Report of a Muscular Dystrophy Campaign funded workshop Birmingham, UK, January 16th 2004. Osteoporosis in Duchenne muscular dystrophy; its prevalence, treatment and prevention

Abstract

A Muscular Dystrophy Campaign funded workshop to look into the potential problems of osteoporosis occurring in boys with DMD treated with steroids took place in Birmingham (UK) on the 16th January 2004. Fourteen participants met from varied backgrounds including, paediatric neuromuscular disease, neurology, paediatric and adult metabolic bone disease, paediatric rheumatology, genetics, physiotherapy and medical physics together with a representative from the Muscular Dystrophy Campaign. The aims of the workshop were to assess the evidence for the risk of osteoporosis in Duchenne muscular dystrophy (DMD), to assess the adverse effects of corticosteroid (steroid) treatment relating to bone mineral density and longitudinal growth and to assess the current evidence for the prevention and treatment of osteoporosis. Steroids are increasingly used in boys with DMD following the evidence from randomised controlled trials on their short-term benefit. However, the balance between long-term benefit and side effects has not been established. Long-term steroid use may be associated with significant side effects including weight gain, growth failure, cataracts and osteoporosis, so the development of strategies to prevent or treat these complications is important. We reviewed the literature to determine the prevalence of osteoporosis in DMD before and after the use of steroids and its treatment and prevention. Adnan Manzur [[1]Manzur A. Kuntzer T. Pike M. Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy.Cochrane Database Syst Rev. 2004; 2: CD003725PubMed Google Scholar] presented the data published in a Cochrane systematic review of steroids in DMD. The use of steroids to slow progression in DMD was first suggested in the 1970s [[2]Demos J. Tuil D. Berthelon M. et al.Progressive muscular dystrophy. Functional improvement after a renal allograft.J Neurol Sci. 1976; 30: 41-53Abstract Full Text PDF PubMed Scopus (6) Google Scholar]. Since then many studies have been undertaken and patients in many countries are now routinely offered steroid treatment, though there is a lack of international consensus on which steroids are more beneficial and which dosage regimes are best [[3]Dubowitz V. 75th ENMC international workshop: treatment of muscular dystrophy, Baarn 10–12 Dec, 1999.Neuromusc Disord. 2000; 10: 313-320Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Steroids are not a cure, but they do improve muscle strength. How this benefit occurs is not known; theories include a reduction in the rate of muscle breakdown, reduction of focal inflammation and necrosis [[4]Kissel J.T. Burrow K. Rammohan K.W. et al.Mononuclear cell analysis of muscle biopsies in prednisolone and azathioprine treated Duchenne muscular dystrophy.Neurology. 1991; 41: 667-672Crossref PubMed Scopus (86) Google Scholar], or stimulation of muscle regeneration [5Bal E. Sanwall W. A synergistic effect of glucocorticsteroids and insulin on the differention of myoblasts.J Cell Physiol. 1980; 102: 27-36Crossref PubMed Scopus (41) Google Scholar, 6Anderson J.E. Weber M. Vargas C. Deflazacort increases laminin expression and myogenic repair, and induces early persistent functional gain in mdx mouse muscular dystrophy.Cell Transplant. 2000; 9: 551-564Crossref PubMed Scopus (54) Google Scholar]. The Cochrane systematic review concluded that there is evidence from randomised controlled trials that steroids do improve strength outcomes in DMD. The primary outcome measure for the Cochrane review was prolongation of walking while secondary outcome measures included an increase in muscle strength and muscle function (such as walking, rising, climbing stairs) and the forced vital capacity (FVC). Any adverse events were also recorded. The reviewers assessed 11 randomised controlled trials of which five were suitable for inclusion, however, for meta-analysis data was available from only four studies [7Mendell J.R. Moxley R.T. Griggs R.C. et al.Randomized controlled trial of prednisolone in Duchenne's muscular dystrophy.N Engl J Med. 1989; 320: 1592-1597Crossref PubMed Scopus (411) Google Scholar, 8Griggs R.C. Moxley R.T. Mendell J.R. et al.Prednisolone in Duchenne dystrophy: a randomised trial defining the time course and dose response.Arch Neurol. 