As a rheumatologist with an interest in bone, I was anticipating the release of the “Updated American College of Rheumatology Guidelines for the Prevention and Treatment of Glucocorticoid Induced Osteoporosis.” The updated guidelines are less prescriptive and include romosozumab, an anabolic agent that was not approved at the time of the prior guidelines. The aim of medical guidelines is to ensure that care processes take place in an evidence-based and structured manner. These guidelines are not evidence-based, in my opinion. In these guidelines, raloxifene, romosozumab and abaloparatide are recommended to be used to treat glucocorticoid-induced osteoporosis (GIO) in men when none of these are FDA-approved to be used to treat men. Also, none of these drugs are approved for treating glucocorticoid-induced osteoporosis.
The American College of Rheumatology Guidelines for the prevention and treatment of GIO should mirror those of other societies that treat this condition so our patients can be treated in a similar fashion by either an endocrinologist or rheumatologist, for example. Although the ACR guidelines are risk-based by using a steroid dose-adjusted FRAX calculation, no mention is made of the very high risk patients with GIO, who are at the greatest risk of fracture. The Endocrine Society Updates of the 2019 Osteoporosis Guideline add romozosumab as a treatment option for postmenopausal women with very high fracture risk; the 2019 guidelines recommended anabolic therapy with abaloparatide or teriparatide for these very high risk patients.
When discussing the epidemiology of GIO, it is established that patients on glucocorticoids fracture at a higher bone density as measured by DXA than non-GIO treated patients. This technology does not measure bone quality but only bone mineralization. Patients on steroids have a 3.65 times higher risk of vertebral fractures and in this population up to 50% of patients have asymptomatic vertebral fractures. Given this information, I feel that vertebral fracture assessment (VFA) should be included in the recommendations to evaluate the patient’s GIO as the presence of even an asymptomatic vertebral fracture increases the patient’s risk, perhaps placing them in the very high risk of fracture and need for anabolic therapy.
I feel that in an attempt not to be too prescriptive, the various treatments are not prioritized. For adults 40 years of age or older with moderate fracture risk as defined by the GC-adjusted FRAX oral or IV bisphosphonate, PTH/PTHrp or denosumab therapy is recommended. In the package inserts for PTH analog therapies and denosumab the indication is for high fracture; therefore, I feel that for moderate fracture risk the oral and IV bisphosphonates should be prioritized. With moderate fracture risk using a SERM, romosozumab is conditionally recommended against due to risk of life-threatening harms. As mentioned above, neither of these drug categories are indicated for the treatment of GIO but I feel that the risk of harm is exaggerated. The warning in the raloxifene package insert states that raloxifene is contraindicated in “women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis." The increased risk of stroke with raloxifene was seen in the RUTH trial of postmenopausal women with an average age of 67 with known heart disease or at high risk of a coronary event. Even if raloxifene were approved for treating GIO I feel that this risk of harm does not pertain to many of our GIO patients. With regards to the harm associated with romosozumab (with the caveat that it is not approved for the treatment of GIO) in the ARCH trial where romosozumab was compared to alendronate, the hazard ratio for MACE was 1.87, but in the STAND trial when romosozumab was compared to placebo no increased CV risk was seen. Stating that romosozumab is associated with “risk of life-threatening harms” excludes patients who are unable to afford PTH-analog therapy from being prescribed anabolic therapy.
When mentioning treating patients with denosumab, there is no discussion of the recommendation that once a patient starts on denosumab therapy, it should not be discontinued due to the possibility of a sudden decrease in bone density and the occurrence of one or more vertebral fractures. In my opinion this needs to be taken into consideration whenever recommending denosumab therapy. In the treatment recommendations, when a new fracture occurs after twelve or more months of initial osteoporosis treatment, if the initial therapy is denosumab, the recommendation for switch therapies are oral/IV bisphosphonates, SERM (avoid PTH/PTHrp). In a review of the literature there is no therapeutic option that totally prevents the rapid loss of bone density after stopping denosumab therapy. This rapid drop appears to occur after a patient has received three or four denosumab injections. If the patient is switched to raloxifene, this rapid reduction In bone density occurs. The current evidence suggests that if a patient MUST stop denosumab, IV zoledronate should be given when the next denosumab injection was scheduled, followed by another zoledronate infusion six months later. Discontinuing denosumab should be greatly discouraged due to this sudden decrease in BMD and increased risk of vertebral fractures. The guidelines state that patient preference should be taken into consideration in determining therapy; I do not feel that this should apply to stopping denosumab.
Another option on the switch slide recommends that romosozumab can be given after PTH/PTHrp or that therapy with PTH/PTHrp can be followed by romosozumab. There is no evidence to support this recommendation. Typically it is not recommended to follow one course of anabolic therapy with another anabolic therapy as the anabolic effect is severely blunted (if there would be any anabolic effect at all).
Case studies were presented after the GIO guidelines were introduced. Many of the recommendations in the cases were not evidence-based. One case of a 22-year-old on 10mg of prednisone recommended bisphosphonates, denosumab, a SERM or romosozumab. Only bisphosphonates are approved for use in this age group.
In summary, these guidelines are not evidence-based. In my opinion, they should be updated immediately with more evidence-based recommendations.
Dr. Dore has no conflicts of interest to report.
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