ORLANDO—In the past several years, the osteoporosis treatment landscape has widened. New therapies are welcome in our armamentarium, especially for those with comorbidities. At the 2022 ACR Education Exchange, April 28–May 1, Kenneth G. Saag, MD, MSc, ACR president, professor of medicine and director, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, shared his expertise. Using three complicated cases, he walked through his thought process and the literature.
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A 75-year-old Asian woman with a history of breast cancer following surgery and radiation, and osteoporosis treated with alendronate for the past seven years presented to a clinic for further care. She had not suffered any interval fractures. Bone mineral density (BMD) T-scores at the lumbar spine, total hip and femoral neck were stable and improved on repeat dual-energy X-ray absorptiometry (DXA). Bone turnover markers suggested the bisphosphonate was functioning appropriately. She was worried about the “terrible side effects” of alendronate and wanted advice regarding continuation, discontinuation or change of therapy.
When polled, 60% of audience members elected to stop all therapy. Dr. Saag agreed with this approach given bisphosphonate safety considerations, such as osteonecrosis of the jaw and atypical femoral fractures, which increase with longer durations of bisphosphonate therapy. During a drug holiday, the rationale is that the risk of adverse events will decline rapidly, but the risk of osteoporotic fractures will increase slowly.
Assuming a risk of eight atypical (stress) fractures in 10,000 per year of treatment, the number needed to treat a patient with a bisphosphonate for three years to prevent hip fracture is 91, and to prevent radiographic vertebral fracture the number needed to treat a patient is 14. On the other hand, the number needed to harm in a three-year treatment period is 417. Thus, for each atypical fracture caused by bisphosphonates, at least 30 vertebral and five hip fractures are prevented.1,2
“It’s all about balancing risks and benefits,” Dr. Saag. “The risk of adverse events with bisphosphonates is higher in later years with greater exposure. [After] you stop therapy, the risk goes down.”
He was careful to note that among Asian women, the risk for atypical femoral fractures does seem to be higher than that of other women.3 “We aren’t sure why this is. It could be related to genetic factors or hip axis length geometry. But we’ve seen an increased risk in this group consistently,” he said.
Dr. Saag was careful to remind us that fracture risk does begin to increase the longer the time off therapy. Example: Discontinuing alendronate or risedronate for more than two years was associated with increased risk of hip and clinical vertebral fractures in a large observational cohort study of Medicare patients who had been taking bisphosphonates for at least three years.4
“Remember, it’s just a holiday,” he said. “It’s not a complete cessation of therapy. Osteoporotic risk goes up after two years off therapy, and just how much depends on what bisphosphonate [the patient] took before. Some bisphosphonates are stickier to bone than others. Risedronate is the least sticky.”
If you aren’t certain whether a drug holiday is appropriate for your patient, the American Society for Bone and Mineral Research Algorithm for Management of Postmenopausal Women on Long Term Bisphosphonate Therapy may help. Of note, the suggested approach is “based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations.”5
In this patient’s case, a holiday was deemed appropriate given improved hip BMD with a T-score greater than or equal to -2.5, no interval fractures and Asian ethnicity conferring a higher risk of adverse events with continued bisphosphonate therapy.
A 92-year-old woman with a history of chronic kidney disease (CKD), with glomerular filtration rate (GFR) of 32, and bilateral sacral alar fractures presented to establish care. In the past, she took alendronate, but had been off therapy for many years. Recent DXA revealed a T-score of -3.4 at the femoral neck. Metabolic bone evaluation was notable for a slightly low parathyroid hormone and slightly elevated alkaline phosphatase, consistent with remodeling of recent pelvic fractures. Calcium, phosphorous and 25-hydroxy vitamin D levels were normal.
