Treatment Considerations for the Worldwide Osteoporosis Pandemic
SINGAPORE—In many countries around the world, societies are dealing with the effects of an aging population. This trend has been particularly pronounced in Asia, where the phenomenon even has a striking label: the Silver Tsunami.
At the 26th Congress of the Asia Pacific League of Associations for Rheumatology (APLAR) in August 2024, Kenneth Saag, MD, MSc, professor of medicine, Jane Knight Lowe Endowed Chair in the Department of Medicine, division director of Clinical Immunology and Rheumatology, the University of Alabama at Birmingham, gave a talk focused on critical challenges and solutions in the field of osteoporosis management, a timely and important topic related to this larger theme.
Bisphosphonate Use
Dr. Saag began his lecture with several items of particular interest to the audience at this conference, which focused on issues relevant to patients and providers in the Asia-Pacific region. He noted that, by 2050, about 50% of all hip fractures worldwide are expected to occur in Asia—particularly in China.1 Additionally, Asian patients appear to be at an increased risk of atypical femur fractures—a rare, but significant, potential side effect of bisphosphonate medications—than non-Asian individuals.2
This combination of circumstances poses a challenge for clinicians in the Asia-Pacific region, as well as for those caring for patients of Asian descent in all countries. The situation further demonstrates the importance of balancing the risks and benefits of treatments for osteoporosis, something rheumatologists are quite familiar with in recent years.
Drug Holidays
Long-term bisphosphonate use has been associated with atypical femur fractures and osteonecrosis of the jaw. Thus, the concept of drug holidays emerged with the goal of reducing the risk of insufficiency fractures while sustaining the durable, long-term treatment effects of preventing fragility fractures.
The National Osteoporosis Foundation has recommended a comprehensive risk assessment after three to five years of bisphosphonate treatment. The assessment should focus on intercurrent fractures, chronic diseases and medications, height measurements, vertebral imaging and bone mineral density testing to evaluate if a drug holiday is reasonable.3 In this same vein, the American Society for Bone and Mineral Research recommends initiating a drug holiday after three years of intravenous (IV) bisphosphonate use or five years of oral bisphosphonate use in postmenopausal patients with low fracture risk and a T-score of more than -2.5 at the hip.4
Dr. Saag stressed that decisions about continuing or pausing therapy should be tailored to each individual patient. Clinicians should engage in shared decision making with patients when it comes to such choices.
Zoledronic Acid
Of note, Dr. Saag referenced data that raises the possibility that doses of less than 5 mg of zoledronic acid, an IV bisphosphonate, and/or administration of the medication less frequently than the general practice of once per year may still be effective for the treatment of osteoporosis.
In 2002, Reid et al. published a phase 2 clinical trial that lasted for one year and enrolled postmenopausal women who were then randomized to receive placebo or one of six treatments with IV zoledronate. For the active treatment groups, total doses of zoledronate included 1 mg, 2 mg and 4 mg doses and the interval of administration could be at three, six or 12 months. Overall, the effects of each treatment on surrogate markers (i.e., bone health, bone turnover markers and bone density) were superior to those of placebo and similar to one another in the treatment arms.5 A 5 mg annual dose was ultimately chosen to be studied in the subsequent phase 3 trial. However, the phase 2 study indicates that this may not be the only dose and interval at which the medication is effective.
Indeed, Dr. Saag noted that, in certain lower risk patients who he sees in clinical practice, he will sometimes dose IV zoledronic acid less frequently than once per year.
Alternatives
Dr. Saag discussed the twists and turns in the story of denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), as an osteoporosis treatment.
In 2009, Cummings et al. published the FREEDOM trial, which demonstrated that administration of twice yearly subcutaneous denosumab for 36 months was associated with reduced risk of vertebral, nonvertebral and hip fractures in postmenopausal women with osteoporosis.6 However, a post-hoc analysis of the trial and its extension study showed that the rate of vertebral fractures increased in patients who discontinued denosumab and that a majority of these patients had multiple vertebral fractures.7 These data led to the recommendation that, in patients who discontinue denosumab, the transition to a different antiresorptive agent should be made quickly.
Dr. Saag agreed with this concept and proposed IV zoledronic acid as a potential treatment option. He also stated that it’s important to discuss with patients the potential risks of starting and then stopping denosumab therapy. It’s essential to have a long-term plan in mind when initiating treatment.
Romosozumab
Next, Dr. Saag discussed romosozumab, a humanized monoclonal antibody sclerostin inhibitor that is approved by the U.S. Food & Drug Administration for the treatment of postmenopausal women with osteoporosis.
The history behind the development of romosozumab is fascinating and has to do with a condition known as sclerosteosis, a rare bone dysplasia most common among Dutch Afrikaners in South Africa. Sclerosteosis is caused by six different types of loss-of-function mutations of the SOST gene. In homozygous patients, the condition results in a reduced production of sclerostin and subsequent bony deformities and the impingement of nerves, such as cranial nerves, due to an overgrowth of bones in the skull, ribs, mandible, clavicles, pelvis and long bones. However, heterozygous carriers of these mutations experience increased bone mass in the absence of symptoms. Thus, scientists identified sclerostin as a novel target for drug development and, ultimately, produced romosozumab, which is given as a monthly subcutaneous injection for 12 months.8
In 2016, Cosman et al. published the FRAME study, which demonstrated that treatment with romosozumab was associated with a decreased risk of vertebral fracture compared with placebo in postmenopausal women with osteoporosis.8 Dr. Saag explained that, when indicated, it’s best to use romosozumab before an antiresorptive agent because doing so yields larger mean bone mineral density increases and greater bone mineral density responder rates than using romosozumab after an antiresorptive medication.9
In Sum
Although osteoporosis can be a silent but morbid condition, the lessons imparted by Dr. Saag in his lecture were helpful to an audience eager to aid patients around the globe. Although much work remains to be done for the appropriate screening and treatment of these patients, the future is looking better thanks to the work of many in the field.
Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.
References
- Zhang C, Feng J, Wang S, et al. Incidence of and trends in hip fracture among adults in urban China: A nationwide retrospective cohort study. PLoS Med. 2020 Aug 6;17(8):e1003180.
- Nguyen HH, Lakhani A, Shore-Lorenti C, et al. Asian ethnicity is associated with atypical femur fractures in an Australian population study. Bone. 2020 Jun;135:115319.
- Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359–2381. Erratum in: Osteoporos Int. 2015 Jul;26(7):2045–2047.
- 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. Erratum in: J Bone Miner Res. 2016 Oct;31(10):1910.
- Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002 Feb 28;346(9):653–661.
- Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756–765. Erratum in: N Engl J Med. 2009 Nov 5;361(19):1914.
- Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018 Feb;33(2):190–198.
- 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.
- Cosman F, Kendler DL, Langdahl BL, et al. Romosozumab and antiresorptive treatment: The importance of treatment sequence. Osteoporos Int. 2022 Jun;33(6):1243–1256.
