium levels trigger the parathyroid glands to produce parathyroid hormone (PTH) (Peacock 2010). This hormone stimulates osteoclasts and bone resorption. If the blood calcium levels are higher than normal, the C cells within the thyroid gland respond by producing the hormone calcitonin, which inhibits osteoclast activity, promoting bone formation and storage of excess calcium in the bone matrix. A balanced diet that includes good sources of calcium such as milk products, dark green leafy vegetables, beans, oranges, calcium-rich mineral water, seeds, and nuts is recommended as the best long-term strategy to maintain adequate calcium levels (Bacciottini 2004; Biggar 2005; Sunyecz 2008). Calcium supplements in healthy children have shown short-term improvements in bone mineral density (Winzenberg 2006). Intestinal calcium absorption is dependent on other factors such as vitamin D levels.

Vitamin D

Vitamin D is vital for intestinal calcium absorption and optimal calcium blood levels (Frolik 1971; Wei 2010). It may also have its own protective effect on bone and has an important role in muscle function (Bartoszewska 2010; Peppone 2010). Vitamin D2 (ergocalciferol) is largely man-made and present in supplemented food. The skin synthesises vitamin D3 (cholecalciferol) after exposure to sunlight, and other sources are foods, for example, fish and eggs (Misra 2008), and oral supplements. In the liver, vitamin D is metabolised to 25-dihydroxyvitamin D, known as calcifediol, which in the kidneys is converted to the active 1,25-dihydroxyvitamin D hormone, known as calcitriol (Peppone 2010). The level of serum 25-hydroxyvitamin D (25OHD) is a good indicator of vitamin D synthesis from food, sunlight or supplement intake (Brannon 2008; Davis 2007; Karalus 2011; Pela 2012; Rosen 2011; Wolpowitz 2006). Hypovitaminosis D, that is, vitamin D deficiency, can cause rickets in children and osteomalacia in adults from poor bone mineralisation (Holick 2007; Pela 2012; Misra 2008; Wagner 2008; Ward 2007). To a lesser extent, vitamin D deficiency contributes to bone resorption and osteoporosis (Joyce 2012; Lips 2006). Many children and young adults in the UK have vitamin D insufficiency from increased use of sunscreens and reduced outdoor activities (Biggar 2005; Davies 2011; Lips 2012; Misra 2008; Pela 2012). It is largely an underestimated problem and more prevalent in non-white families (Ahmed 2011; Kehler 2013; Lips 2010; Shaw 2011; Zipitis 2006). The reported overall incidence of vitamin D deficiency disease in the UK is 7.5 per 100,000 in all children; 38 per 100,000 in those of south Asian ethnic origin and 95 per 100,000 in children of black African or African-Caribbean ethnic origin (Callaghan 2006). Those at highest risk are infants, toddlers and adolescents, in whom rapid growth increases vitamin D demand (Ladhani 2004).

Significantly lower serum 25OHD levels have been highlighted in boys with DMD, especially in those taking glucocorticoid steroids (Bianchi 2003; Bianchi 2011). People taking glucocorticoid steroids are twice as likely to have low 25OHD levels than those not on steroids (OR 2.36, 95% CI 1.25 to 4.45) (Skversky 2011). Dhawan 2010 proposed that glucocorticoid steroids may inactivate 25OHD by increasing the activity of the enzyme 24-hydroxylase. Additionally, those taking glucocorticosteroid steroids may have poor nutrition and a lack of sun exposure as a secondary consequence of their primary illness (Skversky 2011).

However, data on vitamin D levels collected in DMD boys aged from 1.5 to 15.5 years, prior to starting corticosteroid treatment, revealed that 78% had inadequate levels and 15% qualified as deficient (Munot 2010). In two other studies, 54% to 70% of DMD patients on glucocorticoid steroids were vitamin D deficient (Manzur 2010; Wong 2010). Shapira 1984 discovered that DMD patients have a lower level of the serum vitamin D metabolite, 24,25-dihydroxyvitamin D than age-matched healthy controls (0.69 ng/ml, 0.52 to 0.86 ng/ml versus 2.13 ng/ml, 0.98 to 2.28 ng/ml). This may influence the role of vitamin D metabolites in calcium absorption.

Weight-bearing exercise

In DMD patients over eight years of age, there is a gradual decline in physical activity due to the natural disease progression (Mazzone 2011; McDonald 2010). Weight-bearing exercise, for example walking, where the muscles apply tension to the bones, stimulates bone regeneration. Dynamic loading activity achieves greater gains in bone tissue than static activity (Lanyon 1984). Unfortunately, muscle weakness hinders dynamic weight-bearing exercise and has a negative impact on bone development. Disuse of the skeleton as a result of prolonged inactivity degenerates bone tissue further. Mechanical loading through weight-bearing exercise is a major factor in bone development during childhood and adolescence, and is recommended for bone mass maintenance (Stuberg 1992).

How the intervention might work

In children with steroid-induced osteoporosis, the rate of bone resorption exceeds that of bone formation. This results in reduced bone mineral density and an increased risk of fractures (Larson 2000; Teitelbaum 2000). The main focus of each intervention is to either slow bone resorption or promote bone formation to increase bone mineral density bone whilst receiving steroid therapy. These interventions can be used alone or in combination to prevent or treat bone loss.

