OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Brett A. Freedman, MD, in response to a study published in JAMA about a new agent to prevent fractures in postmenopausal women with osteoporosis.
The August 16, 2016 issue of JAMA published the results of the ACTIVE (Abaloparatide Comparator Trial In Vertebral Endpoints) trial. This 28-site randomized trial allocated postmenopausal women with low bone mineral density (BMD) and/or a prior fragility fracture into one of three arms: abaloparatide (80 µg subcutaneously, daily ) vs. daily placebo injection vs. teriparatide (20 µg subcutaneously, daily). The primary end point was new vertebral fracture over the 18-month trial.
As expected, both anabolic agents significantly outperformed placebo, with incident vertebral fractures occurring in only 4 subjects in the abaloparatide arm (0.6%) and 6 in the teriparatide arm (0.8%), while there were 30 in the placebo arm (4.2%). Although the study was not powered to evaluate differences between the two anabolic agents, the results suggest that abaloparatide and teriparatide performed essentially the same over the 18-month period.
In an accompanying commentary,1 Cappola and Shoback note that institutional review boards (IRBs) approved a prospective clinical trial protocol in which patients with known osteoporosis and/or a prior fragility fracture were allowed to be randomized to a non-treatment arm for 18 months. Subjects whose BMD dropped more than 7% from baseline and those who experienced an incident fracture during the trial “were offered an option to discontinue and receive alternative treatment,” but in some sense IRB approval of this protocol implicitly acknowledged that osteoporosis is undertreated.
Turning back to the study itself, I noted with interest that subjects who had regularly used bisphosphonates in the last 5 years or denosumab in the last year were excluded. So, none of the 2463 subjects who were randomized had received any active treatment for osteoporosis in the 1 to 5 years prior to enrollment, despite the fact that the average T-score in the lumbar spine (-2.9 for all 3 arms) was in the osteoporotic range and that almost one-third of subjects had had at least one prior fragility fracture.
This is a sad commentary on “our” (meaning all providers involved in bone health) continued inability to diagnose and treat osteoporosis effectively. Despite the “National Bone and Joint Health Decade” (2002-2011) and our continued attempts to “Own the Bone,” we have made little progress in recognizing and treating the osteoporosis underlying the fragility fractures that we so frequently treat. Colleagues of mine and I published that only 38% of patients in 2002 with clinically diagnosed vertebral compression fragility fractures were receiving active treatment for osteoporosis.2 Over the ensuing decade, Solomon et al. showed that that figure actually decreased to 20%.3
This JAMA study provides empiric Level-I support for the efficacy of another anabolic agent to treat osteoporosis. Cost, subcutaneous delivery, and osteosarcoma concerns have limited the only FDA-approved anabolic osteoporosis medication, teriparatide, to second-line status, behind bisphosphonates. If and when approved, abaloparatide will probably bump up against the same limitations. Still, the parathyroid hormone receptor agonists are particularly pertinent to orthopaedic surgeons, because they are the most effective secondary fracture prevention agents—and the only ones that show meaningful improvement in bone mineral density. This bone-building property has also led to progressive acceptance of teriparatide as an important perioperative adjunct for instrumented spinal fusion surgery in patients with known osteoporosis.
However, as has been repeatedly shown, parathyroid receptor agonists only work when they are prescribed, and they are only prescribed when osteoporosis is diagnosed.2,3 Patients with incident clinical fragility fractures need to be effectively educated about osteoporosis, its treatment, and the impact of failing to treat it. Orthopaedic surgeons need to continue to set the signal flares and advocate for our patients to receive effective treatment for all their chronic musculoskeletal illnesses, not the least of which is osteoporosis.
- Cappola AR, Shoback DM. Osteoporosis Therapy in Postmenopausal Women With High Risk of Fracture. JAMA. 2016 Aug 16;316(7):715-6.
- Freedman BA, Potter BK, Nesti LJ, Giuliani JR, Hampton C, Kuklo TR. Osteoporosis and vertebral compression fractures-continued missed opportunities.Spine J. 2008 Sep-Oct;8(5):756-62.
- Solomon DH, Johnston SS, Boytsov NN, McMorrow D, Lane JM, Krohn KD. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. 2014 Sep;29(9):1929-37.
One thought on “Guest Post: Osteoporosis Treatment Still Lacking”
It is with some irony that although clinicians are well aware that all bones are not made the same way, many still fall into the trap that bone regulation is the same for different type of bones, and subsequently osteoporotic drugs works similarly in all part of the body.
Orthopaedic surgeons learn very early in their training that to ‘fix’ fracture, different screws are used for cortical and cancellous bones; Similarly we continue to see phenotypically different cohort of patients presenting with 2 different types of hip fractures. Yet we continue to lull ourselves into trusting our medical colleagues and researchers to differentiate the two when analysing the data on fragility fractures.
Patients with vertebral fracture from osteoporosis are more likely to have trochanteric hip fracture rather than subcapital/transcervical neck of femur fractures; however, this association is not that well known. It is also found that one of the most widely used form of anti-osteoporosis medication, the antiresorptive bisphosphonates, are far more effective in secondary prevention of vertebral fractures, but their efficacy is tenuous at best in “hip fracture.” Unfortunately it is not so clear whether this is actually true if hip fractures are properly differentiated; there is some suggestion that the trabecular bone quality in both vertebral bone and intertochanteric region of the proximal femur improved after bisphosphonate therapy. It is, however, not as certain if the same treatment improves the strength of cortical bone in a similar way. Thus it is not unusual to find that the promotional flyers for bisphosphonate medication depict diagrams that show improvement of trabecular bone rather than compact bone.
Even now, we have increasing evidence of differences in signalling pathways, that cortical-bone and trabecular-bone homeostasis are governed by different mechanism (http://www.nejm.org/doi/full/10.1056/NEJMoa1509342). It is time not just for orthopaedic surgeons to take ownership of getting patients with fragility fractures to be on osteoporosis therapy, but also the push for researchers and clinicians to differentiate among bone fractures when investigating the efficacy of drugs on osteoporotic fracture prevention.
After all, although both the body and the engine of a car can be made of the same metal, you hardly use the same tool to fix faults between them!