Abstract
Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently increased our options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving bone qualities as well as increasing bone mass. The anabolic agent currently approved for osteoporosis, teriparatide (recombinant human parathyroid hormone[1–34]), has emerged as a major approach for selected patients with osteoporosis. Parathyroid hormone(1–84) is also available in Europe. Teriparatide increases bone density and bone turnover, improves microarchitecture and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. A current concept in the mechanism of teriparatide action is related to its effect of stimulating processes associated with bone formation before processes associated with bone resorption. This sequence of events has led to the concept of the anabolic window, the period of time when teriparatide is maximally anabolic. Newer approaches to the use of teriparatide alone and in combination with antiresorptive agents has led to ways in which the anabolic window can be expanded.
Keywords
Until recently, antiresorptive agents were the exclusive pharmacological approach to osteoporosis. With the introduction of teriparatide, parathyroid hormone (PTH)(1–34), and, more recently, PTH(1–84) as treatments for osteoporosis, anabolic skeletal therapy is now available. By stimulating bone formation to a greater extent and earlier than bone resorption, PTH(1–34) and the full-length molecule, PTH(1–84), positively affect a number of skeletal properties besides bone density. These include bone size and microarchitecture. They thus have the potential to reconstruct the skeleton, an end point not shared by any of the antiresorptives [1]. Further work has provided new insights into how antiresorptive agents and PTH can be used in sequence or in combination for maximal skeletal benefits.
Parathyroid hormone as an anabolic agent
In primary hyperparathyroidism (PHPT), a disorder of chronic, continuous secretion of excess PTH, catabolic effects primarily at cortical sites, such as the distal 1/3 radius, are common. Nevertheless, even in this disorder of chronic PTH secretion, salutary effects at the cancellous skeleton, such as the lumbar spine, can be seen [2]. The clinical clue to the utility of PTH as an anabolic skeletal agent came with the recognition that its anabolic potential is seen much more clearly with low-dose, intermittent administration. PTH is currently available in many countries as the recombinant human PTH(1–34) fragment, known as teriparatide. The full-length molecule, human recombinant PTH(1–84), has been approved for use in some European countries and is currently under investigation in the USA. Teriparatide leads to a rapid increase in bone formation markers, followed sometime thereafter by increases in bone resorption markers. If these markers reflect physiological events, PTH may initially stimulate processes associated with bone formation (bone modeling) and only later promote those associated with bone remodeling, in which bone resorption predominates. This sequence of events has led to the concept of the ‘anabolic window’, a period of time when the actions of PTH are maximally anabolic [3] (Figure 1).
The anabolic window.
The beneficial effects of teriparatide on bone qualities such as bone density, microarchitecture and bone geometry are seen in the cancellous skeleton [4]. At a cortical skeletal site, such as the distal 1/3 radius, PTH typically does not increase bone density. In fact, there may be a small decline in bone mineral density (BMD) in association with an increase in cortical porosity. However, this does not translate into decreased bone strength because the increased porosity occurs only in the inner third of bone, where the mechanical effect is minimal. Even more importantly, other positive effects of teriparatide at cortical bone, such as changes in bone geometry and microarchitecture, adequately compensate for any increase in cortical porosity [5]. PTH stimulates periosteal apposition, which leads to increases in cortical area and cortical thickness, and an overall increase in cross-sectional area [5–6]. Moreover, microarchitectural changes due to teriparatide are also evident at cortical sites such as the distal 1/3 radius. These geometrical and microarchitectural changes strengthen cortical bone despite the small reduction in bone density [7].
Indications for teriparatide
Teriparatide is used in postmenopausal women and men with osteoporosis who are at high risk for fracture. In Europe, teriparatide and PTH(1–84) are approved for use only in post-menopausal women. To help select patients for teriparatide, useful guidelines have been published [1]. Patients who have already sustained an osteoporotic fracture are among the highest-risk group, as the likelihood of sustaining another fracture is very high [8]. In many countries, in fact, a previous osteoporotic fracture is a requirement for coverage with teriparatide. However, the T-score itself, even without an osteoporotic fracture, can confer high risk, especially if the T-score is very low (i.e., <−3.0). The age of the patient is also important, as it confers greater risk for any given T-score. A 75-year-old woman with a T-score of −2.5 is at greater risk of a fracture than a 55-year-old women with the same T-score. Other potential candidates for teriparatide are patients for whom one might consider a bisphosphonate but who cannot tolerate the drug. In addition, patients who fracture while on antiresorptive therapy could be considered to be at high risk and, thus, candidates for teriparatide. In most countries, teriparatide is approved for a limited period of time (18–24 months).
