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

Susan L. Greenspan, MD; Henry G. Bone, MD; Mark P. Ettinger, MD; David A. Hanley, MD; Robert Lindsay, MD; Jose R. Zanchetta, MD; Consuelo M. Blosch, MD; Annette L. Mathisen, PhD; Stephen A. Morris, MD; Thomas B. Marriott, PhD, Treatment of Osteoporosis with Parathyroid Hormone Study Group*
[+] Article and Author 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.


Ann Intern Med. 2007;146(5):326-339. doi:10.7326/0003-4819-146-5-200703060-00005
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We screened 10 749 women between April 2000 and March 2002. We randomly assigned 2532 women (1246 to the placebo group and 1286 to the PTH group) who received at least 1 dose of study drug and became part of the modified ITT population that was analyzed for efficacy and safety (Figure 1). Of these women, 1701 (877 [70%] in the placebo group and 824 [64%] in the PTH group) completed the study. More women in the PTH group (186 [14.5%]) than in the placebo group (111 [8.9%]) discontinued drug therapy within 3 months; thereafter, similar numbers of women discontinued in both groups (258 [20.7%] in the placebo group vs. 276 [21.5%] in the PTH group). At the time of discontinuation of drug therapy or on study completion, 852 (66%) women in the PTH group versus 1137 (91%) in the placebo group had received daily injection with or without supplemental calcium; 265 (21%) versus 60 (5%) had received every-other-day injection without calcium; and 169 (13%) versus 49 (4%) had received once- or twice-weekly injection without calcium.

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Figures

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Figure 1.
Study flow diagram.

The modified intention-to-treat (ITT) population was the primary population analyzed for efficacy and safety and included all women who received at least 1 dose of parathyroid hormone (1-84) (PTH) or placebo. The modified ITT analysis for the primary end point assumed that women who discontinued without a final radiograph did not have a new or worsened vertebral fracture; sensitivity analyses were performed to evaluate this assumption. * Confirmed bone loss was a prespecified reason for discontinuation. † Defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or substantial disability or incapacity, or was a congenital anomaly or birth defect. ‡ An incident lumbar vertebral fracture was a prespecified reason for discontinuation. New vertebral fractures were also found in women who discontinued for other reasons. § An incident hip fracture was a prespecified reason for discontinuation.

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Figure 2.
Expected mean (± SE) percentage change from baseline (linear mixed-effects model) in bone mineral density measured by dual-energy x-ray absorptiometry with parathyroid hormone (1-84) (PTH) or placebo.

Whole-body and forearm bone mineral density were measured only in a subset of approximately 300 women from selected sites by using appropriate software. *P < 0.050. †P < 0.001 versus placebo. ‡P < 0.010.

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Figure 3.
Expected mean (±SE) percentage change from baseline (linear mixed-effects model) in serum bone-specific alkaline phosphatase and N-telopeptides of type I collagen [NTx]–creatinine ratio.

A subset of approximately 600 women was evaluated. *P < 0.001 versus placebo.

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Thiazolidinediones, parathyroid hormone and fractures.
Posted on March 8, 2007
Luca Mascitelli
Comando Brigata alpina Julia, Udine 33100 Italy
Conflict of Interest: None Declared

TO THE EDITOR "“ Greenspan and colleagues (1) found that recombinant human parathyroid hormone reduced the risk for new or worsened vertebral fractures in postmenopausal women with or without previous vertebral fracture. Women who were taking medications known to affect bone mineral metabolism were excluded from the study (1). However, only recently (2) it has been suggested that the antidiabetic drugs thiazolidinediones (TZD) may have a detrimental action on bone. In fact, a recent observational study (3) found that treatment of diabetic women with TZD was associated with a significant 50% increase in the annualized rate of whole-body bone loss. Furthermore, even short-term therapy with rosiglitazone, a commonly prescribed TZD, has been shown to inhibit bone formation and accelerate bone loss in healthy postmenopausal women (4). Indeed, it has been recently reported (5) a higher incidence of fractures, detected as adverse events, in female diabetic subjects randomized to receive rosiglitazone compared to those randomized to receive either metformin or glyburide, during a 4 years study of glycemic durability of oral monotherapies. Therefore, given its detrimental effects on bone, TZD assumption might have been a confounder in the study by Greenspan and colleagues (1).