Bisphosphates

Trials of alendronate and zoledronic acid in postmenopausal women showed a significant reduction of vertebral fractures (P ≤ 0.001) and increased bone mineral density (P ≤ 0.001) (Black 1996; Black 2007; Cranney 2002). Intravenous bisphosphonates are used to treat painful vertebral fractures and are associated with improvements in back pain (Sbrocchi 2012). It is unclear if this treatment will prevent new vertebral fractures from occurring in boys with DMD who have an increased risk of vertebral fractures (Sbrocchi 2012). The use of bisphosphonate treatment in children is relatively new, but there are growing numbers of trials suggesting benefit, particularly in children with osteogenesis imperfecta (Allington 2005; Bianchi 2000; Brumsen 1997; Glorieux 1998; Hawker 2005; Henderson 2002; Palomo 2011; Plotkin 2000; Rauch 2002; Rudge 2005; Sbrocchi 2012; Shaw 2000; Sholas 2005; Wagner 2011).

Bisphosphonates appear to be well tolerated by children for periods of up to three years (Shaw 2005; Ward 2011). Dosing regimes differ among paediatric studies (Ward 2011). Oral bisphosphonates are prescribed according to body weight (mg/kg) (Bianchi 2000; Hawker 2005; Rudge 2005) and intravenous bisphosphonates are usually administered at a dose of 1 to 1.5 mg/kg but within minimum and maximum dosing limits (Acott 2005; Shaw 2000).

Treatment is usually combined with vitamin D and calcium supplements to minimise the risk of hypocalcaemia (Maalouf 2006; Poole 2012); however, the absorption of bisphosphonates is reduced by calcium supplements. Adverse effects are more common with intravenous than oral bisphosphonates (Somalo 2007). The United States Food and Drug Adminstration (FDA) has received reports of femoral fractures in people taking bisphosphonates and is reviewing long-term use (FDA 2011). Atypical fractures occurring with prolonged bisphosphonate therapy have been a featured concern in recent publications (Compston 2011; Edwards 2010; Girgis 2010; Isaacs 2010; Shane 2010), and there have been cautions that high and prolonged doses may paradoxically induce osteoporosis (Whyte 2008).

Calcium

Although genetics determine 60% to 80% of attained peak bone mass, calcium influences changes in the remaining bone mass, which could be predictive of fracture risk in children with medical conditions affecting bone health (Ferrari 1998; Goulding 2005; Harvey 2012; Quinlivan 2010; Winzenberg 2006). Studies have investigated low calcium intake as a risk factor for fractures but, because the association was marginally significant, many of them could not conclude that calcium alone would reduce the incidence of fractures (Black 2002; Goulding 1998; Goulding 2004; Petridou 1997; Winzenberg 2006). Patients with more fractures had lower bone mineral density (Goulding 1998). A review of calcium supplementation for improving bone mineral density in children showed no effect on spinal bone mineral density, but a small effect on total body bone mineral content (BMC) (Winzenberg 2006). A double-blind, placebo-controlled study of 149 girls did show an increase in bone mineral density in girls taking calcium supplemented food compared to those who did not (Bonjour 1997). Patients with DMD have increased their bone mineral content and bone mineral density by taking adequate dietary calcium and vitamin D (Bianchi 2011). The relationship between calcium intake and bone mass is complicated in DMD patients because corticosteroid treatment induces bone resorption, transferring calcium from bone to blood. High blood calcium levels prevent further intestinal calcium absorption to build bone. Evidence that calcium alone has a positive effect on bone health in boys with DMD is limited. However, adequate calcium intake could slow bone resorption to help to achieve optimal bone mass for DMD boys during childhood and adolescence (Bianchi 2011; Quinlivan 2010). Many intervention studies in DMD patients have advised a daily calcium supplement of 750 mg (Hawker 2005; Mayo 2012).

Vitamin D

Calcitriol slows bone resorption and enhances bone mineralisation because it aids calcium absorption. Additionally, it controls neuromuscular function and influences the genes that control cell proliferation, differentiation and apoptosis (Banerjee 2003; Carlberg 2003; Garcia 2011). During infancy, vitamin D supplementation is associated with increased bone mineral density at specific skeletal sites later in childhood (Zamora 1999), but there is little evidence that increasing vitamin D intake alone reduces the risk of fractures (Bischoff-Ferrari 2005; DIPART 2010; Looker 2008).

A Cochrane review found no change in bone mineral content in healthy children taking vitamin D supplements; however, in those with low 25OHD levels it did show that vitamin D intake increased bone mineral density of the spine (Winzenberg 2006). When investigators examined vitamin D levels at the time of a vertebral fracture in boys with DMD, they categorised the mean serum vitamin D levels as insufficient (Manzur 2010). The vitamin D Individual Patient Analysis of Randomized Trials (DIPART 2010) showed that vitamin D given alone was not effective in preventing fractures, RR 0.92 (95% CI 0.86 to 0.99, P = 0.025), but if taken with calcium, the combination reduced the risk of vertebral fragility fractures. Evidence from randomised and cross-over design trials and meta-analysis supports the use of calcium in combination with vitamin D as a preventive treatment for bone loss in the spine of people treated with corticosteroids, and adults over 50 years of age (Amin 1999; Homik 2000; Rianthavorn 2012; Tang 2007; Warady 1994). Further research is required to investigate the effect of vitamin D levels on bone strength of patients with DMD (Wong 2010).