1991; 48: 383-388Crossref PubMed Scopus (239) Google Scholar, 9Angenlini C. Pegoraro E. Turella E. et al.Deflazacort in Duchenne dystrophy: study of long-term effect.Muscle Nerve. 1994; 17: 386-391Crossref PubMed Scopus (135) Google Scholar, 10Rahman M.M. Hannan M.M. Mondol B.A. Bhoumick N.B. Haque A. Prednisolone in Duchenne muscular dystrophy.Bangladesh Med Res Counc Bull. 2001; 27: 38-42PubMed Google Scholar]. These studies included 249 participants, 88 of whom were given placebo and 161 steroid treatment: prednisone (n=134), prednisolone (n=10) and deflazacort (n=17). Only one study used prolongation of walking as an outcome measure [[9]Angenlini C. Pegoraro E. Turella E. et al.Deflazacort in Duchenne dystrophy: study of long-term effect.Muscle Nerve. 1994; 17: 386-391Crossref PubMed Scopus (135) Google Scholar], but this was not demonstrated with valid statistical methods. A meta-analysis of the secondary outcome measures of three studies demonstrated improved muscle function and strength over a 6-month period. One trial [[9]Angenlini C. Pegoraro E. Turella E. et al.Deflazacort in Duchenne dystrophy: study of long-term effect.Muscle Nerve. 1994; 17: 386-391Crossref PubMed Scopus (135) Google Scholar] showed stabilisation of muscle strength and function for up to 2 years. In these studies the side effects observed included excessive weight gain, behavioural changes, cushingoid appearance and hirsuitism. None of the randomised controlled trials ran for long enough to assess long-term outcomes. However, two non-randomised cohort studies, one using prednisolone and the other deflazacort, do record long-term improvement in functional outcomes including prolongation of walking to a mean age of 14.5 years, preservation of lung function, reduction in the need for scoliosis surgery and possibly a reduced incidence of cardiomyopathy. Deflazacort has been used in DMD because of its potential ‘bone-sparing’ effect and some studies have demonstrated equal effectiveness with prednisolone [11Bonifati M.D. Ruzza G. Bonometto P. et al.A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy.Muscle Nerve. 2000; 23: 1344-1347Crossref PubMed Scopus (164) Google Scholar, 12Reitter B. Deflazacort vs. prednisone in Duchenne muscular dystrophy: trends of an ongoing study.Brain Dev. 1995; 17: 39-43Abstract Full Text PDF PubMed Scopus (57) Google Scholar] with possibly less risk of weight gain [[6]Anderson J.E. Weber M. Vargas C. Deflazacort increases laminin expression and myogenic repair, and induces early persistent functional gain in mdx mouse muscular dystrophy.Cell Transplant. 2000; 9: 551-564Crossref PubMed Scopus (54) Google Scholar]. However, the development of cataracts was more frequent occurring in 16 out of 44 patients compared with only 1 in 36 of the prednisolone group [[12]Reitter B. Deflazacort vs. prednisone in Duchenne muscular dystrophy: trends of an ongoing study.Brain Dev. 1995; 17: 39-43Abstract Full Text PDF PubMed Scopus (57) Google Scholar]. In a non-randomised study Biggar et al [[13]Biggar W.D. Gingras M. Fehlings D.L. Harris V.A. Steele C.A. Deflazacort treatment of Duchenne muscular dystrophy.J Pediatr. 2001; 138: 45-50Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar] long-term benefit with deflazacort was shown with preserved lung function compared with untreated controls. Silversides [[14]Silversides C.K. Webb G.D. Harris V.A. Biggar D.W. Effects of Deflazacort on left ventricular function in patients with Duchenne muscular dystrophy.Am J Cardiol. 