patient care perspectives

Risks vs Benefits of Osteoporosis Medications: Cutting Through the Noise

by Tom Iarocci, MD


The risk-benefit ratio is positive for most women with postmenopausal osteoporosis, but many are more comfortable forgoing treatment. For those patients aged 65 years and older with vertebral or hip fractures, there is consensus that the benefits of treatment almost always outweigh the risks.

Expert Commentary

Tom Iarocci, MD

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

Over the years, antiresorptive and anabolic medications have improved the health of patients by reducing the risk of fracture. Decades of data from randomized controlled trials have demonstrated that osteoporosis medications can reduce vertebral fractures by 40% to 70%, nonvertebral fractures by 20% to 36%, and hip fractures by up to 40%. Guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology strongly recommend pharmacologic therapy for patients with osteopenia or low bone mass and a history of fragility fracture of the hip or spine, as well as for those with a T-score of -2.5 or lower (in the lumbar spine, femoral neck, total hip, or distal one-third radius). When the T-score is between -1.0 and -2.5, pharmacologic treatment is strongly recommended in the United States if the 10-year probability of major osteoporotic fracture is 20% or higher or if the 10-year probability of hip fracture is 3% or higher.

Nonetheless, patients may favor forgoing treatment. The treatment of osteoporosis does include important nonpharmacologic components, such as physical activity, risk factor reduction, and calcium and vitamin D supplementation. However, these measures have not been shown to produce the sizable, significant reduction in fracture risk that is sought in the treatment of high-risk patients.

“Black and colleagues recommend framing the patient discussion such that the potential risks of these rare events are raised, but in the context of the much greater anticipated benefits in terms of overall reduction in the risk of fractures.”

Tom Iarocci, MD

Many patients with osteoporosis have concerns about the side effects of osteoporosis medications, including atypical fractures and osteonecrosis of the jaw. Fear of these events leads some patients to forgo or discontinue pharmacologic treatment for their osteoporosis. Barring contraindication, bisphosphonates are the preferred initial treatment and are effective in preventing symptomatic fragility fractures during the first few years of use. Prolongation of bisphosphonate treatment does not appear to improve the initial benefit any further, and the risk of atypical femoral fracture increases with every year of use, so treatment should not be continued indefinitely. Thus, the concept of 3 to 5 years of bisphosphonate therapy followed by reevaluation has been advanced, with the potential for a drug holiday in low-risk patients. Multiple studies have found a relatively low incidence of the 2 rare treatment-associated adverse events (ie, osteonecrosis of the jaw, atypical fracture), which may be reassuring to patients.

•    In systematic review by Khan et al, the incidence of osteonecrosis of the jaw was estimated at 0.001% to 0.01% in the osteoporosis patient population, which is only slightly higher than in the general population. The more markedly increased incidence that raised concerns initially was seen in oncologic patients, who receive different treatment regimens (eg, higher doses of parenteral bisphosphonates and denosumab). 

•    In multiple studies of atypical fractures and osteoporosis treatment (mostly bisphosphonates), the incidence of these fractures was low, ranging from approximately 1 in 100,000 to 5 in 10,000 among bisphosphonate users. 

•    According to Black et al, results data from reviews and meta-analyses suggest a highly favorable risk-benefit ratio associated with treatment for up to 5 years in women with osteoporosis, with fewer than 1 event caused per 100 fractures prevented. Further, the risk-benefit ratio for osteoporosis treatment is positive for most women with osteoporosis. 

Black and colleagues recommend framing the patient discussion such that the potential risks of these rare events are raised, but in the context of the much greater anticipated benefits in terms of overall reduction in the risk of fractures. 

“For those patients aged 65 years and older with vertebral or hip fractures, there is consensus that the benefits of treatment almost always outweigh the risks. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce the risk of future fracture.”

Tom Iarocci, MD

A history of fragility fracture is an important risk factor for subsequent fracture in both men and women. For those patients aged 65 years and older with vertebral or hip fractures, there is consensus that the benefits of treatment almost always outweigh the risks. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce the risk of future fracture. 

The American Society for Bone and Mineral Research engaged the Center for Medical Technology Policy to help develop a consensus of a broad multistakeholder coalition regarding several aspects of osteoporosis treatment. The coalition developed numerous recommendations, including increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. It also emphasized that the occurrence of hip or vertebral fracture is sufficient to establish a diagnosis of osteoporosis regardless of bone mineral density, and that patients with bone mineral density results that fall outside the “usual” diagnostic parameters for osteoporosis can benefit from pharmacotherapy. Oral bisphosphonates alendronate and risedronate are first-line options post fracture and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Medicare Part A (hospital insurance) and Medicare Part B (medical insurance) help to pay for an injectable drug for osteoporosis and visits from a home health nurse to inject the drug if conditions are met, and a bone fracture that a doctor certifies as being related to postmenopausal osteoporosis is one of these conditions. The optimal duration of pharmacotherapy is unknown; however, the risk for second fractures is highest in the early post-fracture period, so prompt treatment is recommended. 