Weight-bearing exercise

In DMD, increasing muscle weakness leads to the loss of physical activity. Glucocorticoid steroids exacerbate the situation further by inducing osteoporosis and increasing the risk of vertebral fragility fractures (Larson 2000; Quinlivan 2010). The most evident decline in vertebral bone mineral density in DMD appears to occur with the loss of independent ambulation, regardless of whether or not the patient is taking glucocorticoid steroids (Biggar 2004; Crabtree 2010; Mayo 2012). A reduction in mechanical loading reduces osteoblast bone formation and promotes osteoclast-mediated bone resorption (Takata 2001). A study of boys with DMD versus healthy children revealed a significant reduction in the bone mineral density of the lower limbs and spine as a consequence of reduced weight-bearing exercise (Bianchi 2003). When the investigators applied interventions of additional exercise and calcium, the bone mineral density, assessed by DXA, was increased at a number of sites, including the lumbar spine (Bass 2007; Iuliano-Burns 2003; Stear 2003). This shows that a positive association exists between physical activity and the bone mass in children, particularly in prepubertal ages (Janz 2001; Janz 2006; Macdonald 2006; McKay 2000; McKay 2008). The Iowa Bone Development Study found significant longitudinal associations between physical activity that increased the mechanical loading of the skeleton in boys aged five years and bone mineral content of the hip at eight and 11 years of age (Janz 2010). Growing bone adapts to withstand mechanical loading. In boys with DMD, standing programs and prolongation of walking using mechanical walking aids are common components of management and have shown improvement in vertebral bone mineral density and function capacity (Caulton 2004; Spencer 1962). More recently, high frequency, low intensity whole body vibration appeared to improve bone health in disabled children (Reyes 2011), and in young females with low bone mineral density (Gilsanz 2006). Regular low intensity and appropriate exercise strengthens bone tissue as well as improving the balance of action between opposing muscle groups and standing and moving balance (Bushby 2010; Grange 2007; Jansen 2010). These interventions could reduce the risk of fractures in non-ambulant boys (Ward 2004).

Why it is important to do this review

Glucocorticoid steroids delay the loss of ambulation and cardiorespiratory failure in DMD. However, treatment is required for many years and the risk of vertebral fragility and possibly long bone fractures is high. Identifying treatment strategies to treat or delay the onset of these fractures would have a significant effect in improving quality of life for these patients.

Objectives

Primary objective

To assess the effects of interventions to delay or treat osteoporosis in DMD patients treated with glucocorticoid steroids.

Secondary objectives

To assess the effects of interventions to delay or treat osteoporosis in DMD on the frequency of vertebral fragility fractures and long bone fractures in DMD patients treated with glucocorticoid steroids.

Methods

Criteria for considering studies for this review

Types of studies

Randomsed controlled trials (RCTs) and quasi-RCTs will be eligible for inclusion. Quasi-RCTs are trials where participants are allocated to treatment arms by a method that is not considered truly random (for example, by alternation, or using date of birth or hospital number).

Types of participants

We will consider all children and adults with a diagnosis of DMD, with any pathogenic mutation, deletion or duplication confirmed by genetic testing and/or muscle biopsy showing complete absence of dystrophin.

Types of interventions

We will consider any intervention to prevent steroid-induced osteoporosis and osteoporotic fractures in DMD compared to placebo, another intervention or no treatment (no available standard care).

Possible interventions include: oral and intravenous bisphosphonates (including both non-amino and amino groups), which will be examined separately, vitamin D supplements, calcium supplements, dietary calcium, and weight bearing activity.

Types of outcome measures

The outcomes listed here are not eligibility criteria for this review, but are outcomes of interest within whichever studies are included.

Primary outcomes

The primary outcome will be change in vertebral bone mineral density measured by DXA and expressed as a Z-score (which is based on age-matched results with a correction for body height) between baseline and 24 months of intervention.

The presence of vertebral compression fractures can artificially increase bone mineral density and produce higher Z-scores in an individual patient. However, we consider this effect unlikely to influence the outcome of a meta-analysis.

Secondary outcomes
  1. The number of vertebral fragility fractures, defined as one or a combination of the following: end-plate deformity with a reduction in the mid-vertebral height (biconcavity), decrease in the anterior vertebral height (wedging) or reduction in the anterior and posterior vertebral height (compression or crush) between baseline and 24 months of intervention. Identification of such vertebral fractures will be based on visual evaluation with an assessment of grade or severity linked to vertebrae height, shape and appearance (Baim 2008), for example using the Genant visual semi-quantitative method (Genant 1993). Detection will be with lateral spinal X-ray, DXA vertebral fracture assessment (VFA), computed tomography (CT) scans or MRI.

  2. The number of long bone fractures between baseline and 24 months of intervention.

  3. Change in reported bone pain measured using a standardised pain score (McGrath 2008), such as the visual analogue scale (VAS) (Scott 1979; Zebracki 2008) between baseline and 24 months of intervention.

  4. Change in quality of life as stated by author between baseline and 24 months of intervention, measured using a validated rating scale; for example, the Pediatric Quality of Life (PedsQL) (Varni 2001), Inventory Neuromuscular Module and Generic Core Scales (Davis 2010).

  5. Any adverse events, adverse events leading to withdrawal of treatment, serious adverse events which are fatal, life-threatening or lead to prolonged hospitalisation, and specific adverse events such as jaw osteonecrosis and atypical femur fractures.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Neuromuscular Group Specialized Register (10 December 2013), CENTRAL (2013, Issue 12 in The Cochrane Library), MEDLINE (January 1966 to November 2013), EMBASE (January 1980 to December 2013) and CINAHL Plus (January 1982 to December 2013) to identify potentially eligible trials. We did not limit our search by language or publication status.

