Hypophosphatasia

Aminobisphosphonates offer promise, while bone marrow transplants remain experimental

Research in osteogenesis imperfecta (the brittle bone syndrome) has contributed exciting new chapters in bone biology, but little advance in treatment (International Conference on Osteogenesis Imperfecta, Montreal 1999).[1] Specialised rehabilitation and timely appropriate surgery remain the therapeutic cornerstones. Calcitonin (to reduce bone resorption) and sodium fluoride (to increase formation) are ineffective, Two new approaches using the aminobisphosphonates and stromal cell transplantation now deserve our critical attention.[2 3]

In osteogenesis imperfecta causal mutations in the genes for type I collagen explain the skeletal fragility, but the clinical range is wide and the relation between genotype and phenotype complex. Thus in type I osteogenesis imperfecta a non-functional allele for type I collagen halves collagen synthesis and causes mild bone disease. In contrast, in severe osteogenesis imperfecta--types II, III, and IV--mutations replace the essential helical glycine with larger amino acids; this wrecks collagen helix formation, produces unstable molecules, and dramatically reduces the amount of normal collagen. These changes may be lethal, as in type II osteogenesis imperfecta. Type HI osteogenesis imperfecta is the most severe form in which the child survives. The deformity may be so severe, the fractures so numerous, and the disability so profound, however, that almost any form of treatment deserves consideration.

The young skeleton, abnormal or not, is constantly changing, being formed and resorbed, modelled and remodelled. In theory blocking osteoclastic resorption or encouraging osteoblastic bone formation could produce useful increases in bone tissue even when--as in osteogenesis imperfecta--the primary event is defective osteogenesis.

The first therapeutic option accepts the mutant skeleton as it is but drastically blocks the activity of the osteoclast. Progressive side chain modification has now greatly increased the antiresorptive activity of the bisphosphonates (pyrophosphate analogues with a basic P-C-P structure).[4] All are poorly absorbed and some are given parenterally. The aminobisphosphonate pamidronate (3-amino-1-hydroxypropylidene-1,1-bisphosphonate, APD), used in Paget's disease and tumour hypercalcaemia, is one example. The main published study describes the effects of intravenous pamidronate at a daily dose of 1.5-3.0 mg/kg body weight for three days every four to six months for 1-5 years in 30 children with severe osteogenesis imperfecta.[2] All took 800-1000 mg of calcium and not less than 400 IU of vitamin D daily. Biochemically assessed bone turnover rate fell; age corrected bone mineral density (Z score) and metacarpal cortical thickness both increased, and the number of radiologically confirmed fractures also fell. Growth, which was unaffected, could be estimated by the distance between the transverse metaphyseal sclerotic bands on radiographs, corresponding to each cycle of pamidronate. The reduction in pain and increase in well being and ability were impressive and agreed with other reports.[5 6]

This study was observational, and intravenous treatment by enthusiastic investigators has a considerable placebo effect. A sensible interpretation of bone mineral density in small disabled children of abnormal proportions and composition is well nigh impossible. Fracture rates change unpredictably in osteogenesis imperfecta. Nevertheless these results are important.

The second option, to transplant normal osteoblast precursors, must be regarded as experimental.[3] The skeleton is the home and protector of the bone marrow, which contains haemopoietic precursors and multipotential mesenchymal stromal cells capable of forming osteoblasts (as well as chondrocytes, fibroblasts, adipocytes, and muscle cells). Haemopoietic stem cells engraft and function alter successful bone marrow transplantation; the evidence that in humans stromal cells can do the same is not convincing.

Horwitz et al took their cue from the mouse,[3] where transplanted bone marrow-derived mesenchymal cells became incorporated into the bone and cartilage of sublethally irradiated transgenic mice with an osteogenesis imperfecta phenotype.[7] Three children with severe osteogenesis imperfecta received allogeneic bone marrow transplants; in two osteoblast engraftment (1.5 and 2%) was shown. Bone mineral content and growth increased, bone histology improved, and the incidence of fractures fell; follow up described two more subjects, one with engraftment (Horwitz, International Conference on Osteogenesis Imperfecta, Montreal, 1999).

Interpretation of these results is controversial.[8 9] In particular it is difficult to understand how the improvements described could result from the low percentage of engrafted normal osteoblasts. If' transplanted stromal cells could permanently engraft in humans this would be a breakthrough.[10] Hypophosphatasia could test this since there are biochemical indicators--alkaline phosphatase and its putative substrates--as well as clinical and radiological change.

A 6 month old gift with potentially lethal hypophophatasia had bone marrow transplanted from a healthy sister, with rapid reversal of radiographic abnormalities and healing of "rachitic" defects.[11] Subsequent deterioration was followed by improvement after a non-T cell depleted boost with stromal cell expansion, again from her sister. Strangely there was never any evidence of biochemical improvement.

So where do we go from here? There is a danger that infants and children will be given powerful bisphosphonates indiscriminately and nothing will be learnt. It is important that a formal trial is conducted, however difficult that may be. For bone marrow transplantation there will be no rush. The investigators, rightly, regard their work as a test of principle and for the moment it should remain so.

R Smith consultant orthopaedic physician Nuffield Orthopaedic Centre, Oxford OX3 7LD

[1] Marini JC. Osteogenesis imperfecta: managing brittle bones. N Engl J Med 1998;339:986-7.

[2] Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998;339:947-52.

[3] Horwitz EM, Prockop DW, Fitzpatrick LA, Koo WWK, Gordon PL, Neel M, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999;5:309-13.

[4] Russell RGG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999;25:97-106.

[5] Brumsen C, Handy NAT, Papapoulos SE. Long term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis. Medicine 1997;76:266-83.

[6] Bembi B, Parma A, Bottega M. Ceschel S, Zanatta M, Martini C, et al. Intravenous pamidronate treatment in osteogenesis imperfecta. J Pediatrics 1997; 131:622-5.

[7] Pereira RF, O'Hara MD, Laptev AV, Halford KW, Pollard MI), Class R, et al. Marrow stromal cells as a source of progenitor cells for non haematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci USA 1998;95:1142-7.

[8] Marini JC. Osteogenesis imperfecta calls for caution. Nat Med 1999;5:466.

[9] Bishop NJ. Osteogenesis imperfecta calls for caution. Nat Med 1999;5:466-7.

[10] Gerson SL. Mesenchymal stem cells: no longer second class marrow citizens. Nat Med 1999;5:262-4.

[11] Whyte MP, Kurtzburg J, Gottesman GS, McAlister WH, Coburn SP, Ryan LM, et al. Marked clinical and radiographic improvement in infantile hypophosphatasia transiently after haploidentical bone marrow transplantation. Bone 1998;25 (suppl):S191.

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