Introduction Low trauma fractures due to osteoporosis are a major health concern worldwide. Despite the availability of many therapeutic compounds to reduce fracture risk, osteoporosis remains undertreated and the burden of osteoporotic fractures remains high. Denosumab is a novel agent that acts to reduce bone turnover, improve bone mineral density, and reduce fracture risk, offering a favorable efficacy and safety profile. Areas covered This review covers the pharmacology and major clinical trials with extension/post-marketing follow-up, including trials for all FDA-approved indications of denosumab to date. Expert Opinion Denosumab is an efficacious and safe osteoporosis treatment option, with current data up to 8 years of continued use showing continued improvement in bone density with sustained fracture risk reduction. Safety profiles overall are similar to placebo, with no new safety concerns in extension trials, though a theoretical increased risk of infection exists with RANKL inhibition. Future considerations include safety of prolonged treatment beyond 8 years, and efficacy/fracture risk after discontinuation or with non-adherence, given the characteristic pharmacodynamic profile of denosumab.

Thiazide diuretic (TZ) use is associated with higher bone mineral density, whereas loop diuretic (LD) use is associated with lower bone density and incident fracture. Dihydropyridine-sensitive calcium channels are expressed on parathyroid cells and may play a role in parathyroid hormone (PTH) regulation. The potential for diuretics and calcium-channel blockers (CCBs) to modulate PTH and calcium homeostasis may represent a mechanism by which they influence skeletal outcomes. We hypothesized that the use of LD and dihydropyridine CCBs is associated with higher PTH, and TZ use is associated with lower PTH. We conducted cross-sectional analyses of participants treated for hypertension in the Multi-Ethnic Study of Atherosclerosis who did not have primary hyperparathyroidism or chronic kidney disease (n =1888). We used adjusted regression models to evaluate the independent association between TZ, LD, and CCB medication classes and PTH. TZ use was associated with lower PTH when compared with non-TZ use (44.4 versus 46.9 pg/mL, p =0.02), whereas the use of LD and CCBs was associated with higher PTH when compared with non-users of each medication class (LD: 60.7 versus 45.5 pg/mL, p <0.0001; CCB: 49.5 versus. 44.4 pg/mL, p <0.0001). Adjusted regression models confirmed independent associations between TZ use and lower PTH (β =−3.2 pg/mL, p =0.0007), and LD or CCB use and higher PTH (LD: β =+12.0 pg/mL, p <0.0001; CCB: +3.7 pg/mL, p <0.0001). Among CCB users, the use of dihydropyridines was independently associated with higher PTH (β =+5.0 pg/mL, p <0.0001), whereas non-dihydropyridine use was not (β =+0.58 pg/mL, p =0.68). We conclude that in a large community-based cohort with normal kidney function, TZ use is associated with lower PTH, whereas LD and dihydropyridine CCB use is associated with higher PTH. These associations may provide a mechanistic explanation linking use of these medications to the development of skeletal outcomes.

In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health.