Duchenne muscular dystrophy (DMD)

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 one in 3500 to one in 6000 male live births (Emery 1991; Emery 2003; Flanigan 2012). DMD is caused by deletions, duplications or mutations in the dystrophin gene located at Xp21, resulting in the absence or low levels of the protein known as dystrophin (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; Deconinck 2007). Affected boys appear normal at birth and first show signs of muscle weakness in early childhood, often as a toddler. Without treatment, they become wheelchair dependent by 13 years of age. Without respiratory support, death occurs in the late teens or early twenties. Because of postural imbalance and reduced muscular support to the spine, scoliosis (spinal deformity) typically develops. Scoliosis of the thoracic region restricts movement of the ribs making breathing even more difficult for already weakened respiratory muscles. However, in recent years, prognosis has improved substantially with the introduction of non‐invasive ventilation support along with cough‐assist technology and co‐ordinated multidisciplinary care (Bushby 2010; Passamano 2012).

Corticosteroid treatment is now considered the 'gold standard' for DMD, and corticosteroid‐induced osteoporosis is an important emerging problem (Bushby 2010). Corticosteroids 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 seven to 13 years for non‐treated boys (Matthews 2010; Ricotti 2012). Physicians usually start treatment during the 'plateau phase' of the condition (usually between four and six years of age) (Bushby 2010). Doses of prednisone, prednisolone, or deflazacort are either taken daily, Biggar 2004; Fenichel 1991; Griggs 1991; Matthews 2010; Mesa 1991, or intermittently, Dubowitz 2002; Kinali 2002. Treatment that is continued after the loss of ambulation may preserve upper body strength, respiratory and cardiac function, and delay the onset of scoliosis (Balaban 2005; Biggar 2004; Biggar 2006; Daftary 2007; Hussein 2014; King 2007; Lebel 2013; Manzur 2008; Schram 2013). Corticosteroids have significant side‐effects, which require proactive management (Angelini 2007; Balaban 2005; Biggar 2006; Bonifati 2000; Bushby 2004; Bushby 2010; Houde 2008; King 2007; Manzur 2008; Matthews 2010; Merlini 2012; Moxley 2010). One such side‐effect is corticosteroid‐induced osteoporosis, which includes the increased risk of vertebral fractures (Angelini 2012; Bachrach 2005; Balaban 2005; Bothwell 2003; Bianchi 2003; Canalis 2004; Houde 2008; King 2007; Mayo 2012; Quinlivan 2010; Soderpalm 2007; Van Staa 2003; Weldon 2009).

Osteoporosis

Osteoporosis is a progressive, systemic skeletal disease, characterised by reduced bone mass and micro‐architectural deterioration of bone tissue. As a result, bone is increasingly fragile and more susceptible to fracture (NICE 2012). Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. Osteoporotic fragility fractures are defined as fractures associated with low bone mineral density and include spine, forearm, hip, and shoulder fractures.

In children and adolescents, osteoporosis is defined as low bone mineral content or bone mineral density for chronological age. The diagnosis of osteoporosis requires the presence of both a clinically significant fracture history, for example, vertebral compression fracture or long‐bone fractures, and low bone mineral content or bone mineral density. Low bone mineral content or bone mineral density is defined as bones with a Z‐score that is less than or equal to ‐2.0, adjusted for age, gender, and body size, as appropriate (ISCD 2007).

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 magnetic resonance imaging (MRI) are also used (Bachrach 2011; Buckner 2015). 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 (Bianchi 2014). Bone mineral density is measured as age‐based and height‐adjusted Z‐scores (Bachrach 2011; Baim 2008; Bianchi 2010; Crabtree 2014; Fewtrell 2003). 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).