The detailed search strategies are in the appendices: NMD Register Appendix 1, CENTRAL Appendix 2, MEDLINE Appendix 3, EMBASE Appendix 4 and CINAHL Plus Appendix 5.

Searching other resources

In addition, we will search the Web of Science ISI Proceedings (2001 to present), the National Research Register (NRR) archive, ClinicalTrials.gov (www.clinicaltrials.gov), Current Controlled Trials (www.controlled-trials.com), and the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch), to identify unpublished data, unpublished studies and ongoing trials. We will contact the correspondence author of studies included in the review to obtain further information on unpublished studies or work in progress.

Data collection and analysis

Selection of studies

Two review authors (JMB and MS) will independently select titles and abstracts that meet the inclusion criteria from the electronic searches. We will obtain the full text of all potentially relevant studies for further assessment. The two authors will independently select the studies which meet the inclusion criteria using a checklist developed for this purpose (Appendix 6). We will attempt to resolve any disagreements by discussion initially, then by arbitration with a third author (BB) if necessary.

We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (JMB and MS) will independently extract data using a standard data extraction form (see Appendix 6). One author (JMB) will enter data into the Cochrane software Review Manager 5 (RevMan) (RevMan 2011) and a second author (MS) will check data entry. JMB will contact study authors directly for any additional or missing data required. We will note in the 'Characteristics of included studies' table if outcome data are not reported in a usable way.

Where studies provide data on our outcomes at time points less than or more than 24 months, we will extrapolate the data to 24 months when it is reasonable to do so. We will assume a linear response rate but carry out a sensitivity analysis to assess the effects of the imputation, by re-analysis using alternative imputed values.

Assessment of risk of bias in included studies

Two review authors (JMB and MS) will independently assess the risk of bias in the included studies and a third (BB) will verify the assessments. We will use the domain-based evaluation described in The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). The domains will include:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of participants and personnel;

  4. blinding of outcome assessors;

  5. incomplete outcome data;

  6. selective reporting; and

  7. other bias.

For each domain, the risk of bias will be graded as "high risk of bias", "low risk of bias", or "unclear risk of bias" (Higgins 2011a). We will endeavour to contact the trial corresponding author for clarification if there is insufficient detail in the study report. We will resolve disagreements by discussion with the other authors. Once we have reached a consensus, we will assign studies to the following categories.

1. Low risk of bias: all domains at low risk of bias.

2. High risk of bias: two or more domains at high risk of bias.

3. Unclear risk of bias: one or more domains at unclear risk of bias.

We will construct a ‘Risk of bias’ table using RevMan to present the results. When considering treatment effects, we will take into account the risk of bias in the studies that contribute to that outcome.

We will use the 'Risk of bias' assessments to perform sensitivity analyses, as required.

Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

Assesment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

Statistical methods used to measure treatment effects will be in accordance with The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). 

We will analyse dichotomous data as risk ratios (RR) and continuous data as mean difference, or standardised mean difference for results across studies with outcomes that are conceptually the same but measured in different ways. We will report these measures of effect with 95% confidence intervals (CI).

We will undertake meta-analyses, using RevMan, only where this is meaningful, that is if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.

Unit of analysis issues

Where a single trial includes multiple trial arms, we will include only the relevant arms. If we combine two comparisons (e.g. drug A versus placebo and drug B versus placebo) in the same meta-analysis, we will halve the control group to avoid double-counting. For each participant there may be multiple observations for the same outcome.

Dealing with missing data

We will attempt to contact the trial correspondence author to obtain any missing data. If we are unable to obtain data, we will try to find out why the data are missing and decide, based on whether they are missing at random or not, whether to analyse available data or impute missing values using a statistical model. We will consider how best to include missing data where baseline-observation-carried-forward (BOCF) or last- observation-carried-forward (LOCF) methods have been used for imputation and attempt to standardise these between studies (LOCF being preferable).

We will address the potential implications of missing data (for example, loss to follow-up and no outcome obtained, lack of compliance) in the 'Discussion'.

Assessment of heterogeneity

We will assess clinical heterogeneity by judging, qualitatively, the differences between studies regarding the participants, therapies, and reporting of important study outcomes.

We will statistically test heterogeneity of intervention effects among trials using the standard Chi2 statistic (P value) and the Higgins I2 statistic expressed as a percentage. We will take P values of less than 0.05 as evidence of heterogeneity. We will interpret I2 for heterogeneity as follows:

• 0% to 40%: may not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

If we identify substantial unexplained heterogeneity we will report it and explore possible causes by prespecified subgroup analysis (Higgins 2011b).

Assessment of reporting biases

To detect the presence of publication bias, we will construct a funnel plot using Revman, if there are a reasonable number of studies (at least 10 in the same meta-analysis). We will use Beggs’s and Egger’s tests to verify the bias (Begg 1994; Egger 1997).

Data synthesis

If there is no substantial or considerable heterogeneity, we will synthesise the data in a meta-analysis using RevMan. We will perform both fixed-effect and random-effects models for comparison purposes and use the most appropriate, depending upon the degree of heterogeneity.

If the review includes more than one comparison, and they cannot be included in the same analysis, we will report the results for each comparison separately.

Cost-utility analyses

We will consider cost effectiveness of interventions per QALY (quality-adjusted-life-year) in the Discussion, where data are available.