2003; 91: 769-772Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar] demonstrated long-term benefit in cardiac function with deflazacort, after 5 years on treatment. Echocardiography demonstrated a mean fractional shortening of 33% compared with 21% in the untreated group. Asymptomatic cataracts were found in one half of the boys taking deflazacort. Thus, there is controlled evidence that in the short-term (6 months to 2 years) steroids significantly improve muscle strength and function in DMD and there is uncontrolled evidence of a longer-term benefit. Of the dose regimens that have been used, prednisolone 0.75 mg/kg or deflazacort 0.9 mg/kg per day are probably the most effective. Given the long periods that young people with DMD may be treated with steroids, it is important to address the prevalence and management of long-term side effects, which may include weight gain, behavioural changes, vertebral fractures secondary to osteoporosis and cataracts. Zulf Mughal presented background information on the definition and investigation of osteoporosis. Osteoporosis is characterised by low bone mass and micro-architectural deterioration of bone tissue, leading to an increase in bone fragility and increased susceptibility to fracture. Childhood conditions that reduce mobility, including muscular dystrophy, are associated with an increased risk of long bone fractures. Bone strength is determined by the size and shape of bones as well as the bone mineral content and its density. Muscle provides the greatest force in loading bone, increasing muscle pull widens the cross-sectional area of bone increasing its strength. Thus, loss of muscle strength is a particular risk factor for loss of bone strength. There are two major types of bone: 80% of bone is cortical bone and 20% trabecular, with particular concentration of the latter in the spine and distal long bones. With osteoporosis in cortical bone, bone loss occurs first at the endosteal surface, widening the bone marrow cavity and then producing larger lacunae in the cortex. In trabecular bone, the effect of unloading caused by muscle weakness is to lead to a thinning of the trabeculae, disturbing the micro-architectural stability by disconnecting the trabecular struts. Osteoporosis may be assessed by plain radiography, bone densitometry, the measurement of biochemical markers of bone turnover in blood and by bone biopsy and histochemistry. When relying on radiological evidence for osteoporosis there must be a 30–40% reduction in bone mineral density before any visible change is evident on plain radiographs. Radiological features suggestive of osteoporosis are the appearance of gracile bones and as bone remodelling fails with a lack of muscle pull, thinning of the cortices and washing out of the diaphyses occurs. Because these changes occur only with advanced osteoporosis, routine radiological screening for osteoporosis is not helpful. Dual energy X-ray absorptiometry (DXA) is the preferred method for measuring bone mineral density as it is widely available and relatively cheap with low radiation exposure. This technique uses low radiation X-ray beams of different energies and the attenuation of the two beams is detected to give a measure of absorption. The measurement of bone mineral density is dependent upon the projected area, which is conical in shape. It is important to note that DXA gives a 2-dimensional reading to 3-dimensional bone mass (g/cm2). As a consequence, the apparent results are determined by the size of the bone with small bones producing spuriously low results and vice versa for large bones [15Molgaard C. Thomsen B.L. Prentice A. et al.Whole body bone mineral content in healthy children and adolescents.Arch Dis Child. 1997; 76: 9-15Crossref PubMed Scopus (294) Google Scholar, 16Schonau E. Problems of bone analysis in childhood and adolescence.Paediatr Nephrol. 1998; 12: 420-429Crossref PubMed Scopus (126) Google Scholar]. Joint contractures and spinal rods may also interfere with the results. Interpretation of DXA scans in children with small and deformed bones is therefore particularly problematic [[15]Molgaard C. Thomsen B.L. Prentice A. et al.Whole body bone mineral content in healthy children and adolescents.Arch Dis Child. 1997; 76: 9-15Crossref PubMed Scopus (294) Google Scholar]. These factors must be taken into account in the interpretation of the results. Other areas of potential difficulty in interpreting DXA results in children include the need for appropriate normative data including information from populations of different ethnicity. DXA scanning produces measurements of total body and spinal bone mineral density. Spinal bone mineral density is particularly useful in this context, since vertebral bone seems particularly vulnerable to the effects of steroids. Bone mineral density in children is expressed as a Z score, indicating the number of standard deviations that the bone mineral density is from the age related mean. However, Z scores refer to chronological age rather than size or sexual maturity, care needs to be taken in interpretation of such results unless they are size adjusted Z scores as decribed by Molgaard et al. [[15]Molgaard C. Thomsen B.L. Prentice A. et al.Whole body bone mineral content in healthy children and adolescents.Arch Dis Child. 