Bone is a living tissue, which bone formation and bone resorption constantly remodels (Joyce 2012). Factors that affect bone health include genetics, nutrition, physical activity (loading), age, and hormones. Corticosteroid treatment affects endocrine function, suppressing growth, delaying puberty, reducing bone mineral density, and increasing body weight (Bianchi 2011a; Dooley 2013; Wood 2015). Corticosteroids induce bone loss by 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 that break down bone) (Popp 2006). 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 to a reduction in bone mineral density (Allen 1998; Bianchi 2011a; Dooley 2013). Bone mineral density is difficult to assess in DMD due to lack of normative curves, short stature, delayed bone age, etc. Corticosteroid treatment may not appear to reduce bone mineral density to the same extent as in adults. Soderpalm 2008 commented that lower bone mineral density in boys with DMD is likely to be the combined result of corticosteroid treatment, muscle loss from the 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 boys with DMD who are corticosteroid‐naive (that is, those who have not previously been exposed to corticosteroids) are at increased risk of long‐bone fractures (Biggar 2006; Granata 1991; Houde 2008; Hsu 1979; Larson 2000; McDonald 2002; Vestergaard 2001), implying that corticosteroids are not the only cause for these fractures and causation is complex.

Osteoporotic fragility fractures

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). Vertebral fragility fractures have not been reported in corticosteroid‐naive patients with DMD of any age (Alman 2004; Houde 2008; King 2007), and very often, vertebral fractures are not tracked in children with DMD (especially those not treated with steroids). In boys with DMD taking corticosteroids, the occurrence of vertebral fractures ranges from 15% to 75% after 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, however, similar in treated and untreated patients (Houde 2008; McDonald 2002) (24% and 26%, respectively, in Houde 2008).

Those treated with corticosteroids tend to be more ambulant, and patients who are more ambulant are more likely to fall and sustain a long‐bone fracture. Non‐ambulatory patients appear to be at an increased risk of vertebral fractures (Larson 2000; Mayo 2012). Previous surgical intervention for scoliosis may also prevent vertebral fragility fractures (Mayo 2012). Lack of ambulation, taking steroids previously, or both, may lead to a greater body fat composition in patients with DMD. Body fat percentage was reported as 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).

Vertebral fractures can be symptomatic or asymptomatic. Acute back pain is closely associated with symptomatic vertebral fragility fractures (odds ratio (OR) 10.6, 95% confidence interval (CI) 2.1 to 53.8, P = 0.004) and requires radiological investigation to confirm the diagnosis (Huber 2010; Talim 2002), but an estimated 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 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, as well as the degree of deformity (Genant 1993; Lenchik 2004; Quinlivan 2010).

The occurrence of fractures is significantly related to low bone mineral density in DMD (Aparicio 2002; Khatri 2008; Larson 2000). Bone mineral density is often lower than normal for the age of the patient (Bianchi 2003; Crabtree 2010; Mayo 2012; Soderpalm 2012). In children and adolescents with DMD, the baseline bone mineral density is low due to lack of weight‐bearing activity. It is probably lowered further by corticosteroids. While some studies have shown no reduction in spinal bone mineral density after 30 months of corticosteroid therapy for DMD in prepubertal boys (Crabtree 2010), or only a marginal reduction in children and adolescents taking corticosteroids (Cohran 2008), others reported a substantially lowered bone mineral density in boys (children and adolescents) taking corticosteroids, particularly those with reduced mobility (Bianchi 2003; Hawker 2005; Mayo 2012).

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). Recent advances in treatments for muscle loss have enabled people with DMD to actively participate in life for longer. 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 corticosteroid‐induced osteoporosis and prevent often painful fragility fractures in DMD may have a significant effect in improving quality of life for these patients.

Bisphosphonates

Intravenous bisphosphonates are used to treat painful vertebral fractures in boys with DMD and are associated with improvements in back pain (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 (bone fragility) (Allington 2005; Bianchi 2000; Brumsen 1997; Glorieux 1998; Hawker 2005; Henderson 2002; Houston 2014; Palomo 2011; Plotkin 2000; Plotkin 2006; Rauch 2002; Rudge 2005; Sbrocchi 2012; Shaw 2000; Sholas 2005; Wagner 2011; Ward 2011). A randomised controlled trial (RCT) to investigate the efficacy and safety of daily oral alendronate in children and adolescents with osteogenesis imperfecta over two years found that the mean spine area Z‐score increased from ‐4.6 to ‐3.3 compared to ‐4.6 to ‐4.5 in the placebo group. Long‐bone fracture incidence and bone pain were similar between groups (Ward 2011).