Subgroup analysis and investigation of heterogeneity

If there are sufficient data, we plan to undertake the following subgroup analyses using the outcome vertebral fractures:

  1. ambulant versus non-ambulant (due to disease progression these groups will reflect age groups); and

  2. intervention versus intervention combination.

Within each group we will use the I2 statistic for heterogeneity and if its value is greater than 50% we will scrutinise the trials and forest plots for differences to explain the heterogeneity. If we find no explanation, we will repeat the analysis using a random-effects model.

'Summary of findings' table

We will create a 'Summary of findings' table using the following outcomes:

  • change in bone mineral density as assessed by Z-score;

  • frequency of vertebral fragility fractures; and

  • adverse events.

We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes). We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a) using GRADEpro software. We will justify all decisions to down- or upgrade the quality of studies using footnotes and we will make comments to aid readers' understanding of the review where necessary.

Sensitivity analysis

We will perform a sensitivity analysis to determine whether conclusions are robust by undertaking both fixed-effect and random-effects meta-analysis. We will perform sensitivity analyses to assess the effect of including studies at high risk of bias on the change in vertebral bone mineral density (body height corrected Z-scores), and by repeating the meta-analysis excluding any studies at high risk of bias. If we have imputed missing data we will assess the effects of the imputation by re-analysis using several alternative imputed values.

Acknowledgements

Angela Gunn, Trials Search Co-ordinator, Cochrane Neuromuscular Disease Group, who assisted with development of the search strategy.

Appendices

Appendix 1. Cochrane Neuromuscular Disease Group Specialized Register (CRS) search strategy

#1 muscular NEAR5 dystroph* [REFERENCE] [STANDARD]
#2 duchenne or dystrophinopathy [REFERENCE] [STANDARD]
#3 #1 or #2 [REFERENCE] [STANDARD]
#4 "vertebral deformity" or fracture or compression or crush or wedging or biconcavity [REFERENCE] [STANDARD]
#5 osteoporosis [REFERENCE] [STANDARD]
#6 bone or bmc [REFERENCE] [STANDARD]
#7 (bone or bmc):so [REFERENCE] [STANDARD]
#8 #6 not #7 [REFERENCE] [STANDARD]
#9 lumbar or spine [REFERENCE] [STANDARD]
#10 MeSH DESCRIPTOR Diphosphonates Explode All [REFERENCE] [STANDARD]
#11 bisphosphonate* or diphosphonate* [REFERENCE] [STANDARD]
#12 alendronate or clodronate or etidronate or ibandronate or incadronate or opadronate or pamidronate or risedronate or tiludronate or zolendronate [REFERENCE] [STANDARD]
#13 calcitonin or calcium or calcitriol or cholecalciferol* or Ergocalciferol* [REFERENCE] [STANDARD]
#14 "vitamin D" [REFERENCE] [STANDARD]
#15 "dietary supplements" [REFERENCE] [STANDARD]
#16 Teriparatide or "weight bearing" or diet or exercise [REFERENCE] [STANDARD]
#17 "non drug" NEXT therapy [REFERENCE] [STANDARD]
#18 #4 or #5 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 [REFERENCE] [STANDARD]
#19 #3 and #18 [REFERENCE] [STANDARD]
#20 (#3 and #18) AND (INREGISTER) [REFERENCE] [STANDARD]

Appendix 2. CENTRAL search strategy

#1 muscular near dystrophy or duchenne near dystrophy or dystrophinopathy
#2 "vertebral deformity" or fracture or compression or crush or wedging or biconcavity
#3 steroid near/1 induced and osteoporosis
#4 steroid near/1 induced and "bone loss"
#5 steroid near/1 induced and osteopenia
#6 MeSH descriptor: [Osteoporosis] this term only and with qualifier(s): [Chemically induced - CI]
#7 secondary next osteoporosis
#8 bone next strength
#9 bone next fragil*
#10 bone next loss
#11 "bone density" or "bone mineral density" or "bone mineral content" or bmc
#12 bone next deformity or lumbar next spine
#13 MeSH descriptor: [Spine] explode all trees
#14 MeSH descriptor: [Diphosphonates] explode all trees
#15 bisphosphonate* or diphosphonate*
#16 alendronate or clodronate or etidronate or ibandronate or incadronate or opadronate or pamidronate or risedronate or tiludronate or zolendronate
#17 calcitonin or calcium or celcitriol or ergocalciferol* or "vitamin D"
#18 MeSH descriptor: [Cholecalciferol] explode all trees
#19 "dietary supplements" or teriparatide
#20 "non drug" next therapy
#21 diet or exercise or "weight bearing"
#22 #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21
#23 #1 and #22

