Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism.

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone.

CONTEXT: Fibrous dysplasia (FD) is a rare skeletal disorder, resulting in deformity, fracture, functional impairment, and pain. Bisphosphonates have been advocated as a potential treatment. OBJECTIVE: To determine the efficacy of alendronate for treatment of FD. DESIGN: Two-year randomized, double-blind, placebo-controlled trial. SETTING: Clinical research center. PATIENTS: Forty subjects with polyostotic FD (24 adults, 16 children). Subjects were randomized and stratified by age. INTERVENTIONS: Study drug was administered over a 24 month period in 6 month cycles (6 months on, 6 months off). Alendronate dosing was stratified: 40 mg daily for subjects >50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg. MAIN OUTCOME MEASURES: Primary endpoints were bone turnover markers, including serum osteocalcin, and urinary NTX-telopeptides. Secondary endpoints included areal bone mineral density (aBMD), pain, skeletal disease burden score, and functional parameters including the 9-min walk test and manual muscle testing. RESULTS: Clinical data was collected on 35 subjects who completed the study. There was a decline in NTX-telopeptides in the alendronate group (P = .006), but no significant difference in osteocalcin between groups. The alendronate group had an increase in areal BMD in normal bone at the lumbar spine (P = .006), and in predetermined regions of FD (P < .001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups. CONCLUSIONS: Alendronate treatment led to a reduction in the bone resorption marker NTX-telopeptides, and improvement in aBMD, but no significant effect on serum osteocalcin, pain, or functional parameters.

Optic neuropathy in McCune-Albright syndrome: effects of early diagnosis and treatment of growth hormone excess.

CONTEXT: GH excess is a serious complication of McCune-Albright syndrome (MAS) and has been associated with craniofacial morbidity. OBJECTIVE: The aim of the study was to determine whether early diagnosis and treatment of MAS-associated GH excess prevents optic neuropathy and hearing impairment, the major morbidities associated with GH excess. DESIGN AND SETTING: A retrospective cross-sectional analysis was conducted at a clinical research center. PATIENTS: Twenty-two subjects with MAS-associated GH excess and 21 control MAS subjects without GH excess were included in the study. INTERVENTION: Biochemical testing included random GH, nadir GH after glucose load, nadir GH on frequent sampling, and IGF-I Z-score. Subjects underwent imaging, ophthalmological, audiological, and otolaryngological assessment. Treatment included octreotide, pegvisomant, transphenoidal surgery, and/or radiotherapy as indicated. MAIN OUTCOME MEASURE: Association of optic neuropathy and hearing impairment to age at GH excess diagnosis/treatment was measured. RESULTS: Of 129 MAS subjects, 26 (20%) were diagnosed with GH excess based on elevation of two measures of GH function. Of these, 22 subjects were candidates for pharmacological intervention. Optic neuropathy was significantly correlated with intervention status, with no cases in the early intervention group (diagnosed/treated before age 18) or the control group, and four of seven (57%) in the late intervention group (diagnosed/treated after age 18) (Fisher's exact test; odds ratio, 0.027; P = 0.0058). Early diagnosis/intervention was not associated with reduction in hearing deficits (odds ratio, 1.25; P = 1.00). Mean head circumference SD score was significantly higher in the late (6.08; range, 2.70 to 22.56) than the early intervention (2.67; range, -0.65 to 6.72) or control groups (2.13; range, -2.06 to 7.79) (P = 0.003). CONCLUSIONS: Early diagnosis/treatment of GH excess in MAS is important to prevent optic neuropathy and craniofacial expansion. The relationship between hearing deficits and GH excess remains less clear and requires further study.

Daily parathyroid hormone 1-34 replacement therapy for hypoparathyroidism induces marked changes in bone turnover and structure.

Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic and leads to osteoporosis; yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated 5 hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected two to three times daily for 18 months, with doses individualized to maintain serum calcium at 1.9 to 2.25 mmol/L. Biochemical markers and bone mineral density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged; however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores were unchanged at the spine and femoral neck. Total hip Z-scores increased; however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in hypoparathyroid adults and adolescents has varying effects in the different skeletal compartments, leading to an increase in trabecular bone and an apparent trabecularization of cortical bone.

Denosumab treatment for fibrous dysplasia.

Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.

Selective venous catheterization for the localization of phosphaturic mesenchymal tumors.

Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies.

Cushing syndrome in the McCune-Albright syndrome.

