Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis

A Randomized Trial

6 March 2007 | Volume 146 Issue 5 | Pages 326-339

Background: Recombinant human parathyroid hormone (1-84) (PTH) increases bone mass and strength and improves bone quality by stimulating new bone formation.

Objective: To determine the safety of PTH and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis.

Design: 18-month, randomized, double-blind, placebo-controlled, parallel-group study.

Setting: 168 centers in 9 countries.

Patients: 2532 postmenopausal women with low bone mineral density at the hip or lumbar spine.

Interventions: Women received 100 µg of recombinant human PTH or placebo daily by subcutaneous injection. All received calcium, 700 mg/d, and vitamin D₃, 400 U/d.

Measurements: New or worsened vertebral fractures (primary outcome) and changes in bone mineral density and safety (secondary outcomes).

Results: 67.2% of patients who received at least 1 dose of the study drug completed the study. Parathyroid hormone reduced the risk for new or worsened vertebral fractures, but in sensitivity analyses, the magnitude of the reduction was changed with assumptions about fracture incidence in patients who did not complete the study (relative risk assuming no fractures, 0.42 [95% CI, 0.24 to 0.72] [P = 0.001]; relative risk assuming fracture incidence observed in all patients who completed the trial, 0.60 [CI, 0.36 to 1.00] [P = 0.05]; relative risk assuming fracture incidence observed in the placebo group, 0.62 [CI, 0.37 to 1.04] [P = 0.07]). Compared with placebo, mean bone mineral density increased at the spine by 6.9% (CI, 6.4% to 7.4%) and at the hip by 2.1% (CI, 1.7% to 2.5%) but decreased at the forearm in the PTH-treated group. Parathyroid hormone treatment increased the percentage of participants with hypercalciuria, hypercalcemia, and nausea by 24% (CI, 20% to 27%), 23% (CI, 21% to 26%), and 14% (CI, 11% to 16%), respectively, compared with placebo.

Limitations: Baseline serum PTH and vitamin D levels were not measured. Many patients discontinued the trial prematurely.

Conclusions: Parathyroid hormone (1-84) reduced the overall risk for new or worsened vertebral fracture in postmenopausal women with osteoporosis. Hypercalciuria, hypercalcemia, and nausea were more common in women who took the drug. Although the magnitude of the reduction was sensitive to assumptions about fracture incidence in patients who did not complete the study, the findings suggest that PTH provides an alternative therapeutic option for fracture prevention.

*For a list of members of the Treatment of Osteoporosis with Parathyroid Hormone Study Group, see the Appendix.

ClinicalTrials.gov registration number: NCT00172081.

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Editors' Notes Context Researchers have not previously reported the efficacy and safety of parathyroid hormone (1-84) (PTH) for the primary prevention of osteoporotic fractures. Contributions Among 2532 postmenopausal women with osteoporosis randomly assigned to receive PTH or placebo, PTH decreased new vertebral fractures. The magnitude of the effect depended on assumptions about fractures in the one third of patients who withdrew from the trial prematurely. Adverse effects included hypercalciuria, hypercalcemia, and nausea. Caution Endogenous PTH and vitamin D levels could affect patients’ response to the drug but were not assessed in the study. Implications Parathyroid hormone (1-84) effectively prevented new vertebral fractures but also increased hypercalciuria, hypercalcemia, and nausea. —The Editors

 

Author and Article Information

From University of Pittsburgh, Pittsburgh, Pennsylvania; Michigan Bone and Mineral Clinic, Detroit, Michigan; Radiant Research Center of South Florida and The Regional Osteoporosis Center, Stuart, Florida; University of Calgary Health Sciences Center, Calgary, Alberta, Canada; Helen Hayes Hospital, Regional Bone Center, West Haverstraw, New York; Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina; and NPS Pharmaceuticals, Inc., Parsippany, New Jersey.

Note: MedDRA is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations.

Acknowledgments: The authors thank Drs. Dennis Black and Roger Flora for their comments on the statistical design of the study; the women who participated in the study; Ms. Anna Metcalfe, Dr. James Heusner, Mr. Tim Considine, Ms. Jennifer Lopansri, and the Data Safety Monitoring Board and Clinical Advisory Board for their contributions during the conduct of the study; and Dr. John Fox for his comments on this manuscript.

Grant Support: By NPS Pharmaceuticals, Inc.

