ACR CONVERGENCE 2020—Bisphosphonates are an important treatment for millions of older Americans with osteoporosis because the drugs inhibit osteoclastic bone resorption to reduce the risk of painful, debilitating fractures.1
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More than 20 years ago, data emerged that bisphosphonates have a long terminal half-life.2 So after years of therapy, could some patients take a drug holiday? At the ACR Convergence 2020 session Bone for the Holidays: Antiresorptives, Atypical Fractures and Other Adverse Events, osteoporosis experts shared updated treatment recommendations on bisphosphonate holidays and discussed serious, atypical fractures that affect a small number of patients who take bisphosphonates and even those who have discontinued therapy.
Bisphosphonate holiday benefits include a reduced risk of such side effects as osteonecrosis of the jaw, subtrochanteric fractures and gastric irritation, although one concern is patients could have another fracture, said rheumatologist Karen E. Hansen, MD, MS, professor of medicine at the University of Wisconsin School of Medicine and Public Health, Madison.
“A person taking a drug holiday might have a decline in bone density or may be lost to follow-up and then have a fracture. They may reduce their adherence to a bone-healthy lifestyle—including exercise, adequate calcium and vitamin D intake, and avoidance of bone toxins like alcohol and tobacco,” Dr. Hansen said.
Fracture Risk Differences
Two major trials explored holiday benefits and risks. In an extension trial of 2,629 post-menopausal women who had already received three annual doses of intravenous zoledronic acid, participants received either three more years of zoledronate or placebo.3 Women who continued zoledronic acid had fewer vertebral fractures, but other fractures were not reduced, and the absolute difference in fracture risk between the two groups was 3%, small but significant.
In another trial, 3,236 post-menopausal women who had previously taken three or more years of alendronate and who also had either stable or increased hip T-score above -3.5 were recruited for an extension trial. After some exclusions, 1,099 women were randomized to receive either alendronate or placebo for five or 10 more years. The primary outcome for this trial was total hip bone mineral density, which did drop slightly in the placebo group. But bone density was maintained in the trochanter and femoral neck bones, and it also rose in the lumbar spines of patients in the placebo group.4
“What was fascinating was that there was no difference in radiographic vertebral fractures or non-spine fractures whether the women took alendronate for five or 10 years,” said Dr. Hansen. “There was a small difference in painful compression fractures in this trial, with a benefit to continue alendronate.”
According to one post-hoc analysis of this trial’s data, women whose hip T-scores remained low seem to benefit from continuing alendronate.5 Another post-hoc analysis looked at the 437 women in the placebo group and found their new fractures were not predicted by three important markers of declining bone: one-year changes in hip bone density, one-year changes in the bone resorption marker N-telopeptide or one-year changes in bone-specific alkaline phosphatase. They were at higher risk for new fractures if their femoral neck T-score was -2.5 or lower when they stopped alendronate or if they had a 3% or greater decline in total hip bone mineral density over two years.6
In 2016, the American Society for Bone and Mineral Research (ASBMR) updated its guideline on bisphosphonate holidays. In post-menopausal women treated with oral bisphosphonates for five or more years or intravenous therapy for three or more years, it recommends:
- If the patient has had a hip, spine or multiple other osteoporotic fractures before or during bisphosphonate therapy, consider continuing the current bisphosphonate or changing to an alternative drug, then reassess every two to three years.
- If the patient has not had one of these fractures before or during therapy, consider if their hip bone mineral density T-score is 2.5 or lower or if they are at a high fracture risk.
- If so, consider continuing bisphosphonates for up to 10 more years or changing to an alternative drug, then reassess every two to three years.
- If not, consider a drug holiday and reassess every two to three years.
According to the guideline, high fracture risk factors include being age 70 or older and a Fracture Risk Assessment Tool (FRAX) score above their country-specific threshold for treatment, a low hip T-score, a major osteoporotic fracture before or during bisphosphonate therapy or a new diagnosis or drug that may affect bone density, such as glucocorticoids or aromatase inhibitors.7
Questions to Consider
When considering a drug holiday for her patients, Dr. Hansen looks at their current FRAX and hip T-score, past adherence to therapy, whether they sustained a spine or hip fracture before or during therapy, whether their bone mineral density changed during therapy, how often they fall, and if they have any ongoing risk factors for bone loss, including glucocorticoids, cancer or weight loss. She also asks her patients about their preferences. Some are eager to stop their bisphosphonates, and others fear fracture risk and wish to continue their therapy, she said.
“We ask them to continue their healthy lifestyle habits. Exercise, especially to improve strength and balance, is very important, because this reduces the risk of falling.” Dr. Hansen counsels patients to consume adequate calcium, vitamin D and protein, and to avoid tobacco and excess alcohol. “We also ask patients to contact us if they have a clinical fracture or any evidence of a silent compression fracture, such as sudden height loss.”
