Biphosphonates
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Archives of Disease in Childhood 1997;76:73–75 73 CURRENT TOPIC Biphosphonates Jeremy Allgrove Background tiludronate. These alter the pharmacological The bisphosphonates (previously referred to as profiles and influence the extent to which bone biphosphonates or diphosphonates) are a formation as well as bone resorption is group of agents which are analogues of inhibited. They may also determine side pyrophosphate. When administered either eVects. Some bisphosphonate preparations are orally or parenterally they are adsorbed onto used after technetium labelling as bone scan- hydroxyapatite crystals in bone mineral and, ning agents. because their structure renders them resistant Little is known of the pharmacology of the to enzyme degradation, they act principally by bisphosphonates in children as no specific inhibiting bone resorption, although some studies have been undertaken and all the infor- eVect on bone formation probably also occurs.1 mation that is available has been obtained in The net eVect is to promote bone mineral adult subjects. They can be administered either accretion while at the same time considerably intravenously or orally. If given orally, only a reducing bone turnover. Because of this latter small proportion (about 2%) is absorbed, the eVect, there have been concerns about the use rest remaining within the bowel lumen. The of bisphosphonates in children in whom bone amount absorbed is dependent on the time of turnover is normally much greater than in administration in relation to food and it is usu- adults. As a result, there have been fears that ally recommended that food is avoided for at interference with the rapid remodelling proc- least two hours before or after administration. ess, which is necessary in growing bones, might However, bisphosphonates are readily soluble result in bone deformity or serious disruption in water and can be made up in diVerent of the normal mineralisation process. The lim- strengths for paediatric use. ited experience of their use has, so far, largely Only four agents, etidronate, pamidronate, proved these fears to be groundless. clodronate, and alendronate have been given Wide experience of the use of bisphospho- product licences in the UK. None of these is nates has been gained in adults, principally for recommended for use in children and therefore the treatment of involutional osteoporosis, no dosage schedules are available. In the Paget’s osteitis deformans, and the hypercal- published paediatric studies intravenous ad- caemia and bone pain of malignancy. Several ministration has been given daily for between hundred papers have been published on these one and 18 days in doses ranging between topics, many of them as a result of properly approximately 0.2 and 1.0 mg/kg/day. In some controlled trials. In contrast, very few studies in reports these doses have been repeated after children have been published.2–25 These are all three or six months, depending on the anecdotal and only one study included any condition being treated. In others, the initial control subjects.15 Nevertheless, the limited intravenous treatment has been followed by experience of the use of bisphosphonates in oral administration and oral treatment alone children and adolescents which has so far been has also been used. The duration of oral treat- gained does suggest that, for some conditions ment has varied from one to 83 months, but such as osteogenesis imperfecta and perhaps has mostly been for between six and 24 months juvenile osteoporosis, wider use is indicated either continuously or intermittently in doses and may provide a useful additional therapeu- approximately 20 to 40 times that of tic measure. intravenous use (reflecting the poor bioavail- ability via the oral route). Department of Pharmacology Paediatrics, Newham General Hospital and The bisphosphonates are pharmacologically Clinical usage St Bartholomew’s and simple compounds that all have a phosphorus- The conditions for which bisphosphonates the Royal London carbon-phosphorus structure (compare with have been used in children are more diverse School of Medicine the phosphorus-oxygen-phosphorus structure than those of adults and can broadly be divided and Dentistry, London of pyrophosphate). The presence of carbon into four groups: those in which (1) there is a rather than oxygen allows the addition of side primary defect in bone mineralisation (for Correspondence to: Dr J Allgrove, Department of chains to the carbon atom that determine the example juvenile osteoporosis); (2) bone ma- Paediatrics, Newham specific properties of any individual com- trix abnormalities are seen (for example osteo- Community NHS Trust, pound. Thus nitrogen is present in pamidro- genesis imperfecta); (3) bone abnormalities