Endocrinology and Metabolism Clinics of North America
Combination Anabolic and Antiresorptive Therapy for Osteoporosis
Introduction
The full-length molecule of parathyroid hormone, PTH(1–84), and its fully active, foreshortened variant, PTH(1–34) (teriparatide), represent the only available osteoanabolic treatments for osteoporosis at this time. Osteoanabolic agents are an attractive therapeutic option for postmenopausal women and for men with osteoporosis because of their direct stimulation of bone formation, an action that is not shared by any antiresorptive agent. PTH increases bone mineral density (BMD) at the lumbar spine, primarily a cancellous site, with more modest increases in the hip region, a site that is an admixture of cancellous and cortical bone. The early effect of PTH is an initial rapid increase in bone formation markers, subsequently followed by an increase in bone resorption markers. The pharmacokinetics of this effect suggest that PTH can initially stimulate processes associated with bone formation before bone resorption is stimulated. Bone biopsies from subjects treated with PTH(1–34) have confirmed that bone formation occurs first on quiescent surfaces in a manner that suggests a modeling mechanism.1 The modeling process is a characteristic of the growing skeleton and is not usually seen in the mature human skeleton. The adult human skeleton typically demonstrates bone remodeling, a process by which mature bone is replaced by more resilient, young bone. Continued therapy with PTH does lead to a stimulation of bone remodeling, but in this setting bone formation exceeds bone resorption so that bone accrual is favored, even when remodeling is stimulated by PTH. It is estimated that 70% of the ultimate anabolic effect is due to remodeling.
The concept of the anabolic window describes the period of time when PTH directly stimulates bone formation before stimulation of bone remodeling, but it also includes, to a lesser extent, the period of time during remodeling when bone formation is favored over bone resorption (Fig. 1).2 These actions of PTH on skeletal dynamics are limited. Over a 2-year treatment period, the increased rate of bone turnover is mitigated, with levels falling toward baseline. The 18- to 24-month approval period of PTH(1–84) and PTH(1–34) is consistent with these modeling and remodeling dynamics. PTH(1–34) is approved worldwide, including in Europe and the United States, for the treatment of advanced osteoporosis in men and postmenopausal women at high risk for fracture, as well as for the treatment of glucocorticoid-induced osteoporosis. PTH(1–84) is approved in Europe and elsewhere, but not in the United States, for the treatment of postmenopausal osteoporosis.
The anabolic actions of PTH are confirmed further by detailed skeletal microstructure studies of Dempster and colleagues.3 Their study evaluated paired iliac crest bone biopsy specimens from both men and women with osteoporosis before and after treatment with PTH(1–34) 400 IU daily (approximately equivalent to 25 μg daily). By histomorphometry, cortical width was maintained in men and significantly increased in women (632 ± 95 μm at baseline to 951 ± 130 μm posttreatment, P<.001). There was no increase in cortical porosity. There was a significant increase in the width of bone packets on the endocortical surface in both men and women, associated with a significant decrease in the eroded perimeter. Microcomputed tomography of the bone biopsy specimens confirmed these findings, and in addition demonstrated an increase in trabecular connectivity, to as much as 253% (Fig. 2). Graeff and colleagues3 evaluated high-resolution computed tomography imaging data from a subset of participants in the European Study of Forsteo (EUROFORS) treated with PTH(1–34) 20 μg daily for 12 months. In treatment-naïve patients, there were significant increases in apparent trabecular number (+12.9% ± 22% from baseline to 12 months; P<.05) and trabecular thickness (+8.4% ± 7% from baseline to 12 months; P<.001), accompanied by reductions in trabecular separation (−10.5% ± 18%; P not significant).
Given that osteoanabolic therapy uniquely helps to restore deteriorated skeletal microstructure that forms the structural basis for osteoporosis, it may be expected that this approach would be routinely used as first-line treatment for osteoporosis. However, anabolic therapy is restricted in time and to subjects who are at high risk for fracture. It is thus used in a very small number of patients with osteoporosis. The study population that led to approval of PTH(1–34) had advanced osteoporosis. The trial was shortened to an average of only 21 months in women and 11 months in men, because of the discovery of rat osteosarcoma in toxicity studies (see later discussion). These explanations are the obvious ones for why the drug is limited in use with a black-box warning in the United States. Other limitations to more widespread use include that it has to be given by daily subcutaneous injection, a route and frequency of administration that are not ideal. The drugs are also very expensive. Another point is that the antiresorptive agents such as alendronate,4 risedronate,5 and zoledronic acid6 have also been shown to be efficacious in severely osteoporotic individuals, and their use is associated with greater convenience and less expense. The only head-to-head comparison between PTH(1–34) and an antiresorptive dealt with a special group of individuals who had glucocorticoid-induced osteoporosis. In that study by Saag and colleagues,7, 8 PTH(1–34) was superior to alendronate in protecting against vertebral fractures over a 3-year period.
The points covered in this review address questions regarding sequential and combination therapy with osteoanabolic and antiresorptive drugs. Most patients who receive PTH(1–34) or PTH(1–84) have previously received an antiresorptive drug; is there an influence of previous antiresorptive treatment on subsequent therapy with PTH? In patients who have been treated with antiresorptive therapy, is it better to add the osteoanabolic agent or it is better to switch from the antiresorptive to the osteoanabolic alone? Can one use simultaneous de novo osteoanabolic and antiresorptive agents in a manner that will expand the anabolic window? Finally, because PTH(1–34) and PTH(1–84) are approved only for up to 2 years, is it necessary to follow this treatment course with antiresorptive therapy? These questions are addressed in this article.