Teriparatide as single therapy in postmenopausal osteoporosis
In the randomized, double-blind, pivotal clinical trial of Neer and colleagues, women with severe osteoporosis were treated with subcutaneous injections of placebo, or 20 or 40 μg of teriparatide. The average number of fragility fractures per patient was more than two, clearly defining this group as at high risk. [9]. Over a follow-up period of 21 months, BMD increased by an average of 10–14%. Total hip BMD also improved, but more slowly and to a smaller extent (approximately 3%) in comparison with the lumbar spine. At 20 μg of teriparatide, BMD did not change at the distal radius (Figure 2). The most important findings of the teriparatide trial by Neer and colleagues were significant reductions in new vertebral and nonvertebral fractures (Figure 3). This drug is also associated with dramatic improvements in microarchitectural features of bone (Figure 4). By post hoc analysis, the reduction in fracture incidence due to teriparatide was not related to the number, severity or site of previous fractures [10]. Further post hoc analysis of this cohort demonstrated that the fracture-risk reduction was largely independent of age and initial BMD [11]. In an observational cohort from this trial, fracture reduction was sustained for up to 30 months after teriparatide discontinuation, although many individuals in the original and treatment groups received bisphosphonate therapy during this follow-up period [12].
The effect of teriparatide on bone density.
Fracture incidence after treatment with teriparatide.
Microarchitectural changes with teriparatide.
Parathyroid hormone(1–84) in postmenopausal osteoporosis
PTH(1–84), registered in Europe, has been studied less intensively than teriparatide. In a preliminary clinical trial, preparatory to the definitive clinical trial, subjects were administered placebo, or one of three doses of PTH(1–84) (50, 75 or 100 μg) for 12 months [13]. There were time- and dose-related increases in lumbar spine BMD. Similar to the teriparatide studies, bone turnover markers rose quickly. Histomorphometric analysis of bone biopsy specimens confirmed an anabolic response to PTH(1–84), with an increase in bone formation and improvements in cancellous architecture [14]. In contrast to the study by Neer and colleagues, in which the average number of fragility fractures per study subject was greater than two, the incidence of baseline fragility fractures in the Phase III PTH(1–84) study was only 19%. Nevertheless, a reduction in new vertebral fracture incidence was seen with PTH(1–84) in women both with and without prior vertebral fractures [15]. A reduction in nonvertebral fractures was not demonstrated.
Teriparatide in men with osteoporosis
In the first randomized, double-blinded, controlled trial of teriparatide in men, Kurland and colleagues studied 23 men with 400 U/day of teriparatide (equivalent to 25 μg/day) or placebo for 18 months [16]. The men who received teriparatide demonstrated an impressive 13.5% increase in lumbar spine bone density. Hip BMD increased significantly but more slowly, and to a smaller extent, in comparison with the lumbar spine. Cortical bone density at the distal radius did not change as compared with placebo. Bone turnover markers rose quickly and substantially in the men treated with teriparatide, with bone formation markers rising and peaking earlier than bone resorption markers. In a larger trial of 437 men that was the counterpart of the pivotal trial of Neer and colleagues in postmenopausal women, Orwoll and colleagues followed a protocol that was essentially identical to the study of Neer and colleagues [17]. BMD increased significantly in the 20 μg treatment group, by 5.9% at the lumbar spine and by 1.5% at the femoral neck. These increases were independent of gonadal status. Although fractures could not be assessed during the short 11-month trial, they were assessed in a follow-up observational period of 30 months. A total of 279 men from the original cohort had lateral thoracic and lumbar spine x-rays 18 months after treatment was stopped. In the combined teriparatide treatment groups (20 and 40 μg), the risk of vertebral fracture was reduced by 51% (p = 0.07). Significant reductions were seen in the combined group compared with placebo when only moderate or severe fractures were considered (6.8 vs 1.1%; p < 0.02) [18]. As was the case in the observational follow-up period in postmenopausal women, a substantial number of male study subjects in all groups (25–30%) reported use of antiresorptive therapy during the follow-up period. Men treated with placebo utilized antiresorptive therapy to a greater extent than those who were treated with either dose of teriparatide (36 vs 25%).