1997; 76: 9-15Crossref PubMed Scopus (294) Google Scholar]. Unlike in adults, there are still no prospective studies which identify a ‘fracture threshold’ in children for any given Z score. The WHO criteria for osteoporosis (based upon adult data) is a T score that is −2.5 standard deviations or greater from the young adult mean, while −1 to −2.5 standard deviations from the mean is defined as osteopenia [[17]WHO assessment of fracture risk and its application to screening for post-menopausal osteoporosis. Report of a WHO study group. WHO technical report series; 1994;843:1–29.Google Scholar]. Studies on bone mass in children have used various criteria to define significant osteopenia [[18]Leonard M.B. Propert K.J. Kemel B.S. et al.Discrepancies in paediatric bone mineral density reference data: potential for misdiagnosis of osteopenia.J Paediatr. 1999; 135: 182-188Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar] although most investigators tend to define osteopenia in young people at Z scores of less than −1.5. Several authors have reported correlation between quantitative ultrasound and DXA [[19]Njeh C.F. Shaw N. Gardner-Medwin J.M. et al.Use of quantitative ultrasound to assess bone status in children with juvenile idiopathic arthritis.J Clin Densiton. 2000; 3: 251-260Crossref PubMed Scopus (35) Google Scholar]. Quantitative ultrasound has been used to assess bone status in children with juvenile idiopathic arthritis [[20]Falcini F. Bindi G. Ermini M. et al.Comparison of quantitative calcaneal ultrasound and dual energy x ray absorptiometry in the evaluation of osteoporotic risk in children with chronic rheumatic diseases.Calcif Tissue Int. 2000; 67: 19-23Crossref PubMed Scopus (65) Google Scholar]. Such methods have the distinct advantage of absence of radiation dose, reduced price and increased speed. Quantitative computed tomography (QTC) can measure changes in trabecular bone, which derives a total bone mineral density rather than that of individual components, this is not possible with DXA. Peripheral quantitative computer tomography provides volumetric data on the tibia or radius, differentiating the cortex from the inner trabecular components. These alternative methods for assessing bone mineral density are less widely available than DXA. Mike Davie explained that bone turnover may be measured by bone turnover markers. Assessment of bone formation may be made by serum osteocalcin, bone specific alkaline Phosphatase, as well as markers of collagen formation such as N or C terminal telopeptide. Bone breakdown may be assessed by measurement of collagen degradation products in serum or urine. Collagen is degraded in defined enzymatic steps and the products such as NTx, CTx or the pyridinoline cross links between the collagen chains can all be measured [21Seibel M.J. Biochemical markers of bone remodelling.Endocrinol Metab Clin North Am. 2003; 32: 83-113Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 22Delmas P.D. Markers of bone turnover for monitoring treatment of osteoporosis with antiresorptive drugs.Osteoporos Int. 2000; 11: S66-S76Crossref PubMed Scopus (108) Google Scholar, 23Gundberg C.M. Biochemical markers of bone formation.Clin Lab Med. 2000; 20: 489-501Abstract Full Text PDF PubMed Google Scholar]. At present these assays are available only through specialised services and experience in children is limited. Trephine bone biopsy through the iliac crest bone, often considered the gold standard, has the advantage of providing data about actual bone cell activity and of bone resorption and formation rates measured directly. It is an invasive procedure, often requiring anaesthetic, and is usually limited to one episode. Normative data are now becoming available against which measurements in patients may be compared [24Glorieux F.H. Travers R. Taylor