Hypophosphatasia: Management

INTRODUCTION — 

Hypophosphatasia (HPP) is an inherited metabolic disease with a broad spectrum of clinical manifestations. It is caused by loss-of-function variants in the ALPL gene, which encodes the tissue nonspecific alkaline phosphatase (TNSALP) enzyme [1]. This enzyme is widely expressed throughout the body and is essential for numerous physiologic processes including bone mineralization and the transport of vitamin B6 into cells [2]. In HPP, deficient TNSALP activity leads to low levels of serum alkaline phosphatase (ALP) activity with accumulation of natural substrates like inorganic pyrophosphate (PPi) [3] and pyridoxal 5'-phosphate (PLP) [4], and gives rise to mineralization defects, neuronal dysfunction, and systemic complications [5]. The clinical severity of HPP roughly correlates with residual TNSALP function and age of onset, resulting in a nosology based on the age at which symptoms first occurred [6,7]. However, disease severity can vary dramatically even among family members with the same ALPL variant, highlighting an incomplete understanding of disease physiology [8].

This topic will review the management of hypophosphatasia. The clinical manifestations and diagnosis of hypophosphatasia are reviewed separately. (See "Hypophosphatasia: Clinical manifestations and diagnosis".)

The management of other forms of osteomalacia in adults is also reviewed separately. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults".)

MANAGEMENT APPROACH FOR ALL PATIENTS

Management goals — Management of hypophosphatasia (HPP) is multifaceted, involving symptom-directed care, prevention strategies, and pharmacologic therapies. The primary goals of management are to [9,10]:

●Alleviate symptoms

●Prevent complications

●Avoid harmful treatments

●Improve quality of life

Symptom-directed management — Symptom-directed care for patients with HPP varies significantly depending on the severity of the disease, which ranges from life-threatening complications in severe cases to chronic pain and weakness in adults.

Severe forms of HPP — In the most severe forms of hypophosphatasia (HPP), often presenting in infancy, management focuses on addressing critical complications that can be life-threatening. Respiratory support is paramount for infants experiencing respiratory distress due to pulmonary insufficiency, which may require mechanical ventilation or continuous positive airway pressure (CPAP). Nutritional support is also crucial, as ensuring adequate caloric intake is essential for growth and development. This often involves the use of nasogastric or gastrostomy feeding to meet the high energy demands of these patients. Neurologic interventions may be required for managing vitamin B6-dependent seizures and increased intracranial pressure due to craniosynostosis. Early intervention with physical therapy is critical to improve motor function, and in some cases, orthopedic interventions such as braces, orthotics, or corrective surgery are necessary to manage skeletal deformities and prevent fractures [1,4,6,11].

Less severe forms of HPP — In less severe forms of hypophosphatasia (HPP) without pulmonary complications or severe rickets, symptom-directed care often involves a multidisciplinary, highly individualized approach with various specialists [4,9].

●Pain management – Pain management is a significant aspect of care for many adults with HPP, as chronic pain and muscle weakness can severely impact quality of life. A combination of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and physical therapy is often employed to manage pain. Severe cases may require consultation with pain specialists for more advanced interventions. Additionally, rheumatologic input is often needed to manage joint pain, chondrocalcinosis, and other musculoskeletal complications.

●Other facets of management – Dental care is important due to the risk of premature tooth loss and other dental abnormalities associated with HPP. Nephrologists and endocrinologists often help manage kidney stone risk and optimize mineral balance, which are particularly important facets of care in adults. Mental health specialists and therapists can be helpful, as chronic pain and disability often have a profound psychological impact.

Prevention of complications — Preventing complications in patients with HPP is essential to improve quality of life and reduce the risk of significant health issues.

Dental care — Regular dental care is a crucial aspect of prevention, as patients with HPP are prone to premature tooth loss and other dental abnormalities [4,9]. Routine dental hygiene practices, including brushing, flossing, and professional cleanings, are essential. Close follow-up with a dentist familiar with HPP is recommended to monitor for early signs of dental complications and to implement timely interventions.

Kidney stone prevention — The prevention of kidney stones and nephrocalcinosis is another critical aspect of managing HPP. Due to impaired bone mineralization, patients may experience hypercalciuria and increased risk of kidney stones. While adequate calcium and vitamin D intake are important to support bone health, excessive intake of these nutrients should be avoided, as it may exacerbate the risk of stone formation [4,9]. Adequate hydration is crucial, and patients should be advised to maintain good fluid intake and avoid activities that may predispose them to dehydration, further increasing the risk of kidney stones. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)

Atypical femur fracture prevention — In adult patients with HPP, the prevention of atypical femur fractures is vital. Patients with HPP should generally avoid antiresorptive agents used for osteoporosis treatment [12-17], as antiresorptive therapy may further impair bone mineralization in HPP and increase risk of atypical femur fracture. Instead, management should focus on other strategies to maintain bone health and prevent fractures, with careful monitoring for any signs of skeletal complications.

