Bone Therapeutics: Safety Considerations,Session Summary

Abstract

This session was a series of presentations focused on safety considerations for late stage or currently marketed bone therapeutic agents. The first presentation was an overview of a major regulatory requirement in the nonclinical filing package for bone therapeutics, studies designed to assess the impact of an agent on bone quality. Two presentations focused on safety issues associated with drugs whose primary mechanism of action is inhibition of bone resorption. Typical findings associated with this class of agents in general and reproductive toxicology studies were reviewed, highlighting INHAND (International Harmonization of Nomenclature and Diagnostic Criteria) nomenclature. This was followed by an overview of safety issues that have been identified largely through clinical experience. Similar presentations followed emphasizing safety and regulatory issues associated with classes of drugs whose primary mechanism of action is stimulation of bone formation known broadly as bone anabolic agents. The major focus of these discussions was carcinogenicity risk assessment. The final presentation was an introduction to a rapidly evolving area in bone therapeutics, treatment of rare genetic bone diseases, and the developmental challenges associated with these indications and novel therapeutic modalities.

Regulatory Requirements for Assessment of Bone Safety (Opening Session)

The goal of any osteoporosis therapeutic is to reduce fracture risk by increasing the mass and strength of the skeleton. Because bone strength is not readily assessable in clinical studies, nonclinical studies are required for drug registration to demonstrate that the therapeutic increases in bone mass yield proportional increases in bone strength. This assessment of “bone quality” captures such features as size, shape, and material properties of bone that can influence susceptibility to fracture that are not explained by bone mass (Hernandez and Keaveny 2006). The requirement for these studies evolved largely from the clinical experiences with fluoride as a bone therapeutic agent, where a dissociation between effects on bone mass and fracture rates was observed (Colman 2003). Although fluoride effected improvements in bone mass, it resulted in an increase in fractures, considered a consequence of the negative effects of fluoride on bone material properties (Riggs et al. 1990; Mosekilde, Kragstrup, and Richards 1987). The design of these bone quality studies is typically discussed with regulatory agencies at the end of phase II meetings and conducted during phase III trials. Regulatory guidances for assessment of bone quality requires studies in 2 species, the ovariectomized rat and an ovariectomized nonrodent species that exhibits intracortical remodeling, most frequently the cynomolgus monkey (EMA 2006; US FDA 2016). Rat studies are generally 1 year in duration. The duration of nonrodent studies for therapeutics intended for chronic use is recommended to provide an equivalent of 4 years of exposure based on comparative durations of the remodeling cycle in the nonrodent species and human (typically 16 months). Pharmacodynamic evaluation in these studies includes serum/urine biomarkers and histomorphometry (effects on bone formation and resorption and particularly the dynamics of bone mineralization), in vivo and ex vivo densitometry (effects on bone mass and architecture), and ex vivo destructive biomechanics (effects on whole bone strength and bone matrix material properties). Bone mass and strength data, collected at clinically relevant fracture sites such as the vertebra and proximal femur, are then subjected to correlation analysis to ensure that the normally strong, positive relationship between biomechanical parameters is not significantly altered by treatment. The results of these nonclinical bone quality studies have demonstrated the bone safety of currently approved osteoporosis therapeutics and provide a clear path forward for the nonclinical assessment of future therapies.

Antiresorptives Safety Concerns—Clinical Perspective (Jacques Brown)

A summary of this presentation is provided in a separate paper in this issue.

Antiresorptives—Toxicology Perspective (Rogely Boyce)

Several antiresorptive therapeutics have been developed that effect inhibition of bone resorption by different mechanisms of action. In toxicity studies, there are microscopic findings common to these therapeutics as well as unique findings based on the mechanisms of action. In the mature skeleton, qualitative changes in response to antiresorptive agents are difficult to detect in standard hematoxylin and eosin (H&E) sections and are best appreciated in undecalcified unstained sections of bones from animals administered in vivo flurochrome labels such as calcein green that are deposited at sites of active bone mineralization to detect quantitative changes in dynamic bone formation that occur secondary to inhibition of resorption. Although standard H&E sections are generally unrevealing, class-specific qualitative effects may be appreciated. An example is large hypernucleated osteoclasts often with pycnotic nuclei suggestive of osteoclast apoptosis that are observed with nitrogen-containing bisphosphonates (Jain and Weinstein 2009). In the growing skeleton with active endochondral ossification, antiresorptives result in increased bone in metaphyseal trabecular bone characterized by retention of primary spongiosa (Schenk et al. 1973; Pataki et al. 1997), morphological changes consistently observed in congenital osteopetrosis. The severity of this change will be dependent upon the rate of growth, antiresorptive potency, and duration of treatment. For classes of antiresorptive agents that result in an absence of osteoclasts due to inhibition of osteoclastogenesis, such as inhibitors of receptor activator of nuclear factor kappa-B ligand (RANKL) or colony-stimulating factor 1 (CSF-1) signaling, increased thickness of the physis is observed in conjunction with increased bone (Odgren et al., 2003). These growth plate changes occurring with inhibitors that result in an absence of osteoclasts support the concept that osteoclasts do more than resorb bone but play a key role in regulation of growth plate dynamics (Boyce et al., 2009). Increased thickness of the physis may be uniform or segmental and is frequently associated with physeal dysplasia characterized by disorganization of chondrocyte columns. The severity of growth plate changes with osteoclastogenesis inhibitors reflects the underlying rate of endochondral ossification and is less severe in adolescent animals with lower rates of longitudinal bone growth (Bussiere and Pyrah 2012). Because the severity of bone changes is most severe in the rapidly growing skeleton, dramatic effects of antiresorptive agents have been reported in neonatal animals (Boyce et al. 2014), which also demonstrate the remarkable ability of the skeleton to remodel and restore bone structure during recovery.

