Romosozumab, a targeted monoclonal antibody against sclerostin, represents a cutting-edge therapeutic approach for osteoporosis by simultaneously promoting bone formation and diminishing bone resorption via its dual-action mechanism.[ 1] Approved by the U.S. Food and Drug Administration (FDA) in April 2019 for the management of osteoporosis, it has nevertheless been linked to an elevated risk of major adverse cardiovascular events in comparison to alendronate during a phase 3 clinical trial.[2] This association prompted an FDA advisory on its usage in patients with a history of cardiovascular diseases due to potential hazards. The precise pathway through which romosozumab might escalate cardiovascular disease risk remains elusive.[3] Several theories posit that it may increase platelet counts, thereby possibly encouraging thromboembolic events, although definitive evidence is still forthcoming. In this report, we present a case in which a patient diagnosed with immune thrombocytopenic purpura (ITP) experienced a normalization of platelet counts following romosozumab treatment for osteoporosis. Our goal is to investigate the possible link between romosozumab administration and alterations in platelet counts through this case observation.

A 60-year-old Korean female was referred to our Endocrinology department due to a recent diagnosis of osteoporosis. She received a diagnosis of ITP one year prior. No instances of ITP were documented in her family history. At the time of her diagnosis with ITP, she has a tendency to easy bruising. Petechiae, purpura, and other bleeding tendencies were not observed. A complete blood count disclosed moderate thrombocytopenia, with a platelet count recorded at 73×10⁹/L (N, 150-410×10⁹/L). The peripheral blood smear examination unveiled no anomalies in differential leukocyte count or erythrocytic morphology. Bleeding time, prothrombin time, and activated partial thromboplastin time were normal. Bone marrow examination yielded a normal pattern, showing adequate megakaryocytes. Additional tests included a urea breath test for helicobacter pylori, which returned negative results. Screening for auto-immune diseases and viral infections such as human immunodeficiency virus and hepatitis B/C, also showed negative results. These findings led to the conclusive diagnosis of ITP, with a management plan of only periodic monitoring absent of any additional medication. Upon her evaluation by the Endocrinology department, it was noted that she was postmenopausal and not undergoing hormone replacement therapy. Her medical history included hypertension; however, she had no instances of diabetes mellitus, nor a significant family history of osteoporosis. She was not on any osteoporosis medications, and there were no reported fractures associated with osteoporosis. Clinical examination revealed the patient to be in favorable clinical condition. Measurements recorded her height as 147 cm, body weight as 43 kg, and body mass index as 19.9 kg/m². Initial laboratory examinations confirmed a normal white cell count (5.75×10⁹/L; N, 4.30-10.40×10⁹/L), but pointed out continued thrombocytopenia (96×10⁹/L). Creatinine, serum calcium, phosphorus, parathyroid hormone, and alkaline phosphatase levels were within normal ranges (Table 1). Bone turnover markers, C-terminal telopeptide of type I collagen, and total procollagen type I N-terminal propeptide, were measured at 0.944 ng/mL (normal, less than 1.008 ng/mL) and 73.0 ng/mL (normal, 20.25-76.31 ng/mL), respectively. X-ray imaging of the spine detected no abnormalities. Dual energy X-ray absorptiometry scanning reported a T-score of −4.6 at the lumbar vertebrae (bone mineral density [BMD], 0.578 g/cm²), −3.5 at the femoral neck (BMD, 0.457 g/cm²), and −2.8 at the total hip (BMD, 0.597 g/cm²). The initial fracture risk assessment tool evaluation estimated a 12% risk of major osteoporotic fracture and a 6.4% risk of hip fracture, categorizing the patient as being at an extremely high risk for fracture. Considering her postmenopausal status and elevated fracture risk, treatment commenced with vitamin D3 and 210 mg of romosozumab administered monthly. She didn’t receive any ITP treatment during the administration of romosozumab. Following 6 cycles of romosozumab treatment, her platelet count increased to 121×10⁹/L (Fig. 1). After completing 12 cycles, the platelet count reached 199×10⁹/L (Fig. 1). A white cell count was 4.99×10⁹/L. The stability in leukocyte counts was observed before and after romosozumab treatment. No cardiovascular events were reported. The patient tolerated the osteoporosis treatment well. Throughout the treatment, she incurred no fractures, nor reported any adverse effects specific to romosozumab. Post-treatment, the BMD of the lumbar spine improved to 0.666 g/cm², with a T-score of −3.5, marking a 15.2% increase from pre-romosozumab levels. The T-scores for the femoral neck and total hip also showed improvement to −3.1 and −2.3, up from −3.5 and −2.8, respectively, after a year of romosozumab treatment. The patient’s treatment for osteoporosis continues with denosumab, 60 mg every 6 months. Six months after starting sequential therapy with denosumab, the platelet count was checked 156×10⁹/L (Fig. 1).

