Osteoporosis is a debilitating disease characterized by reduced bone mineral density and an increased risk of fractures. This review aims to provide a comprehensive overview of, and map current knowledge, obtained from preclinical and clinical studies of the osteoanabolic agent abaloparatide. PubMed and Embase were meticulously searched from inception to May 4, 2021.178 titles and abstracts were screened, and 57 full-text articles were assessed for inclusion. A total of 55 articles were included; 5 (9%) in vitro studies, 21 (38%) in vivo studies, and 29 (53%) clinical studies. Preclinical in vitro studies have demonstrated receptor conformation preferability, structural insights into the receptor-agonist complex, and proliferative effects of abaloparatide on osteoblasts. Preclinical studies have shown abaloparatide to be similarly effective to teriparatide using comparable doses in both ambulating mice and rats challenged by disuse. Other animal studies have reported that abaloparatide effectively mitigates or prevents bone loss from ovariectomy, orchiectomy, and glucocorticoids and improves fracture healing. The pivotal clinical study ACTIVE demonstrated 18 months of treatment with abaloparatide substantially increase bone mineral density and reduce fracture risk in post-menopausal women compared with placebo. The extension study ACTIVExtend highlighted that subsequent treatment with alendronate sustained the bone gained by abaloparatide treatment and the reduced fracture risk for up to two years. Post-hoc sub-group analyses have also supported the efficacy and safety of abaloparatide treatment independent of various baseline risk factors. In conclusion, mounting evidence from preclinical and clinical studies has uniformly reported that abaloparatide increases bone mineral density and reduces fracture risk.

Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.

Mountaineering and exposure to high altitude result in physiological adaptations to the reduced inspiratory oxygen availability. Acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) are well-described harmful effects of exposure to high altitude. Common to AMS, HAPE, and HACE are distinct clinical signs and symptoms of impaired function. However, several studies have suggested that high altitude might result in a substantial bone loss, which usually does not produce any apparent symptoms. This review aims to provide a comprehensive overview of, and map current knowledge of the skeletal effects of hypobaric hypoxia and high altitude. PubMed and Embase were searched from inception to September 6, 2021, to identify studies investigating the skeletal effects of exposure to hypobaric hypoxia and high altitude. Three hundred sixty titles and abstracts were screened, and 20 full-text articles were included (16 in vivo studies and four real-world human studies). In rodents, simulated high altitude up to 2900 m did not result in any adverse skeletal effects. In contrast, studies exposing animals to very high altitude (3500-5500 m) reported substantial reductions in BMD, cortical morphology, and bone strength, as well as deteriorated trabecular microstructure. Detrimental microstructural effects were also reported in rats exposed to simulated extreme altitude (6000 m). Finally, real-world human studies in mountaineers suggested high altitude exposure reduced bone mineral density (BMD) and that the harmful skeletal effects of hypobaric hypoxia were not entirely recovered after 12 months. In conclusion, in vivo and real-world studies demonstrated high altitude exposure results in adverse skeletal effects. The underlying mechanism for hypobaric hypoxia-induced bone loss is not elucidated.

Mountaineers at high altitude are at increased risk of acute mountain sickness as well as high altitude pulmonary and cerebral edema. A densitometric study in mountaineers has suggested that expeditions at high altitude decrease bone mineral density. Surprisingly, the in vivo skeletal effects of hypobaric hypoxia are largely unknown, and have not been studied using advanced contemporary methods to assess bone microstructure. Eighty-four 22-week-old female mice were divided into seven groups with 12 mice in each group: 1. Baseline; 2. Normobaric, 4 weeks; 3. Hypobaric hypoxia, 4 weeks; 4. Normobaric, 8 weeks; 5. Hypobaric hypoxia, 8 weeks; 6. Normobaric, 12 weeks; and 7. Hypobaric hypoxia, 12 weeks. Hypobaric hypoxia mice were housed in hypobaric chambers at an ambient pressure of 500 mbar (5500 m altitude), while normobaric mice were housed at sea level atmospheric pressure for 4, 8, or 12 weeks, respectively. Hypobaric hypoxia had a profound impact on femoral cortical bone and L4 trabecular bone, while the effect on femoral trabecular bone was less pronounced. Hypobaric hypoxia reduced the bone strength of the femoral mid-diaphysis and L4 at all time-points. At femoral cortical bone, hypobaric hypoxia reduced bone formation through fewer mineralizing surfaces and lower bone formation rate after 2 weeks. In addition, bone strength decreased, and C-terminal telopeptide of type I collagen (CTX-I) increased independently of the duration of exposure to simulated high altitude. At L4, hypobaric hypoxia resulted in a substantial reduction in bone volume fraction, trabecular thickness, and trabecular number after 4 weeks of exposure. Hypobaric hypoxia reduced bone strength and femoral bone mass, while femoral trabecular bone was much less affected, indicating the skeletal response to hypobaric hypoxia differ between cortical and trabecular bone. These findings provide initial preclinical support for future clinical studies in mountaineers to assess bone status and bone strength after exposure to prolonged high altitude exposure.