Conference Report, July 2001

Consensus Conference on the Diagnosis and Management of Osteoporosis in Osteogenesis Imperfecta July 27th, 2001 The First National Conference on the use of bisphosphonates in the treatment of genetic and metabolic bone disorders in children and adolescents was held at the Royal North Shore Hospital in Sydney in July 2001. The major focus for the meeting was advances made in the evaluation of osteoporosis in the Osteogenesis Imperfecta (Brittle Bone) Syndromes and the use of bisphosphonates in the treatment of the osteoporosis. Professor Nick Bishop, Paediatric Metabolic Bone Diseases, Sheffield Children’s Hospital, was the keynote speaker. The Pathogenesis and Management of Brittle Bone Disorders Professor Bishop reminded the registrants that Osteogenesis Imperfecta (OI) was a highly heterogenous group of disorders. He discussed six numbered types of OI, OI types I - VI. He also discussed other types of OI which are not numbered but which fall into the classification. In the latest international classification of OI there are at least 12 syndromes (Table 1) (1) and a miscellaneous group included under Other Types. Although for a long time, the OI syndromes were thought to be inborn errors of Type I collagen metabolism, the consensus view is that most types of OI result from a net excess of bone resorption over bone formation which in turn results in a small negative increment in bone mass, or, a failure of net bone production to keep up with the normal increases in bone mass seen during growth. While at the cellular level, there is a net reduction in the production of bone collagen in OI types I – IV, at the whole skeletal level there is a recruitment of bone forming cells so that patients with OI Type I, for example, have 140% of normal bone formation. Osteoporosis commonly results where bone loss is greater than bone production. Bone pathophysiology is evaluated by the use of measurement of bone density by densitometry, measurement of serum and urine markers of bone turnover and bone histomorphometry. Therapy in Osteogenesis Imperfecta can be broadly subdivided into: i) Anti-resorptive therapy ii) Proformation therapy iii) Somatic cell therapies Anti-resorptive Therapy The bisphosphonates are the major class of anti-resorptive therapies. In children the most extensive experience with bisphosphonates comes from treatment with periodic infusions of intravenous Pamidronate. Two regimens have been employed. A monthly infusion regimen was pioneered in Sweden in the early 1990’s (2). A dose on three consecutive days every 3-4 months, introduced by Glorieux and colleagues has been used extensively in North American centres (3). Treatment outcomes are measured by documentation of quality of life, the frequency of fractures, changes in serum and urine parameters of bone turnover and changes in bone densitometry measured by dual energy x-ray absorptiometry (DXA). Cyclic Intravenous Pamidronate therapy uniformly results in improvement with increased mobility, decreased pain, increased feeling of well-being, decreased fractures, and an increase in bone density. For many children there is a return to normal ranges of bone density within two to three years of commencing therapy. The largest changes are visible in infants and during puberty. The aminobisphosphonates which include Pamidronate®, Alendronate® and Risendronate® have their mode of action through the inhibition of resorption by osteoclasts. This is achieved by a reduction in the number of osteoclasts but also through interference with osteoclast metabolism. The bisphosphonates inhibit crenylation, and phosphorylation of farnesyl and geranylgeranyl phosphates and other phosphorylated intermediates. Other agents such as parathyroid hormone, and prostaglandins have been studied but at the present time have no therapeutic application in the Brittle Bone Disorders. Somatic cell therapy such as bone marrow transplantation has no place at the present time in the management of OI. Stem cell therapies are being investigated in laboratory and animal studies. Current therapy is therefore focused on bisphosphonates. The best drug and the dose and route of administration are still being investigated. Short-term safety has been established however long-term safety remains a concern. For example, the safety of pregnancy in adults who have received bisphosphonates for many years in childhood has yet to be established. Other drugs and types of therapies are presently being developed or investigated at the present time, for example, studies with osteoprotogerin. Paediatric experience with bisphosphonates in Australia. The main theme of the conference was the treatment with Cyclic Intravenous Pamidronate of the osteoporosis in subjects with OI. Presentations were given from of five treatment centres in Australia