Osteogenesis imperfecta (OI) is a genetic disorder caused by collagen-related mutations which leads to increased bone fragility and low bone mass. Although the past decade has been marked by numerous advances in therapies that aim to stabilize the onset of metabolic bone disease, current treatment strategies leave room for substantial improvements. The studies that will be presented in this thesis focus on designing systematic treatments for two challenging clinical scenarios that require novel approaches. All studies have been approached in the context of OI using the Brtl/+ mouse model.

While the maternal skeleton goes through significant bone loss during pregnancy and lactation, this period of skeletal vulnerability can exacerbate an underlying metabolic bone condition like OI. In view of increasing use of bisphosphonates (BP) in premenopausal women to treat OI, the potential risks from long-term exposure on both maternal and neonatal skeleton during pregnancy and lactation remain inconclusive. When we assessed the maternal skeletal changes during pregnancy and lactation in Brtl/+ dams, pregnancy led to maternal trabecular gains in vertebral bone mass, while lactation induced maternal cortical and trabecular bone loss in both vertebra and femur. When BPs were administered prior to conception, bone mass gains due to pregnancy were amplified and lactation-induced bone loss was prevented. However, this protective effect was more modest with BP intervention during pregnancy, and ceased to exist in the late stages of lactation. Despite preventing lactation-induced maternal bone loss, no negative skeletal effects of BPs on offspring were observed. These findings indicate that during this period of significant imbalance between bone resorption and formation, BPs can help reduce the risk of maternal bone fragility in OI by inhibiting lactation-induced bone resorption without affecting bone development in their offspring.

The second half of this thesis explores clinical cases with a critically depleted bone structure, such as severe OI. These cases pose a challenge to current antiresorptive and anabolic therapeutics since their response mechanisms target different abnormalities in the bone remodeling cycle. In this study, rapidly growing Brtl/+ mice were treated with a combination of pamidronate (PAM) and an anabolic (SclAb) in order to attain superior bone mass and strength effects compared to monotherapy. Results from this study showed that following one cycle of combination therapy, a single dose of PAM in combination with SclAb led to a cumulative effect on bone mass, but each through independent means. PAM retention mechanism led to an increase in trabecular number as the dosage increased while no additional gains were observed with SclAb. Conversely, while PAM showed no significant effect on trabecular thickness, SclAb induced a consistent trabecular thickening across all BP dosages. Chronic effects of concurrent administration of BP and SclAb revealed that accumulating cycles conferred synergistic gains in trabecular mass and vertebral stiffness, suggesting a distinct advantage of both therapies combined.

Given the lack of knowledge regarding the effects of BPs during reproductive periods and lack of treatment options for patients with severe OI, this thesis provides valuable insight that can help develop patient-specific treatment plans. By understanding the changes in bone metabolism of the clinical conditions we are trying to resolve, and by combining this knowledge with our understanding of the targeted pathways of available pharmaceuticals, we can strategically and systematically optimize bone therapeutics so that the best clinical outcome can be achieved.