Menopause Live - IMS Updates

Date of release: 16 February, 2015

Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches

In the recent BoneKEy Reports review [1], it was noted that combinations of anabolic and antiresorptive agents have potential to improve bone density and bone strength more than either agent as monotherapy. Small clinical trials have been performed evaluating combinations of parathyroid hormone (PTH) – PTH 1-34 (teriparatide) or PTH 1-84 – with a variety of antiresorptives including hormone/estrogen therapy, raloxifene, alendronate, risedronate, ibandronate, zoledronic acid, and denosumab. Most of the studies evaluate dual-energy X-ray absorptiometry outcomes, and a few trials report bone mineral density (BMD) by quantitative computed tomography, followed by finite element modeling to calculate bone strength. None of the studies has been powered to assess differences in fracture incidence between combination therapy and monotherapy. BMD outcomes vary based on the timing of introduction of the anabolic agent (before, during, or after antiresorptive treatment), as well as the specific anabolic and antiresorptive used. Furthermore, effects of combination therapies are site-dependent. The most consistent effect of combining antiresorptive agents with PTH 1-84 or teriparatide is a superior hip BMD outcome compared with teriparatide/PTH 1-84 alone. This is most evident when teriparatide/PTH 1-84 is combined with a bisphosphonate or denosumab. In contrast to findings in the hip, in the majority of studies, there is no benefit to spine BMD with combination therapy vs. monotherapy. The two exceptions to this are when teriparatide is combined with denosumab and when teriparatide is given as monotherapy first for 9 months, followed by the addition of alendronate (with continuation administration of teriparatide). Based on what we now know, in patients previously treated with bisphosphonates who suffer hip fractures or who have very low or declining hip BMD, strong consideration should be given to starting teriparatide and continuing a potent antiresorptive agent (possibly switching to zoledronic acid or denosumab) to improve hip BMD and strength quickly. Furthermore, in treatment-naïve individuals with very severe osteoporosis, such as those with spine and hip fractures, combination therapy with teriparatide and denosumab or teriparatide followed by combination treatment with a potent bisphosphonate or denosumab should be considered to maximize early increases in BMD throughout the skeleton.


The concept of anabolic treatment for osteoporosis is based on directly stimulating bone formation, in order to increase not only bone density and strength but also to reduce osteoporotic fractures. This agent is parathyroid hormone (PTH) in its two presentations: the fraction 1-34 or teriparatide and the intact molecule PTH 1-84 [2, 3]. Therefore its bone-forming effect can be used as monotherapy or in combination therapy according to the characteristics of the patients, especially those who do not respond to other kinds of drugs. 
Clinical trials have shown how the combination of anabolics and antiresorptives can improve the density and quality of bone even more than monotherapy [4], and effects are now documented that occur in bone in patients with naïve treatment or in those who were already receiving another type of management.
The use of teriparatide in patients previously or currently managed with hormone replacement therapy or raloxifene provided additional effects on BMD in both hips (up by 16%) and spine (an increase of 6%), showing an additive effect [5].
When we refer to combination therapy with bisphosphonates, there are different results according to which agent is being used. PTH in combination therapy with alendronate or zoledronic acid shows no increase in spine BMD greater than that observed with monotherapy with teriparatide/PTH 1-84 [6] (PTH 6.3% vs. PTH + alendronate 6.1%) but shows a more consistent increase in hip BMD than monotherapy (teriparatide + zoledronic acid 2.2% vs. teriparatide monotherapy 1.1%) [7]. Studies show that ibandronate use for 18 months in combination therapy with PTH increases not only BMD but also bone formation markers.
During the first year of therapy, the combination of teriparatide with denosumab showed a greater increase in BMD at the spine, hip and femoral neck (9.1%, 4.9%, 4.2%, respectively) than with teriparatide monotherapy (6.2%, 0.7%, 0.8%), or denosumab monotherapy (5.5%, 2.5%, 2.1%). However, there were no group differences in the magnitude of these increments in the second year with the combination of teriparatide with denosumab vs. monotherapy.
There was no statistical significance in BMD increases when compared with the combined therapy of teriparatide + zoledronic acid [8].
Patients being treated for osteoporosis with any other therapy and in whom teriparatide treatment is initiated in addition have shown a rapid increase in bone formation markers and a decrease in bone resorption markers. This is called the anabolic window and represents the greatest opportunity for bone formation [9, 10].
It is important to note that approximately 50% of treatments with teriparatide or PTH 1-84 are initiated in patients who are already using antiresorptives and independently of whether they are used as monotherapy [11, 12] or combined therapy [13, 14]; it should be noted that in some patients such as the non-responders, anabolic therapy is an option to increase BMD.
In conclusion, this is a type of treatment for osteoporosis that is based on a powerful bone-forming effect and should be considered as an option at the time of patient management. Its use either alone or in combination with other drugs will be a possibly common strategy for management of osteoporosis [2].

Andrea Mejia

Santiago Palacios
Palacios Institute of Womens Health, Madrid, Spain


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