Advances and Unmet Needs in the Therapeutics of Bone Fragility

Abstract

The prevalence of fragility fractures increases as longevity increases the proportion of the elderly in the community. Until recently, the majority of studies have targeted women with osteoporosis defined as a bone mineral density (BMD) T score of < −2.5 SD, despite evidence that the population burden of fractures arises from women with osteopenia. Antiresorptive agents reduce vertebral and hip fracture risk by ~50 percent during 3 years but efficacy against non-vertebral fractures, 80% of all fractures in the community, is reported in few studies, and of those, the risk reduction is only 20–30%. Recent advances in the use of antiresorptives and anabolic agents has addressed some of these unmet needs. Zoledronic acid is now reported to reduce vertebral and non-vertebral fractures rates in women with osteopenia. Studies using teriparatide demonstrate better vertebral and clinical (symptomatic vertebral and non-vertebral) antifracture efficacy than risedronate. Abaloparatide, a peptide sharing amino acid sequences with teriparatide, reduces vertebral and non-vertebral fractures. Romosozumab, a monoclonal antibody suppressing sclerostin, reduces vertebral and non-vertebral fractures within a year of starting treatment, and does so more greatly than alendronate. Some recent studies signal undesirable effects of therapy but provide essential cautionary insights into long term management. Cessation of denosumab is associated with a rapid increase in bone remodeling and the uncommon but clinically important observation of increased multiple vertebral fractures suggesting the need to start alternative anti-resorptive therapy around the time of stopping denosumab. Antiresorptives like bisphosphonates and denosumab suppress remodeling but not completely. Antifracture efficacy may be limited, in part, as a consequence of continued unsuppressed remodeling, particularly in cortical bone. Bisphosphonates may not distribute in deeper cortical bone, so unbalanced intracortical remodeling continues to cause microstructural deterioration. In addition, suppressed remodeling may compromise the material composition by increasing matrix mineral density and glycosylation of collagen. As antiresorptive agents do not restore microstructural deterioration existing at the time of starting treatment, under some circumstances, anabolic therapy may be more appropriate first line treatment. Combining antiresorptive and anabolic therapy is an alternative but whether anti-fracture efficacy is greater than that achieved by either treatment alone is not known.

Therapeutic Irradiation: Consequences for Bone and Bone Marrow Adipose Tissue

“…Studies have shown that osteoanabolic agents stimulate bone formation and reduce fracture risk in patients with low bone density (18–20). Since an adverse side effect of irradiation is decreased bone density and increased bone fragility, combination therapies of osteoanabolic, or anti-resorptive agents may be useful for patients receiving irradiation therapies.…”

<p>Pharmacological Therapy of Osteoporosis: What’s New?</p>

“…29 Furthermore, although findings about fracture prevention are encouraging, the assertion that abaloparatide is more effective than teriparatide in reducing fracture risk seems somewhat questionable. In fact, a large number of patients reporting a fragility fracture in the placebo and teriparatide groups sustained the traumatic event during the first few weeks of treatment 28,30 and the differences in fracture rates between the two treatment arms were minimal at 12 and 18 months. 9,30,31 Moreover, the observations of both enhanced anabolic effect and lower bone resorption with abaloparatide use compared to teriparatide therapy have also been questioned.…”

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

“…It is to emphasize that remodelling imbalance occurring around the ages of 45-50 years, produce irreversible deficits in bone volume, microstructural deterioration and bone fragility. Starting an anti-resorptive therapy in late postmenopause doesn't reverse existing microstructural deterioration and doesn't abolish bone fragility [215]. Despite the concern emerging from the large, long-term RCT Women's Health Initiative (WHI) study about the safety of hormonal replacement treatment, post hoc subgroup analyses, stratifying women according to their age and time since menopause, have allowed to better understand the relationship between MHT and cardio-vascular risk.…”