summarising various aspects of their experience. Four centres (New South Wales, Queensland, South Australia and Western Australia) have followed the regimen recommended by European investigators and studied the use of intravenous Pamidronate given monthly or second monthly. The Victorian (VIC) trial investigated the use of a regimen of the three doses on consecutive days every 3-4 months recommended in North American centres. Over 120 patients were being studied throughout Australia including Tasmania. The numbers of patients are summarised in Table 2. Evaluation in all the programs is undertaken regularly at approximately six monthly intervals. The New South Wales (NSW) program reported the results of a randomised study of cyclic intravenous Pamidronate 30 mg/M2 given monthly versus second monthly. After 12 months of treatment, the groups were crossed over so that after 24 months, the subjects received the same total amount of Pamidronate. Evaluation was undertaken at six months intervals. The treatment is co-ordinated by one centre, although 63% of the patients are being treated in local hospitals under the supervision of paediatricians or family doctors. The study demonstrated that in the 19 subjects who have completed therapy, monthly therapy results in a slightly greater increment in bone mineral density (BMD) than second monthly therapy. However, with both monthly and second monthly therapy, the increment in BMD in the first six months of therapy is statistically significant compared with the second six months for either regimen. In Queensland (QLD), South Australia and Western Australia (WA) thirty-one children were randomised for therapy. The analysis of results is being undertaken. All studies observed a trend towards decreased fracture frequency. The QLD study confirmed increased mobility in their subjects. The WA study also demonstrated an increase in measures of functional independence in severely affected children with OI. In the VIC study, this improvement in measures of mobility and functional independence was also confirmed along with a decrease in fracture frequency. Diagnosis and assessment of osteoporosis Dr Roger Price, Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, spoke on the standardisation of bone densitometry. Fracture risk depends on quantity and bone quality. Clinical bone densitometry is an important tool for preventing and assessing the risk of osteoporosis and fractures and for verifying treatment efficacy (4). Bone mineral density varies with gender and age at both the childhood and aging ends of the range. The standardisation of reference ranges is therefore of considerable importance both for age, population and patient sex. Dr Price went further to describe the standardisation between DXA technologies, reference ranges, measurement sites, BMD criteria for defining disease and risk status. DXA measures bone mineral content (BMC) and area (cm2) (projected area of scanned bone). The BMD equals BMC/area and the measurement is expressed in g/cm2. An adjustment can be made for bone size/or volume but this requires further data and measurements. Measurement of BMD in children is more demanding. Age specific norms require that a cohort of normal children at each age can be analysed. Data for children younger than five years of age is still very limited in most centres. Whilst BMD for young adults can be expressed and compared with a T score (mean values at 20-45 years of age), for children 0-18 years, age specific "z" or standard deviation scores need to be derived. In children with genetic and metabolic bone disorders, height and weight often are not normal so that z score values by age, height and weight are useful in assessing children with these disorders. A substantial body of data has been derived by Lu and colleagues for normal (5) and OI children in the Australian population. Volumetric BMD of the femoral neck can be derived from DXA and this measurement shows a remarkable constancy in the 5-25 year age bracket (6). Volumetric BMD of the spine, on the other hand, shows a gradual increase in the 5-25 year old age group. The treatment of children with Osteogenesis Imperfecta requires the careful monitoring of BMD, thus services which undertake the treatment of children with OI should have access to facilities which can measure BMD serially in children. This would ensure that the anti-resorptive therapies are given only to children who have osteoporosis. It would also allow quantification of response, so that when BMD has returned to normal, treatment can be ceased. The diagnosis of Osteogenesis Imperfecta in children was discussed by Professor Sillence. The success of anti-resorptive therapies, coupled with major advances in the genetics and biochemistry of OI has completely changed our definitions of these disorders. There are at