Hypophosphatemic RicketsEdit

Hypophosphatemic rickets refers to a group of inherited disorders characterized by renal phosphate wasting that leads to low serum phosphate and impaired bone mineralization in growing individuals. The most common form is X-linked hypophosphatemic rickets (XLH), but autosomal dominant and autosomal recessive forms exist, each rooted in genetic mutations that disrupt phosphate handling in the kidneys or bone signaling networks. Conventional understanding centers on the need to correct phosphate balance and vitamin D metabolism to prevent deformities, fractures, and growth impairment associated with chronic hypophosphatemia. In recent years, advances in biology and therapeutics have introduced targeted options that address the underlying hormone signaling, notably antagonists of fibroblast growth factor 23 (FGF23). These developments have stirred ongoing discussion about optimal management, costs, and long-term outcomes in various health care systems.

The clinical picture typically emerges in childhood, with bone pain, growth retardation, and characteristic deformities such as bowing of the legs. Dental problems, including recurrent abscesses, are also common due to defective dentin mineralization. If untreated, the condition can persist into adulthood, leading to osteomalacia, reduced mobility, and quality of life challenges. While XLH is the most widely recognized form, other genetic etiologies of hypophosphatemic rickets involve different gene mutations that disrupt phosphate reabsorption in the kidneys or phosphate-regulating signaling pathways. See X-linked hypophosphatemic rickets, FGF23, PHEX, and hypophosphatemia for related concepts.

Pathophysiology

Genetic basis

Hypophosphatemic rickets encompasses several genetic disorders. The predominant form, XLH, results from mutations in the PHEX gene, which normally helps regulate phosphate reabsorption in the proximal tubules of the kidney and modulates FGF23 activity. Other forms arise from mutations in genes such as FGF23, leading to excess circulating FGF23 and subsequent renal phosphate wasting. In addition to XLH, newer discoveries have identified autosomal dominant and autosomal recessive conditions that involve different components of phosphate handling or bone mineralization pathways, including mutations in other phosphate-regulating genes.

Mechanism

The central pathogenic mechanism is renal phosphate wasting driven by elevated activity of FGF23, a hormone that reduces phosphate reabsorption in the kidney and decreases production of 1,25-dihydroxyvitamin D. The resulting hypophosphatemia impairs mineralization at the growth plate, producing rachitic changes in children and osteomalacic changes in adults. The consequence is defective bone formation, skeletal deformities, and dental abnormalities. See bone mineralization and osteomalacia for broader discussions of the tissue effects.

Clinical features

Skeletal manifestations

Progressive bowing of the legs and other growth-related deformities in children.
Short stature relative to age- and sex-matched peers.
Fractures with minimal trauma due to weakened bone strength.
Gait disturbances and reduced physical function.

Extraskeletal manifestations

Dental problems, including recurrent dental abscesses from defective dentin mineralization.
Joint and bone pain in some patients.
Hearing issues can occur in a subset of individuals with long-standing deformities.

Diagnosis

Laboratory assessment

Low serum phosphate with inappropriately normal or reduced 1,25-dihydroxyvitamin D levels relative to the degree of hypophosphatemia.
Elevated alkaline phosphatase reflecting active bone turnover.
Inappropriately high urinary phosphate excretion indicating renal phosphate wasting.
Circulating FGF23 levels may be elevated in many forms, supporting a phosphate-wasting etiology.
Serum parathyroid hormone and calcium are typically normal or only mildly affected.

Imaging and genetic testing

Radiographs show rachitic metaphyseal changes, with cupping and fraying of the growth plates in affected children.
Bone age may be delayed.
Genetic testing can confirm specific mutations in genes such as PHEX or FGF23 and help distinguish XLH from other hypophosphatemic conditions. See radiography and bone imaging references for more detail.

Treatment and management

Conventional therapy

Oral phosphate supplementation several times daily to improve serum phosphate levels.
Active vitamin D analogs (such as calcitriol) to enhance intestinal absorption of calcium and phosphate and support bone mineralization.
Regular monitoring for potential adverse effects, including nephrocalcinosis, secondary hyperparathyroidism, and nephrolithiasis.
Physical therapy and orthopedic interventions as needed to address deformities and functional limitations.

Targeted therapy and newer approaches

Burosumab (a monoclonal antibody against FGF23) represents a targeted approach that directly counters the excess FGF23–driven phosphate wasting. It can improve phosphate reabsorption, normalize phosphate metabolism, and support bone healing and growth. See burosumab and FGF23 for details.
The choice between conventional therapy and targeted therapy depends on factors such as disease severity, age, long-term goals, access, and cost considerations. Burosumab has been approved in many regions for XLH and is increasingly used in both pediatric and adult patients, with ongoing assessment of long-term outcomes.

Supportive care

Dental care to manage and prevent abscesses through preventive and restorative strategies.
Orthopedic management to correct or mitigate deformities, guided by growth and functional status.
Diet and nutrition to support overall bone health, within the context of phosphate balance and vitamin D status.

Controversies and debates

Cost and access to therapy: Burosumab offers a path to potentially better disease control with fewer daily interventions, but its high cost raises questions about health care funding, equity of access, and appropriateness of use in different health systems. Proponents argue that improved growth, fewer procedures, and better quality of life can justify the expense, while critics emphasize budget impact and the need for robust long-term comparative data against conventional therapy.
Long-term outcomes and safety: While targeted therapy addresses the underlying hormonal driver, long-term comparative data on growth outcomes, skeletal health, and dental preservation versus traditional phosphate and calcitriol regimens remain an area of active study. Advocates for cautious adoption stress the value of real-world experience, while others push for earlier use in children to maximize potential benefits.
Individualized treatment decisions: Given the genetic heterogeneity of hypophosphatemic rickets, some patients respond differently to therapies. A conservative, stepwise approach may be favored in some cases to balance efficacy, safety, and cost, whereas others advocate for more aggressive early intervention to prevent deformity and fracture.
Regulatory and policy considerations: Debates around orphan drugs, accelerated approvals, and payer policies influence how rapidly new therapies reach patients. From a policy perspective, supporters of market-based health care contend that competition and innovation benefit patients, while critics caution that price pressures can limit access for those with the greatest need.