Clinical Characteristics and Management of Rare Metabolic Bone Diseases: An Audit of the Rare Metabolic Bone Disease Registry of India.

Rare diseases, defined by the 2002 Rare Disease Act, affect fewer than 5 in 10,000 individuals. Rare metabolic bone diseases (MBDs), such as osteogenesis imperfecta, hypophosphatasia, osteopetrosis, and other unclassified disorders, can disrupt bone development and remodeling, posing diagnostic and management challenges. This study analyzed data from the rarembd.in registry (2010-2024), a 15-year database documenting only rare MBDs. Clinical presentation and demographic data of patients with rare MBDs were collated. Common MBDs (osteoporosis, primary hyperparathyroidism) were excluded. Genetic testing was performed in a subset of patients. There was a total of 218 patients with an almost equal gender distribution (male-to-female ratio of 1:1.07) and a mean age of 29.1 ± 18.9 years. The registry identified 29 rare MBDs with three main disease categories: demineralization disorders (50.4%), disorders of bone matrix and cartilage formation (32.5%), and sclerotic disorders (13.7%); with a smaller proportion categorized as unclassified bone disorders (2.7%). Rickets/osteomalacia (27.1%) was the most common, followed by osteogenesis imperfecta (23.4%) and fibrous dysplasia/McCune-Albright syndrome (18.8%). Fractures affected 57.7% of patients, with 24.5% experiencing multiple fractures, while 31.1% exhibited skeletal deformities. Mutation analysis in our registry identified pathogenic variants in the SOST, TGFβ1, SLC34A3, ALPL, and VCP genes, confirming the genetic basis of sclerosteosis, Camurati-Engelmann disease, hypophosphatemic rickets, hypophosphatasia, and IBMPFD, respectively. Different management strategies were used that included teriparatide, bisphosphonates (zoledronate or alendronate) with total contact casting, intralesional zoledronate, denosumab, calcium, active vitamin D, and recombinant human growth hormone. Total parathyroidectomy was performed in specific cases. The registry classified RMBDs into four categories, with demineralization disorders being the most common, followed by bone matrix/cartilage formation disorders, sclerotic diseases, and unclassified cases. There were 29 RMBDs, and rickets/osteomalacia was the most prevalent subtype, tumor-induced osteomalacia followed by familial hypophosphatemic osteomalacia. Among the unclassified bone disorders, fragility fractures emerged as the most common presentation.