least 12 OI syndromes (Table 1). More than 10% of cases of OI are not due to mutations affecting Type I procollagens. In the past, much weight has been given to the findings of studies of cellular synthesis and secretion. For example, in Osteogenesis Imperfecta Type I, there is a 50% reduction in the secretion of Type I collagen from individual cells in vitro. At the level of the whole skeleton, there is recruitment of additional bone forming cells so that total synthesis of bone is increased (by up to 140%). As both synthesis and resorption are coupled, there is a corresponding increase in bone resorption. In many affected OI patients, resorption is in excess of bone production, leading to a net loss of bone. OI is defined as a group of connective tissue dysplasia syndromes characterised by liability to fractures throughout life. Osteoporosis is not a primary defect in all patients. There are associated features in some types of OI, for example, distinct blueness of the sclera in OI Type I. Diagnosis, therefore, depends on a combination of clinical, radiographic, biochemical and molecular findings. In approximately 50% of cases there is a family history. In Osteogenesis Imperfecta Type II, a perinatally lethal form, there is 100% mortality in the perinatal period or early life. Similarly, in progressively deforming OI Type III, there was a tendency in the past for early demise. The inheritance pattern may be useful in defining the type of OI. Serum and urine markers of bone turnover are useful in assessing children who appear to have primary osteopenic bone disorders. In OI, these markers are characteristically but not always, elevated. Bone histomorphometry is a useful diagnostic and evaluative tool but requires special techniques and expertise. Some types of OI such as the two Bruck types characterised by bone fragility with congenital joint contractures are diagnosed almost exclusively by inheritance pattern, urinary markers of bone turnover and natural history. Collagen biochemistry and molecular pathology are important research techniques. Dr Zacharin reviewed the experience with the use of bisphosphonates, specifically cyclic intravenous Pamidronate, in the treatment of polyostotic fibrous dysplasia associated with the McCune-Albright syndrome (7). Experience with five children and four young adults having intravenous Pamidronate 1mg/kg/day for three days every six months for two years was described. All subjects reported marked reduction in bone pain and increased mobility was observed. Several other groups reported experience with a monthly treatment regimen in McCune -Albright syndrome. However, the majority of studies have employed 1 mg/kg/day for three days every six months. Dr Paul Hoffman and colleagues from the Starship Children’s Hospital in Auckland, reported on their experience of Pamidronate in young adults with Mucolipidosis Type III. These children received 15 mg/M2/month with dramatic reduction in bone pain, increased mobility and markedly improved quality of life. Trials of Pamidronate in small numbers of patients are being considered by investigators in each of the states. Dr David Little, Orthopaedic Research Unit, The Children’s Hospital at Westmead, reported on studies of Pamidronate and a new potent bisphosphonate, Zoledronate ®, in experimental distraction osteogenesis. These results are extraordinarily promising and suggest that immobilisation bone loss can be prevented by the use of intravenous bisphosphonate prior to the procedure. Patient trials are currently being undertaken. Summing up and recommendations The panel consisting of Drs Perry-Keene (QLD), Zacharin (VIC), Couper (SA), Davis (WA), Sillence (NSW), Cowell (The Children’s Hospital at Westmead), Hooper (Concord Hospital, Sydney), Bishop (Sheffield Children's Hospital) discussed the present status of bisphosphonate therapy in children. The discussion concluded Cyclic intravenous Pamidronate is a safe short-term therapy for the treatment of osteoporosis in children with Osteogenesis Imperfecta. Treatment is followed by a rapid reduction in bone pain, and improved mobility, decreased fracture frequency and improved quality of life. Bone densitometry can be standardised for children and cyclic intravenous Pamidronate can be shown to increase BMD throughout the skeleton. There is a positive enhancement of growth, a trend towards normal remodelling of long bones and spine. Two regimens have been effective - A single intravenous dose given either monthly or second monthly or Three doses given on consecutive days every three-four months. While monitoring needs to be undertaken in centres equipped to undertake this, therapy can be given at local hospitals supervised by paediatricians or family practitioners. Overall, both treatment regimens deliver Pamidronate at approximately 12 