Combination antiresorptive and osteoanabolic therapy for osteoporosis: We are not there yet

Abstract

Osteoanabolic therapy is theoretically and practically an appealing therapeutic option for men and postmenopausal women with osteoporosis because bone formation is directly stimulated, an action that is not shared by any antiresorptive agent. Parathyroid hormone (PTH), in the form of the full-length molecule (PTH[1-84]) and its fully active but truncated amino-terminal fragment teriparatide (PTH[1-34]), belong to this osteoanabolic class. Both formulations of PTH increase bone mineral density, increase biochemical markers of bone turnover, and reduce fracture incidence. They improve skeletal microstructure. While antiresorptive agents are considered by most to be first line for the treatment of osteoporosis, there are situations when anabolic therapy could be reasonably considered as first line. In most situations, however, treatment with PTH follows a course of antiresorptive therapy. Simultaneous combination therapy with PTH and an antiresorptive drug does not appear to provide any advantages over monotherapy. After the recommended 2-year period of PTH treatment, an antiresorptive should be used to maintain densitometric gains. The drugs are well tolerated. Early safety concerns about osteosarcoma in rats have not been borne out after almost 9 years experience with human subjects.

Key words::

• Alendronate
• Osteoporosis
• PTH(1-84)
• Risedronate
• Sequential therapy
• Teriparatide

In the June 2011 issue of Current Medical Research and Opinion, Boonen et al.1 review the use of anabolic therapy for osteoporosis focusing upon how antiresorptive agents could be used before, during, and after treatment with parathyroid hormone (PTH). PTH(1-84) and its fully active, foreshortened variant, teriparatide (PTH[1-34]), represent the only available anabolic treatments for osteoporosis at this time. In contrast to antiresorptive therapies, which are the mainstay of osteoporotic treatment, these osteoanabolic agents directly stimulate bone formation, and improve both bone mass and skeletal microarchitecture. PTH increases bone mineral density (BMD) at the lumbar spine, a site rich in cancellous bone, with more modest increases in the hip region. The early effect of PTH is an initial rapid increase in biochemical markers of bone formation that is subsequently followed by an increase in biochemical markers of bone resorption. The pharmacokinetics of this effect suggests that PTH can initially stimulate processes associated with bone formation without concomitant stimulation of bone resorption. By dynamic histomorphometry, bone biopsies from subjects treated with teriparatide have confirmed that bone formation occurs first in a manner that suggests a modeling mechanism2. Bone modeling is not usually seen in the mature human skeleton but rather is a characteristic of the growing skeleton. Subsequently, bone remodeling is stimulated, signaled by increases in bone resorption markers. The increase in bone turnover, however, continues to favor bone accrual, at least for a finite period of time. The concept of the ‘anabolic window’ explains the period of time when PTH directly stimulates bone formation before bone remodeling is stimulated3. The ‘anabolic window’ extends to the period when bone turnover is stimulated as long as bone formation exceeds bone resorption. Thereafter, the effect of PTH on these skeletal dynamics appears to be mitigated with bone turnover falling towards, or frankly to, baseline levels. Generally, the stimulation of bone modeling, approximately 30% of the overall anabolic effect, and remodeling, accounting for approximately 70% of the anabolic effect, begin to wane after 2 years. The 2-year approval period of PTH(1-84) and teriparatide is consistent with these modeling and remodeling dynamics. The indication for teriparatide in Europe and the United States is for the treatment of advanced osteoporosis in men and postmenopausal women at high risk for fracture. It is also approved for the treatment of glucocorticoid-induced osteoporosis. In Europe, but not in the United States, PTH(1-84) is approved for the treatment of postmenopausal osteoporosis.

Given that the structural basis for osteoporosis is deteriorated skeletal microstructure and that anabolic therapy helps to restore this fundamental deficit, one could reasonably ask why anabolic therapy is not routinely used as first line treatment for osteoporosis. If skeletal microarchitecture is improved with a drug like teriparatide or PTH(1-84), it would seem logical to initiate therapy in this manner and to follow such therapy with an antiresorptive agent. The antiresorptive drug would maintain gains achieved by the anabolic approach but would not itself have such an effect. This logic is indeed implemented after a course of teriparatide or PTH(1-84), but it is not often employed at the outset, namely in severely osteoporotic individuals who have not been treated previously with an approved drug. The reasons for this are several-fold. First, anabolic therapy is given by daily subcutaneous injection, not exactly an ideal route or frequency of administration. Second, the drugs are very expensive. Third, some of the antiresorptive drugs that were studied in clinical trials such as alendronate4 and risedronate5 also enrolled very severely osteoporotic individuals and were shown to be efficacious. Fourth, despite the dramatic microstructural improvements with anabolic therapy, there have been no head-to-head studies demonstrating clear superiority of anabolic therapy over antiresorptive therapy, when fracture is considered as an endpoint. An exception to this statement is the work of Saag et al., who compared teriparatide to alendronate in glucocorticoid-induced osteoporosis6,7. Saag et al. demonstrated the superiority of teriparatide over alendronate in protecting against vertebral fractures in glucocorticoid-induced osteoporosis over a 3-year period of time.

