The emerging osteo-metabolic phenotype of COVID-19: clinical
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The clinical course of COVID-19; caused by SARS-CoV-2 is mainly characterized by respiratory features and can range from asymptomatic or mild disease to severe forms with a high risk of death. During the spread of the pandemic, several studies have shown that the endocrine and metabolic features of COVID-19 were strongly relevant clinical manifestations1. Some papers have now highlighted an emerging osteo-metabolic phenotype of COVID-19, which might influence COVID-19 severity and clinical outcomes. This phenotype is typically characterized by widespread acute hypocalcaemia and chronic hypovitaminosis D, as well as a high prevalence of morphometric vertebral fractures.

The initial reports of clinical and laboratory characteristics of patients with COVID-19 did not include population data on mineral metabolism. In April 2020, a case of severe acute hypocalcaemia in an Italian patient with SARS-CoV-2 infection who had previously undergone thyroidectomy was reported. This report suggested that COVID-19 was a possible precipitating cause of subclinical post-surgical hypoparathyroidism5. Interestingly, previous reports on patients with SARS and Ebola virus infection had described hypocalcaemia as a highly prevalent biochemical abnormality, ranging from 60% of patients at hospital admission to 75% during hospitalization.

Following the first reported case of acute hypocalcaemia in a patient with COVID-19, several studies worldwide showed a very high prevalence of hypocalcaemia in hospitalized patients with COVID-19, ranging from 62.6% to 87.2%, depending on the definition criteria. Furthermore, low calcium levels were associated with worse disease outcomes, increased levels of markers for biochemical inflammation and thrombosis (such as C-reactive protein, lactate dehydrogenase, IL-6 and D-dimer) and an increased risk of in-hospital short-term and 28-day mortality. Hypocalcaemia, detected at first evaluation on admission to an emergency department for COVID-19, was also identified as a significant independent risk factor for hospitalization.

Several pathophysiological mechanisms have been investigated to clarify COVID-19-related hypocalcaemia. These mechanisms include increased calcium depletion due to the calcium-dependent mechanisms of action of the virus, acute malnutrition during critical illness, the role of calcium ions in coagulation and prothrombotic status, high levels of unbound and unsaturated fatty acids in the inflammatory response and hypovitaminosis D. In addition, as hypocalcaemia also seems to be a distinctive biochemical feature of COVID-19, calcium levels might be a useful laboratory marker of disease aggressiveness as well as a potential therapeutic target that can be easily evaluated in emergency referrals.