We demonstrated the clinical features of growing pains in Taiwanese children with mean age at diagnosis of 4.9 years and slight male predominance. For diagnostic tests, plain radiographs and laboratory tests were performed in 26% of the patients. Only 14% of our patients needed oral medication for pain relief. We found that serum levels of ALP and LDH were elevated in 38% and 14% patients with growing pains, respectively. In an observational study by Qamar et al., elevated ALP was found in 38% patients of growing pains, of whom 97.3% had vitamin D deficiency [13]. However, the association between serum ALP levels and growing pains was not significant in two previous studies [7, 14]. Signaling pathways including Wnt/β-catenin/TCF, BMP2/Smad/RUNX2, IGF/PI3K/RUNX2, and FGF/MAPK/ERK have been reported to induce ALP expression and bone mineralization. ALP expression is also restricted and regulated by 1,25(OH)2-vitamin D, retinoic acid, and parathyroid hormone [15]. Hypovitaminosis D reduces calcium absorption and serum calcium levels, triggering secondary hyperparathyroidism which subsequently increases bone resorption and serum ALP level [16]. Although ALP levels are thought to be elevated in children’s rapid growth phase, our data showed that growing pains is not associated with rapid growth of body height and weight within 2 years of onset of symptoms [7].
In growing pains, whether there is a causal relationship with hypovitaminosis D or whether hypovitaminosis D is a risk factor for severe pain through peripheral and central mechanisms is unclear. Growing pains could be an early manifestation of histological changes in bone matrix associated with hypovitaminosis D [13]. In addition, vitamin D interacts with the nuclear receptors in the muscle tissues to increase muscle strength. Vitamin D deficiency is associated with chronic muscular pain or fibromyalgia in adults [17]. Women with chronic musculoskeletal pain and hypovitaminosis D had significant higher pain scores, compared with patients with normal vitamin D levels [18].
High prevalence (57–94%) of hypovitaminosis D was found among the children with growing pains in comparison with population prevalence [19]. Oral vitamin D supplementation has been shown to be effective in increasing serum vitamin D levels and reducing pain severity in children with growing pains, although there were no control groups for comparison in these studies [19–22]. However, children with growing pains with high BMI and elevated serum ALP levels showed less benefit from vitamin D therapy than those with lower BMI and normal ALP levels [19]. Half of our patients with high ALP levels had elevated levels of LDH at diagnosis. Those patients with elevated ALP and LDH levels might have mild inflammation that may cause musculoskeletal pain.
According to a population-based cohort study, vitamin D deficiency defined as a 25(OH)-vitamin D level < 20 ng/mL (50 nmol/l) and vitamin D insufficiency defined as a 25(OH)-vitamin D level of 21–29 ng/mL (52.5–72.5 nmol/l) were observed in 51% and 90.3% of Taiwanese children aged 5 to 18 years [23]. Since low serum 25(OH)-vitamin D levels are common in Taiwanese children, we recommend monitoring serum vitamin D and ALP levels at diagnosis and during follow-up and providing vitamin D supplements for children with growing pains and vitamin D insufficiency/deficiency.
The major limitation of the study was that we did not check serum vitamin D levels at disease diagnosis; this could not be overcome due to the retrospective study design. Another study limitation was the lack of healthy controls for the comparison of biomarkers, BW and BH. We used age-adjusted normal ranges of laboratory data and growth charts in percentile and z-score instead. Further large-scale prospective studies to investigate the association between vitamin D levels, serum ALP levels, the severity of growing pains, and lifestyle are warranted. It is possible that vitamin D deficiency or insufficiency may be associated with growing pains, and hypovitaminosis D could develop secondarily, as a result of lifestyle, limited outdoor activities, or poor eating habits.
There are several other proposed hypotheses for growing pains, including anatomical factors such as flat feet, over-pronated feet, and joint hypermobility [24–28], lower pain threshold [29, 30], lower skeletal vascular perfusion [24, 31], reduced bone strength [32, 33], and psychological factors [34–36]. Various factors, individually or in association, might be responsible for the onset of growing pains. In our study, we excluded 31 patients with musculoskeletal diagnoses, including 21 children with over-pronated feet, flat feet, developmental dysplasia of the hip, and genu valgum. Careful evaluation by orthopedic surgeons for anatomical abnormalities in children with aching legs is important [37]. In a study by Lee et al., over-pronated feet accounts for 75% of pediatric patients with growing pains, and pain episodes were significantly reduced using foot orthoses [27].