Newham General Hospital, Glen Road, Plaistow, London nate, alendronate and neridronate, chlorine in result from systemic disease or the eVects of E13 8RU. clodronate and tiludronate, and sulphur in treatment of systemic disease (for example 74 Allgrove steroid treatment of juvenile chronic arthritis Bone abnormalities secondary to or immobilisation after severe neurological systemic disease damage); and (4) there is significant soft tissue This forms the largest group of children (20) calcification with no significant bone abnor- who have been treated with bisphosphonates. mality (for example myositis ossificans or In most cases this resulted either from infantile arterial calcification). Three other immobilisation (with or without hypercalcae- conditions, hyperphosphatasia, Gaucher’s dis- mia) after tetraplegia,12 13 or cerebral palsy,14 or ease and polyostotic fibrous dysplasia, with or from steroid treatment of juvenile chronic without McCune-Albright syndrome, have also arthritis.315 One further child was treated for been treated and, for the purposes of this hypercalcaemia associated with acute discussion have been placed in the second leukaemia,16 another had hypercalcaemia after group. In addition, one patient who had immobilisation after a liver transplant,17 a third primary oxalosis and one with malignant had severe osteoporosis associated with con- osteopetrosis were treated. Both of these have genital neutropenia,18 a fourth girl with pri- been placed in the third group. It should be mary oxalosis was treated for hypercalcaemia noted that this classification is, to a certain after transplantation with either liver and/or extent, arbitrary and is intended to help clarify kidney,19 and a fifth child with malignant the uses of bisphosphonates. Furthermore, osteopetrosis was treated for hypercalcaemia some conditions can be considered to fall into after bone marrow transplantation.20 In all more than one group. cases hypercalcaemia, where present, was corrected and in many the osteoporosis im- Primary defects in bone mineralisation proved. Juvenile osteoporosis is a rare condition that usually occurs in preadolescent children. The Soft tissue calcification aetiology is unknown, although some degree of The first report of the paediatric use of bone rarefaction may occur in association with bisphosphonates was in three children with other conditions (for example some forms of myositis ossificans.21 One further report of their osteogenesis imperfecta). It is sometimes ac- use subsequently appeared,22 23 together with companied by mild hypercalciuria.24Diagnosis three reports of the treatment of severe of juvenile osteoporosis therefore depends on infantile arterial calcification.23–25 Both of these exclusion of other causes of secondary oste- conditions are rare and either severely debili- oporosis. It is usually self limiting and shows a tating or fatal and in all cases soft tissue calcifi- marked improvement during adolescence. cation regressed markedly, although the total However, although logic dictates that this is duration of treatment is not always specified likely to be a suitable case for treatment, there and the final outcome is not clear. are only three reports of the use of bisphospho- nates in juvenile osteoporosis.2–4 All three Adverse eVects patients showed a marked improvement in The use of bisphosphonates in children ap- symptoms on treatment with reduction in pears to be relatively safe even when used for hypercalciuria, but assessment of the eVect is quite long periods. All of the preparations used extremely diYcult in view of the natural have an influence on bone turnover and in improvement in the condition.26 It should also those conditions in which increased turnover is be noted that, where these compounds have present, this eVect is desirable and is reflected been used to treat postmenopausal osteoporo- in a reduction in plasma alkaline phosphatase. sis, the initial increase in bone density showed However, an increase in translucent areas in a plateau eVect after the first year. Further- bone,22 and widening of the growth plate,11 more, increased bone density does not neces- have been reported and, in one instance of sarily equate to increased bone strength. juvenile osteoporosis, there was an initial dete- rioration in spinal fractures before overall Primary bone matrix abnormalities improvement occurred.2 Transient hypocalcae- Osteogenesis imperfecta has been treated in six mia, which may be symptomatic, can also be a children.3–6 In all cases improvement in fracture problem, although this is only temporary.10–12 rate and increase in bone density occurred. In Both of these eVects are more likely to occur three of the reports this was the primary aim of with intravenous than with oral treatment. It treatment, but in the fourth,4