Bisphosphonates appear to be well tolerated by children for periods of up to three years (Shaw 2005; Ward 2007b). Dosing regimes differ among paediatric studies (Ward 2007b). Oral bisphosphonates are prescribed according to body weight (mg/kg) (Bianchi 2000; Hawker 2005; Rudge 2005). Intravenous bisphosphonates are usually administered at a dose of 1 mg/kg to 1.5 mg/kg (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, calcium supplements reduce the absorption of bisphosphonates. Adverse effects are more common with intravenous than oral bisphosphonates (Somalo 2007). The U.S. Food and Drug Adminstration (FDA) 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

A balanced calcium‐rich diet 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.

Genetics determine 60% to 80% of attained peak bone mass, and environmental factors, such as nutrition, exercise, and disease, determine the remainder (Quinlivan 2010). Bone mineral density can vary between individuals from early childhood and be predictive of a potential fracture risk in children with medical conditions affecting bone health (Ferrari 1998; Goulding 2005; Harvey 2012; Quinlivan 2010; Winzenberg 2006). 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 showed an increase in bone mineral density in those taking calcium‐supplemented food compared to those who did not (Bonjour 1997). There is poor evidence to indicate whether calcium supplementation alone reduces the risk of fractures (Black 2002; Bolland 2015; Goulding 1998; Goulding 2004; Petridou 1997; Winzenberg 2006). The consumption of adequate dietary calcium and vitamin D can increase bone mineral density in patients with DMD (Bianchi 2011). Evidence that calcium alone has a positive effect on bone health in boys with DMD is limited.

Vitamin D

Significantly lower serum 25OHD levels have been highlighted in boys with DMD, especially in those taking corticosteroids (Bianchi 2003; Bianchi 2011). People taking corticosteroids are twice as likely to have low 25OHD levels as those not on corticosteroids (OR 2.36, 95% CI 1.25 to 4.45) (Skversky 2011). Dhawan 2010 proposed that corticosteroids may inactivate 25OHD by increasing the activity of the enzyme 24‐hydroxylase.

Vitamin D levels collected in boys with DMD 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 those with DMD on corticosteroids were vitamin D deficient (Manzur 2010; Wong 2010).

In a Cochrane Review, the bone mineral density in healthy children taking vitamin D supplements did not change, but bone mineral density did increase in those with low 25OHD levels (Winzenberg 2010). 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).

Testosterone

Testosterone is the primary sex hormone for the maturation of sex characteristics in adolescent males. It is also involved in the increase in muscle strength and bone mineral content during puberty (Seeman 2001; Wood 2015). Testosterone is a steroid hormone produced by the testes and the adrenal glands and belongs to a group of male hormones known as androgens. The production of this hormone is regulated by the hypothalamus and pituitary gland.

Long‐term corticosteroid treatment in prepubertal boys can slow down growth and delay puberty compared to their healthy peers (Wood 2015). All but one of 44 boys with DMD aged 13 years and upwards assessed at Cincinnati Children's Hospital were prepubertal, compared to the 50% of healthy UK boys who are in puberty by 12 years of age (Bianchi 2011a; Bonifati 2000). Although not clearly understood, high doses of corticosteroids inhibit or reduce the secretion of gonadotrophin‐releasing hormone by the hypothalamus, which in turn down‐regulates pituitary gonadotrophin production. Corticosteroids may also have a direct effect on the testes to reduce testosterone production. A deficiency in testosterone can delay the onset of puberty (Al‐Harbi 2008; Eastell 1998; Hampson 2002; Kamischke 1998a; Reid 1985).

The absence or delay of puberty has a significant adverse effect on bone health, which is already poor in those with DMD due to corticosteroid treatment, diminishing muscle mass, and reduced mobility (Bianchi 2011a; Fairfield 2001; Guzman 2012; Reid 1985). Hypogonadism increases the risk of osteoporosis and fractures. Testosterone is an important hormone involved in the development of bone and in the maintenance of bone mineral density in adolescence and adulthood (Amory 2004; Devogelaer 1992; Katznelson 1996; Kenny 2001; Leder 2002; Tenover 1992).

Weight‐bearing exercise

In DMD patients over eight years of age, there is a gradual decline in physical activity due to natural disease progression (Mazzone 2011; McDonald 2010). Weight‐bearing exercise, for example, walking, stimulates bone regeneration. Dynamic‐loading activity achieves greater gains in bone tissue than static activity (Lanyon 1984). 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.