Patients on a drug holiday should have periodic dual X-ray absorptiometry (DXA) to watch for bone density declines that indicate increased fracture risk, Dr. Hansen said. Obtaining a baseline total hip T-score as their holidays begin may guide clinicians on how often to scan, according to recent data that suggested patients with higher scores may not need another bone density scan for five years.8
Atypical Femur Fractures
Elizabeth Shane, MD, professor of medicine at Columbia University’s College of Physicians and Surgeons, New York City, discussed atypical femur fractures (AFFs), which—along with osteonecrosis of the jaw—are a rare but serious possible adverse event associated with bisphosphonates that cause alarm and a drop in prescriptions.
“A portion of this decline may be appropriate, relative to the precise targeting of people who may be at greater fracture risk or when it comes to initiating drug holidays,” said Dr. Shane, who expressed concern that both media reports and U.S. Food & Drug Administration safety warnings about atypical femur fractures caused patients to avoid therapy that not only reduces hip fractures but saves lives, she said. 9,10
Ordinary femoral neck and intertrochanteric hip fractures account for up to 95% of hip fractures in elderly patients, and atypical femur fractures are only a small subset and account for less than five of every 1,000 hip fractures.11
On imaging, AFFs are more horizontal and have much thicker cortices than other hip fractures, Dr. Shane said. In 2014, the ASBMR revised its definition of AFFs; four out of five features are now required for diagnosis:12
- Minimal or no trauma;
- Fracture line originates at the lateral cortex, is substantially transverse in orientation and may become oblique as it progresses medially;
- Non-comminuted or minimally comminuted fracture;
- Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex; and
- Localized periosteal or endosteal thickening of the lateral cortex at the fracture site, also called beaking or flaring.
Atypical femur fractures also tend to cause prodromal pain in the groin or thigh in 70% of patients, unlike other hip fractures, and about 26% of patients are slow to heal. Although bilaterality is seen in only 28% of patients with AFFs, up to 60% have radiographic changes on their other side.13
Even though these fractures are relatively rare, recent data show “consistent evidence of increased AFF incidence with longer duration of bisphosphonate treatment, especially greater than five years,” said Dr. Shane.14
In a 2020 study of 1.1 million women aged 50 and older, including 18% who had used bisphosphonates, incidence of atypical femur fractures was very low, or 1.74 cases per 10,000 person-years, and very few cases were seen among women who had never taken the drugs. AFFs were highest among women between ages 65 and 84, and more prevalent in Asian women than white women. AFF incidence decreased over the time span since the women discontinued bisphosphonates, the study found. “Within just three months of stopping, incidence of AFFs decreased markedly,” encouraging data for people who are considering a drug holiday, Dr. Shane said.
According to the study, important risk factors for AFFs include glucocorticoid use, shorter height and higher body weight, but no association was found between AFF risk and bone mineral density, and no statistically significant increased risk among women who smoke. The estimated number of hip and clinical fractures prevented by five years of bisphosphonates outweighed the number of AFFs in both white and Asian women in the study.15
We have to find more effective ways to communicate that osteoporotic fractures have devastating effects on people’s lives.—Elizabeth Shane, MD
Atypical Femur Fractures Pathogenesis
Because AFFs often cause prodromal pain, unlike other hip fractures, they may have a distinct pathogenesis, and “it’s very likely that they are a form of stress or insufficiency fracture,” Dr. Shane said. AFFs affect bones subjected to repetitive loading, and microcracks often develop in areas where tensional stress is high, or where the convex curve of the femur straightens and tensile forces concentrate.12
“We also think that there is increased homogeneity of osteons, because bisphosphonates increase tissue age and mineralization, permitting these microcracks to accumulate and coalesce over time, then gradually aggregate and propagate across the bone,” Dr. Shane explained.
Women with a varus hip angle, bowed femurs or smaller bones may be at risk for AFFs, because these factors place stress on the lateral femur, she said. This extra stress may account for cortical thickening common in AFFs, but is not associated with bisphosphonate use.16
Stress fractures also heal differently, which may lead to delayed healing. “They heal by osteoclasts resorbing damaged bone and then osteoblasts depositing new bone at that site.17 But bisphosphonates localize at the site of microdamage and stress fractures, and they inhibit osteoclast-mediated bone resorption. Over time, bisphosphonates could both facilitate the development of microcracks and delay their repair, allowing them to progress to a stress fracture,” Dr. Shane said.18
Prevention & Treatment
Strategies to reduce AFF risk in patients on bisphosphonates include drug holidays, but rheumatologists may also watch for prodromal pain symptoms, and ask patients about unexplained hip or thigh pain at office visits.18,13 Imaging, including extended femur DXA scans or single-energy femoral scans, may help identify incipient AFFs.19,20
Surgical treatments include fixation with intramedullary, full-length nails and fracture augmentation with bone marrow aspirate.21,22 After surgery, physicians should image the contralateral femur to assess for incomplete fracture on the other side, because bilaterality is so common, Dr. Shane noted.