In the special case of postmenopausal women who have been taking bisphosphonates for less than 5 years and who have a typical osteoporotic fragility fracture, practitioners may or may not decide to discontinue bisphosphonates; additional evaluation and consideration of alternative therapy might be needed (eg, when there are concerns that the patient is not absorbing or responding to bisphosphonates). In the case of an atypical fracture, however, the continued use of bisphosphonates has been associated with delayed healing.

The risks of untreated osteoporosis are generally well known to providers, but perhaps less so to patients. Fractures of the hip are associated with an increased mortality rate of 10% to 20% and substantial morbidity, with limitation of ambulation, loss of independence, chronic pain, and depression. For patients, some treatment reluctance may relate to a low perceived need, due to a low perceived individual risk from osteoporosis. Thus, many at-risk patients may benefit from revisiting the risk of nontreatment. 

For patients at high risk of fracture, particularly those with vertebral fractures, the coalition stated that anabolic agents may be useful, although consultation with or referral to a specialist would also be appropriate. The authors noted that primary care providers who are treating patients aged 65 years and older with a hip or vertebral fracture may also want to consider referral to an endocrinologist or osteoporosis specialist for those patients who, while on pharmacotherapy, continue to experience fractures or bone loss without an obvious cause or who have comorbidities or other factors that complicate treatment (eg, hyperparathyroidism, chronic kidney disease).


Alami S, Hervouet L, Poiraudeau S, Briot K, Roux C. Barriers to effective postmenopausal osteoporosis treatment: a qualitative study of patients’ and practitioners’ views. PLoS One. 2016;11(6):e0158365.

Black DM, Kelly MP, Genant HK, et al; Fracture Intervention Trial Steering Committee; HORIZON Pivotal Fracture Trial Steering Committee. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 2010;362(19):1761-1771.

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.

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.

Conley RB, Adib G, Adler RA, et al. Secondary fracture prevention: consensus clinical recommendations from a multistakeholder coalition. J Bone Miner Res. 2020;35(1):36-52.

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.

Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review. Ann Intern Med. 2014;161(10):711-723.

Danila MI, Outman RC, Rahn EJ, et al. Evaluation of a multimodal, direct-to-patient educational intervention targeting barriers to osteoporosis care: a randomized clinical trial. J Bone Miner Res. 2018;33(5):763-772.

Edwards BJ, Bunta AD, Lane J, et al. Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project. J Bone Joint Surg Am. 2013;95(4):297-307.

Feldstein AC, Black D, Perrin N, et al. Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res2012;27(5):977-986.

Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res. 2013;28(8):1729-1737.

Ioannidis G, Papaioannou A, Hopman WM, et al. Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study. CMAJ. 2009;181(5):265-271.

Khan AA, Morrison A, Hanley DA, et al; International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3-23. Osteoporosis drugs. Accessed January 23, 2020.

Riggs BL, Melton LJ III. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone. 1995;17(5 Suppl):505S-511S.

Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop. 2015;86(1):100-107.

Weaver J, Sajjan S, Lewiecki EM, Harris ST, Marvos P. Prevalence and cost of subsequent fractures among U.S. patients with an incident fracture. J Manag Care Spec Pharm. 2017;23(4):461-471.

Yun H, Curtis JR, Guo L, et al. Patterns and predictors of osteoporosis medication discontinuation and switching among Medicare beneficiaries. BMC Musculoskelet Disord2014;15:112.

More in Osteoporosis



Preventing an Epidemic of New Osteoporotic Fractures in America

Clinical Topic Updates by Tom Iarocci, MD

The long-standing gap in osteoporosis care is poised to usher in an epidemic of new fractures, threatening a return to high rates of hip fracture a...READ MORE



Antiresorptive and Anabolic Agents for Postmenopausal Osteoporosis

Patient Care Perspectives by Tom Iarocci, MD

Antiresorptive therapy with bisphosphonates is the mainstay of first-line postmenopausal osteoporosis treatment. Anabolic agents are increasingly r...READ MORE



Updated Osteoporosis Treatment Recommendations Begin Consensus Building

Clinical Topic Updates by Tom Iarocci, MD

A multistakeholder coalition assembled by the American Society for Bone and Mineral Research reached agreement in key areas after recognizing a lac...READ MORE

More In Osteoporosis


Osteoporosis Care: Innovations and Paths to Success

Clinical Topic Updates by Tom Iarocci, MD


Osteoporotic Fracture Risk in Patients With Age-Associated Comorbidities

Patient Care Perspectives by Tom Iarocci, MD