In this case, Dr. Saag preferred either a parathyroid hormone analog, such as teriparatide or abaloparatide, or romosozumab because the patient was at very high fracture risk. In the Vertebral Fracture Comparisons in Severe Osteoporosis trial, the first active comparator study examining a parathyroid hormone analog (i.e., teriparatide) and bisphosphonate (i.e., risedronate) in a high-risk population, teriparatide conferred a significant risk reduction in people who previously had a major fracture.6
When it comes to parathyroid hormone analogs, clinicians must be aware of a few issues. Parathyroid hormone analogs may cause hypercalcemia, flushing and/or myalgia and arthralgia. The black box warning for osteosarcoma has been removed from both drugs given longitudinal experience, but they should be avoided in patients with a history of skeletal malignancies, bone metastases or skeletal radiation for this reason. Unfortunately, out-of-pocket cost remains prohibitive for many patients, which was also true for this patient. Thus, Dr. Saag opted for treatment with romosozumab followed by denosumab.
Romosozumab is a monoclonal antibody that inhibits sclerostin, “with a dual effect of increasing bone formation and decreasing bone resorption,”7 Dr. Saag said. “Romosozumab is an inhibitor of bone formation and, thus, highly anabolic. When compared with teriparatide and alendronate, it’s really the most impressive in terms of increasing BMD.”8
When compared with alendronate, romosozumab also significantly reduced the risk of new vertebral fracture at 12 and 24 months.9
After receiving romosozumab, the patient was switched to denosumab. Dr. Saag said, “After we use an osteoanabolic drug, we should follow it with an antiresorptive. The pivotal study by Cosman et al. demonstrated the importance of this [approach].”7
‘Osteoporotic risk goes up after two years off therapy, & just how much depends on what bisphosphonate [the patient] took before. Some bisphosphonates are stickier to bone than others.’ —Dr. Saag
A 48-year-old man with ulcerative colitis and spondyloarthritis on adalimumab, CKD with a GFR of 26, vertebral compression fracture on imaging and T-scores in the osteopenic range was referred for management. Although very low in the past, the patient’s 25-hydroxy vitamin D levels had normalized with supplementation. Calcium, phosphorous and 1,25-dihydroxyvitamin D levels were also normal. Parathyroid hormone and bone-specific alkaline phosphatase were slightly elevated. In the past, he was treated with several months of high-dose glucocorticoids.
Given the complexity of the case, Dr. Saag walked us through his thought process. The differential diagnosis included glucocorticoid-induced osteoporosis, metabolic bone disease due to CKD and vitamin D malabsorption with possible secondary hyperparathyroidism.
When it came to therapy, Dr. Saag said, “I wasn’t sure any of our drugs were good options, or that he even had osteoporosis. About 15% of men have evidence of vertebral compression fractures on imaging prior to the age of 50—so this may not have been an osteoporotic fracture after all. And for him, I was particularly worried about adynamic bone disease, which is a contraindication to antiresorptives.”
Adynamic bone disease is a type of renal osteodystrophy characterized by low or absent bone turnover in the context of a marked reduction in both osteoblast and osteoclast numbers. Bone biopsy remains the gold standard for diagnosis.
For this patient, Dr. Saag opted not to treat for osteoporosis. Instead, he recommended maintaining adequate vitamin D levels, monitoring for hyperparathyroidism and consideration of a bone biopsy.
The treatment of osteoporosis includes more than just bisphosphonates these days, and that’s a good thing. But careful consideration of a patient’s comorbidities—as well as the risks and benefits of continuing and discontinuing therapy—are paramount when it comes to protecting our patients from fractures.=
Samantha C. Shapiro, MD, is an academic rheumatologist and an affiliate faculty member of the Dell Medical School at the University of Texas at Austin. She received her training in internal medicine and rheumatology at Johns Hopkins University, Baltimore. She is also a member of the ACR Insurance Subcommittee.
- Stevenson JC. Bisphosphonates and atypical femoral shaft fractures. N Engl J Med. 2011 Jul 28;365(4):377; author reply 377.
- Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011 May 5;364(18):1728–1737.
- Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020 Aug 20;383(8):743–753.
- Curtis JR, Saag KG, Arora T, et al. Duration of bisphosphonate drug holidays and associated fracture risk. Med Care. 2020 May;58(5):419–426.
- 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.
- Kendler DL, Marin F, Zerbini CAF, et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): A multicentre, double-blind, double-dummy, randomised controlled trial. Lancet. 2018 Jan 20;391(10117):230–240.
- Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016 Oct 20;375(16):1532–1543.
- McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014 Jan 30;370(5):412–420.
- Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 2017 Oct 12;377(15):1417–1427.