LAUSR

Combining anabolic therapy, which increases bone formation, with antiresorptive therapies offers hope to increase bone strength and reduce fracture risk more than monotherapy with either type of agent. The study by Cosman and colleagues adds to the rapidly expanding literature on optimizing anabolic therapy. The study compared two different methods of combining denosumab (DMAB) with teriparatide (TPTD) over 36 months: as 3 cycles of 12 months (6 months of TPTD, then 6 months of DMAB) versus 18 months of TPTD followed by 18 months of DMAB. The two regimens increased bone mineral density (BMD) similarly over 3 years at the hip, distal radius, and in the total body, although the increases in the spine over 36 months with the 18/18 regimen were somewhat lower than with the cyclic combination. At 18 months, there was a suggestion of a larger increase at sites with more cortical bone but no difference at cortical sites by 24 months. The authors suggested that if there is a choice between these two specific treatment combinations, the 6-month cycles might be preferred for patients at high short-term risk of fracture at cortical rich sites. Although this study was too small for fracture assessment, recent work suggests that there is a quantitative relationship between larger BMD increases in studies and larger fracture reductions. This study adds to the recent acceleration of research with combination anabolic/antiresorptive therapy showing that impressive gains in bone density are possible. The present study showed the “standard” regimen (18 months of TPTD followed by 18 months of DMAB) resulted in a 3-year BMD gain of 4% at total hip and 16% at the spine. Gains from other anabolic/antiresorptive combinations have been even larger, particularly at the hip. For example, a recent study of 1 year of romosozumab followed by 2 years of alendronate increased total hip BMD by about 7% and lumbar spine BMD by 15%. Romosozumab for 1 year followed by 1 year of DMAB increased total hip BMD by 8.8% and spine BMD over 17%. An 18-month course of abaloparatide, followed by 24 months of alendronate increased total hip BMD by about 6% and spine BMDby about 15%. These large studies, including active (rather than placebo) controls also showed commensurate fracture reductions. A small BMD-only endpoint study with 69 patients studying the concurrent combination of TPTD and DMAB over 15 months showed an increase of 17.5% at the spine and 6.8% in the femoral neck with a 40 mcg dose of TPTD (twice the approved dose). The most potent antiresorptive therapies (eg, DMAB, zoledronic acid), used as monotherapy, increase total hip BMD over 3 years by about 6% and lumbar spine BMD by 7% to 9%. Therefore, gains at the hip for combination therapies are similar or only slightly larger than the most potent antiresorptive, but gains at the spine are much higher with anabolic combinations than can be achieved with monotherapy with antiresorptive drugs. The results are encouraging in showing that at the spine over 2 to 4 years it is possible to achieve much larger increases in BMDwith combination therapy than can be achieved with any current monotherapy and suggest that it may soon be possible to “treat to target BMD.” Clinicians embarking on any nonbisphosphonate therapy program must be vigilant in planning for long-term treatment. Cessation of all other osteoporosis pharmacotherapies including anabolic agents (TPTD as well as abaloparatide and romozumab), DMAB, selective estrogen receptor modulators (SERMS), and estrogen is associated with rapid loss of BMD and of other benefits. For anabolic agents, several studies have shown that full loss of benefits occurs within 1 to 2 years of cessation. Use of alendronate after cessation of anabolic agents can retain and even enhance these benefits and is routinely used. The present study and others have shown that DMAB can also enhance benefits after anabolic therapy. A rapid loss of benefits after DMAB treatment is also well known, including a rapid rise in bone resorption, above pretreatment levels. In addition, there may be an increase in multiple and severe vertebral fracture risk within months after missing a DMAB injection. Bisphosphonates after DMAB could be effective in maintaining benefits, but evidence is limited. One study suggested that alendronate after 1 year of DMAB might be effective in maintaining BMD. However, effectiveness and optimal timing of alendronate after longer courses of DMAB is unknown. Oral risedronate was only partially effective at preventing bone loss after 7 years of DMAB therapy. Zoledronic acid also can potentially maintain bone density after DMAB, but the effectiveness of a single dose of zoledronic acid given 6 months after the last denosumab dose may depend on the duration of prior DMAB. In one study, a single dose of zoledronic acid was less effective at maintaining bone density after longer durations of treatment than after shorter durations of treatment. Delaying the zoledronic acid dose appears to preserve a larger amount of bone density, but the benefit of delaying bisphosphonate therapy has to be weighed against a possible increased risk of multiple vertebral fractures during the untreated time frame. More research is needed into the optimal approach to treatment after DMAB discontinuation and whether approaches such as monitoring bone turnover