A. et al.Normative data for iliac bone histomorphometry in growing children.Bone. 2000; 26: 103-109Crossref PubMed Scopus (252) Google Scholar, 25Rauch F. Travers R. Norman M.E. et al.Deficient bone formation in idiopathic juvenile osteoporosis: a histomorphometric study of cancellous iliac bone.J Bone Miner Res. 2000; 15: 957-963Crossref PubMed Scopus (78) Google Scholar]. Mike Davie presented a review of the literature published on long-term corticosteroid treatment which has profound effects on growth and vertebral fracture rates. Height gain is abolished by 90 mg cortisone daily (∼3 mg/kg body weight) and limited by doses of 75 and 50 mg daily [26Blodgett F.M. Burgin L. Iezzoni D. Gribetz D. Talbot N.B. Effects of prolonged cortisone therapy on the statural growth, skeletal maturation and metabolic status of children.New Engl J Med. 1956; 254: 636-641Crossref PubMed Scopus (235) Google Scholar, 27Kerrebijn K.F. de Kroon J.P.M. Effect on height of corticosteroid therapy in asthmatic children.Arch Dis Child. 1968; 43: 556-561Crossref PubMed Scopus (58) Google Scholar]. Leg length growth is significantly suppressed by 5 mg prednisolone daily, an effect which occurs within 2–3 days of starting corticosteroids, although the effect is reversed rapidly after treatment ceases [[28]Wolthers O.D. Pedersen S. Short term linear growth in asthmatic children during treatment with prednisolone Br Med J. 1990; 301: 145-148Google Scholar]. Even lower doses of 3.0–3.9 mg prednisolone/m2 per day may have adverse effects on height velocity [27Kerrebijn K.F. de Kroon J.P.M. Effect on height of corticosteroid therapy in asthmatic children.Arch Dis Child. 1968; 43: 556-561Crossref PubMed Scopus (58) Google Scholar, 29Oberger E. Engstrom I. Karlberg J. Long term treatment with glucocorticoids/ACTH in Asthmatic children.Acta Paediatr Scand. 1990; 79: 77-83Crossref PubMed Google Scholar]. Catch up growth may occur, but the onset of puberty may limit the capacity to achieve expected final adult height [[30]Emma F. Sesto A. Rizzono G. Long term linear growth of children with severe corticosteroid responsive nephrotic syndrome.Pediatr Nephrol. 2003; 18: 783-788Crossref PubMed Scopus (48) Google Scholar] and children taking corticosteroids often fail to achieve their expected mid parental standard deviation scores when growth finishes [[29]Oberger E. Engstrom I. Karlberg J. Long term treatment with glucocorticoids/ACTH in Asthmatic children.Acta Paediatr Scand. 1990; 79: 77-83Crossref PubMed Google Scholar]. In all the studies of height velocity in children taking corticosteroids, the presence of underlying disease being treated is important. Nevertheless, the short term and the longitudinal studies suggest that a true corticosteroid effect is taking place. Vertebral fracture, leading to loss of height gain, also complicates corticosteroid treatment in children with vertebral levels most frequently affected being D6–D8 in Juvenile idiopathic arthritis (JIA). Once a total of 5 g prednisolone had been ingested, vertebral fractures occurred at a rate inversely proportional to the daily prednisolone dosage [31Loftus J. Allen R. Hesp R. et al.Randomised, double blind trial of Deflazocort versus Prednisolone in Juvenile Chronic Arthritis: a relatively bone sparing effect of Deflazocort.Pediatrics. 1991; 88: 428-436PubMed Google Scholar, 32Varonos S. Ansell B.M. Reeve J. Vertebral collapse in juvenile chronic arthritis: its relationship with corticosteroid therapy.Calcif Tissue Intl. 1987; 41: 75-78Crossref PubMed Scopus (104) Google Scholar]. In the whole study a mean daily dose of was 0.62 mg prednisolone /kg per day was associated with a mean time to vertebral collapse of 2 year 7 month. It has been suggested that Deflazocort may offer a sparing effect on bone, but in a study comparing the effect of Deflazocort or prednisolone on vertebral fracture in JCA, both groups had similar vertebral fracture rates although bone density increased slightly on Deflazocort and fell on prednisolone [[31]Loftus J. Allen R. Hesp R. et al.Randomised, double blind trial of Deflazocort versus Prednisolone in Juvenile Chronic Arthritis: a relatively bone sparing effect of Deflazocort.Pediatrics. 