The why and how of sequential and combination therapy in osteoporosis. A review of the current evidence

Abstract

It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.

Insights and implications of sexual dimorphism in osteoporosis

“… 119 , 462 Treatment sequence matters when sequential therapy is carried out with anabolic medications, such as PTH, teriparatide, and antiresorptive agents. 471 – 473 For instance, adding alendronate to the teriparatide treatment regimen was not shown to benefit male patients with osteoporosis. 474 Therefore, in sequential therapy for sex-specific populations, including postmenopausal osteoporosis in women and GC-induced osteoporosis in men and women who are at a very high risk of fractures, anabolic medications are recommended to be used first for a short time to improve BMD and bone strength by boosting bone formation, followed by the long-term use of antiresorptive drugs.…”

Asia-Pacific consensus on long-term and sequential therapy for osteoporosis

“…The specialists attending the consensus meeting highlighted the concept that long-term and sequential therapy are essential strategies for primary and secondary fracture prevention [ 14 , 15 ]. Therefore, developing a strategy for prolonged periods of time and sequential therapy for osteoporotic medication treatment that is both effective and safe is mandatory [ [8] , [9] , [10] ].…”

“…Recognizing the significance of long-term and sequential therapy [ [8] , [9] , [10] ], the Taiwanese Osteoporosis Association (TOA) organized the “Asia-Pacific Consensus Meeting on Long-term and Sequential Therapy for Osteoporosis” in Taiwan on October 12 and 13, 2023. Endorsed by the Asian Federation of Osteoporosis Societies (AFOS), the conference convened AP experts to assess and refine strategies for preventing fragility fractures.…”

Sex differences in musculoskeletal injury and disease risks across the lifespan: Are there unique subsets of females at higher risk than males for these conditions at distinct stages of the life cycle?

“…However, this treatment option is now being revisited. In light of such reluctance regarding use of HRT, a number of other options have been developed including bisphosphonates, monoclonal antibodies against proteins involved in bone cell function, vitamin D, and anabolic peptides such as parathyroid hormone fragment and calcitonin ( Zhou et al, 2014 ; Mulder et al, 2016 ; Chandran, 2022 ; Lim, 2022 ; Zhu and March 2022 ). Such interventions vary in effectiveness and side-effects, and thus, many patients are now using those with lower risks.…”