Potential Financial Conflicts of Interest: Employment: C.M. Blosch (formerly employed by NPS Pharmaceuticals, Inc., Benaroya Research Institute), A.L. Mathisen (formerly employed by NPS Pharmaceuticals, Inc.), S.A. Morris (NPS Pharmaceuticals, Inc.), T.B. Marriott (formerly employed by NPS Pharmaceuticals, Inc.); Consultancies: S.L. Greenspan (NPS Pharmaceuticals, Inc.), H.G. Bone (NPS Pharmaceuticals, Inc.), M.P. Ettinger (NPS Pharmaceuticals, Inc., Roche Laboratories, GlaxoSmithKline, Merck & Co. Inc., P&GP–Aventis [alliance], Pfizer Inc.), D.A. Hanley (NPS Pharmaceuticals, Inc.), R. Lindsay (NPS Pharmaceuticals, Inc.), J.R. Zanchetta (NPS Pharmaceuticals, Inc.), C.M. Blosch (NPS Pharmaceuticals, Inc.), T.B. Marriott (NPS Pharmaceuticals, Inc.); Honoraria: S.L. Greenspan (NPS Pharmaceuticals, Inc.), D.A. Hanley (NPS Pharmaceuticals, Inc.); Stock ownership or options (other than mutual funds): M.P. Ettinger (Pfizer Inc.), A.L. Mathisen (NPS Pharmaceuticals, Inc.), T.B. Marriott (NPS Pharmaceuticals, Inc.); Grants received: S.L. Greenspan (NPS Pharmaceuticals, Inc.), H.G. Bone (NPS Pharmaceuticals, Inc.), M.P. Ettinger (NPS Pharmaceuticals, Inc., Roche Laboratories, GlaxoSmithKline, Merck & Co. Inc., P&GP, Aventis, Lilly, Pfizer Inc., Novartis, Wyeth, Amgen), D.A. Hanley (NPS Pharmaceuticals, Inc.).

Requests for Single Reprints: Susan L. Greenspan, MD, University of Pittsburgh, Osteoporosis Prevention and Treatment Center, Kaufmann Medical Building, Suite 1110, 3471 Fifth Avenue, Pittsburgh, PA 15213.

Current Author Addresses: Dr. Greenspan: University of Pittsburgh, 3471 Fifth Avenue, Suite 1110, Pittsburgh, PA 15213.

Dr. Bone: Michigan Bone and Mineral Clinic, 22201 Moross Road, Detroit, MI 48236.

Dr. Ettinger: Radiant Research, Regional Osteoporosis Center, 2081 East Ocean Boulevard, Suite 1A, Stuart, FL 34996.

Dr. Hanley: University of Calgary Health Sciences, 3330 Hospital Drive, Calgary, Alberta T2N4N1, Canada.

Dr. Lindsay: Helen Hayes Hospital, Route 9 West, West Haversham, NY 10993.

Dr. Zanchetta: IDiM, Libertad 836 2 #32, Buenos Aires C1012AAR, Argentina.

Dr. Blosch: Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101-2795.

Dr. Mathisen: QST Consultations, Ltd., 6410 Lake Michigan Drive, Allendale, MI 49401.

Dr. Morris: NPS Pharmaceuticals, Inc., 300 Interpace Parkway, Building B, 4th Floor, Parsippany, NJ 07054.

Dr. Marriott: TOP Pharmaceutical Consulting, LLC, 8 Birchtree Lane, Sandy, UT 84092.

Author Contributions: Analysis and interpretation of the data: S.L. Greenspan, H.G. Bone, M.P. Ettinger, D.A. Hanley, R. Lindsay, J.R. Zanchetta, C.M. Blosch, A.L. Mathisen, S.A. Morris, T.B. Marriott.

Drafting of the article: S.L. Greenspan, H.G. Bone, M.P. Ettinger, D.A. Hanley, R. Lindsay, J.R. Zanchetta, S.A. Morris, T.B. Marriott.

Critical revision of the article for important intellectual content: S.L. Greenspan, H.G. Bone, M.P. Ettinger, D.A. Hanley, R. Lindsay, J.R. Zanchetta, C.M. Blosch, A.L. Mathisen, S.A. Morris, T.B. Marriott.

Provision of study materials or patients: S.L. Greenspan, H.G. Bone, M.P. Ettinger, D.A. Hanley, J.R. Zanchetta, C.M. Blosch, T.B. Marriott.

Statistical expertise: A.L. Mathisen.

Administrative, technical or logistical support: C.M. Blosch, S.A. Morris, T.B. Marriott.

Collection and assembly of data: C.M. Blosch, A.L. Mathisen.

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