Appendix 3. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to November Week 3 2013>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (390995)
2 controlled clinical trial.pt. (90070)
3 randomized.ab. (288395)
4 placebo.ab. (157299)
5 drug therapy.fs. (1772029)
6 randomly.ab. (200079)
7 trial.ab. (303857)
8 groups.ab. (1280166)
9 or/1-8 (3308511)
10 exp animals/ not humans.sh. (4066609)
11 9 not 10 (2817704)
12 exp muscular dystrophy/ (21893)
13 ((muscular adj5 dystrophy) or duchenne or dystrophinopathy).tw. (17298)
14 or/12-13 (26183)
15 (vertebral deformity or fracture or compression or crush or wedging or biconcavity).mp. (208111)
16 ((steroid adj1 induced) and osteoporosis).tw. (223)
17 ((steroid adj1 induced) and bone loss).tw. (75)
18 ((steroid adj1 induced) and osteopenia).tw. (37)
19 osteoporosis/ci (2629)
20 secondary osteoporosis.tw. (563)
21 (bone adj1 strength).tw. (3223)
22 (bone adj1 fragil$).tw. (1215)
23 (bone adj1 loss).tw. (18613)
24 (bone mineral density or bone mineral content or bmc).mp. (31547)
25 Bone Density/ (41566)
26 (bone adj1 deformity).tw. (237)
27 (lumbar adj1 spine).tw. (19341)
28 Lumbar Vertebrae/ (39168)
29 exp Spine/ (107497)
30 exp Diphosphonates/ (21384)
31 (bisphosphonate$ or diphosphonate$).tw. (13803)
32 (alendronate or clodronate or etidronate or ibandronate or incadronate or opadronate or pamidronate or risedronate or tiludronate or zolendronate).tw. (7915)
33 Calcitonin/ (14046)
34 calcium/ (249466)
35 Calcitriol/ (13201)
36 exp Cholecalciferol/ (23626)
37 Ergocalciferols/ (2433)
38 Vitamin D/ (22775)
39 Dietary Supplements/ (31848)
40 Teriparatide/ (1397)
41 Weight-Bearing/ (15661)
42 (non-drug adj1 therapy).tw. (92)
43 (diet or exercise).tw. (369324)
44 or/15-43 (1023368)
45 11 and 14 and 44 (175)
46 remove duplicates from 45 (154)

Appendix 4. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2013 Week 49>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (39140)
2 double-blind procedure.sh. (119029)
3 single-blind procedure.sh. (18610)
4 randomized controlled trial.sh. (361465)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (1021823)
6 trial.ti. (156546)
7 or/1-6 (1160227)
8 exp animal/ or exp invertebrate/ or animal.hw. or non human/ or nonhuman/ (20283159)
9 human/ or human cell/ or human tissue/ or normal human/ (15097177)
10 8 not 9 (5218620)
11 7 not 10 (1018358)
12 limit 11 to embase (781489)
13 exp muscular dystrophy/ (30601)
14 ((muscular adj5 dystrophy) or duchenne or dystrophinopathy).tw. (19359)
15 13 or 14 (33153)
16 vertebra malformation/ (2190)
17 (vertebral deformity or fracture or compression or crush or wedging or biconcavity).mp. (354852)
18 corticosteroid induced osteoporosis/ (1584)
19 ((steroid adj1 induced) and osteoporosis).tw. (328)
20 ((steroid adj1 induced) and bone loss).tw. (98)
21 ((steroid adj1 induced) and osteopenia).tw. (44)
22 osteoporosis/pc [Prevention] (9583)
23 secondary osteoporosis.tw. (979)
24 (bone adj1 strength).tw. (4181)
25 (bone adj1 fragil$).tw. (1714)
26 (bone adj1 loss).tw. (22556)
27 (bone mineral density or bone mineral content or bmc).mp. (41554)
28 bone density/ (56391)
29 bone malformation/ (4171)
30 (((bone adj1 density) or bone) adj1 deformity).tw. (325)
31 exp spine/ (121970)
32 (lumbar vertebra$ or lumbar spine).tw. (31403)
33 bisphosphonic acid derivative/ (23932)
34 (bisphosphonate$ or diphosphonate$).tw. (18985)
35 (alendronate or clodronate or etidronate or ibandronate or incadronate or opadronate or pamidronate or risedronate or tiludronate or zolendronate).tw. (10970)
36 calcitonin/ (20461)
37 calcium/ (229733)
38 calcitriol/ (23701)
39 colecalciferol/ (12139)
40 ergocalciferol/ (6206)
41 vitamin D/ (43671)
42 diet supplementation/ (62636)
43 "parathyroid hormone[1-34]"/ (4137)
44 resistance training/ (4812)
45 weight bearing.mp. (25302)
46 (non-drug adj1 therapy).tw. (133)
47 (diet or exercise).tw. (448958)
48 or/16-47 (1273925)
49 12 and 15 and 48 (62)
50 remove duplicates from 49 (60)

