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University of Pittsburgh Medical Center Division of Endocrinology and Metabolism Pittsburgh, Pennsylvania 15213
Address correspondence and requests for reprints to: Susan L. Greenspan, M.D., University of Pittsburgh Medical Center, Osteoporosis Prevention and Treatment Center, 1110 Kaufmann Building, 3471 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail: greenspans{at}msx.dept-med.pitt.edu
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The study by Rittmaster et al. (13) suggests a possible solution to several of these concerns. At the conclusion of a 1-yr, double-blind, placebo-controlled study in postmenopausal women with daily sc injections of PTH(1-84) at three doses (50, 70, and 100 µg) vs. placebo, a small subset of patients (n = 75) were treated with 10 mg open-label alendronate daily for the following year. Patients received 500 mg supplementary calcium and 400 IU vitamin D. After the 1st year of PTH therapy, there were no significant changes in femoral neck bone mineral density (BMD) accompanied by decreases of 3.5% and 2.8% in total body bone mass in the patients who received the two highest doses of PTH, along with increases of 6.9% and 9.2% at the spine. Given the low turnover of cortical bone at the hip, changes at the total hip or femoral neck may not be observed in 1 yr, especially in a small cohort. However, patients treated with several antiresorptive agents in large clinical trials have demonstrated improvements at the hip after only 1 yr (2, 3, 14). The investigators observed further increases of up to 14% in spinal bone mass during the subsequent year of treatment with alendronate in the group that had previously received the highest dose of PTH. Although they observed a trend in improved hip bone mass compared with baseline, this was not statistically significant at two of the doses of PTH, including the highest dose after 2 yr of this sequential therapy. Whole body BMD (primarily composed of cortical bone) did improve compared with baseline in three of four groups after the year of alendronate therapy. Therefore, whereas the sequential anabolic therapy, followed by antiresorptive therapy, was able to improve the total body bone mass in the highest dose, there was no significant gain in hip BMD at this same dose. The sequential therapy did, however, halt further loss of cortical bone and resulted in further improvement in trabecular bone at the spine. Alternatively, the reversal of cortical bone loss may also be dependent on the duration of PTH therapy. In a study with women who were estrogen deficient from GnRH therapy, Finkelstein et al. (12) observed significant losses at the femoral neck and hip trochanter after 6 months of PTH therapy. However, by 12 months PTH therapy prevented loss from the proximal femur (15). Because the number of participants in the open-label extension was small, the authors did not observe a consistent effect at all doses and sites. Therefore, although the trends are encouraging, we do not know whether we have paid off Peter, or if sequential therapy of PTH, followed by alendronate, is more advantageous than a single antiresorptive agent that could significantly improve hip bone mass after 2 yr (14).
Other studies have shown that the combination of simultaneous hormone replacement therapy (HRT) and PTH (or PTH added to women who are on HRT) provides further increases in spine, total body, and hip BMD (16, 17). Furthermore, Lindsay et al. (16) noted a reduction in vertebral fractures (assessed as a 15% decrease in vertebral height). Although the study by Rittmaster et al. (13) was not powered to examine reduction in vertebral fractures, the outcomes of concern are still fracture reduction. A combination of simultaneous anabolic and antiresorptive therapy may be a better pattern of therapy if it results in significant gains at both the spine and the hip with trends for fracture reduction.
This study is important because it lends further support to the ongoing body of evidence about the role of combination therapy for the treatment of osteoporosis. The study shows the success of sequential therapy for greater improvements in vertebral bone mass, prevention of bone loss following therapeutic withdrawal of PTH, and reversal of cortical bone loss. However, further research is needed to demonstrate improvement in hip bone mass with this kind of sequential therapy, with the goal that such therapy would ultimately be associated with reduction in hip fractures. This study also lays the foundation for examination of simultaneous anabolic and antiresorptive therapy with this combination of PTH and bisphosphonate. Furthermore, the clinical implications suggest that a potential future treatment for osteoporosis may consist of baseline continuous antiresorptive therapy with agents such as HRT, selective estrogen receptor modulators, or bisphosphonates, with an intermittent bolus of an anabolic therapy like PTH to improve bone mass further and potentially reduce fractures. The next step is the examination of biomechanical strength and a larger-scale clinical trial of combination therapy powered to assess fractures as an end point. We have previously witnessed the fallout from fluoride (18, 19), another anabolic agent, which resulted in a significant increase in bone mass that was biomechanically inferior and resulted in an increase in vertebral fractures. Because fracture outcome and, most importantly, hip fracture reduction are the ultimate targets for osteoporosis treatment, we need to ensure that new anabolic therapy or combinations of anabolic and antiresorptive therapies are in a pattern simultaneously rewarding Peter and Paul.
Received March 20, 2000.
Accepted April 5, 2000.
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