Nonpharmacologic strategies include maintaining adequate but not excessive calcium and vitamin D intake to support bone health while avoiding risks of biochemical abnormalities (eg, hypercalcemia) and ectopic calcifications. Lifestyle modifications should be tailored to achieve and maintain healthy body weight and should include exercises that promote balance and flexibility. Behaviors that increase fall and/or fracture risk (eg, smoking, excessive alcohol intake) should be avoided. Patients with HPP should be monitored for new or unusual thigh or groin pain that may indicate early signs of stress fractures of the femoral shaft. If such symptoms develop, imaging studies are warranted. (See "Femoral stress fractures in adults", section on 'Diagnostic imaging'.)

PHARMACOTHERAPY FOR SELECTED PATIENTS

Enzyme replacement therapy — Asfotase alfa, a recombinant tissue nonspecific alkaline phosphatase (TNSALP) targeted to bone, is the primary pharmacologic treatment for perinatal and infantile hypophosphatasia (HPP). It improves survival, pulmonary function, bone mineralization, hypercalcemia, hyperphosphatemia, and muscle weakness, especially in severely affected patients [18-20].

Candidates for treatment — In Japan, asfotase alfa has regulatory approval for the treatment of all patients with HPP. Regulatory approval in the United States and European Union is limited to pediatric-onset HPP. Thus, in these regions, HPP manifestations during childhood must be documented prior to treatment initiation in adults. (See 'Distinguishing adult- from childhood-onset HPP' below.)

Severely affected pediatric patients — In pediatric patients with severe disease, particularly those with perinatal- or infantile-onset HPP, asfotase alfa can be lifesaving [18-20]. It has remarkable efficacy in improving skeletal abnormalities, reversing respiratory insufficiency, and enhancing overall growth and development. In clinical trials, treatment with asfotase alfa led to substantial improvements in bone mineralization, reducing the severity of rickets, preventing fractures, and improving functional disability [18,21,22]. These improvements are critical for enhancing mobility and reducing pain, thus significantly improving quality of life for young patients.

For example, in studies comparing 37 pediatric patients who received asfotase alfa with 48 historical controls who received supportive care alone, asfotase alfa therapy was associated with greater survival at age 1 year (95 versus 42 percent with supportive care) and at age 5 years (84 versus 27 percent with supportive care) [20].

Less severely affected patients — In less severe disease, the decision to start enzyme replacement therapy needs to be individualized, as access to asfotase alfa is limited due to cost and availability, studies showing efficacy are small, and limited long-term safety data are available. The decision to initiate asfotase alfa therapy requires careful discussion and shared decision-making. Cost-benefit decisions need to include considerations regarding financial burden to the patient, potential side effects, expected benefits of enzyme replacement therapy, and availability of other therapies.

●Benefits of treatment – For pediatric and adult patients with childhood-onset HPP who have continued functional impairment despite conservative measures, asfotase alfa may provide improvements in physical function, pain, quality of life, depressive symptoms, and the ability to perform daily activities [23-27]. Asfotase alfa lowers inorganic pyrophosphate (PPi) levels [28-30] and improves bone mineral density (BMD) and strength [31,32], presumably reducing the risk of fractures and skeletal deformities that are prevalent in untreated HPP. Enzyme replacement therapy also facilitates healing of fractures and pseudofractures [33]. Thus, asfotase alfa helps mitigate the progressive nature of the disease, allowing for better symptom management and improved prognosis. However, long-term efficacy and safety data are limited, particularly in older adults.

For example, an open-label trial in 19 adolescents and adults (aged 13 to 66 years) with hypophosphatasia (18 of 19 with infantile- or juvenile-onset hypophosphatasia) compared asfotase alfa (0.3 or 0.5 mg/kg/day) with no treatment (control) for six months followed by a 4.5-year extension phase in which all participants received enzyme replacement therapy [27]. Participants who received asfotase alfa during the primary treatment phase exhibited a decrease in mineralization lag time after one year of treatment. In the overall cohort, median distance walked during the six-minute walk test increased between baseline and five years. In a small subset of adult participants (n = 6) with long-term follow-up, improvement in functional disability was lost after discontinuation of enzyme replacement therapy [34].