Bisphosphonates

Bisphosphonates are 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). Bisphosphonates 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 (Allington 2005; Black 2012; Brumsen 1997; Hawker 2005; Poole 2012; Rudge 2005; Schwartz 2010; Sholas 2005).

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 bone matrix hydroxyapatite, which provides compressional strength in bone (Bonjour 2011; Peacock 2010). During remodelling, bone turns over calcium. Remodelling activity determines the amount of calcium required to maintain bone health, and this varies 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). Calcium deficiency can contribute to the development of osteoporosis. Not only is there inadequate calcium for bone mineralisation, but bone calcium stores are deleted to maintain blood calcium levels. Reduced blood calcium levels triggers parathyroid hormone (PTH) release (Peacock 2010). PTH stimulates osteoclasts and bone resorption. High blood calcium levels result in calcitonin release, which inhibits osteoclast activity, promoting bone formation and storage of excess calcium in the bone matrix.

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. However, adequate calcium intake could slow bone resorption and contribute to improving bone health in boys and adolescents with DMD (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

Vitamin D is vital for intestinal calcium absorption (Frolik 1971; Wei 2010). It may also have its own protective effect on bone (Bartoszewska 2010; Peppone 2010). Vitamin D₂ (ergocalciferol) is largely man‐made and present in supplemented food. The skin synthesises vitamin Dɜ (cholecalciferol) after exposure to sunlight, and it is also available in the diet (Misra 2008). The liver metabolises vitamin D into calcifediol (25‐dihydroxyvitamin Dɜ (25OHD)), which the kidneys convert to the active calcitriol (1,25‐dihydroxyvitamin Dɜ) (Peppone 2010). 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 2007a). 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). Its prevalence, especially in non‐white families, is underappreciated (Ahmed 2011; Kehler 2013; Lips 2010; Shaw 2011; Zipitis 2006).

Calcitriol slows bone resorption and enhances bone mineralisation because it aids calcium absorption. Calcitriol influences the genes that control neuromuscular cell proliferation, differentiation, and apoptosis (Banerjee 2003; Carlberg 2003; Garcia 2011). There is little evidence that increasing vitamin D intake alone reduces the risk of fractures (Bischoff‐Ferrari 2005; DIPART 2010; Looker 2008).

Testosterone

Testosterone therapy increases trabecular bone density (Katznelson 1996). Testosterone is used to reverse delayed puberty, reduced growth, and osteoporosis exacerbated by corticosteroid use in DMD (Bianchi 2011a).

Testosterone replacement therapy is started in low doses at around 14 years of age and increased over three to four years until adult levels are reached. The expected benefits include an increase in bone density, muscle strength, and energy levels from a pubertal growth spurt.

Testosterone supplementation can also increase height and improve quality of life during adolescence and young adulthood from an improved body image (Landon 1984; Mason 2011). A meta‐analysis of eight RCTs examining the use of testosterone in 365 men found moderate gains in lumbar bone density (Tracz 2006). Three of the eight studies included men taking corticosteroids (N = 87). The meta‐analysis concluded that the effect of testosterone was weak with regard to osteoporosis prevention and treatment in men, as no bone fracture data were available. Another review of RCTs for the effects of testosterone on body composition in middle‐aged men found that testosterone improved bone mineral density at the lumbar spine by 3.7% (CI 1.0% to 6.4%) compared to placebo (Isidori 2005).

Weight‐bearing exercise

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 corticosteroids (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 revealed that bone mineral density at a number of sites including the lumbar spine improved with calcium and exercise in prepubertal and early pubertal boys (Bass 2007; Iuliano‐Burns 2003; Stear 2003). 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 (Pedlow 2015), and boys have shown improvement in vertebral bone mineral density and function capacity (Bianchi 2013; Spencer 1962). More recently, high‐frequency, low‐intensity whole‐body vibration appeared to improve bone health in children and adolescents with a disability (Matute‐Llorente 2015; Reyes 2011;Ruck 2010), but was inconclusive in people with DMD (Söderpalm 2013). Regular low‐intensity and appropriate exercise strengthens bone tissue, as well as improving the balance of action between opposing muscle groups and balance while standing and moving (Bushby 2010; Grange 2007; Jansen 2010). These interventions could reduce the risk of fractures in non‐ambulant boys (Ward 2004).