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X-linked hypophosphatemia (XLH) is characterized by increased FGF23, which impairs activation of vitamin D and promotes renal phosphate wasting leading to osteomalacia and rickets. Current treatment using 1,25- dihydroxyvitamin D(calcitriol) and phosphate is often complicated by hypercalcemia and nephrocalcinosis and does not always prevent hyperparathyroidism. Furthermore, it does not normalize growth. Thus, the study team undertook a pre-clinical study in the Hyp mouse model of XLH, to compare the effects of calcitriol alone vs treatment with FGF23 blocking antibodies on growth, serum and urine mineral ions as well as histological, histomorphometric, microarchitectural and biomechanical properties of bones. These studies revealed that calcitriol monotherapy improves growth, prevents rickets and improves the microarchitectural and biomechanical properties of bone without phosphate supplementation. The beneficial effects of calcitriol were superior to those of the FGF23 blocking antibody employed, perhaps because, as in humans, FGF23 blocking antibodies were not able to sustain increased levels of 1,25-dihydroxyvitamin D. It is notable that the beneficial effects of calcitriol occur in spite of a significant increase in circulating FGF23 and bone FGF23 mRNA expression.
Based on these pre-clinical data, the current proposal aims to address the hypothesis that optimizing calcitriol therapy in humans with XLH, without phosphate supplementation, will have beneficial effects. The study team hypothesizes that optimizing calcitriol will obviate the need for phosphate supplementation, thus increasing compliance and decreasing complications of current therapy which include nephrocalcinosis and hyperparathyroidism. Optimizing calcitrol therapy is also expected to improve skeletal microarchitecture in all subjects with XLH and improve growth and prevent rachitic changes in pediatric subjects. Subjects with XLH will be recruited from adult and pediatric Endocrine and Nephrology clinics. Therapy will be stopped for 2 weeks, following which baseline labs will be obtained and calcitriol therapy will be initiated. The dose of calcitriol will be increased over a three-month period to identify the highest subject-specific dose that does not lead to hypercalcemia or hypercalciuria.
Ages Eligible for Study: 6 Years to 70 Years (Child, Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
- Clinical diagnosis of XLH with family history excluding male-to-male transmission, or positive genotype for PHEX mutation
- Serum PTH levels less than 1.5x the upper limit of normal
- Serum calcium levels less than 10.0 mg/dl
- eGFR >= 60 mL/min/1.73m2
- 25(OH) vitamin D level >= 20 ng/dL
- Known allergy to calcitriol
- Pregnancy or breast feeding
- Use of skeletally active agents such as bisphosphonates, teriparatide, SERMS, hormone replacement therapy and progesterone-only contraceptive agents (combination oral contraceptive use in premenopausal women is not an exclusion criterion).
- Unwilling or unable to stop therapy with calcitriol and phosphate therapy for two weeks prior to study
- Therapy with cinacalcet within the past two weeks
- Current use of growth hormone therapy
- Use of diuretics or medications that alter renal handling of mineral ions.
- Use of glucocorticoids for more than 14 days in the past 12 months with the exception of inhaled agents.
- History of malignancy except basal and squamous cell carcinoma of the skin.
- Significant history of psychiatric disease per DSM-5.
- Substance use disorder per DSM-5.
- Significant cardiopulmonary disease (unstable CAD or stage D ACC/AHA heart failure).
- Absence of laboratory values for serum calcium, phosphate and creatinine in the 24 months prior to enrollment.
Allocation: Non- Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Massachusetts General Hospital, Boston, Massachusetts, United States, 02114