Sequential & combination therapy with teriparatide & an antiresorptive agent
Previous use of an antiresorptive
Many patients who are considered candidates for teriparatide have previously been treated with bisphosphonates or other antiresorptives. Cosman and colleagues treated postmenopausal women, previously given estrogen for at least 1 year, with teriparatide [19]. Increases in vertebral BMD began with no delay and increased in a linear fashion during the entire 3-year study. Ettinger and colleagues studied the influence of raloxifene or alendronate prior to treatment with teriparatide [20]. A total of 59 postmenopausal women with T-scores of −2.0 or less had been treated for an average of 28 months with either raloxifene or alendronate. In most respects, subjects were well matched in terms of age, body mass index and T-scores. Similar to the study of Lindsay and colleagues for estrogen, raloxifene did not impede the ability of teriparatide to increase BMD rapidly and linearly. By contrast, alendronate was associated with a 6-month delay before BMD in the lumbar spine began to increase. After 18 months, lumbar spine BMD increased by 10.2% in the prior raloxifene-treated group compared with only 4.1% in the prior-alendronate treated subjects (p < 0.05). The alendronate-treated group showed an initial decline in hip BMD at 6 months, but at 18 months, mean total hip BMD was not different from baseline. During teriparatide treatment, bone markers in prior alendronate patients increased later, and peaked at approximately 1/3 lower levels compared with prior raloxifene-treated patients.
These results imply that the potency of the antiresorptive to control bone turnover can determine the early response to teriparatide. Cosman and colleagues have helped to refine this point in a study of teriparatide in postmenopausal women who had also previously received alendronate for the same period of time [21]. In contrast to the study of Ettinger and colleagues, their subjects responded to teriparatide with rapid increases in BMD. To account for these differences, it is noteworthy that the baseline bone turnover markers prior to the initiation of teriparatide therapy were markedly different in the two studies. In the study by Ettinger and colleagues, bone turnover markers were almost completely suppressed. By comparison, in the study of Cosman and colleagues, bone turnover markers were less suppressed and more in the range that one tends to find in subjects after alendronate therapy. Therefore, it is distinctly possible that it is not so much the specific antiresorptive used prior to teriparatide that dictates the subsequent densitometric response to teriparatide, but rather the extent to which bone turnover is reduced by the antiresorptive agent. To support this idea, the response to teriparatide has been shown to be a function of the level of baseline bone turnover in subjects not previously treated with any therapy for osteoporosis: the higher the level of turnover, the more robust the densitometric response to teriparatide [16].
Concurrent use of anabolic & antiresorptive therapy
It is attractive to consider combination therapy with an antiresorptive and PTH as potentially more beneficial than monotherapy, given that their mechanisms of action are quite different from each other. If bone resorption is being inhibited (antiresorptive) while bone formation is being stimulated (anabolic), combination therapy might give better results than with either agent alone. Despite the intuitive appeal of this reasoning, important data to the contrary have been provided by Black and colleagues [22] and Finkelstein and colleagues [23]. These two groups independently completed trials using a form of PTH alone, alendronate alone, or the combination of a PTH form and alendronate. Black and colleagues studied postmenopausal women with 100 μg of PTH(1–84). The study of Finkelstein and colleagues involved men treated with 40 μg of teriparatide. Both studies utilized dual-energy x-ray absorptiometry and quantitative computed tomography (QCT) to measure areal or volumetric BMD, respectively. With either measurement, monotherapy with PTH exceeded densitometric gains with combination therapy or alendronate alone at the lumbar spine. Measurement of trabecular bone by QCT, in fact, showed that combination therapy was associated with substantially smaller increases in BMD than monotherapy with PTH (Figure 5). Bone turnover markers followed the expected course for anabolic (increases) or antiresorptive (decreases) therapy alone. However, for combination therapy, bone markers followed the course of alendronate, not PTH, therapy, with reductions in bone formation and bone resorption markers. This suggests that the impaired response to combination therapy, in comparison with PTH alone, might be due to the dominating effects of the antiresorptive agent on bone dynamics when both drugs are used together. Since we do not have data referent to other aspects of bone quality, such as actual bone strength, it may be premature to reach the conclusion that combination therapy is necessarily not as good as, or even inferior to, monotherapy. In fact, recent data by Deal and colleagues argue that under certain circumstances, combination therapy can appear to be superior to monotherapy [24]. In a 6-month clinical trial, Deal and colleagues reported that the combination of teriparatide and raloxifene may have more beneficial effects than monotherapy with teriparatide in postmenopausal osteoporosis [24]. Bone formation markers increased similarly in both groups. Bone resorption markers, however, were reduced in the combination group. BMD increased to a similar extent in the lumbar spine and femoral neck in both groups, but the increase in total hip BMD was significantly greater in subjects treated with both teriparatide and raloxifene (Figure 6). The effect of raloxifene, a less potent antiresorptive than alendronate, appears to allow teriparatide to stimulate bone formation, unimpeded, but does impair the ability of teriparatide to stimulate bone resorption. These actions may, thus, expand the anabolic window beyond that seen with teriparatide alone.