For these reasons, most patients who are going to be treated with either teriparatide or PTH(1-84) have previously been treated with a bisphosphonate or other antiresorptive agent. A relevant question, therefore, is whether the previous use of an antiresorptive agent may influence the subsequent response to the anabolic agent. As reviewed by Boonen et al.1, the potency of the antiresorptive drug tends to determine whether or not there will be a delay in responsiveness to teriparatide. The study by Ettinger et al.8 gave support to this idea when they showed that previous treatment with alendronate was associated with a delay in responsiveness to teriparatide while raloxifene, a drug with less potent antiresorptive properties, permitted more rapid responsiveness to teriparatide. The Optamise trial9 appeared to support this concept further by studying subjects who had been treated for two or more years with risedronate or alendronate, followed by teriparatide alone. At baseline, prior to teriparatide therapy, bone turnover markers were higher in the risedronate group than the alendronate group and, as expected, subjects previously treated with risedronate responded more quickly and to a greater extent to teriparatide than those who had previously been treated with alendronate9. The surprise of this study was that the results could not be explained by the smaller effect of risedronate than alendronate to reduce bone turnover markers. Boonen et al.1 discuss differences in physical properties and pharmacokinetics of the bisphosphonates. These concepts may be more relevant to the actions of antiresorptive therapy to be permissive or not when anabolic therapy is initiated than the effect of bisphosphonates on bone turnover per se.

What is the bottom line here? It is that regardless of prior antiresorptive therapy and whether or not there is a delay in responsiveness, bone turnover markers and BMD will increase with teriparatide or PTH(1-84) therapy. The short delay, in some cases, is immaterial to the eventual major anabolic effect of teriparatide and PTH(1-84) on bone. Thus, there is no general recommendation for a waiting period before teriparatide or PTH(1-84) is begun after a course of bisphosphonate or other antiresorptive therapy. It should be noted that this recommendation is based upon bone turnover and densitometric data because there are no fracture data with which to address this issue.

Boonen et al.1 also discuss simultaneous combination therapy with anabolic and antiresorptive drugs. Despite many attempts to show an advantage to combination therapy, most studies have shown that monotherapy is as good, if not better than, combination therapy. The PaTH study was pivotal in this regard10. When PTH(1-84) was used alone or in combination with alendronate, the increase in BMD, as determined by dual-energy x-ray absorptiometry or by quantitative computed tomography, was greater with PTH(1-84) alone than with combination therapy. Bone turnover markers in the combination therapy arm tracked along the suppression curve described by the alendronate-only arm, suggesting that alendronate was ‘trumping’ the effect of PTH(1-84) to stimulate bone formation10–12. Using a less potent antiresorptive, Deal et al.13 showed that the combination of raloxifene and teriparatide did result in an advantage in terms of bone turnover markers and hip bone mineral density. More recently, Cosman et al.14 used a single intravenous dose of zoledronic acid in combination with daily teriparatide. There was a greater increase in BMD at 6 months at the spine and hip when the combination arm was compared to either zoledronic acid or teriparatide alone. By 12 months, however, these differences were much less apparent. Although data will not be available at a 2-year time point, because the study was discontinued, the slope of the curves suggests that the early advantage of combination therapy may well be lost by that time. There is no information available on the effects of denosumab, a new antiresorptive agent, in combination with teriparatide.

Bone density at the lumbar spine and hip falls precipitously in both men and women when teriparatide is not followed by an antiresorptive agent15,16. Gains in BMD are maintained in subjects treated with antiresorptive therapy after PTH15–17. The results of these and other studies establish the importance of maintenance treatment with an antiresorptive following the recommended 2-year course of teriparatide therapy, despite the lack of fracture outcome data.

PTH therapy is well tolerated for the recommended 2-year treatment period. In animal toxicity studies, male and female rats treated with teriparatide or PTH(1-84) at doses that were 3–58 times the equivalent dose to human subjects for 75 years of equivalent human time develop osteosarcoma18. The results are consistent with exposure of an anabolic agent to an animal that is always growing and has little in the way of a remodeling system. Such uncontrolled, exuberant effects in rats are not seen in the human skeleton. Eventually, in human subjects, the remodeling system takes over after exposure to teriparatide or PTH(1-84) limiting the extent to which PTH can stimulate bone formation exclusively. Clinical experience with teriparatide extends to almost 9 years. The number of reported cases of osteosarcoma in human subjects treated with teriparatide does not even reach the level that one would expect on the basis of the epidemiology of osteosarcoma in the adult human population19,20. While one always wants to be vigilant with regard to such a serious toxicity, the data so far do not support a relationship between PTH and osteosarcoma in human subjects.

PTH therapy is a powerful tool in our therapeutic armamentarium for the treatment of osteoporosis. The review by Boonen et al.1 highlights key clinical questions regarding the best course for patients with osteoporosis that are candidates for anabolic treatment.

Transparency

Declaration of financial/other relationships

J.P.B is a consultant for Eli Lilly, NPS Pharmaceuticals, Merck, Warner-Chilcott, GSK, Novartis, and Amgen, and receives research support from NPS Pharmaceuticals and GSK. N.E.C. has disclosed that she has no significant relationships with or financial interests in any commercial companies related to this study or article.