●Off-label use in adult-onset disease – In the United States and European Union, asfotase alfa does not have regulatory approval for treatment of adult-onset HPP. Nonetheless, enzyme replacement therapy may be clinically justified for adult-onset HPP based on disease burden and functional impairment rather than an arbitrary age-of-onset distinction. The pathophysiology of HPP does not fundamentally differ between adults with onset of disease before or after 18 years of age; therefore, asfotase alfa may be a reasonable option for adults with significant, debilitating symptoms, including recurrent fractures or pseudofractures, severe musculoskeletal pain, or profound weakness that limits daily activities. The feasibility of treatment depends on multiple factors, including insurance coverage, cost considerations, and patient preference, and requires a careful assessment of risks and benefits. Efzimfotase alfa, an investigational second-generation enzyme replacement therapy, may provide a new treatment option for this patient population.

Dosing — Asfotase alfa is given subcutaneously, either 1 mg/kg administered six times per week or 2 mg/kg administered three times per week. The dose is not titrated. Injection sites should be rotated to avoid skin reactions. The solution should be refrigerated and protected from light during storage and allowed to reach room temperature prior to injection [35].

Adverse effects — Common adverse reactions of asfotase alfa include localized injection site reactions, such as erythema, pain, pruritus, and swelling. Lipoatrophy, characterized by the loss of fat at injection sites, has also been observed and can become more pronounced with long-term use. Systemic hypersensitivity reactions, including fever, chills, and anaphylaxis, have been reported and necessitate immediate medical attention. Additionally, some patients may experience ectopic calcification, which requires careful monitoring and management by the prescribing provider [9,21,30].

Less common but serious side effects include craniosynostosis in pediatric patients, which involves the premature fusion of skull bones and can impact brain development. In some instances, patients might develop systemic inflammatory responses, including fever and arthralgia [9,21,30]. Given these potential risks, patients receiving asfotase alfa must undergo routine monitoring, reviewed immediately below.

Monitoring — Monitoring during asfotase alfa therapy is crucial for ensuring treatment safety and efficacy.

●Biochemical monitoring – Serum levels of alkaline phosphatase (ALP), calcium, phosphate, and 25-hydroxyvitamin D, as well as kidney function, should be monitored routinely, with more frequent measurements required in severe HPP. Generally, these tests should be done at baseline and one, three, six, and 12 months after starting therapy for perinatal or infantile disease. Thereafter, monitoring every six to 12 months is reasonable. In childhood and adult HPP, measurements can be obtained at baseline and three, six, and 12 months initially after starting treatment and every six to 12 months thereafter. Serum ALP activity rises from below normal to supraphysiologic levels and is a key metric of treatment efficacy. Serum parathyroid hormone (PTH) levels should be monitored periodically based on serum calcium, 25-hydroxyvitamin D, and phosphate levels to detect potential mineral imbalances that may result from treatment. Hypocalcemia or hypercalcemia may require dose adjustments or additional interventions like fluid administration [9,21,30].

●Clinical and radiologic monitoring – Patients should undergo routine physical examinations to assess for any signs of ectopic calcification, which can occur in various tissues, including the kidneys and eyes. Ocular and renal calcifications are known complications of HPP, and it is not clear whether development of calcifications is due to treatment with asfotase alfa or to the underlying disease. Imaging studies such as radiographs or ultrasounds may be employed at baseline to detect early signs of calcification or other skeletal abnormalities. Imaging should be repeated at variable intervals, depending on initial findings, to monitor for improvement and/or new calcification. Pediatric patients should undergo regular assessment of growth parameters and developmental milestones to ensure appropriate physical development and to identify any potential complications such as craniosynostosis, which requires prompt attention [9,21,30].

Patients should also be monitored for adverse reactions at injection sites, including erythema, pain, and lipoatrophy. Patients should be routinely queried about systemic hypersensitivity reactions, such as fever, chills, and anaphylaxis. Any signs of systemic hypersensitivity reactions require early intervention and management. Additionally, clinicians should remain vigilant for signs of systemic inflammatory responses and other serious side effects [9,21,30]. Painful injection site reactions can sometimes require temporary treatment interruption but typically respond to antihistamines. Treatment should be immediately discontinued if the patient develops anaphylaxis.