The effect of combination therapy with parathyroid hormone(1–84) and alendronate on bone density of the lumbar spine.
The effect of combination therapy with teriparatide and raloxifene on indices of bone formation and bone resorption.
Consequences of discontinuing anabolic therapy with parathyroid hormone
Teriparatide is approved in most countries for a treatment period of 18–24 months. There are obvious concerns regarding the consequences of discontinuing therapy following this relatively short period of time. Some a priori concerns relate to the fact that new bone matrix is not fully mineralized following PTH therapy. Therefore, this new bone matrix could be at risk of resorption if a period of consolidation with an antiresorptive is not used [25].
Published data addressing this concern were initially based on observational trials [22]. These studies, using either bisphosphonate [12,26,27] or estrogen [28–29] therapy following PTH, suggested that antiresorptive treatment may be necessary to maintain densitometric gains achieved during PTH administration. With a stronger experimental design, the Parathyroid Hormone and Alendronate for Osteoporosis (PaTH) study provided prospective data in a rigorously controlled, blinded fashion to address this issue [30]. Postmenopausal women who had received PTH(1–84) for 12 months were randomly assigned to an additional 12 months of therapy with 10 mg/day of alendronate, or placebo. In subjects who received alendronate there was a further 4.9% gain in lumbar spine BMD, while those who received placebo experienced a substantial decline. By QCT analysis, the net increase over 24 months in lumbar spine BMD among those treated with alendronate after PTH(1–84) was 30%. In those who received placebo after PTH(1–84), the net change in bone density was only 13% (Figure 7). There were similar dramatic differences in hip BMD when those who followed PTH with alendronate were compared with those who were treated with placebo (13 vs 5%). The results of this study establish the importance of following PTH or teriparatide therapy with an antiresorptive.
Discontinuation of parathyroid hormone(1–84) therapy after 1 year.
Fracture efficacy was reported in the 30-month observational cohort following the trial of Neer and colleagues [12]. Subjects were given the option of switching to a bisphosphonate or not taking any further medications following teriparatide. A majority (60%) were treated with antiresorptive therapy after PTH discontinuation. Gains in bone density were maintained in those who chose to begin antiresorptive therapy immediately after teriparatide. Reductions in BMD were progressive throughout the 30-month observational period in subjects who elected not to follow teriparatide with any therapy. In a group who did not begin antiresorptive therapy until 6 months after teriparatide discontinuation, major reductions in BMD were seen during the first 6 months but no further reductions were observed after antiresorptive initiation [26]. Despite these densitometric data, the effect of previous therapy with teriparatide and/or subsequent therapy with a bisphosphonate on fracture prevention persisted for as long as 31 months after teriparatide discontinuation. Nonvertebral fragility fractures were reported by proportionately fewer women previously treated with PTH (with or without a bisphosphonate) compared with those treated with placebo (with or without a bisphosphonate) (p < 0.03). In a logistic regression model, bisphosphonate use for 12 months or longer was said to add little to overall risk reduction of new vertebral fractures in this post-treatment period. However, it is hard to be sure of this conclusion as the data were not actually separately analyzed as those who did or did not follow teriparatide treatment with an antiresorptive. In addition, the above findings were in an observational study in which participants self-selected for the use of antiresorptive therapy after PTH treatment, making the results even more difficult to interpret. One might anticipate a residual but transient protection against fracture after PTH treatment without follow-up antiresorptive therapy, which could wane over time. Additional studies are needed to address fracture outcomes specifically. However, based particularly on the PaTH trial, the importance of following PTH or teriparatide therapy with an antiresorptive to maintain increases in bone mass is clear.