1991; 88: 428-436PubMed Google Scholar]. Michelle Eagle reviewed the evidence for osteoporosis in DMD. Osteoporosis is known to occur in children with physical disabilities, such as cerebral palsy, Spinal muscular atrophy (SMA) and muscular dystrophy [33Aparicio L.F. Jurkovic M. DeLullo J. Decreased bone density in ambulatory patients with duchenne muscular dystrophy.J Pediatr Orthop. 2002; 22: 179-181Crossref PubMed Scopus (66) Google Scholar, 34Vestergaard P. Glerup H. Steffenson B.F. et al.Fracture risk in patients with Duchenne muscular dystrophy and spinal muscular atrophy.J Rehabil Med. 2001; 33: 150-155Crossref PubMed Scopus (90) Google Scholar]. Compared with the normal population, there is a relatively high incidence of long bone fractures in boys with DMD, with a reported incidence to be between 21 and 40% of boys [35Larson C.M. Henderson R.C. Bone mineral density and fractures in boys with Duchenne muscular dystrophy.J Pediatr Orthop. 2000; 20: 71-74Crossref PubMed Google Scholar, 36McDonald D.G. Kinali M. Gallagher A.C. et al.Fracture prevalence in Duchenne muscular dystrophy.Dev Med Child Neurol. 2002; 44: 695-698Crossref PubMed Scopus (130) Google Scholar]. The long bones (femur, humerus and tibia) are the most common sites for fractures and the peak age is 8–11 years. Vertebral fractures are very uncommon in individuals with DMD who do not receive steroid treatment. Healing and recovery do not seem to be impaired but active remobilisation is essential as loss of function is a frequent consequence of a long bone fracture in the ambulant stages. Larsen et al. [[35]Larson C.M. Henderson R.C. Bone mineral density and fractures in boys with Duchenne muscular dystrophy.J Pediatr Orthop. 2000; 20: 71-74Crossref PubMed Google Scholar] studied 41 boys with DMD, 31 of whom were non-ambulant aged between 4 and 23 years. None of the patients had received steroid treatment 44% of the boys had sustained a long bone fracture, 40% of which occurred in ambulant boys, and 64% of the fractures involved an upper limb. 60% of fractures occurred in non-ambulant boys, the majority of which involved a lower limb. Overall 2/3 of boys over the age of 14 years had sustained a fracture. Unfortunately, the authors did not record the frequency of falls. DXA scans of the lumbar spine and femur were undertaken and 25 patients underwent serial DXA scans, of whom 13 were studied for more than 4 years. In the 17 ambulant boys the mean lumbar spine density Z score was −0.8±0.2 (below average but within the normal range). However, in the non-ambulant boys (n=29) the mean lumbar spine Z score was −1.7±0.2 (statistically different P=0.004) though no vertebral fractures were reported. The bone mineral densities in the proximal femur were lower than in the lumbar spine. The authors concluded that bone density in the lumbar spine is only slightly below average in non-steroid treated ambulant boys, but that lumbar spinal bone density decreases after loss of ambulation. Bone mineral density in the proximal femur is already very low in ambulant boys and continues to fall before and after loss of ambulation. In a more recent study, Aparicio et al. [[33]Aparicio L.F. Jurkovic M. DeLullo J. Decreased bone density in ambulatory patients with duchenne muscular dystrophy.J Pediatr Orthop. 2002; 22: 179-181Crossref PubMed Scopus (66) Google Scholar] found significantly reduced bone mineral density in the lumbar spine and femoral neck in 10 boys with DMD. Margueritte Hill undertook a literature research on the subject of fractures and osteoporosis in adults with neuromuscular disorders. A paucity of prevalence studies in adults was noted, there were no publications looking into the prevalence and treatment of osteoporosis in adults with neuromuscular disease, while there were two studies on fracture prevalence which combined adult and paediatric data [34Vestergaard P. Glerup H. Steffenson B.F. et al.Fracture risk in patients with Duchenne muscular dystrophy and spinal muscular atrophy.J Rehabil Med. 2001; 33: 150-155Crossref PubMed Scopus (90) Google Scholar, 37Granata C. Giannini S. Villa D. Bonfiglioli Stagni S. Merlini L. Fractures in myopathies.Chirurgia Degli Organi di Movimento. 