Differential diagnosis of heritable and acquired osteomalacia in children: biochemical and biomaterial signatures.

Defective mineralization of bone matrix results in osteomalacia, which universally affects the skeletal system and dentition and manifests alongside the clinically and radiologically more obvious growth plate disorder rickets in young children. Given that radiological signs of osteomalacia are limited, most hypomineralization disorders are diagnosed based on their clinical features and/or typical biochemical signatures, especially after the closure of growth plates. Evaluation of histomorphometry (HM) parameters and bone mineral density distribution (BMDD) via quantitative backscattered electron imaging (qBEI) from transiliac bone biopsy samples enables the exploration of the true skeletal disease burden of osteomalacia and the assessment of the impact of treatment. The diagnosis of various acquired and heritable disorders of osteomalacia based on clinical, biochemical, radiological and biomaterial HM features is discussed here. The most common acquired cause of osteomalacia remains dietary calcium and solar/dietary vitamin D deficiencies. Rare heritable causes result from mutations in genes involved in calcitriol synthesis and action (resulting in calcipaenia), fibroblast growth factor 23 production or degradation or tubulopathies (resulting in phosphopaenia) or reduced hydrolysis of the mineralization blocker inorganic pyrophosphate (resulting from hypophosphatasia). On bone biopsy, osteomalacia manifests as increased osteoid indices on static HM, with mineralization lag on tetracycline-labelled dynamic HM. Calcipaenic disorders typically display additional HM features of secondary hyperparathyroidism which include increased osteocyte surface from increased bone turnover, peritrabecular marrow fibrosis and cortical thinning. BMDD in osteomalacic conditions shows an increased amount of lowly mineralized bone tissue and increased heterogeneity in mineralization when compared to normal individuals. Medical assessment should focus on identification of biochemical disease signatures which differ between these osteomalacic entities but are essential for early diagnosis and treatment monitoring, with the aim of achieving full matrix mineralization and prevention of this hidden disease.