Osteoporosis is commonly treated with antiresorptive drugs (bisphosphonates) that slow bone remodeling and increase the amount of bone formed in remodeling sites, thereby raising bone mineral density (BMD). However, anabolic drugs hold promise to make even more impressive improvements with regard to increasing bone strength by stimulating bone formation, bone size, and microarchitecture. Ultimately, this class of agents could at least theoretically reconstruct the skeleton, an achievement not possible with current antiresorptive drugs. The only anabolic agent currently approved for osteoporosis in the United States is teriparatide, which is recombinant human parathyroid hormone (PTH) [1-34]. As well as teriparatide, the full-length molecule, human recombinant PTH (1-84), under review by the Food and Drug Administration (FDA), has been approved in a number of European countries.
John P. Bilezikian, M.D., Professor of Medicine and Pharmacology at Columbia University's College of Physicians and Surgeons in New York City, gave an overview of the latest in treating osteoporosis at a Clinical Endocrinology Update (CEU) lecture held by The Endocrine Society last October. With his acknowledged expertise and the clarity with which he conveys the latest research, the lecture room was overflowing with attendees. "It was one of the most insightful and lucid talks that I've ever heard," said Robert A. Kreisberg, M.D., M.A.C.P., Clinical Professor of Medicine at the University of Alabama who attended the session and is also chair of the 2007 CEU. "We plan to invite him to come and update his talk in 2007."
Below is a summary of Dr. Bilezikian's sold-out talk.
In primary hyperparathyroidism (PHPT), a disorder of chronic, continuous secretion of excess PTH, catabolic effects are common, primarily at cortical sites such as the distal 1/3 radius. Nevertheless, even in this disorder of chronic PTH secretion, salutary effects on the cancellous skeleton, such as the lumbar spine, can be seen. The clinical clue to PTH's use as an anabolic skeletal agent came with the recognition that its potential is seen much more clearly with low-dose, intermittent administration. 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 likely initially stimulates processes associated with bone formation (bone modeling), and only later promotes 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.
Teriparatide is used in postmenopausal women and men with osteoporosis who are at high risk for fracture. To help select patients for teriparatide, useful guidelines have been published. Patients who have already sustained an osteoporotic fracture are among the highest risk group because the likelihood of sustaining another fracture is very high. Other potential candidates for teriparatide are patients for whom one might consider a bisphosphonate but who cannot tolerate the drug or who are noncompliant. In addition, patients who fracture while on antiresorptive therapy are at high risk and thus, in the view of many, candidates for teriparatide.
In the randomized, double-blind, pivotal clinical trial by Neer and coworkers, women with severe osteoporosis were treated with daily subcutaneous injections of placebo, 20 µg, or 40 µg teriparatide, with significant reductions in new vertebral and nonvertebral fractures. 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. Associated with fracture reduction are important improvements in bone mineral density, bone size, and microarchitecture of the skeleton.
Orwoll and colleagues followed a treatment protocol of teriparatide in men that was essentially identical to the Neer study, only that trial was shorter than the Neer trial in postmenopausal women by 10 months (11 vs. 21 months). In the combined teriparatide treatment groups, (20 µg and 40 µg), the risk of vertebral fracture was reduced by 51%. Significant reductions were seen in the combined group as compared to placebo when only moderate or severe fractures were considered (6.8% vs. 1.1%). However, the prospective data evaluated without these post-hoc groupings were not able to actually document fracture protection. It is likely that the study's short duration precluded definitive conclusions in this male osteoporosis trial with teriparatide.
PTH (1-84) has had only limited study. Nevertheless, a reduction in new vertebral fracture incidence has been seen with PTH (1-84) in women both with and without prior vertebral fractures. The data by Greenspan et al. published last month provide more information (Greenspan S et al. Annals Int Med, March 6, 2007).
It is attractive to consider combination therapy with an antiresorptive and PTH as potentially more beneficial than monotherapy, given that antiresorptives and PTH use different mechanisms of action. 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 in postmenopausal women and by Finkelstein and coworkers in men. These two groups independently completed trials using a form of PTH alone, alendronate alone, or both. The results showed an impaired densitometric response to combination therapy, as compared to PTH alone, which might be due to the dominating effects of the antiresorptive agent on bone dynamics when both drugs are used together.
Teriparatide is approved in the United States for a treatment period of 24 months and in Europe for 18 months. There are obvious concerns regarding consequences of discontinuing therapy following this relatively short period. 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 for resorption if a period of consolidation with an antiresorptive is not used.
However, based particularly on a key PaTH study by Black and coworkers, the importance of following PTH or teriparatide therapy with an antiresorptive to maintain increases in bone mass is clear.
Overall, PTH is well tolerated. Osteosarcoma has been seen in rats that have been given very high doses of either teriparatide or PTH (1-84) for prolonged periods of time. This animal toxicity is unlikely related to human skeletal physiology, but in the United States a warning is included in the labeling instructions.
In the future, PTH may be modified for easier and more targeted delivery. Parathyroid hormone-related protein (PTHrP) has also been studied as an anabolic skeletal agent. Less frequent administration of PTH (e.g., once weekly) might also be an effective treatment option.
Recent data suggest that a future paradigm might be a second course of PTH 12 months after the first in patients who remain at high fracture risk.
Although antiresorptives remain the mainstay of osteoporosis treatment, the advent of anabolic skeletal agents is changing our approach to therapy. PTH is the first member of this new therapeutic class. For the first time, a drug is available that not only improves bone density, features of bone turnover, and reduces fracture incidence, but also significantly improves the microarchitecture and geometric properties of bone. The changes in bone quality induced by teriparatide are attractive, considering that the goal of osteoporosis therapy is to improve the basic underlying abnormalities that give rise to skeletal fragility. Recent studies have given insight on the optimal use of this agent, including the importance of subsequent antiresorptive treatment to preserve gains in bone mass. With the development of additional and more cost-effective therapies, the use of anabolic agents will likely increase in the years to come.