1991; 76(1): 1991Google Scholar]. Dr Hill presented data from her own patient group, which demonstrated a fracture prevalence of 42% in adults with neuromuscular disorders. The causes of fracture were thought to be multi-factorial, 72.5% patients fell at least once a year. Bone mineral density data were not available for this group, thus the aetiology of fractures in this population cannot be attributed to low bone mineral density. Vertebral fractures have been reported as a side effect of long-term steroid treatment in DMD with both deflazacort and prednisolone. Michelle Eagle presented three recent publications: Talim et al. [[38]Talim B. Malaguti C. Gnudi S. et al.Vertebral compression in Duchenne muscular dystrophy following deflazacort.Neuromuscul Disord. 2002; 12: 294-295Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar] reported a patient with DMD who had received deflazacort for 7 years in whom three vertebral fractures occurred. Bothwell et al. [[39]Bothwell J.E. Gordon K.E. Dooley J.M. et al.Vertebral fractures in boys with Duchenne muscular dystrophy.Clin Pediatr (Phila). 2003; 42: 353-356Crossref PubMed Scopus (98) Google Scholar] reviewed data from 33 boys with DMD, 25 of whom were taking steroids (predominantly deflazacort), the mean duration of treatment was 4½ years. All had received calcium supplementation and 25-OH vitamin D supplementation. Nine of the 33 boys had sustained a long bone fracture and 10 of the steroid-treated group had sustained vertebral fractures (four of whom were still ambulant). Based upon the observed data, a Kaplan Meier statistical analysis was used to predict fracture risk for boys taking steroids. The authors predicted that 75% of boys with DMD might be expected to develop vertebral fractures after 100 months of steroid treatment. Bianchi et al. [[40]Bianchi M.L. Mazzanti A. Galbiati E. et al.Bone mineral density and bone metabolism in Duchenne muscular dystrophy.Osteoporos Int. 2003; 14: 761-767Crossref PubMed Scopus (147) Google Scholar] studied 32 ambulant DMD boys, 22 of whom were taking prednisolone 0.75 mg/kg per day, the mean duration of treatment was 38.5 months (age range 4–17 years). All patients were instructed to have a dietary intake of calcium 1 g per day. The prevalence of long bone fractures was 18%. Amongst the whole cohort there was a correlation between muscle strength and bone mineral density. In all the DMD boys the bone mineral density was lower than normal but in the steroid-treated group bone mineral density was even lower. Furthermore, there was a negative correlation between the cumulative steroid dose and vertebral bone mineral density. Serum calcium and phosphate measurements were normal in all patients, but serum osteocalcin (a marker of bone formation) was found to be at the upper limit of normal. 1,25 hydroxy-vitamin D levels were normal, but the 25 hydroxy-vitamin D levels were low in both groups and lower in the steroid-treated group. The authors concluded that the main factors influencing bone mineral density in the lower limbs appeared to be muscle strength, while in the spine it was the cumulative steroid dose. Low levels of 25 hydroxy-vitamin D may lead to restricted absorption with negative influence on bone metabolism. Janet McDonagh led the discussion on the use of calcium and vitamin D supplementation for long-term prevention of osteoporosis. Calcium and vitamin D have been suggested as a treatment for steroid induced osteoporosis since the late 1970s. Homik et al. [[41]Homik J. Suarez-Almazor M.E. Shea B. et al.Calcium and vitamin D for corticosteroid-induced osteoporosis.Cochrane Database Syst Rev. 2000; : CD000952PubMed Google Scholar] undertook a meta-analysis of randomised controlled trials of calcium and either vitamin D (cholecalciferol) or dihydroxyvitamin D (calcitriol) with calcium versus calcium alone or placebo. There was a significant difference between treatment and control groups for lumbar spine and radius bone mineral density but not for the femoral neck. However, the treatment produced no significant reduction in non-traumatic fractures. Currently, in the UK there is no recommendation for the primary prevention of osteoporosis in children on long-term steroid therapy for chronic inflammatory conditions such as JIA. Factors which influence the development of osteoporosis in these disorders include: the impact of the disease, the degree o