Division of Kidney Diseases, Department of Pediatrics, Children's Memorial Hospital and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614
Address all correspondence and requests for reprints to: Craig B. Langman, M.D., Isaac A. Abt, M.D. Professor of Kidney Diseases, Northwestern University, Feinberg School of Medicine, Children's Memorial Hospital, 2300 Childrens Plaza, MS #37, Chicago, Illinois 60614. E-mail: c-langman{at}northwestern.edu.
Collagen is the most abundant protein in bone, with the single largest entity represented by type I collagen. Osteogenesis imperfecta (OI) is the clinically heterogeneous disease resulting from one of numerous described, and several yet undescribed, mutations in one of the several collagen genes of bony tissue (1). As its name implies, most of the clinical problems reside in inadequate bone development, and this leads to fragility fractures, linear growth failure, or even death in the most severe phenotypes (2). Extra-osseous complications are recognized, too. A classification system that is widely accepted has been in use for over 3 decades (3).
Although the molecular understanding of OI has been known for some time, specific therapy to relieve the fracturing bone disease has lagged far behind the science of the disorder. Promising, new therapies for patients with OI have been put forward and later rejected because of lack of efficacy or safety. These include the use of GH (4), calcitonin (5), and other bone-active agents used primarily for the treatment of postmenopausal osteoporosis. Although conceptually amenable to gene replacement strategies, there is no widespread or uniform understanding of how to accomplish this.
However, pioneering work by Prof. Francis Glorieux and colleagues (6) in the last decade demonstrated the efficacy and safety of cyclical pamidronate therapy for infants and children with OI at improvements in bone fractures and growth failure. The study in this issue of the Journal by Rauch et al. (7) extends the observations from the group at Shriner's Hospital in Montreal by providing biochemical evidence whereby pamidronate exerts its positive effect at fracture reduction, gain in bone mass, and improvement in linear growth failure in infants, children, and adolescents with OI.
Amino-bisphosphonates, derived in basic structure from pyrophosphate, but whose central oxygen moiety has been substituted by a carbon atom, and in which one of its side-chains contains an amino-nitrogen structure, is without the presence of a mammalian enzyme for degradation (8). The absence of such an enzyme leads to a prolonged action when compared with most other drugs used clinically. Bisphosphonates, as potent bone-active agents, are becoming quickly the standard of care in OI, based on the numerous reports from many centers over the past 2 years (9, 10, 11).
Bone loss in early postmenopausal osteoporosis is associated with an increase in osteoclastic-mediated bone resorption (12). The rationale for the use of amino-bisphosphonates in postmenopausal osteoporosis is based on their ability to lower bone resorption effectively (13), by achieving a high concentration in bone at sites of active osteoclastic-mediated resorption (14), and subsequent inhibition of those processes. Several biochemical actions of amino-bisphosphonates include their ability to block farnesyl-pyrophosphate synthase (a key enzyme in the HMG-CoA pathway of cholesterol synthesis), leading to defective protein isoprenylation, and to activate apoptotic cell death by activation of caspase-specific pathways (15). Such pathway inhibitions in osteoclasts reduce both active osteoclast resorption, as well as, osteoclatogenesis, and overall, a decrease in both local bone resorption and overall bone mass loss.
How might an amino-bisphosphonate like pamidronate be rationalized for use in children with OI, where the defective collagen expression is expressed almost exclusively in the osteoblast, rather than the osteoclast? The data from Rauch et al. (7) shed new light on the area, and I offer a new interpretation as well.
Growth of bone in children occurs through the process of modeling (16) and is spatially distinct, whereby endocortical resorption is apposed by periosteal formation. Successful outcomes of modeling lead to proper tubulation, lengthening, and proportioning of bone along genetic potential. In adults and children, subsequent remodeling of bone (17), a process that occurs on synchronous surfaces, allows precise, microstructural changes to occur that support gravitational needs. The mechanostat that supplies the signal for remodeling features may be the osteocyte (18).
Recent, dynamic histomorphometric studies of bone in children with OI support the concept that in the modeling process, there is a relative overactivity of endocortical resorption, and due to the defective collagen molecule, a relative paucity of periosteal new bone formation (19). The resultant deficiency in bone size, when compared with normal children and even after accounting for the linear growth failure of children with OI, is an important determinant in predilection for fractures with normal activities of daily living that occur in such patients. As a secondary process, the formation of trabecular bone is deficient, too, and results in a lower than normal number of trabeculae, and in decreased width of individual trabeculae. This is an independent factor in the susceptibility to fractures in patients with OI.
Given this imbalance in bone formation and bone resorption activities that characterize OI, and one that favors net bone loss over gain, it is not too surprising at first glance that an intervention that reduces, primarily, the bone resorptive process, would shift the balance. Thus, selective inhibition of the osteoclast allows the rate of bone formation, albeit lower in the patient with OI than in normals, to carry forth and allow for net bone accretion still at a greater amount than in the bisphosphonate-untreated patient with OI. Over time, this shift in balance would be expected to lead to more bone formation, and perhaps, fracture reduction. The data from Rauch et al. (7) support this concept, because a marker of bone resorption, the urinary excretion of type I collagen N-linked telopeptide, was reduced from a value before therapy that is 32% greater than normal children to a value only one half that of normal children after 4 years of therapy.
However, the slight shift in bone balance resulting from inhibition of resorption seems out of proportion to the pronounced clinical effect that occurs. Could there be an additional benefit of pamidronate therapy in this disease? Rauch et al. (7) demonstrated that cyclical pamidronate leads to reproducible short-term reductions in blood ionized calcium levels (Ca2+) of a mean level of (-)0.14 mM. Such physiological reductions in Ca2+ would be expected to lead to marked increases in synthesis and release of PTH, and they demonstrated this, too.
What is the effect of such cyclical elevations in the synthesis and release of PTH, with overall increases of 30% after 4 years in children with OI? I believe that the cyclical, intermittent use of amino-bisphosphonates like pamidronate may simulate the bony effects that result from the intermittent administration of synthetic PTH itself in osteoporotic individuals, by causing transient but repetitive elevation of PTH in the blood (20). Such osteoporotic individuals treated with synthetic PTH have improvements in both diminished trabecular number, and perhaps in width, and improvement of bone mass at sites of predominant cortical bone, such as the femur, in addition to enhancement of cancellous bone volume (21). PTH is a potent stimulator of the osteoblast (22). The histomorphometric changes resulting from pamidronate therapy administered to children with OI support this hypothesis of additional benefit from pamidronate therapy. Would direct administration of PTH be useful in children with OI? At this time, the Food and Drug Administration has not licensed the use of synthetic PTH for use in children, so we will have to wait to the future for an answer.
The outlook for the child with OI has been changed fundamentally to the good by the cyclical use of amino-bisphosphonates. Therapy has been associated with relief of fracturing osteopenia and linear growth failure. The mechanisms of action seem to involve both inhibition of osteoclastic resorption and stimulation of PTH-mediated anabolic effects on osteoblastic processes. As newer parenteral and oral amino-bisphosphonates are developed for human use, and genetic approaches appear on the horizon (23), it may be easier to treat children with OI in the near future. Longer-term studies for safety and continued efficacy of pamidronate are continuing, but the possibility of near-normal lifestyle activities is achievable now for the owner of these forms of genetic, brittle bone disease.
Footnotes
Abbreviation: OI, Osteogenesis imperfecta.
Received January 21, 2003.
Accepted January 22, 2002.
References
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