Many disorders cause osteosclerosis, and many exclusively affect adults. Pediatricians are likely to encounter those that are Mendelian diseases, with most still classified as dysplasias although now understood at the gene level. Thus, there is promise for defining their molecular and biochemical pathogeneses, and for developing targeted medical treatments. Sclerosing bone dysplasias too have become the turf of the metabolic bone disease specialist. However, their clinical spectrum ranges broadly from autosomal dominant typically benign findings exemplified by Worth-type endosteal hyperostosis in adults due to LRP5 activation, to autosomal recessive severe sclerosteosis, van Buchem disease, or lethal types of infantile (malignant) osteopetrosis (OPT) that require treatment. The causal genes regulate primarily the cells for bone apposition or for bone resorption; e.g., osteosclerosis from LRP5 activation with increased osteoblast activity, or the osteopetroses (OPTs) from impaired osteoclast (OC) formation or function.
The major treatment concern for pediatricians is infantile OPT. We know the pathogenesis of the skeletal disease for all genuine OPTs is a life-long block of OC-mediated bone resorption due to defects in various genes. Bone biopsy will confirm the failed OC action by showing unresorbed calcified primary spongiosa. Now, progress from the identification of causal genes for OPT has impacted importantly on potentially curative bone marrow transplantation (BMT) aimed to replace defective OCs. Most OPTs involve dysfunctional OCs that can be seen on bone histology, explaining why BMT therapy is useful. However, significant genetic heterogeneity now underlies the OPTs. In especially rare OPTs, the defective bone resorption is not intrinsic to the OC, but lies elsewhere (e.g., RANKL deficiency), and is not corrected by conventional BMT. Therefore, important distinction between OC-rich and OC-poor OPTs is now crucial when considering BMT treatment. Mutation analysis can distinguish the OPTs that should respond to BMT. Unfortunately, differences in the pathogeneses among the heritable OPTs can impact other organs, including the brain where there can be severe complications not alleviated by BMT. Despite restoration of bone resorption by BMT, these OPTs are nevertheless considered untreatable due to their neurological outcomes. Now, availability of potent antiresorptives presents the specter of iatrogenic OPT if these agents are administered excessively for other disorders of skeletal or mineral homeostasis in infants or children. For BMT directed at severe OPT, time is of the essence because ongoing nerve compression may cause irreversible neurological damage, and further marrow space crowding impairs engraftment of transplanted cells. Unfortunately, reports concerning the techniques for BMT in OPT are now outdated and misleading in terms of donor candidacy, engraftment rates, and graft vs host disease, etc. However, the newer preparative regimens for BMT continue to lack worldwide consensus and uniformity. For infantile OPT, hypocalcemia from blocked bone resorption before BMT can lead to distinctive signs, symptoms, and complications, and often requires pharmacologic treatment. Post-BMT OPT may paradoxically require antiresorptive treatments as restoration of OC action leads temporarily to hypercalcemia. Medical approaches for severe OPT have included the pioneering efforts by Dr Lyndon Key to drive OCs using high-dose 1,25-dihydroxyvitamin D3 together with a low calcium diet, but lacked validation and are losing favor. In contrast, his interferon gamma 1b treatment is having a resurgence of interest. Discovery of the chloride channel 7 defect underlying the one true form of autosomal dominant OPT (Albers-Schönberg disease) is leading to new therapeutic considerations for this often troublesome benign OPT. This arena of treatment for sclerosing bone disease is dynamic, important, and a brief overview is the goal of my presentation.
Disclosure: The author declared no competing interests.
27 - 30 Jun 2015