Off-label treatments (adults) — For adults with HPP who do not qualify for or are unable to obtain enzyme replacement therapy and who have skeletal HPP manifestations that are unresponsive to conservative measures, anabolic bone therapy (eg, teriparatide, romosozumab) has occasionally been used off-label to stimulate bone formation and potentially improve bone density. Although some improvements in metabolic and skeletal metrics have been observed with these agents, anabolic therapy is used for only one to two years, and long-term benefits have not been demonstrated. Further, rapid bone resorption can occur after discontinuation of romosozumab, and antiresorptive therapies (eg, bisphosphonates) typically used to prevent this bone loss are generally avoided in HPP due to their potential to further impair mineralization and exacerbate risk of atypical femur fractures. Careful patient selection, monitoring, and shared decision-making are essential when considering anabolic therapy. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Romosozumab'.)

●PTH analogs (teriparatide) – Teriparatide has shown potential benefits for adult patients with HPP when asfotase alfa is unavailable. Case reports suggest that treatment with teriparatide, a recombinant form of PTH, can raise ALP activity, improve markers of bone remodeling, increase BMD, and promote fracture healing in some adult patients with HPP [36-43]. Notable improvements have been observed in bone turnover and bone formation markers (eg, C-telopeptide [CTX], osteocalcin, propeptide of type I procollagen [PINP]), and in lumber spine T-scores. Some patients have reported reductions in pain and improvements in mobility, with signs of fracture healing observed in both metatarsal and femoral sites. These benefits have been particularly evident in patients who experience persistent fractures, pain, and functional limitations due to HPP. Similar findings were reported in two patients treated with PTH (1-84) [44].

However, these findings derive solely from case reports rather than randomized controlled trials, and treatment response has been variable. Several patients treated with PTH analogs experienced only partial or transient responses [45], and some had no meaningful clinical improvement [46]. Additionally, no established dosing guidelines exist for HPP treatment with teriparatide, and both the safety and long-term efficacy in this patient population remain unclear. Thus, further research is essential to clarify the efficacy of PTH analogs in HPP.

●Anti-sclerostin therapy (romosozumab) – Sclerostin inhibitors have been utilized as off-label treatment for skeletal complications in adult patients with HPP for whom asfotase alfa is not available. In a small, open-label phase II study in eight adults with HPP, antisclerostin monoclonal antibody treatment increased bone-specific ALP, conferred favorable changes in bone turnover makers, and increased lumbar spine BMD [47]. In two case reports, HPP patients treated with romosozumab exhibited increases in BMD, improvements in fracture healing, and significant pain reduction [48,49]. Although the use of romosozumab in HPP remains experimental and based on limited clinical data, scant available evidence suggests that it may support bone formation and enhance skeletal outcomes, potentially improving quality of life for patients who lack access to enzyme replacement. However, larger studies are needed to confirm its safety and efficacy in HPP patients.

DISTINGUISHING ADULT- FROM CHILDHOOD-ONSET HPP

Clinical utility — In adults with hypophosphatasia (HPP), distinguishing between adult- and childhood-onset forms has important implications for treatment eligibility. However, this distinction is controversial and fraught with confounders. Some adults with HPP have no disease manifestations in childhood and initially develop HPP symptoms in adulthood (adult-onset HPP). Alternatively, symptoms may start in childhood and continue into adulthood or transiently become quiescent and then recur in adulthood (pediatric-onset HPP [ie, infantile- or childhood-onset]). Depending on the time course of symptoms, availability of medical records, recall bias, and recognition of HPP symptoms, adult patients and their providers may not accurately identify prior childhood symptoms as manifestations of HPP [23], thus confounding a clear distinction between childhood- and adult-onset HPP.

Treatment eligibility — In the United States and European Union, enzyme replacement therapy with asfotase alfa has regulatory approval only for pediatric-onset HPP. (See 'Candidates for treatment' above.)

Effective strategies to identify signs of childhood-onset HPP in adults include inquiries into childhood musculoskeletal health, dental issues, and neurologic or pain-related syndromes. Key indicators, such as premature loss of primary teeth with intact roots before age 5 years, can help establish a diagnosis of childhood-onset HPP and may be verified through family photos, old dental records, baby book entries, or parental input. Other potential signs include delayed motor milestones, physical limitations, fractures, orthopedic evaluations, persistent growing pains, and chronic bone or muscle aches, all of which may reflect early musculoskeletal involvement. Additionally, obtaining childhood medical records can uncover previously documented signs, symptoms, radiologic findings, or clinical evaluations suggestive of childhood-onset HPP that may have been forgotten by the patient or their childhood caregivers.

