Hereditary hypophosphataemic rickets is a group of rare genetic disorders that disrupt the body’s ability to maintain healthy phosphate levels, leading to weakened bones, growth problems, and a range of complications that can affect children and adults throughout their lives. Understanding the available treatment approaches—from conventional therapies that have been used for decades to innovative options currently being tested in clinical trials—can help patients and families navigate this complex condition.

How Treatment Helps Manage This Rare Bone Disorder

The primary goals of treating hereditary hypophosphataemic rickets focus on restoring phosphate levels in the blood, supporting proper bone development and strength, reducing pain and physical limitations, and improving overall quality of life. Because this condition affects people differently—even within the same family—treatment plans must be tailored to each person’s specific needs, age, and severity of symptoms.^[1]

Treatment strategies depend heavily on the stage of the disease and individual patient characteristics. Children with active rickets—a term describing the softening and weakening of growing bones—have different needs than adults dealing with osteomalacia, which is the equivalent bone softening that occurs after growth plates have closed. Young patients require treatment that supports ongoing bone growth and prevents progressive deformities such as bowed legs or knock knees, which become apparent when children begin walking and bearing weight.^[1]

Medical societies and expert panels have developed standard treatment protocols based on decades of clinical experience, but they also recognise that hereditary hypophosphataemic rickets is a lifelong condition requiring ongoing management. Beyond established therapies, researchers are actively exploring new treatment approaches through clinical trials. These investigational therapies aim to address the underlying biological mechanisms of the disease more directly than conventional treatments, potentially offering better outcomes with fewer side effects.^[12]

Because hereditary hypophosphataemic rickets affects multiple body systems—bones, teeth, muscles, kidneys, and sometimes even hearing—patients benefit most from care provided by multidisciplinary teams. These teams typically include specialists in metabolic bone diseases, paediatric or adult endocrinologists, nephrologists who understand kidney function, orthopaedic surgeons for skeletal complications, and dental professionals familiar with the condition’s impact on teeth.^[12]

Standard Treatment Approaches

For many years, the cornerstone of treating hereditary hypophosphataemic rickets has been a combination of oral phosphate supplements and active forms of vitamin D. This conventional therapy aims to compensate for the excessive loss of phosphate through the kidneys and support the body’s ability to use whatever phosphate is available for bone formation.^[3]

Phosphate supplements are typically given multiple times throughout the day because the body rapidly excretes excess phosphate through urine. Patients usually need to take these supplements three to five times daily, which can be challenging, especially for children and their families. The doses must be carefully calculated based on body weight and adjusted as children grow or as adults’ needs change over time.^[14]

Alongside phosphate, patients receive calcitriol, which is the activated form of vitamin D (also known as 1,25-dihydroxyvitamin D). Standard vitamin D supplements alone are not sufficient because people with hereditary hypophosphataemic rickets have a defect in how their bodies convert vitamin D into its active form. Calcitriol helps improve calcium absorption from the intestines and works together with phosphate supplements to promote proper bone mineralisation.^[3]

Clinical guidelines recommend that children begin treatment as early as possible, ideally as soon as the diagnosis is confirmed. Early treatment can heal active rickets, limit the formation of dental abscesses caused by poor tooth mineralisation, and prevent progressive growth failure and skeletal deformities. When treatment starts before significant bone deformities develop, outcomes are generally better, though the condition’s variability means some children respond more favourably than others.^[12]

The duration of conventional therapy is typically lifelong, though the intensity and specific doses change throughout different life stages. Children usually require more aggressive treatment during periods of rapid growth, while adults may need ongoing but less intensive therapy to maintain bone strength and prevent fractures. Some patients experience persistent problems despite treatment, including continued bone pain, muscle weakness, and progressive skeletal deformities that may eventually require surgical correction.^[14]

Common side effects of conventional treatment include gastrointestinal discomfort from phosphate supplements, which can cause diarrhoea, nausea, and abdominal cramping. These digestive problems sometimes make it difficult for patients to adhere to the demanding dosing schedule. The risk of developing elevated calcium levels, secondary hyperparathyroidism (where the parathyroid glands become overactive), and kidney complications means patients need regular monitoring through blood tests, urine tests, and kidney imaging studies.^[9]

In addition to medical therapy, standard treatment approaches often include physical therapy to strengthen muscles and improve mobility, orthopaedic interventions for severe bone deformities, and dental care to address the tooth problems common in this condition. Surgical correction of leg bowing or other skeletal abnormalities may be necessary in some patients, particularly those who were diagnosed late or did not respond adequately to medical treatment.^[12]

Innovative Treatments Being Tested in Clinical Trials

Recent advances in understanding the biological mechanisms underlying hereditary hypophosphataemic rickets have opened new avenues for treatment. The most significant breakthrough involves targeting a hormone called fibroblast growth factor 23 (FGF23), which is the primary culprit causing phosphate wasting in this condition.^[9]

In people with hereditary hypophosphataemic rickets, genetic mutations lead to excessive production of FGF23, particularly in bone cells called osteocytes. This hormone instructs the kidneys to excrete too much phosphate into the urine and also interferes with the body’s ability to produce active vitamin D. By blocking FGF23’s activity, researchers hoped to address the root cause of the phosphate imbalance rather than simply trying to compensate for it with supplements.^[1]

