Treatment of postmenopausal osteoporosis with bone-forming and antiresorptive treatments: Combined and sequential approaches

Highlights

• The antiresorptive, bone-forming and dual-action treatments available

• A long-term, individualized management plan

• Treatment target and treatment failure

• Combination therapy; bone-forming treatment in combination with antiresorptive treatment

• Sequential treatment; antiresorptive or bone-forming treatment after other treatment modalities

Abstract

Efficient therapies are available for the treatment of osteoporosis. Bisphosphonates and denosumab are the most commonly used antiresorptive therapies. Despite differences in the increase in bone mineral density seen with these drugs, the reductions in fracture risk are similar; 50–70%, 20%, and 40% for vertebral, non-vertebral and hip fractures, respectively. The bone-forming treatments; teriparatide and abaloparatide increase bone mineral density more than the antiresorptives and the reductions in fracture risk are 85% and 40–50% for vertebral and non-vertebral fractures, respectively, compared to placebo. The VERO study demonstrated a >50% reduction in vertebral and clinical fractures in women treated with teriparatide compared to risedronate. The dual-action treatment; romosozumab leads to more pronounced increases in BMD than other treatment modalities and reduces the risk of vertebral and clinical fractures by 73% and 36% compared to placebo after 12 months and the sequential treatment regime; romosozumab for 12 months followed by alendronate reduced the risk of vertebral, non-vertebral and hip fractures by 48%, 20% and 38%, respectively compared to alendronate after 2–3 years.

The evidence for combination therapy targeting both resorption and formation is limited as only short-term studies with BMD as the endpoint have been performed.

All bone-forming and dual-action treatments increase BMD and reduce the fracture risk, however, the effect wears off with time and treatment is therefore only temporary and should be followed by antiresorptive treatment with a bisphosphonate or denosumab. The sequence of treatment matters as the BMD response to teriparatide is reduced in patients previously treated with bisphosphonates; however, based on the findings of the VERO trial, the anti-fracture efficacy of bone-forming treatment in comparison with risedronate seems to be preserved after bisphosphonate therapy. The DATA study suggested that transitioning from denosumab to teriparatide is problematic due to the increase in bone resorption occurring after stopping denosumab. Studies have shown further improvements in BMD when transitioning from oral bisphosphonates to zoledronic acid or denosumab.

Management of osteoporosis will in many patients include a long-term treatment plan. This will often include sequential therapy which in severe cases preferably should start with bone-forming followed by antiresorptive treatment. The severity of osteoporosis, reaching a treatment goal, and responding to treatment failure are important factors determining the treatment sequence in the individual patient.

Introduction

The treatment options for osteoporosis fall into three categories; antiresorptive, bone-forming and dual-action treatments. Antiresorptive treatments comprise bisphosphonates, denosumab, selective estrogen receptor modulators (SERMs), and estrogen. Teriparatide and abaloparatide constitutes the bone-forming treatments and romosozumab is currently the only dual-action treatment available.

All of these treatments are approved for use as single interventions, sufficient intake of calcium and vitamin D should be secured, but this is usually not considered combination therapy. Why should sequential treatment and even combination treatment be considered? There are several reasons. First of all, many patients with osteoporosis have a long life a head of them after being diagnosed and they therefore need a long-term management plan for osteoporosis. This may include treatment with only one drug; however, in many cases more treatment options need to be considered. Secondly, some patients experience treatment failure in the form of multiple fractures or loss of BMD despite ongoing treatment. In these patients the treatment plan should be revisited and sometimes revised including change of treatment. Third, more and more evidence is being generated pointing towards a treatment target for patients with osteoporosis. Currently it seems that the most likely target will be based on BMD as a meta-analysis of phase 3 clinical trials as well as analyses based on individual data from the same clinical trials found that the most important predictor of treatment mediated fracture risk reduction is the increase in BMD (FNIH Bone Quality Project) [1,2]. Based on analyses from the FREEDOM trial a suggestive target could be hip BMD T-score of −1.5 or −1 [3]. Once this target is reached it will be time to revisit the treatment plan and consider changing treatment or discontinuing treatment.

For the treatment plan to be effective it has to be personalized. This means the patient should be characterized with respect to gender, age, lifestyle, comorbidities and pharmacological treatments for these comorbidities as all of these factors will influence the future fracture risk of the patient. In addition, the evidence for efficacy of the different treatments across these patient characteristics may vary considerably and that may affect the treatment plan and the choice of treatment. Next, the disease should be characterized. It will be important to know about BMD and previous fractures; vertebral fractures and non-vertebral fractures, especially hip fractures and also how recent the fractures are as this information will affect the future risk of fractures substantially [4]. It will also be important to evaluate if osteoporosis is secondary to other diseases or conditions and if these conditions can be modified. In some patients, bone turnover, evaluated by bone turnover markers or bone biopsies, will be important for the treatment plan and especially the choice of initial treatment.

Once the patient and the disease are thoroughly characterized the treatment plan can be developed and the initial treatment can be decided. This can be an antiresorptive, a bone-forming or a dual-action treatment.