Luca Mascitelli, MD Sanitary Service Comando Brigata alpina "Julia" Udine, Italy 33100

Francesca Pezzetta, MD Cardiology Service Ospedale di San Vito al Tagliamento San Vito al Tagliamento, Italy 33078

REFERENCES

1. Greenspan SL, Bone HG, Ettinger MP, et al, for the Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007; 146: 326-39.

2. Mascitelli L, Pezzetta F. Thiazolidinediones. N Engl J Med 2005; 352: 206.

3. Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 2006; 91: 3349-54.

4. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR. The peroxisome-proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 2007 Jan 30; [Epub ahead of print].

5. Kahn SE, Haffner SM, Heise MA, et al, for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43.

Conflict of Interest:

None declared

Predetermination of PTH and Vitamin D levels before Therapy of Osteoporosis with PTH (1-84)
Posted on March 12, 2007
Francisco R. Lafita
Gabinet Mèdic. 43850 Cambrils.Baix Camp. Spain
Conflict of Interest: None Declared

In their interesting study Greenspan and colleagues (1) found that PTH (1-84) effectively prevented the appearing of new or worsened vertebral fractures. However, an important rate of adverse events was observed, which in the PTH group were mainly nausea (22.6%), vomiting (7.7%), dizziness and headache, symptoms that strongly suggest the presence of hypercalcemia (actually found in 27.8% of PTH group).

An important issue missed in this study was the determination of PTH and vitamin D levels (even phosphate levels) before starting PTH therapy. The most common cause of secondary osteoporosis is vitamin D deficiency being secondary hyperparathyroidism a frequent finding in patients with hypovitaminosis D (2, 3). It is not unlike to find increases in serum and urinary calcium levels when patients with raised levels of endogenous PTH are treated with PTH (1-84). Moreover, changes in levels of 1,25 dihydroxyvitamin D (from its baseline value) during treatment with PTH (1- 84) have been found to correlate with larger increases in BMD (4).

Because of the high rate of hypercalcemia / hypercalciuria showed in this study we must be cautious when administering PTH (1-84). Serum PTH and vitamin D levels must be measured before initiating the therapy.

1. Greenspan SL, Bone HG, Ettinger MP, et al, for the Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007; 146: 326-39.

2. Giusti A, Barone A, Razzano M, et al. High prevalence of secondary hyperparathyroidism due to hypovitaminosis D in hospitalized elderly with and without hip fracture. J Endocrinol Invest. 2006 Oct;29(9):809-13.

3. Dobnig H, Piswanger-Solkner JC, Obermayer-Pietsch B, et al. Hip and Non-Vertebral Fracture Prediction in Nursing Home Patients: Role of Bone. Ultrasound and Bone Marker Measurement. J Clin Endocrinol Metab. 2007 Feb 20; [Epub ahead of print]

4. Sellmeyer DE, Black DM, Palermo L, et al. Hetereogeneity in skeletal response to full-length parathyroid hormone in the treatment of osteoporosis. Osteoporos Int. 2007 Feb 28; [Epub ahead of print]

Conflict of Interest:

None declared

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Summary for Patients

Parathyroid Hormone (1-84) and Risk for Spinal Fractures in Women with Osteoporosis

The summary below is from the full report titled “Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis. A Randomized Trial.” It is in the 6 March 2007 issue of Annals of Internal Medicine (volume 146, pages 326-339). The authors are 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, and T.B. Marriott, for the Treatment of Osteoporosis with Parathyroid Hormone Study Group.

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