In this case report, we observed that the administration of romosozumab to a patient with ITP resulted in the normalization of platelet counts. This outcome suggests that romosozumab may have a potential role in modulating platelet dynamics beyond its established effects on bone metabolism. However, it is important to consider other potential factors that could have contributed to this improvement. The natural history of adult ITP is typically chronic, with the condition persisting for more than 12 months. The patient in our case had a stable platelet count for a year prior to starting romosozumab, suggesting a chronic course of ITP. During the study period, no significant changes in her overall health status or other treatments that might have influenced platelet dynamics. While the possibility of spontaneous improvement in ITP cannot be entirely ruled out, the temporal association with romosozumab treatment suggests a potential link. The skeletal and hematopoietic systems are intricately linked, with cell-to-cell interactions that shape the microenvironment supportive of hematopoietic stem cells (HSCs).[4] The Wnt signaling pathway, encompassing both canonical and non-canonical pathways, is pivotal in various physiological processes, including stem cell regeneration, proliferation, and cell fate determination.[5] Both branches of Wnt signaling are integral in maintaining HSCs,[6] with particular emphasis on how the canonical Wnt signaling pathway affects the differentiation of bone marrow mesenchymal stem cells and hematopoietic cell differentiation.[7,8] More specifically, canonical Wnt signaling orchestrates hematopoiesis, inclusive of platelet activation, in a dosage-dependent manner. [9] Sclerostin, a glycoprotein produced by osteocytes, plays a regulatory role in bone turnover by inhibiting canonical Wnt signaling through its interaction with low-density lipoprotein-related proteins 5 and 6 (lipoprotein related peptide [LRP]5 and LRP6).[10] Romosozumab, as a humanized monoclonal antibody, directly targets sclerostin for inhibition. Despite the established connection between canonical Wnt signaling and hematopoiesis, the implications of romosozumab on platelet activation are yet to be unveiled.

Research focusing on sclerostin has delved into its association with hematopoiesis. Sclerostin knockout mice studies in vivo did not exhibit a surge in hematopoiesis but rather showed an increase in granulocyte frequency and heightened inflammatory cytokines in older mice.[11] Aging, a leading risk factor for osteoporosis, correlates with a diminished capacity of HSCs and escalated inflammation. [12] Consequently, the bone marrow’s chronic inflammatory state, associated with aging, immunosenescence, and thrombocytosis, might also be modulated by romosozumab.[ 13] Such inflammation could significantly modify HSC behavior, affecting their functionality and proliferation. Recent investigations have identified a link between Dickkopf- 1(Dkk1) and sclerostin expression, where Dkk1, a suppressor of the Wnt signaling pathway, complexes with LRP6 to manifest its effects.[14] Dkk1 positively influences hematopoietic regeneration both directly and indirectly via niche-mediated mechanisms.[15] Taking into account the complex interplay between sclerostin and Dkk1, the impacts of Dkk1 expression warrant consideration in thrombocytosis cases.[16] The risk of thrombotic complications is associated with clonal thrombocytosis.[17] Atherosclerotic plaque disruption and subsequent thrombus formation are considered to be critical processes involved in the onset of atherothrombotic events.[18] Therefore, the increased platelet count observed in our patient could potentially contribute to a prothrombotic state, thereby increasing the risk of atherothrombosis. However, a study has also indicated that romosozumab did not have a meaningful effect on cardiovascular function in preclinical models, suggesting that the clinical significance of these findings remains to be fully elucidated.[19]

To date, substantial clinical data establishing a direct connection between romosozumab treatment and elevated platelet counts in ITP patients is lacking. The observed increase in our case patient may represent an isolated incident, potentially influenced by overall health, concurrent medications, or lifestyle factors. With these research gaps in mind, our observation could serve as a preliminary basis for hypothesizing that romosozumab may impact platelet dynamics, possibly through direct or indirect pathways mediated by Wnt/β-catenin or alternative mechanisms. Hence, documenting and sharing such cases is imperative for sparking research interest and further exploration into this potential side effect or therapeutic benefit of romosozumab, potentially broadening our understanding of its systemic effects, including on hematopoiesis.