Anabolics—Potential Safety Concerns (Luc Chouinard)

The development of new drugs that stimulate bone formation is a priority for treatment of osteoporosis, fracture healing, and other bone diseases. Currently, teriparatide (hPTH[1-34]) and abaloparatide (a PTHrP analogue) are the only approved anabolic, or bone building, drugs but are associated with dose-dependent increases in the incidence of osteosarcoma in rat 2-year bioassays which limits their clinical use (Vahle et al. 2002; Jolette et al. 2017). There is concern among regulatory agencies and the scientific community that the positive findings in rat carcinogenicity studies with parathyroid hormone (PTH) analogues may represent a class effect for bone-building agents. The potential safety concerns and regulatory issues associated with the development of a new bone-forming agent, romosozumab, a sclerostin antibody in phase III clinical development, were reviewed using a weight-of-evidence approach. Weight-of-evidence factors included contrasting the mode and mechanism of action of romosozumab with PTH, phenotype of loss-of-function mutations in sclerostin in humans, and findings in romosozumab chronic toxicity studies. Although the weight-of-evidence factors supported that romosozumab would pose a low carcinogenic risk to humans, the carcinogenic potential of romosozumab was assessed in a rat lifetime study. There were no romosozumab-related effects on tumor incidence in rats. The findings of the lifetime study and the weight-of-evidence factors collectively indicated that romosozumab administration would not pose a carcinogenic risk to humans. The weight-of-evidence factors, design considerations of a rat lifetime pharmacology study with an antibody immunogenic in rats, and the findings of the romosozumab lifetime study are presented in detail in Chouinard et al. (2016).

Therapeutics for Rare Bone Disease—Clinical Perspective (Frank Rauch)

Rare bone diseases is one of the most active areas of bone research and drug development. Creative therapeutic approaches using established bone drugs have been developed to treat rare bone disorders that lead to fractures or that affect bone mineralization. For bone fragility disorders such as osteogenesis imperfecta, antiresorptive treatment with bisphosphonates is currently the main treatment option (Montpetit et al. 2015; Palomo et al. 2016; Sato et al. 2016). Osteoclast inhibition can also be achieved with denosumab, a drug based on an antibody against RANKL, which seems to have a similar effect on bone tissue as intravenous bisphosphonate treatment in growing children with osteogenesis imperfecta. Another approach to treat osteogenesis imperfecta being explored is to stimulate bone formation through antibody-mediated sclerostin inhibition, a class of drugs in clinical development (Rauch and Adachi 2016; Glorieux et al. 2017). Novel biologics have recently been developed for the treatment of rare bone disease. Hypophosphatasia, a disorder caused by an inactivating mutation in the gene coding for tissue-nonspecific alkaline phosphatase, can now be treated using a bone-targeted enzyme replacement therapy. Regarding mineralization defects, a bone-targeted antifibroblast growth factor 23 antibody is in clinical development for the treatment of hypophosphatemic rickets and tumor-induced osteomalacia.

Rare Bone Disease—Toxicology Perspective (Rogely Boyce)

Therapeutics for rare bone disease fall under the category of and development strategy for orphan drugs. Although the mouse models of these genetic diseases closely recapitulate the clinical features of the diseases and could offer the potential to facilitate toxicity testing, recent regulatory draft guidance suggest that standard toxicology studies would likely be required for development and registration of these therapeutics (US FDA 2015).

Conclusion

For drugs under development for the treatment of osteoporosis, assessment of the impact of a potential therapeutic on bone quality is a regulatory requirement. Safety issues for antiresorptive drugs in the adult population have largely been identified in the clinical setting. However, nonclinical safety testing has successfully identified potential hazards for pediatric use related to the pharmacological activity of antiresorptive agents and the potential for fetal risk. For bone anabolic agents that stimulate bone formation, concern for carcinogenic effects on bone remains based on the occurrence of a high incidence of osteosarcomas in rodent carcinogenicity studies with hPTH and PTH analogues. The search for novel therapeutics for the treatment of rare bone diseases is currently one of the most active areas of bone research and drug development.