The most extensively studied investigational therapy is burosumab, a monoclonal antibody designed to bind to and neutralise FGF23. Monoclonal antibodies are laboratory-made proteins that can target specific molecules in the body with high precision. Burosumab works by attaching to FGF23 molecules and preventing them from activating their receptors on kidney cells, thereby reducing phosphate loss and allowing the body to produce more active vitamin D naturally.^[9]

This therapy has been tested primarily in patients with X-linked hypophosphataemic rickets (XLH), which is the most common form of hereditary hypophosphataemic rickets. Clinical trials have progressed through multiple phases, each designed to answer specific questions about the treatment’s safety and effectiveness.^[3]

Phase I trials focused on basic safety and determining appropriate dosing. These early studies involved small numbers of participants and helped researchers understand how the human body processes burosumab, how long it remains active, and what doses might be effective without causing unacceptable side effects. The results from these initial studies were encouraging enough to proceed to larger trials.^[9]

Phase II trials examined burosumab’s effectiveness in improving clinical parameters. These studies enrolled more patients and measured outcomes such as changes in blood phosphate levels, improvements in rickets severity as seen on X-rays, reduction in bone pain, and changes in physical function. Researchers also continued monitoring safety, looking for any adverse effects that might not have appeared in the smaller Phase I studies.^[9]

Phase III trials compared burosumab against conventional treatment in larger, more diverse patient populations. These trials included children at various ages and adults with different degrees of disease severity. The studies tracked multiple outcomes over extended periods, typically one to two years or longer, to assess not just short-term improvements but sustained benefits and long-term safety.^[12]

Preliminary results from these clinical trials have shown several promising findings. In children, burosumab treatment led to healing of rickets visible on X-rays, with improvements in the mineralisation of growth plates. Blood phosphate levels increased toward normal ranges, and many children experienced improvements in growth velocity, meaning they grew faster during treatment than they had before. Parents and clinicians also reported reductions in leg deformities and improvements in children’s ability to walk and participate in physical activities.^[9]

In adults, clinical trials demonstrated that burosumab could heal pseudofractures—stress fractures that occur due to weakened, poorly mineralised bones—and reduce bone pain. Adults treated with burosumab also showed improvements in physical function tests, such as the ability to walk certain distances or perform daily activities with less difficulty. The treatment appeared to help maintain bone strength and reduce the risk of new fractures developing.^[12]

The safety profile observed in these trials has generally been favourable. Burosumab is administered as an injection under the skin, typically every two to four weeks, which is far less burdensome than taking multiple daily doses of phosphate supplements. Common side effects reported in trials included injection site reactions such as redness or mild pain, tooth abscesses (which also occur with conventional treatment), and restless legs syndrome in some patients. Importantly, burosumab does not appear to cause the kidney complications associated with conventional phosphate and calcitriol therapy, such as nephrocalcinosis or kidney stones.^[9]

Beyond burosumab, researchers are exploring other approaches to treating hereditary hypophosphataemic rickets. Some investigations focus on developing different types of FGF23 inhibitors, including small molecule drugs that might be taken orally rather than by injection. Other research examines combination therapies that might work synergistically to improve outcomes beyond what single treatments can achieve.^[9]

Scientists are also investigating treatments for the less common forms of hereditary hypophosphataemic rickets, such as autosomal dominant and autosomal recessive variants. These forms have different genetic causes but share the common feature of excessive FGF23 activity, suggesting that FGF23-targeting therapies might be beneficial across the spectrum of hereditary hypophosphataemic rickets disorders.^[4]

Clinical trials continue to provide valuable information about optimal dosing strategies, which patient populations benefit most from specific treatments, and how long treatment should continue. Long-term extension studies are following patients for years after their initial trial participation to understand whether benefits are maintained and whether any unexpected long-term effects emerge.^[12]

Most Common Treatment Methods

• Conventional phosphate and calcitriol therapy
  • Oral phosphate supplements taken multiple times daily to compensate for excessive kidney losses
  • Calcitriol (active vitamin D) to improve calcium absorption and bone mineralisation
  • Requires careful dose adjustment and regular monitoring to prevent kidney complications
  • Typically lifelong treatment with intensity varying by age and disease severity
• Anti-FGF23 antibody therapy
  • Burosumab, a monoclonal antibody that neutralises fibroblast growth factor 23
  • Administered as subcutaneous injection every two to four weeks
  • Addresses underlying cause of phosphate wasting rather than just supplementing
  • Studied primarily in X-linked hypophosphataemic rickets in Phase I, II, and III clinical trials
  • Shows improvements in rickets healing, growth, phosphate levels, and physical function
• Supportive and surgical interventions
  • Physical therapy to strengthen muscles and improve mobility
  • Orthopaedic surgery to correct severe bone deformities such as bowed legs
  • Specialised dental care to manage tooth abnormalities and prevent abscesses
  • Pain management strategies for chronic musculoskeletal discomfort
• Monitoring and prevention of complications
  • Regular blood tests to measure phosphate, calcium, alkaline phosphatase, and kidney function
  • Urine tests to detect excess calcium excretion and early kidney problems
  • Periodic X-rays to assess rickets severity and bone healing
  • Kidney imaging studies to detect nephrocalcinosis or stones