<p dir="ltr">Skeletal fragility can be caused by a wide array of diseases and disorders, but the most difficult etiologies to clinically circumvent are those in which the body loses not just bone mass but the ability to create healthy bone tissue. While in conditions such as osteoporosis (the most prevalent cause of age-related skeletal fragility in which elevated resorption without compensatory elevated formation leads to bone loss), interventions can target bone remodeling pathways to protect and increase bone mass, many other diseases are characterized by genetic and metabolic crippling of the remodeling process, rendering those same mass-based interventions less effective at reducing fracture risk. Osteogenesis imperfecta (OI) is a class of genetic disorders in which gene mutations affect the formation of collagen, a crucial building block of bone tissue that makes up 90% of its organic matrix, leading to lost bone mass and quality. As the main genetic causes of OI cannot currently be directly treated, therapeutic OI treatments are needed that improve tissue-level material properties. Similarly, metabolic conditions such as diabetes, a disorder in which the body cannot properly regulate blood sugar due to loss of insulin production and/or efficacy, can have multi-organ impacts including increased risk of developing chronic kidney disease and skeletal fragility. Type 2 diabetes is especially notorious for increasing fracture risk despite maintained or even increased apparent bone mass, which is strong evidence that intrinsic bone material properties are impaired by the disease state. A possible solution to the bone quality problem may be treatments that increase bone water content, as amplifying the water content of bone can improve multi-scale material properties such as collagen fibril elasticity and whole-bone toughness. Therefore, increasing bone hydration could be a way of improving tissue-level material properties, despite being unable to eradicate the genetic or metabolic disorders that alter how collagen is produced and incorporated into the bone matrix. To that end, this dissertation presents several studies that characterize models of osteogenesis imperfecta and diabetic kidney disease in mice and investigate methods of rescuing skeletal fragility in these animals through treatments that target both bone mass and bone quality with ties to tissue hydration.</p>