Safety of parathyroid hormone
Overall, PTH is well tolerated. Osteosarcoma has been seen in rats receiving very high doses of either teriparatide or PTH(1–84) for prolonged periods of time [31]. It is considered unlikely that this animal toxicity is related to human skeletal physiology [32–33], but in the USA a warning is included in the labeling instructions.
Conclusions
Although antiresorptives remain the mainstay of osteoporosis treatment, the advent of anabolic skeletal agents is changing our approach to therapy. Of the anabolic agents discussed above, PTH has clearly emerged as the most promising current treatment. For the first time, a drug is available that not only improves bone density and features of bone turnover, and reduces fracture incidence, but also significantly improves microarchitectural and geometric properties of bone. These changes in bone quality induced by teriparatide are attractive considering the goal of therapy for osteoporosis, namely, to improve the basic underlying abnormalities that give rise to skeletal fragility. Recent studies have given insight into the optimal use of this agent, including the importance of subsequent antiresorptive treatment to preserve gains in bone mass incurred during PTH therapy. With the development of additional and more cost-effective therapies, the use of anabolic agents is likely to increase in the years to come.
Future perspective
In the future, PTH may be modified for easier and more targeted delivery. PTH-related protein (PTHrP) has also been studied as an anabolic skeletal agent. In a small sample of postmenopausal women, subcutaneous administration of PTHrP resulted in a 4.7% increase in lumbar spine density after only 3 months of treatment [34]. Less frequent administration of PTH, such as once weekly, might also be an effective treatment option [35]. Cosman and colleagues reported on the use of cyclical 3-month courses of teriparatide against a backdrop of continued alendronate use [21]. In comparison with regular, uninterrupted teriparatide use, the cyclic administration of teriparatide was associated with similar densitometric gains. Of further interest was the observation that with sequential 3-month cycles of teriparatide, bone formation markers fell quickly when teriparatide was stopped were stimulated to the same degree with each cycle. On the other hand, bone resorption markers showed smaller increases with successive cycles. This observation gives credence to the idea that the anabolic window is actually expanded when teriparatide is used in this context [35–36]. Most recently, Cosman and colleagues have shown that, during long-term alendronate therapy, a rechallenge with PTH after 12 months off PTH increases bone formation, bone resorption and BMD to a similar extent as during the first course of PTH administration [37]. These data suggest that a future paradigm might be a second course of PTH given 12 months after a first course of therapy in patients who remain at high fracture risk. Apart from forms and ways to administer exogenous PTH, Gowen and colleagues described an oral calcilytic molecule that antagonizes the parathyroid cell calcium receptor, thus stimulating the endogenous release of PTH [38]. This approach could represent a novel endogenous delivery system for intermittent PTH administration.
Executive summary
Antiresorptive agents, particulary the bisphosphonates, are the mainstays of therapy for osteoporosis.
A new era of therapeutics has been ushered in with the registration of anabolic agents that work by a different mechanism, namely by stimulating bone formation.
The two forms of parathyroid hormone (PTH) available for use in Europe are recombinant human PTH(1–34) (teriparatide) and recombinant human PTH(1–84). Only teriparatide is available in the USA.
These drugs increase bone density at the lumbar spine and hip.
These drugs increase bone turnover in such a way that bone formation is stimulated earlier than bone resorption.
The difference in the time course between stimulation of bone formation and stimulation of bone resorption is known as the anabolic window.
Osteoporotic fractures are reduced by these agents.
The mechanisms by which fractures are reduced include changes in bone density, bone dynamics, bone size and microarchitecture.
The prior use of an antiresorptive may be associated with a delayed response to PTH in terms of changes in bone density. This is particularly likely if bone turnover markers are markedly suppressed by the antiresorptive drug.
Combination therapy with an antiresorptive agent and PTH has theoretical advantages over monotherapy alone, but it has been difficult to show clear-cut advantages.
It is important to follow the limited period of PTH therapy with an antiresorptive agent in order to maintain the gains achieved with PTH alone.
Footnotes
The author has received honoraria for lectures and for consultation relevant to the subject matter of this chapter from the following companies: Merck, Amgen, NPS Pharmaceuticals and the Alliance for Better Bone Health. He has received research grants from the NIH, Merck and the Alliance for Better Bone Health.