Appendix 5. CINAHL Plus (EBSCOhost) search strategy

Tuesday, December 10, 2013 6:49:12 AM

S46 s45 Limiters - Exclude MEDLINE records13
S45 S18 AND S19 AND S44 98
S44 S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 or S42 or S43 239,546
S43 diet or exercise 149,692
S42 "non drug" W1 therapy 13
S41 weight W1 bearing 5,274
S40 teriparatide 205
S39 vitamin W1 D 10,893
S38 Cholecalciferol* or Ergocalciferol* 540
S37 calcitonin or calcium or calcitriol 23,360
S36 alendronate or clodronate or etidronate or ibandronate or incadronate or opadronate or pamidronate or risedronate or tiludronate or zolendronate 1,797
S35 bisphosphonate* or diphosphonate* 5,423
S34 (MH "Diphosphonates+") 5,628
S33 spine 18,047
S32 lumbar N4 vertebrae 8,255
S31 bone N4 deformity OR lumbar spine 3,557
S30 bone density 11,393
S29 bone mineral density or bone mineral content or bmc 4,468
S28 bone loss 3,393
S27 bone fragil* 160
S26 bone strength 726
S25 secondary osteoporosis 156
S24 (MH "Osteoporosis/CI") 498
S23 steroid W1 induced AND osteopenia 2
S22 steroid W1 induced AND bone loss 7
S21 steroid W1 induced AND osteoporosis 30
S20 vertebral W1 deformity OR ( fracture or compression or crush or wedging or biconcavity ) 33,709
S19 muscular W5 dystrophy OR ( duchenne or dystrophinopathy ) 1,995
S18 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 642,786
S17 ABAB design* Display
S16 TI random* or AB random* Display
S15 ( TI (cross?over or placebo* or control* or factorial or sham? or dummy) ) or ( AB (cross?over or placebo* or control* or factorial or sham? or dummy) ) Display
S14 ( TI (clin* or intervention* or compar* or experiment* or preventive or therapeutic) or AB (clin* or intervention* or compar* or experiment* or preventive or therapeutic) ) and ( TI (trial*) or AB (trial*) ) Display
S13 ( TI (meta?analys* or systematic review*) ) or ( AB (meta?analys* or systematic review*) ) Display
S12 ( TI (single* or doubl* or tripl* or trebl*) or AB (single* or doubl* or tripl* or trebl*) ) and ( TI (blind* or mask*) or AB (blind* or mask*) ) Display
S11 PT ("clinical trial" or "systematic review") Display
S10 (MH "Factorial Design") Display
S9 (MH "Concurrent Prospective Studies") or (MH "Prospective Studies") Display
S8 (MH "Meta Analysis") Display
S7 (MH "Solomon Four-Group Design") or (MH "Static Group Comparison") Display
S6 (MH "Quasi-Experimental Studies") Display
S5 (MH "Placebos") Display
S4 (MH "Double-Blind Studies") or (MH "Triple-Blind Studies") Display
S3 (MH "Clinical Trials+") Display
S2 (MH "Crossover Design") Display
S1 (MH "Random Assignment") or (MH "Random Sample") or (MH "Simple Random Sample") or (MH "Stratified Random Sample") or (MH "Systematic Random Sample") Display
Bottom of Form

Appendix 6. Data extraction form

Review title: Prevention and treatment of steroid induced osteoporosis in DMD

Study ID (first author, year, place of publication e.g. Smith 2001 UK)
 
Report IDs of other reports of this study (e.g. duplicate publications, follow-up studies)
 

1. General Information

Date form completed (dd/mm/yyyy)Location in text (pg & ¶/fig/table)
Initials of review author extracting data 
Report title (title of paper/abstract/report from which data are extracted) 
Report ID (ID for this paper/ abstract/ report) 
Reference details (citation) 
Correspondence author contact details 
Publication type (e.g. full report, abstract, letter) 
Notes: 

2. Study Eligibility

Study Characteristics Eligibility criteriaYesNoUnclear

Location in text

(pg & ¶/fig/table)

Type of studyRandomised Controlled Trial        
Controlled Clinical Trial (quasi-randomised trial)   

 

 

Participants Children & young adults with a definite diagnosis of DMD, taking steroid treatment        
Types of intervention (name intervention drug/supplement / technique)

A. oral bisphosphonates ________

B. intravenous bisphosphonates________

C. vitamin D supplements ________

D. calcium supplements ________

E. non -drug related weight bearing/mechanical loading activity________

        
Types of outcome measuresIncidence of vertebral fractures         
INCLUDE 

EXCLUDE   

DO NOT PROCEED IF STUDY EXCLUDED FROM REVIEW

Reason for exclusion 

Reserve for discussion?

Reason

Yes No

3. Population and setting

 

Description

Include comparative information for each group (i.e. intervention and controls) if available

Location in text

(pg & ¶/fig/table)

Population description (from which study participants are drawn)  
Setting (including location and social context)  
Inclusion criteria  
Exclusion criteria  
Method/s of recruitment of participants  
Informed consent obtainedYes No Unclear  
Notes:

4. Methods

 

Descriptions as stated in report/paper

 

Location in text

(pg & ¶/fig/table)

Aim of study    
Unit of allocation (by individuals, cluster/ groups or body parts)      
Total study duration       
Year(s) study conducted  
Ethical approval needed/ obtained for studyYes No Unclear     
Study funding sources (including role of funders)  
Possible conflicts of interest (for study authors)  
Notes:

5. 'Risk of bias' assessment

See Chapter 8 of the Cochrane Handbook

Domain

Risk of bias

 

Support for judgement

 

Location in text

(pg & ¶/fig/table)

Low riskHigh riskUnclear
Random sequence generation (selection bias)         
Allocation concealment (selection bias)           
Blinding of participants and personnel (performance bias)    Outcome group: All/     
(if required)    Outcome group:     
Blinding of outcome assessors (detection bias)    Outcome group: All/      
(if required)    Outcome group:  
Incomplete outcome data (attrition bias)           
Selective outcome reporting? (reporting bias)         
Other bias          
Notes: 

6. Participants

Provide overall data and, if available, comparative data for each intervention or comparison group.

