Persistent Flu-Like Symptoms in a Patient With Glaucoma and Osteoporosis

Discussion

The ED physician considered viral infection and tested for both influenza and COVID-19. Laboratory results eliminated urinary tract infection and rhabdomyolysis as possible diagnoses. An acute phase reaction to zoledronic acid was determined to be the most likely cause. The patient was treated with IV saline in the ED, and acetaminophen both in the ED and at home.

Although initial nursing triage notes document consideration of acute phase reaction to zoledronic acid, the endocrinology service, which had recommended and arranged the zoledronic acid infusion, was not immediately notified of the reaction. It does not appear any treatment (eg, acetaminophen) was suggested, only that the patient was given advice this may resolve over 3 to 4 days. When he was seen 2 months later for an endocrinology follow-up appointment, he reported that all symptoms (chills, myalgias, and nausea) resolved gradually over 1 week. Since then, he has felt as well as he did before taking zoledronic acid. However, the patient was wary of further zoledronic acid, opting to defer deciding on a second dose until a future appointment.

Prior to starting zoledronic acid therapy, the patient was being treated for vitamin D deficiency. Four months prior to infusion, his 25-hydroxyvitamin D level was 12.0 ng/mL (reference range, 30 to 80 ng/mL). He then started taking cholecalciferol 100 mcg (4000 IU) daily. Eight days prior to infusion his 25-hydroxyvitamin D level was 29.5 ng/mL.

Federal health care practitioners, especially those working in the Veterans Health Administration (VHA), will commonly encounter patients similar to this case. Osteoporosisis is common in the United States with > 10 million diagnoses (including > 2 million men) and in VHA primary care populations.^1,2 Zoledronic acid is a frequently prescribed treatment, appearing in guidelines for osteoporosis management.^3-5

The acute phase reaction is a common adverse effect of both oral and IV bisphosphonates, although it’s substantially more common with IV bisphosphonates such as zoledronic acid. This reaction is characterized by flu-like symptoms of fever, myalgia, and arthralgia that occur within the first few days following bisphosphonate administration, and tends to be rated mild to moderate by patients.⁶ Clinical trial data from > 7000 women with postmenopausal osteoporosis found that 42% experienced ≥ 1 acute phase symptom following the first infusion (fever was most common, followed by musculoskeletal symptoms and gastrointestinal symptoms), compared with 12% for placebo. Incidence decreases with each subsequent infusion.⁷ Risk factors for reactions include low 25-hydroxyvitamin D levels,^8,9 no prior bisphosphonate exposure,⁹ younger age (aged 64-67 years vs 78-89 years),⁷ lower body mass index,¹⁰and higher lymphocyte levels at baseline.¹¹ While most cases are mild and self-limited, severe consequences have been noted, such as precipitation of adrenal crisis.^12,13 Additionally, more prolonged bone pain, sometimes quite severe, has been rarely reported with bisphosphonate use. However, it’s unclear whether this represents a separate adverse effect or a more severe acute phase reaction.⁶

The acute phase reaction is a transient inflammatory state marked by increases in proinflammatory cytokines such as C-reactive protein, interleukin-6, and tumor necrosis factor-α. Proposed mechanisms include: (1) inhibition of farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway, resulting inactivation of γϐ T cells and increased production of proinflammatory cytokines; (2) inhibition of the suppressor of cytokine signalling-3 in the macrophages, resulting in cessation of the suppression in cytokine signaling; or (3) negative regulation of γϐ T-cell expansion and interferon-c production by low serum 25-hydroxyvitamin D concentrations.¹¹