patient care perspectives

Antiresorptive and Anabolic Agents for Postmenopausal Osteoporosis

by Tom Iarocci, MD

Overview

Antiresorptive therapy with bisphosphonates is the mainstay of first-line postmenopausal osteoporosis treatment. Anabolic agents are increasingly recognized as an important part of the treatment armamentarium.

Expert Commentary

Tom Iarocci, MD

Editor-in-Chief, Expert Perspectives in Medicine
University of Maryland School of Medicine
Baltimore, MD

“A radiographically diagnosed incident vertebral fracture imparts a risk that is similar to that seen after clinical fractures, and awareness is growing about the need for the appropriate screening, treatment, and/or referral of post-fracture patients.”

Tom Iarocci, MD

Osteoporosis is diagnosed by the presence of a fragility fracture or by dual-energy x-ray absorptiometry in the absence of a fragility fracture. Antiresorptive treatment remains the mainstay of first-line treatment for postmenopausal osteoporosis and includes the bisphosphonates and the RANKL inhibitor denosumab. Both have been shown to reduce the risk of fracture substantially in those who have been diagnosed with osteoporosis. Anabolic treatments, which build bone, are not considered first-line agents for osteoporosis; however, these agents are rapidly effective and potent such that they might be considered in certain scenarios involving patients who have just sustained an osteoporotic fracture. Costs and the need for daily administration with anabolic agents are prohibitive in some cases. Whichever treatment is deemed appropriate, a radiographically diagnosed incident vertebral fracture imparts a risk that is similar to that seen after clinical fractures, and awareness is growing about the need for the appropriate screening, treatment, and/or referral of post-fracture patients.

US Food and Drug Administration–approved anabolic agents include the parathyroid hormone (PTH)–based treatments teriparatide and abaloparatide, and also the sclerostin inhibitor romosozumab. Both PTH-based treatments have a black box warning for osteosarcoma based on studies in rats, and the maximum treatment duration is capped at 2 years. Osteosarcoma is a very rare cancer, which creates challenges for epidemiologic study. Teriparatide was introduced in 2002, there have been more than 1 million human users, and the rate of osteosarcoma has not been greater than expected. Both teriparatide and abaloparatide exert their effects by binding the PTH receptor in a fashion that stimulates the building of bone, but they differ in their activity at the receptor. Teriparatide is a PTH analog, while abaloparatide is a PTH-related peptide analog. Abaloparatide binds more selectively than teriparatide to a particular conformation of the PTH type 1 receptor and favors bone formation while minimizing the effects of more prolonged activation (eg, bone resorption, hypercalcemia).

“Fragility fractures are estimated to affect 3 million people in the United States each year, and since they are associated with a significant mortality rate, the prevention of these fractures is of the highest importance.”

Tom Iarocci, MD

The evidence base for anabolic agents for fracture reduction is more limited in terms of number of trials and number of patients studied; however, investigations of these agents in a variety of settings have generated positive results. Guidelines vary in their consideration of anabolic agents.

While the optimal sequence and duration of treatment for postmenopausal osteoporosis therapies remain uncertain, most sources are in agreement that the benefits of treatment greatly outweigh the risks for patients who have already incurred a fragility fracture. Fragility fractures are estimated to affect 3 million people in the United States each year, and since they are associated with a significant mortality rate, the prevention of these fractures is of the highest importance. At-risk patients include older individuals and those with thyroid disease, diabetes, hypertension, and heart disease. Lifestyle factors such as smoking and high alcohol intake, as well as the use of oral or systemic glucocorticoids, increase the risk of fragility fractures.

References

Andrews EB, Gilsenan A, Midkiff K, Harris D. Challenges in studying very rare cancer outcomes and infrequent exposures: example of teriparatide and osteosarcoma. Ann Epidemiol. 2016;26(11):751-753.

Black DM, Rosen CJ. Clinical practice. Postmenopausal osteoporosis [published correction appears in N Engl J Med. 2016;374(18):1797]. N Engl J Med. 2016;374(3):254-262. 

Bledsoe L, Alessi K, Toro JB, Giordano B, Hanypsiak BT. Fragility fractures: diagnosis and treatment. Am J Orthop (Belle Mead NJ). 2018;47(12).

Bone HG, Cosman F, Miller PD, et al. ACTIVExtend: 24 months of alendronate after 18 months of abaloparatide or placebo for postmenopausal osteoporosis. J Clin Endocrinol Metab. 2018;103(8):2949-2957.

Boonen S, Marin F, Obermayer‐Pietsch B, et al; EUROFORS Investigators. Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2008;93(3):852-860.

Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016. Endocr Pract. 2016;22(Suppl 4):1-42.

Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis [published correction appears in Osteoporos Int. 2015;26(7):2045-2047]. Osteoporos Int. 2014;25(10):2359-2381.

Cosman F. The evolving role of anabolic therapy in the treatment of osteoporosis. Curr Opin Rheumatol. 2019;31(4):376-380.

Eastell R, Mitlak BH, Wang Y, Hu M, Fitzpatrick LA, Black DM. Bone turnover markers to explain changes in lumbar spine BMD with abaloparatide and teriparatide: results from ACTIVE. Osteoporos Int. 2019;30(3):667-673.

Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society* clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595-1622.

Hattersley G, Dean T, Corbin BA, Bahar H, Gardella TJ. Binding selectivity of abaloparatide for PTH-type-1-receptor conformations and effects on downstream signaling. Endocrinology. 2016;157(1):141-149.

Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285(3):320-323.

Miller PD, Hattersley G, Riis BJ, et al; ACTIVE Study Investigators. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial [published correction appears in JAMA. 2017;317(4):442]. JAMA. 2016;316(7):722-733.

Sleeman A, Clements JN. Abaloparatide: a new pharmacological option for osteoporosis. Am J Health Syst Pharm. 2019;76(3):130-135.

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