Prognostic importance — Little evidence supports the notion that disease severity or progression is significantly affected by the arbitrary distinction between symptom onset before or after 18 years of age [23,50]. In the largest study of adult patients with HPP, 45 percent had adult-onset HPP, 33 percent had pediatric-onset HPP (<5 percent diagnosed before six months of age), and 22 percent had unknown onset of symptoms. No substantial differences in disease burden were seen between adult patients with pediatric-onset disease compared with those classified as having adult-onset disease [23].

Genotype-phenotype correlations — Genetic testing alone does not reliably differentiate between childhood- and adult-onset HPP. Although adult-onset disease is primarily associated with heterozygous rather than biallelic ALPL variants, many individuals with heterozygous pathogenic variants develop symptoms in childhood. This suggests that factors beyond residual tissue nonspecific alkaline phosphatase (TNSALP) activity play a role in determining disease onset. Additionally, some individuals diagnosed with adult-onset HPP may have had subtle, unrecognized symptoms in childhood that were either not evaluated, misattributed to other conditions, or overlooked due to incomplete medical records or recall bias.

The biological basis of incomplete penetrance and variable expressivity of pathogenic ALPL variants remains poorly understood. TNSALP is a promiscuous enzyme with broad tissue distribution and substrate specificity that varies by tissue type. While key substrates such as inorganic pyrophosphate (PPi), phosphorylated osteopontin, and pyridoxal 5'-phosphate (PLP) have been identified, additional, yet undiscovered substrates likely contribute to phenotypic variability. The large number of missense ALPL variants can generate a spectrum of enzymatic activity, altering substrate affinities across different tissues and influencing the timing and severity of disease onset. Further, environmental and age-related factors (such as bone turnover, mechanical stress, and hormonal changes [eg, menopause-related bone loss]) may unmask or exacerbate symptoms in previously asymptomatic individuals.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric bone health".)

SUMMARY AND RECOMMENDATIONS

●Management goals – Management of hypophosphatasia (HPP) is multifaceted, involving symptom-directed care, prevention strategies, and pharmacologic therapies. (See 'Management goals' above.)

●Symptom-directed management – Symptom-directed care for patients with HPP varies significantly depending on the severity of the disease.

•Severe forms of HPP – In the most severe forms of HPP, often presenting in infancy, management focuses on addressing critical complications that can be life-threatening. Respiratory support is paramount for infants experiencing respiratory distress due to pulmonary insufficiency. Nutritional support is also crucial. (See 'Severe forms of HPP' above.)

•Less severe forms of HPP – In less severe forms of HPP without pulmonary complications or severe rickets, symptom-directed care often involves a multidisciplinary, highly individualized approach with various specialists. Pain management is a significant aspect of care for many adults with HPP. (See 'Less severe forms of HPP' above.)

●Prevention of complications – Preventing complications in patients with HPP is essential to improve quality of life and reduce the risk of significant health issues. Complications may include premature tooth loss and other dental problems, kidney stones, and atypical femur fractures. (See 'Prevention of complications' above.)

●Enzyme replacement therapy for selected patients – Asfotase alfa, a recombinant tissue nonspecific alkaline phosphatase (TNSALP) targeted to bone, is the primary pharmacologic treatment for perinatal and infantile HPP. (See 'Enzyme replacement therapy' above.)

•Severe forms of pediatric disease – For patients with severe forms of pediatric-onset HPP, we recommend asfotase alfa rather than supportive care alone (Grade 1A). Asfotase alfa improves survival, pulmonary function, bone mineralization, hypercalcemia, hyperphosphatemia, and muscle weakness, especially in severely affected patients. (See 'Severely affected pediatric patients' above.)

•Less severely affected patients – We suggest asfotase alfa for adults with pediatric-onset HPP and symptoms that interfere with daily function (Grade 2C). In adults with HPP, asfotase alfa treatment has been associated with improvements in physical function and quality of life. (See 'Less severely affected patients' above.)

In Japan, asfotase alfa has regulatory approval for the treatment of all patients with HPP. Regulatory approval in the United States and European Union is limited to pediatric-onset HPP.

●Off-label treatments (adults) – For adults with HPP who do not qualify for or are unable to obtain enzyme replacement therapy and who have skeletal HPP manifestations that are unresponsive to conservative measures, anabolic agents (eg, teriparatide, romosozumab) have occasionally been used for short-term treatment, but long-term benefits have not been demonstrated. Antiresorptive agents should generally be avoided in patients with HPP. (See 'Off-label treatments (adults)' above.)

●Distinguishing adult- from childhood-onset HPP – In adults with HPP, distinguishing between adult- and childhood-onset forms has important implications for treatment eligibility. However, this distinction is controversial and fraught with confounders. (See 'Distinguishing adult- from childhood-onset HPP' above.)