Sequential Parathyroid Hormone/Alendronate Therapy for Osteoporosis—Robbing Peter to Pay Paul?

Mara Horwitz, Andrew Stewart and Susan L. Greenspan

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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 Introduction
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Although we currently have multiple Food and Drug Administration-approved antiresorptive therapies for the treatment of postmenopausal osteoporosis, the gains in vertebral bone mass approach only 6–7% over 3 yr with single-agent antiresorptive therapy (1, 2, 3) and up to 8–9% over 3 yr with two antiresorptive agents given simultaneously (4). Because bone mass has often decreased an average of 30% when postmenopausal women experience fractures and greater increases in bone mass are associated with greater vertebral fracture reduction (5), investigators have, therefore, searched for an ideal agent(s) to increase bone formation while suppressing or maintaining the rate of bone resorption. Previous studies have shown that PTH stimulates both bone formation and resorption with a greater net impact on bone formation, resulting in an increase in bone mass, particularly in trabecular bone (6). However, the "presentation" of PTH is crucial. When PTH is given as a constant infusion to animals or in disease states such as hyperparathyroidism where the levels are constantly elevated, the result is a loss of bone, especially at cortical sites (6, 7, 8). In contrast, like many other endocrine systems, when the hormone is presented in a pulsatile or intermittent fashion, it stimulates a net increase in bone mass at mainly trabecular sites. However, one concern with the anabolic agent PTH, when given as an intermittent injection, has been the potential trade-off of "robbing Peter to pay Paul." Several studies involving PTH treatment have shown either a maintenance or loss of cortical bone at some sites in comparison with improvements in vertebral bone mass, or trabecular bone (9, 10, 11, 12), which may be related to an increase in the remodeling space (6). This is a critical issue because if bone mass is only maintained, potentially lost, or placed in a more fragile and biomechanically insecure state at clinically relevant cortical sites, hip fractures may not be reduced—a much more costly and morbid event than vertebral fractures. However, lack of vitamin D sufficiency in patients at baseline or differences between PTH(1-34) and PTH(1-84) absorption, carriers, and circulating time may contribute to observed differences in cortical bone. A second concern is that, following discontinuation of anabolic therapy with PTH, patients may then lose bone and return to their previous baseline after withdrawal of therapy (9).

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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 Introduction
 References
 

  1. Black DM, Cummings SR, Karpf DB, et al. 1996 Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 348:1535–1541.[CrossRef][Medline]
  2. Writing Group for PEPI Trial. 1996 Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. J Am Med Assoc. 276:1389–1396.[Abstract]
  3. Harris ST, Watts NB, Genant HK, et al. 1999 Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. J Am Med Assoc. 282:1344–1352.[Abstract/Free Full Text]
  4. Greenspan S, Bell N, Bone H, et al. 1999 Differential effects of alendronate and estrogen on the rate of bone loss after discontinuation of treatment (Abstract). J Bone Miner Res. 14(Suppl 1):S158.
  5. Hochberg MC, Ross PD, Black D, et al., for the Fracture Intervention Trial Research Group. 1999 Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Arthritis Rheum. 42:1246–1254.[CrossRef][Medline]
  6. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. 1993 Anabolic actions of parathyroid hormone on bone. Endocr Rev. 14:690–709.[Medline]
  7. Tam CS, Heersche JNM, Murray TM, et al. 1982 Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology. 110:506–512.[Abstract]
  8. Hodsman AB, Fraher LJ, Ostbye T, Adachi JD, Steer BM. 1993 An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis. J Clin Invest. 91:1138–1148.[Medline]
  9. Hodsman A, Fraher L, Adachi J. 1995 A clinical trial of cyclical clodronate as maintenance therapy following withdrawal of parathyroid hormone, in the treatment of postmenopausal osteoporosis (Abstract). J Bone Miner Res. 10(Suppl 1):S200.
  10. Hodsman AB, Fraher LJ, Watson PH, et al. 1997 A randomized controlled trial to compare the efficacy of cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 82:620–628.[Abstract/Free Full Text]
  11. Lindsay R, Hodsman A, Genant H, Bolognese M, Ettinger M for the PTH Working Group. 1998 A randomized controlled multi-center study of 1–84hPTH for treatment of postmenopausal osteoporosis (Abstract). Bone. 23(Suppl 1):S175.
  12. Finkelstein JS, Klibanski A, Schaefer EH, et al. 1994 Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. N Engl J Med. 331:1618–1623.[Abstract/Free Full Text]
  13. Rittmaster RS, Bolognese M, Ettinger MP, et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab. 85:2129–2134.
  14. Liberman UA, Weiss SR, Broll J, et al. 1995 Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 333:1437–1443.[Abstract/Free Full Text]
  15. Finkelstein JS, Klibanski A, Arnold AL, Toth TL, Hornstein MD, Neer RM. 1998 Prevention of estrogen deficiency-related bone loss with human parathyroid hormone—(1-34): a randomized controlled trial. J Am Med Assoc. 280:1067–1073.[Abstract/Free Full Text]
  16. Lindsay R, Nieves J, Formica C, et al. 1997 Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet. 350:550–555.[CrossRef][Medline]
  17. Roe EB, Sanchez SD, del Puerto GA, et al. 1999 Parathyroid hormone 1-34 (hPTH 1-34) and estrogen produce dramatic bone density increases in postmenopausal osteoporosis—results from a placebo-controlled randomized trial (Abstract). J Bone Miner Res. 14(Suppl 1):S137.
  18. Riggs BL, Hodgson SF, O’Fallon WM, et al. 1990 Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med. 322:802–809.[Abstract]
  19. Kleerekoper M, Peterson EL, Nelson DA, et al. 1991 A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis. Osteoporos Int. 1:155–161.[Medline]