Teriparatide Therapy for Osteoporosis

Educational Objectives

The goal of this program is to improve the management of osteoporosis. After hearing and assimilating this program, the clinician will be better able to:

1. Appropriately manage teriparatide therapy in patients with osteoporosis.

Summary

Background: teriparatide, or injectable parathyroid hormone (PTH), is only anabolic agent approved by Food and Drug Administration (FDA) for treatment of osteoporosis; most osteoporosis agents, including bisphosphonates and denosumab, act as antiresorptives (they target osteoclasts and thus block breakdown of bone); anabolic agents target osteoblasts and thereby increase bone formation

Pharmacology: PTH therapy increases bone formation markers; because bone formation coupled with bone resorption, as bone formation increases, so does bone resorption; antiresorptive agents block bone resorption, resulting in coupled decrease in bone formation; intermittent PTH injections increase bone formation before resorption occurs, termed “anabolic window”; however, chronic elevation of PTH (eg, hyperparathyroidism) results in negative skeletal effects

Mechanism of action: PTH is 84-amino acid peptide; most of bone activity located in first 34 amino acids; teriparatide consists of PTH (1-34); full-length molecule (PTH [1-84]) used for osteoporosis in other countries and approved in United States for hypoparathyroidism; teriparatide given as subcutaneous abdominal injection

Pivotal trial: trial of 1637 postmenopausal women randomized to one of 2 doses of teriparatide or placebo found 40 μg dose resulted in ≈9% increase in spinal bone mineral density (BMD) over 21 mo, but had slightly higher rate of side effects compared to 20 μg dose; thus, FDA approved 20 μg dose; hip BMD increased by ≈3% in this trial; teriparatide has greatest effect on trabecular bone, which makes up most of bone in spine; thus spinal BMD responds particularly well to PTH therapy; trial found 65% relative risk reduction in vertebral fracture and 53% relative risk reduction in nonvertebral fracture

Clinical use: approved for 2 yr aggregate use; longer use considered off-label; has had limited adoption into clinical practice; teriparatide (Forteo) costs $500/mo, or $10,000 for 2 yr; many patients find daily subcutaneous injection disagreeable; because of cost and logistical factors, teriparatide often reserved for high-risk patients, including those with current vertebral fracture, severe osteoporosis, other osteoporotic fracture, and low BMD, those who have failed antiresorptive therapy, and those with glucocorticoid-induced osteoporosis

Combination Therapy

Overview: PTH increases bone formation, then resorption; antiresorptives decrease resorption, then formation; logic behind combination therapy proposes that PTH plus antiresorptive therapy synergistically increases bone formation with smaller increase in resorption, without negating each other

Sequential combination therapy: clinically relevant consideration because many patients have already taken antiresorptives; anabolic effect of teriparatide still evident after antiresorptive therapy, but somewhat blunted or delayed compared to treatment-naïve patients

Concurrent combination therapy: PTH and alendronate — study of 238 postmenopausal treatment-naïve women randomized to PTH alone, PTH plus alendronate, or alendronate alone found that PTH alone led to greatest increases in hip and spine BMD; study concluded that concurrent alendronate blunted effect of PTH and thus concurrent therapy not advantageous; zoledronic acid and PTH — trial of 360 patients randomized to PTH alone, zoledronic acid alone, or combination therapy found concurrent therapy had similar effect as PTH alone on spine BMD at 1 yr; concurrent therapy also had similar effect as zoledronic acid alone on hip BMD at 1 yr; although fracture not end point of trial, concurrent therapy cohort had no fractures at 1 yr, whereas groups on individual agents alone did experience fracture; denosumab and PTH — trial comparing each agent alone and combination therapy over 2 yr found that combination increased hip and spine BMD more than either drug alone; thus, PTH and denosumab first combination of drugs found to increase BMD more at spine and hip than either agent alone; denosumab may interfere less with PTH because of its mechanism of action or its potency; concurrent therapy limited by its cost; management of patients after concurrent course unknown

Sequential PTH/antiresorptive therapy: pivotal trial involved osteoporotic women given 1 yr of PTH therapy and then randomized to placebo or alendronate; group who received alendronate had continued increases in BMD, especially in spine, while those on placebo had decreased BMD; study concluded that PTH followed by nothing will result in most, but not all, of BMD gains; bisphosphonates seem to add to BMD gains after PTH therapy; study recommended that PTH therapy be followed by some type of antiresorptive

Readings

Black DM et al: One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 2005 Aug 11;353(6):555-65; Black DM et al: The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003 Sep 25;349(13):1207-15; Canalis E et al: Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 2007 Aug 30;357(9):905-16; Cosman F et al: Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res 2011 Mar;26(3):503-11; Neer RM et al: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001 May 10;344(19):1434-41; Tsai JN et al: Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013 Jul 6;382(9886):50-6.

Disclosures

For this program, the following has been disclosed: Dr. Schafer reported nothing to disclose. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Schwartz Schafer was recorded at the 13th Annual Osteoporosis: New Insights in Research, Diagnosis, and Clinical Care, presented by the Department of Epidemiology and Biostatistics, University of California, San Francisco, School of Medicine, and held July 21-22, 2016, in San Francisco, CA. For information about upcoming CME activities presented by the University of California, San Francisco, School of Medicine, please visit: meded.ucsf.edu/cme. The Audio Digest Foundation thanks the speakers and the University of California, San Francisco, School of Medicine, for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

FP651503

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.