One in three women and one in five men aged 50 years or older will sustain an osteoporotic fracture [2]. Anti-resorptive medications, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Anabolic treatments, teriparatide and romosozumab, have demonstrated superiority in reducing fracture incidence compared with anti-resorptive agents and are recommended for patients at highest fracture risk [3, 4]. Although postmenopausal osteoporosis predominates, between 30 and 80% of men and women have a cause of secondary osteoporosis [1]. Such causes include endocrine disease, chronic inflammation, gastrointestinal conditions, glucocorticoids, chronic kidney disease, neuromuscular conditions, nutritional, malignancy and genetic conditions. The two cases highlight the importance of considering and screening for rare secondary causes of osteoporosis in patients with early-onset, treatment-refractory, or severe osteoporosis. Both patients demonstrated markedly elevated serum IgE levels, with clinical features raising the possibility of underlying Hyper-IgE syndrome (HIES). In Case 1, extensive minimal trauma fractures occurred despite treatment with both anti-resorptive and anabolic agents and appeared discordant with the patient’s bone mineral density. Although Case 1 had long-term inhaled glucocorticoid exposure for asthma, this is unlikely to fully explain the severity and treatment resistance of her osteoporosis. In Case 2, severe osteoporosis failed to respond to bisphosphonate therapy, and the patient developed a novel and severe erythematous skin reaction following romosozumab, raising questions about the safety of some anabolic therapies in patients with potential immune dysregulation.

Hyper-IgE syndrome is characterised by eczema, elevated serum IgE (> 2000 IU/L) and recurrent infections (skin/lung). Other features include skeletal anomalies, scoliosis, osteoporosis, pathological fractures and hyperextensibility [5]. Most (> 90%) cases of autosomal dominant Hyper-IgE syndrome (AD-HIES) are secondary to a loss-of-function mutation in signal transducer and activator of transcription 3 (STAT3) [6]. Autosomal recessive HIES (AR-HIES) is a distinct clinical entity, lacking the connective tissue and skeletal complications associated with AD-HIES. Mutations in the dedicator of cytokinesis-8 gene (DOCK8) have been identified in patients with AR-HIES [7]. The original clinical HIES scoring system was proposed by the National Institute of Health in 1999, based on genetic linkage studies [8]. Further scoring systems have been developed to distinguish patients with and without STAT3 mutations [9].

In individuals with HIES, the degree of fracture burden does not correlate strongly with bone mineral density [5, 10]. As demonstrated in Case 1, numerous minimal trauma fractures may occur that appear discordant with the bone mineral density. Nonetheless, rates of osteoporosis are significant in adults with HIES (~ 80%) and between 40 and 80% of adults in reported HIES cohorts have experienced fragility fractures of long bones, pelvis and ribs [10, 11]. Possible causes of low bone mineral density and increased risk of fracture include chronic inflammation and increased osteoclast function [12]. Osteoclasts generated from monocytes from HIES patients (with STAT3 mutation) exhibit higher levels of bone resorption compared with those from healthy controls [13]. In addition, STAT3-deficient mice have increased osteoclast numbers and activity resulting in osteoporosis [14]. However, the lack of correlation between fractures and bone mineral density suggests that additional contributing factors are likely involved [10]. Limited case reports have demonstrated efficacy for bisphosphonates in the treatment of minimal trauma fractures associated with AD-HIES [15].

Romosozumab, a monoclonal antibody that inhibits sclerostin, is a potent anabolic agent that exerts the dual effects of reducing bone resorption and increasing bone formation [16]. Romosozumab has demonstrated efficacy compared with both placebo and alendronate in clinical trials examining the incidence of new fractures and changes in BMD [16, 17]. Teriparatide, another anabolic treatment option for osteoporosis, exerts its effect via the parathyroid hormone receptor-1 to stimulate coupled bone remodelling and decrease osteoblast apoptosis. Whilst teriparatide was well tolerated in Case 1, Case 2 developed a severe erythematous skin reaction following the fourth dose of romosozumab. Injection site reactions occur in approximately 5% of romosozumab-treated participants and are generally mild [16, 17]. The severity of the reaction observed in Case 2 appears disproportionate to the published safety data. Potential mechanisms include impaired Th17 cell numbers and function, increased risk of Type 1 hypersensitivity reactions (IgE mediated) and the production of anti-romosozumab antibodies that may trigger immune complex-mediated reactions. Beyond local reactions, romosozumab has been associated with cardiovascular events. Compared with alendronate, patients receiving romosozumab reported more serious cardiovascular adverse events (2.5% vs 1.9%, OR 1.31; 95% CI 0.85–2.00), cardiac ischaemic events (0.8% vs. 0.3%, OR 2.65; 95% CI 1.03–6.77) and cerebrovascular events (0.8% vs. 0.3%, OR 2.27, 95% CI 0.93–5.22) [17]. Accordingly, romosozumab is contraindicated in patients with a history of myocardial infarction or stroke [4].

This case report highlights two rare but important clinical observations: elevated serum IgE levels in two postmenopausal women with severe osteoporosis raising the possibility of underlying HIES, and an unexpected severe erythematous drug reaction to romosozumab. Ongoing clinical management includes formal genetic testing to confirm the diagnosis, as well as comprehensive evaluation of family members. Further research is needed to understand the safety profile of anabolic agents like romosozumab in patients with immune dysregulation.