Rickets prevalence and treatment outcome: real-world data from Taiwan
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Key message
Rickets should be recognized as a significant public health concern during infancy and childhood. Recent studies from Taiwan have demonstrated a steady increase in the prevalence of nutritional rickets, and a similar trend is likely to emerge in Korea. Therefore, comprehensive clinical evaluation and appropriate biochemical assessment are essential to prevent long-term skeletal and systemic complications. Prompt diagnosis and timely initiation of appropriate treatment are crucial.
Rickets, a skeletal disease characterized by defective mineralization of the growth plates and bone matrix, is often associated with low serum calcium and/or phosphate levels [1]. Rickets is a significant cause of skeletal deformities and impaired growth that requires early recognition and management [1]. Rickets can be caused by biochemical derangements, such as hypocalcemia or hypophosphatemia, or etiologically, such as via nutritional or hereditary factors. Nutritional rickets (NRs), the most common type worldwide, primarily arises from vitamin D deficiency due to limited ultraviolet exposure and/or insufficient calcium intake, although phosphate deficiency is rare [1]. NR significantly affects skeletal development and a child's long-term health.
Hereditary rickets (HRs) results from pathogenic genetic variants and is divided into impaired phosphate homeostasis (hypophosphatemic rickets) and impaired vitamin D metabolism or signaling (vitamin D-dependent rickets [VDDR]). Hypophosphatemic rickets may be FGF23-dependent, such as X-linked hypophosphatemic rickets (XLH; caused by PHEX mutations), or FGF23-independent due to defects in renal phosphate transporters (e.g., SLC34A3, SLC34A1, NHERF1) or tubular disorders such as Fanconi syndrome and distal renal tubular acidosis [2-4]. Rare FGF23-dependent forms include autosomal dominant hypophosphatemic rickets (ADHR) and autosomal recessive hypophosphatemic rickets type 1 (ARHR1) and type 2 (ARHR2). VDDR arises from mutations that affect vitamin D activation, degradation, or receptor signaling [4]. Its subtypes include VDDR1A (CYP27B1), VDDR1B (CYP2R1), VDDR2A/B (VDR and VDDR2B), and VDDR3 (CYP3A4) [5]. Nonhereditary acquired hypophosphatemic rickets can be caused by increased FGF23 production or iatrogenic factors [6]. Chronic liver or kidney diseases may also impair vitamin D activation and lead to rickets [6]. Hypocalcemia, a unifying biochemical feature across most subtypes, is often accompanied by secondary hyperparathyroidism, underscoring the importance of identifying the underlying etiology to guide its appropriate management.
Rickets treatment and management depend on the underlying cause, which requires diagnostic accuracy. Vitamin D supplementation is essential in NRs, which is caused by vitamin D deficiency. Symptomatic hypocalcemia, such as tetany, seizures, or cardiomyopathy, should initially be treated with intravenous calcium gluconate until normocalcemia is achieved, after which point oral calcium can be given [1]. A daily dose of 500 mg of calcium through diet or supplements is recommended along with vitamin D regardless of age or weight. Alternatively, elemental calcium 30–75 mg/kg/day in three divided doses may be administered for 2–4 weeks.
HR management differs. VDDR1A cells were treated with active vitamin D metabolite (calcitriol) and calcium supplementation. VDDR1B cells required calcifediol instead of native vitamin D along with calcium. FGF23-dependent hypophosphatemic rickets, including XLH, ADHR, ARHR1, and ARHR2, is managed with oral phosphate and active vitamin D analogs (calcitriol or alfacalcidol) [6]. Burosumab, an anti-FGF23 monoclonal antibody, is approved in many countries, including Korea, for treating XLH by improving serum phosphate levels, TmP/GFR, radiographic healing, and musculoskeletal function [7]. FGF23-independent hypophosphatemic rickets typically responds to oral phosphate alone, as active vitamin D is contraindicated due to elevated 1,25(OH)2D levels [7].
NR, the most prevalent form of rickets in low- and middle-income countries, also occurs in high-income nations, particularly among children with immigrant backgrounds, with a prevalence of 10%–70% in Africa, the Middle East, and Asia [1]. Few studies have reported on the prevalence of HR. A UK study showed an estimated prevalence of XLH (not HR) in childhood and adulthood, with 2016 estimates of 15.1 (95% confidence interval [CI], 11.3–20.1) and 15.7 (95% CI, 11.8–20.9) per million, respectively [8]. This study also demonstrated that mortality was significantly increased with a hazard ratio of 2.9 (95% CI, 1.24–6.91) in those with possible XLH versus controls. For NR, a Kenyan study showed a crude hazard ratio of 1.6 (95% CI, 1.16–2.17) [9]. Mortality rates are higher among children with rickets, particularly due to severe pneumonia, hypocalcemic seizures, other infections, malnutrition, and delayed diagnosis and treatment [9]. However, these estimates rely primarily on individual studies, and few have reported the prevalence of both NR and HR.
A recent study utilizing a nationwide real-world dataset from Taiwan, a developed country, provided population-based data on the prevalence of rickets in 2008–2018 [10]. The incidence of rickets in Taiwan increased with an overall annual percentage change (APC) of 13.56 (P=0.002), showing no sex-based difference. The incidence of NR, which exhibited a greater increase than HR, accounted for the main increase, demonstrating that the APC was 17.90 (P=0.001) for NR versus 5.73 (P=0.028) for HR. The mortality rate declined with an APC of -13.48 (P=0.002), with APC values of -46.20 for NR and -4.86 for HR (neither reaching statistical significance), potentially reflecting enhanced clinical recognition and improved management strategies. This study's findings suggest that factors influencing mortality risk, such as family income, anemia, chronic kidney disease, hyperparathyroidism secondary to renal tubulopathies, and length of hospital stay are important considerations in the clinical care of patients with rickets. In particular, this study has great implications for pediatricians in developed countries, including the Republic of Korea, as it was conducted in Taiwan, which is similar to Korea in many ways. Given the Taiwanese findings, a potential increase in the incidence of NR may also occur in Korea, warranting systematic investigation.
In summary, rickets should be recognized as a significant public health concern during infancy and childhood. A thorough clinical evaluation combined with appropriate biochemical assessment is essential to ensuring the early identification of suspected cases. A prompt diagnosis and timely initiation of appropriate therapy are critical to preventing long-term skeletal and systemic complications.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contribution
YSS is the only contributing author listed for this manuscript.