mg/kg/year. The data from the randomised study performed at The Children’s Hospital at Westmead indicates that the maximum treatment effect occurs in the first six months after commencing treatment. Accordingly, we have concluded that the treatment regimen for children commencing therapy for Osteogenesis Imperfecta consist of intravenous Pamidronate 1 mg/kg/month given as a single infusion over two hours in the first six months. Depending on the response, therapy should then be continued with cyclic intravenous Pamidronate given every second monthly until BMD is in the normal range. Outcomes should be evaluated by centres with the experience in the clinical and rehabilitation assessment of metabolic bone disease, and with the laboratory and bone densitometry services able to offer expert monitoring. The use of bisphosphonates in a variety of other clinical situations was reported at this meeting. Trials of these agents in disorders other than Osteogenesis Imperfecta are continuing. Professor Bishop reported on proposed trials of oral bisphosphonates in Osteogenesis Imperfecta. Dr Little reported trials of the use of bisphosphonates in a variety of complications of orthopaedic surgery in children. REFERENCES Anonymous. (1997) The prevention and management of osteoporosis. Consensus statement. Australian National Consensus Conference 1996. [Review] Medical Journal of Australia. 167 Suppl:S1-15, Jul 7. Astrom E, Soderhall S. (1998) Beneficial effect of bisphosphonate during five years of treatment of severe Osteogenesis Imperfecta. Acta Paediatr. 87:64-68. Glorieux F, Bishop N, Plotkin H, Chabot Glanoue G, Travers R. (1998) Cyclic administration of Pamidronate in children with severe Osteogenesis Imperfecta. New Eng J Med. 339:947-952. Lu PW, Briody JN, Ogle GD, Morley KM, Humphries IRJ, Allen J, Howman-Giles R, Sillence D, Cowell CT. (1994) Bone Mineral density of total body, spine and femoral neck in children and young adults: A cross-sectional and longitudinal study. J Bone Miner Res; 9:1451-8. Lu PW, Cowell CT, Lloyd-Jones S, Briody JN, Howman-Giles R. (1996) Volumetric bone mineral density is Independent of Age in Normal Children and Young Adults. J Clin Endo Metab; 81:1586-90. Sillence D.O. (2002) Osteogenesis Imperfecta. In: Encyclopedia of Genetics, edited by S Brenner and J. H. Miller, Orlando, Florida: Academic Press, Vol 3: 1395-1398. Zacharin M. O'Sullivan M. (2000) Intravenous pamidronate treatment of polyostotic fibrous dysplasia associated with the McCune - Albright syndrome. Journal of Pediatrics. 137(3):403-9, Sep. Acknowledgements The conference was supported by The Osteogenesis Imperfecta Society of Australia and New Zealand, Novartis Pharmaceuticals, Aventis, National Osteoporosis Campaign Australia,and The Australian and New Zealand Bone and Mineral Society. The conference was organised celebrating the World Health Organization Bone and Joint Decade 2000 – 2010. Deb Redelman, Research Associate. David Sillence, Head, Connective Tissue Dysplasia Clinic The Children’s Hospital at Westmead Westmead 2145 NSW Australia Conference contributors The Sheffield Children’s Hospital, England Professor Nick Bishop The Concord Hospital, Concord, NSW Clinical Associate Professor Michael Hooper The Children’s Hospital at Westmead, NSW Professor David Sillence Professor Chris Cowell Julie Briody Dr David Little Royal Children’s Hospital, Herston, Brisbane, QLD Dr Don Perry-Keene Professor Jenny Batch Women’s and Children’s Hospital, North Adelaide, SA Dr Jenny Couper Royal Children’s Hospital, Parkville, VIC Dr Margaret Zacharin Princess Margaret Hospital for Children, Perth, WA Dr Elizabeth Davis Sir Charles Gairdner Hospital, Perth, WA Dr Roger Price  TABLES # Disease MIM Inherit Chromosome Gene 1 OI type I - Normal teeth 166200 AD 17q 7q22.1 COL1A1 COL1A2 2 OI type I - Opalescent dentin 166240 AD 7q22.1 COL1A2 3 OI type IIa and IIb 166210 259400 AD AR 17q 7q22.1 COL1A1 COL1A2 3c OI type IIc   AR     4 OI type III - Autosomal Recessive Types(s) 259420 AR Rare 17q 17q 7q22.1 Common COL1A1 COL1A2 Non-COL 5 OI type III - Autosomal Dominant 259420 AD 17q 17q 7q22.1 COL1A1 COL1A2 6 OI type IV - Normal Teeth 166220 AD 7q22.1 17q COL1A2 COL1A1 7 OI type IV - Opalescent Dentin   AD 7q22.1 17q COL1A2 COL1A1 8 OI type V   AD ? ? 9 OI type VI         10 OI with Congenital Joint Contractures Type I (Bruck Syndrome) 259450 AR 17q TLH1 11 OI with Congenital Joint Contractures Type 2 (Bruck Syndrome)   AR   TLH2 12 Osteogenesis Imperfecta with craniosynostosis (Cole-Carpenter) 112240 Sp     Other Type         (Table 1) Nomenclature of OI syndromes 2002     State OI Total OI Randomized Non OI NSW 59 34 10 QLD 15 12 12 WA 19 19   SA 10   8 VIC 18 ? Total (Table 2) Number of OI and Non-OI patients being treated with Pamidronate (July 2001)

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