Dr. Shane said she stops antiresorptive therapy after surgery, and that some physicians prescribe teriparatide after surgery to speed healing. Data from a 2020 study showed 40% of patients with incomplete AFFs progressed while on teriparatide, although patients with complete AFFs seemed to heal faster. However, no evidence has shown teriparatide enhances AFF healing, and in patients with AFFs who are still at high risk for fractures, three to six months of teriparatide may suffice. If patients are on teriparatide for two years, Dr. Shane recommends that physicians monitor bone turnover markers and bone mineral density, and then consider another antiresorptive therapy, such as estrogen, synthetic estrogen receptor modulators, calcitonin, denosumab or bisphosphonates.23
“While AFFs are definitely related to long-term bisphosphonate use, we are not yet sure that it is causal,” said Dr. Shane. “In my patients’ view, AFFs are not rare. They feel that AFFs are underreported, and to quote one of my patients, ‘the risk is low unless it happens to you.’ As clinicians and scientists, we have to find more effective ways to communicate that osteoporotic fractures have devastating effects on people’s lives. Bisphosphonates and denosumab can reduce these fractures. But we need to listen to patients’ concerns.”
Susan Bernstein is a freelance journalist based in Atlanta.
- Solomon CG. Bisphosphonates and osteoporosis. New Engl J Med. 2002 Feb 28;346(9):642.
- Khan SA, Kanis JA, Vasikaran S, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res. 1997 Oct;12(10):1700–1707.
- Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: A randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012 Feb;27(2):243–254.
- Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: The Fracture Intervention Trial Long-Term Extension (FLEX): A randomized trial. JAMA. 2006 Dec 27;296(24):2927–2938.
- Black DM, Bauer DC, Schwartz AV, et al. Continuing bisphosphonate treatment for osteoporosis—For whom and for how long? New Engl J Med. 2012 May 31;366(22):2051–2053.
- Bauer DC, Schwartz AV, Palermo L, et al. Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: The FLEX study. JAMA Intern Med; 2014 Jul;174(7):1126–1134.
- Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016 Jan;31(1):16–35.
- McNabb B, Vittinghoff E, Eastell R, et al. A model of BMD changes after alendronate discontinuation to guide post-alendronate BMD monitoring. J Clin Endocrinol Metab. 2014 Nov;99(11):4094–4100.
- Jha S, Wang Z, Laucis N, et al. Trends in media reports, oral bisphosphonate prescriptions and hip fractures: 1996–2012: An ecological analysis. J Bone Miner Res. 2015 Dec;30(12):2179–2187.
- Kim SC, Kim DH, Mogun H, et al. Impact of U.S. Food and Drug Administration’s safety-related announcements on the use of bisphosphonates after hip fracture. J Bone Miner Res. 2016 Aug;31(8):1536–1540.
- Black DM, Abrahamsen B, Bouxsein ML, et al. Atypical femur fractures: Review of epidemiology, relationship to bisphosphonates, prevention and clinical management. Endocr Rev. 2019 Apr 1;40(2):333–368.
- Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: Second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014 Jan;29(1):1–23.
- Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010 Nov;25(11):2267–2294.
- 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 Aug;28(8):1729–1737.
- Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. New Engl J Med. 2020 Aug 20;383(8):743–753.
- Unnanuntana A, Ton QV, Kleimeyer JP, et al. A fracture does not adversely affect bone mineral density responses after teriparatide treatment. Clin Orthop Relat Res. 2012 Mar;470(3):927–936.
- Unnanuntana A, Rebolledo BJ, Khair MM, et al. Diseases affecting bone quality: Beyond osteoporosis. Clin Orthop Relat Res. 2011 Aug;469(8):2194–2206.
- Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. New Engl J Med. 2011 May 5;364(18):1728–1737.
- Van de Laarschot DM, Smits AA, Buitendijk SK, et al. Screening for atypical femur fractures using extended femur scans by DXA. J Bone Miner Res. 2017 Aug;32(8):1632–1639.
- McKenna MJ, McKiernan FE, McGowan B, et al. Identifying incomplete atypical femoral fractures with single-energy absorptiometry: Declining prevalence. J Endocr Soc. 2017 Feb 13;1(3):211–220.
- Weil YA, Rivkin G, Safran O, et al. The outcome of surgically treated femur fractures associated with long-term bisphosphonate use. J Trauma. 2011 Jul;71(1):186–190.
- Lovy AJ, Kim JS, Di Capua J, et al. Intramedullary nail fixation of atypical femur fractures with bone marrow aspirate concentrate leads to faster union: A case-control study. J Orthop Trauma. 2017 Jul;31(7):358–362.
- Van de Laarschot DM, McKenna MJ, Abrahamsen B, et al. Medical management of patients after atypical femur fractures: A systematic review and recommendations from the European Calcified Tissue Society. J Clin Endocrinol Metab. 2020 May 1;105(5):1682–1699.