 

Description as stated in report/paper

 

Location in text

(pg & ¶/fig/table)

Total number randomised (or total pop. at start of study for NRCTs)          
Clusters (if applicable, no., type, no. people per cluster)          
Baseline imbalances          
Withdrawals and exclusions (if not provided below by outcome)          
Age (state range, mean, SD)          
Ambulant (n %)          
Other treatment received (additional to study intervention)          
Subgroups measured           
Subgroups reported           
Notes:

7. Intervention groups

Copy and paste table for each intervention and comparison group

Intervention Group 1

  Description as stated in report/paper

Location in text

(pg & ¶/fig/table)

Group name           
No. randomised to group (specify whether no. people or clusters)          
Description (include sufficient detail for replication, e.g. content, dose, components)

Drug/supplement/technique:

Dose:

   
Duration of treatment period          
Timing (e.g. frequency, duration of each episode)          
Delivery (e.g. mechanism, medium, intensity, fidelity)          
Providers (e.g. no., profession, training, ethnicity etc. if relevant)          
Co-interventions          
Economic variables (i.e. intervention cost, changes in other costs as result of intervention)          
Resource requirements to replicate intervention (e.g. staff numbers, cold chain, equipment)          
Notes:

8. Outcomes

Copy and paste table for each outcome.

Outcome 1

 

Description as stated in report/paper

 

Location in text

(pg & ¶/fig/table)

Outcome name       
Time points measured      
Time points reported      
Outcome definition (with diagnostic criteria if relevant)      
Person measuring/reporting      
Unit of measurement (if relevant)        
Scales: upper and lower limits (indicate whether high  or low score is good)    
Is outcome/tool validated?

Yes No Unclear         

     

 
Imputation of missing data (e.g. assumptions made for ITT analysis)      
Assumed risk estimate (e.g. baseline or population risk noted  in Background)      
Power      
Notes:

9. Results

Copy and paste the appropriate table for each outcome, including additional tables for each time point and subgroup as required.

Dichotomous outcome

 

Description as stated in report/paper

 

Location in text

(pg & ¶/fig/table)

Outcome  
Comparison  
Timepoint (from start of intervention)  
Results Intervention Comparison 
Number of eventsNumber of participantsNumber of eventsNumber of participants
Any other results reported    
Number of participants missing or moved from other group (reasons)   
Subgroup  
Unit of analysis (by individuals, cluster/groups or body parts)   
Statistical methods used and appropriateness of these methods (e.g. adjustment for correlation)  
Reanalysis required? (specify)  Yes No Unclear 
Reanalysis possible?  Yes No Unclear    
Reanalysed results      
Notes:        

 Continuous outcome

 

Description as stated in report/paper

 

Location in text

(pg & ¶/fig/table)

Outcome          
Comparison          
Timepoint (from start of intervention)          
Post-intervention, between intervention or change from baseline?  
Results Intervention Comparison 
MeanSD (or other variance)Number of participantsMeanSD (or other variance)Number of participants 
Any other results reported          
Number of participants missing or moved from other group (reasons)      
Subgroup         
Unit of analysis (individuals, cluster/ groups or body parts)        
Statistical methods used and appropriateness of these methods (e.g. adjustment for correlation)        
Reanalysis required? (specify)Yes No Unclear             
Reanalysis possible?Yes No Unclear         
Reanalysed results          
Notes: 

 Other outcome

 

Description as stated in report/paper

 

Location in text

(pg & ¶/fig/table)

Outcome          
Comparison          
Timepoint (from start of intervention)          
ResultsIntervention resultSD (or other variance)Control resultSD (or other variance)     
Overall resultsSE (or other variance)
Number of participantsInterventionControl 
Any other results reported                
Number of participants missing or moved from other group (reasons)               
Subgroup          
Unit of analysis (by individuals, cluster/groups or body parts)          
Statistical methods used and appropriateness of these methods          
Reanalysis required? (specify)Yes No Unclear         
Reanalysis possible?Yes No Unclear          
Reanalysed results          
Notes:      

10. Applicability

Have important populations been excluded from the study? (consider disadvantaged populations, and possible differences in the intervention effect)Yes No Unclear
Is the intervention likely to be aimed at disadvantaged groups? (e.g .lower socioeconomic groups)Yes No Unclear
Does the study directly address the review question? (any issues of partial or indirect applicability)Yes No Unclear
Notes:         

11. Other information

 

Description as stated in report/paper

 

Location in text

(pg & ¶/fig/table)

Key conclusions of study authors      
References to other relevant studies          
Correspondence required for further study information (from whom, what and when)     
Notes:  

 

Contributions of authors

Jennifer Bell prepared the protocol with discussion and comments from the other review authors. Dr Janet Watters reviewed the text from the perspective of a health care consumer as the mother of a boy with DMD.

Declarations of interest

JMB: none known

TB: acknowledges financial support received from Servier Laboratories Ltd and Amgen UK Ltd to attend national conferences and payment with respect to chairman and speakers fees.

BB: none known

ME: none known

AH: none known

RQ: is Joint Co-ordinating Editor of the Cochrane Neuromuscular Disease Group and is the author of two consensus workshop reports for bone health in DMD. Dr Quinlivan has received an honorarium from Genzyme for lecturing on metabolic muscle disease and consultancy fees from Novartis and Guidepoint Global.

MDS: has received honoraria from GlaxoSmithKline, AstraZeneca, Novartis, Merck Sharp & Dohme, and Alk-Abello for lectures given at educational meetings and received hospitality to attend the European Respiratory Society and British Thoracic Society annual meetings.

ST: none known

JW: My membership of the charities Action Duchenne and the Muscular Dystrophy Campaign might construe a bias towards finding a treatment that is effective for management of Duchenne Muscular Dystrophy, but I am not aware of ever having spoken publicly about any treatment other than to quote results of research undertaken by others.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Health Research Board/HSC R&D Division Cochrane Fellowship Award, Ireland.

Ancillary