Section snippets
Osteoanabolic therapy following antiresorptive therapy (“switching”)
Kurland and colleagues9 have shown that the level of baseline bone turnover in subjects not previously treated with any antiresorptive therapy affects the subsequent response to PTH(1–34): the lower the level of turnover, the more sluggish the initial densitometric response to PTH(1–34). In support of this idea, Ettinger and colleagues10 showed that in women following an average of 29 months of raloxifene or alendronate treatment, densitometric gains with PTH(1–34) following raloxifene were
Osteoanabolic therapy following ongoing antiresorptive therapy (“adding”)
In postmenopausal women with a history of antecedent estrogen therapy, Lindsay and colleagues16 and Lane and colleagues17 showed rapid and sustained increases in lumbar spine BMD with PTH(1–34) in glucocorticoid-induced osteoporosis. The magnitude of the changes was similar to that when using PTH alone. When Cosman and colleagues18 used alendronate as the antecedent antiresorptive, the addition of PTH(1–34) was also associated with prompt increases in BMD. The same BMD gains were seen whether
Further examination of the question: switching versus adding
In a protocol that focused on regimens of switching versus adding, as well as antiresorptive potency per se, the study of Cosman and colleagues15 is noteworthy. Subjects previously treated with either raloxifene or alendronate for at least 18 months were then administered PTH(1–34) and antiresorptive together (add regimen) or PTH(1–34) alone (switch regimen, antiresorptive discontinued) for the next 18 months. While bone turnover markers increased more in the switch group (from either
Simultaneous use of osteoanabolic and antiresorptive therapy
The idea of using osteoanabolic and antiresorptive therapy together in subjects who have not previously been treated is attractive, based on the different mechanisms of action of these therapeutic classes. If bone resorption is inhibited by an antiresorptive while bone formation is stimulated by an osteoanabolic agent, combination therapy might give better results than therapy with either agent alone. Implicit in this postulate is that the anabolic window is expanded. Despite the intuitive
Antiresorptives after osteoanabolic therapy
Kurland and colleagues26 were the first to show that when PTH(1–34) is not followed by an antiresorptive agent, lumbar spine bone density falls precipitously. These investigators followed 21 men from their initial study10 for up to 2 years after discontinuation of PTH(1–34), 12 of whom opted for immediate treatment with a bisphosponate following PTH(1–34). In the men who began bisphosphonate therapy immediately, there were continued gains of 5.1% at the lumbar spine, compared with a decline of
Safety
PTH therapy is well tolerated for the recommended 2-year treatment period. Clinical trials have shown a very small risk of hypercalcemia at the approved 20-μg dose.29, 32 Hypercalcemia is even less likely to occur if calcium supplementation is reduced to 500 mg/d with the initiation of PTH(1–34). PTH(1–34) does not appear to significantly increase urinary calcium excretion.32, 33 Other possible side effects of therapy include nausea, vomiting, dizziness, headache, and increased serum uric acid
Summary
With the availability of antiresorptives and osteoanabolic therapy for the treatment of osteoporosis, it is still unclear as to how and whether combination or sequential therapeutic approaches can be used in a manner that is advantageous over monotherapy. Despite many attempts to show an advantage of simultaneous combination therapy, most studies have shown that monotherapy with PTH(1–34) or PTH(1–84) is as good, if not better than, combination therapy with osteoanabolic and antiresorptive
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Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism
2016, Seminars in Cell and Developmental BiologyCitation Excerpt :Direct effects of mutant CaSR in chondrocyte and bone cell, however, cannot be ruled out [29–38]. Prolonged elevation of sPTH produces catabolic effects on bone [39–42], but once-daily (or intermittent) injections of supra-physiological doses of PTH1–34 or PTH1–84 increase trabecular bone mass in normal and osteoporotic animal models and in osteoporosis patients [43–47]. The anabolic effect of intermittent PTH (iPTH) appears to rely on its ability to promote bone-forming activities of OBs to a greater extent than the bone-resorbing activities of OCLs at the beginning of the treatment—creating a so-called “anabolic window”, but its underlying cellular and molecular mechanisms remain unclear.
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2015, BiomaterialsCitation Excerpt :Osteoporosis, the most common metabolic bone disease, affects over 200 million people worldwide with 10 million people affected in the United States alone [1–6]. Therapeutic approaches to osteoporotic bone loss have focused thus far on either anabolic or antiresorptive agents [7,8] with only one anabolic agent, parathyroid hormone (PTH), approved by the Food and Drug Administration (FDA) for the temporary treatment of osteoporosis. To address the pressing need for new therapies that are both anabolic and anti-osteoclastic [7,9–11], promising new agents that increase Wnt/β-catenin activity are in development.
NELL-1 expression in benign and malignant bone tumors
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Osteoporosis
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Disclosures: Dr Bilezikian is a consultant for Eli Lilly, NPS Pharmaceuticals, Merck, Warner-Chilcott, GSK, Novartis, and Amgen, and receives research support from NPS Pharmaceuticals and GSK. Dr Cusano has no conflicts of interest to report.