CONTEXT: Cushing syndrome (CS) is a rare but potentially fatal feature of McCune-Albright syndrome (MAS). Optimal management, prognostic features, and long-term follow-up of this disorder have not been described. SETTING: The study was conducted at an academic tertiary care center. PATIENTS: A total of 112 patients participating in a natural history study at the National Institutes of Health (NIH) were evaluated, and 21 published cases were reviewed. INTERVENTIONS: Subjects received observation, medical management, or bilateral adrenalectomy. MAIN OUTCOME MEASURES: We measured prevalence, prognostic factors, and natural history. RESULTS: The prevalence of CS among NIH patients was 7.1%. The median age at diagnosis was 3 months. Clinical features included "Cushingoid facies" (66.7%), failure to thrive (60.0%), low birth weight (50.0%), liver disease (36.7%), and heart disease (26.7%). Six patients (20.0%) died, four after adrenalectomy. Death was more likely in patients with comorbid heart disease (odds ratio, 13.3; P < 0.05). Of 23 survivors, 13 underwent adrenalectomy, and 10 exhibited spontaneous resolution. Two patients with spontaneous resolution who were tested later in life (3 and 15 yr after resolution) continued to have low-level, autonomous adrenal function with biochemical adrenal insufficiency. Compared to MAS patients without CS, patients with CS were more likely to have a cognitive/developmental disorder (44.4 vs. 4.8%; P < 0.001; odds ratio, 8.8). CONCLUSIONS: Comorbid heart and liver disease were poor prognostic markers and may indicate the need for prompt adrenalectomy. The high incidence of cognitive disorders indicates a need for close developmental follow-up and parental counseling. Patients with spontaneous resolution of CS may develop adrenal insufficiency, and they require long-term monitoring.

Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome.

UNLABELLED: Most lesions in FD and their attendant functional disability occur within the first decade; 90% of lesions are present by 15 years, and the median age when assistive devices are needed is 7 years. These findings have implications for prognosis and determining the timing and type of therapy. INTRODUCTION: Fibrous dysplasia of bone (FD) is an uncommon skeletal disorder in which normal bone is replaced by abnormal fibro-osseous tissue. Variable amounts of skeletal involvement and disability occur. The age at which lesions are established, the pace at which the disease progresses, if (or when) the disease plateaus, and how these parameters relate to the onset of disability are unknown. To answer these questions, we performed a retrospective analysis of a group of subjects with FD. MATERIALS AND METHODS: One hundred nine subjects with a spectrum of FD were studied for up to 32 years. Disease progression was assessed in serial (99)Tc-MDP bone scans by determining the location and extent of FD lesions using a validated bone scan scoring tool. Physical function and the need for ambulatory aids were assessed. RESULTS: Ninety percent of the total body disease skeletal burden was established by age 15. Disease was established in a region-specific pattern; in the craniofacial region, 90% of the lesions were present by 3.4 yr, in the extremities, 90% were present by 13.7 yr, and in the axial skeleton, 90% were present by 15.5 yr. Twenty-five of 103 subjects eventually needed ambulatory aids. The median age at which assistance was needed was 7 yr (range, 1-43 yr). The median bone scan score for subjects needing assistance was 64.3 (range, 18.6-75) compared with 23.1 (range, 0.5-63.5) in the unassisted subjects (p < 0.0001). Among subjects needing assistance with ambulation, 92% showed this need by 17 yr. CONCLUSIONS: The majority of skeletal lesions and the associated functional disability occur within the first decade of life. The implication is that the window of time for preventative therapies is narrow. Likewise, therapeutic interventions must be tailored to where the patient is in the natural history of the disease (i.e., progressive disease [young] versus established disease [older subjects]). These findings have implications for prognosis, the timing and type of therapy, and the development of trials of new therapies and their interpretation.

Cinacalcet in the management of tumor-induced osteomalacia.

UNLABELLED: Both FGF-23 and PTH inhibit renal phosphate reabsorption. We treated two patients with TIO and FGF-23-mediated hypophosphatemia with cinacalcet to test the hypothesis that medicinally induced hypoparathyroidism would decrease renal phosphate wasting. Cinacalcet treatment resulted in increased renal phosphate reabsorption, allowed for a decrease in phosphate supplementation, and showed evidence of bone healing in one of the two patients. INTRODUCTION: Tumor-induced osteomalacia (TIO) is a rare, acquired disease of renal phosphate wasting, which results in hypophosphatemia and osteomalacia. It is caused by mesenchymal tumors that produce the phosphate and vitamin D-regulating hormone, fibroblast growth factor (FGF)-23. Removal of the tumor is curative, but the tumors are often difficult to locate. Medical treatment involves high doses of oral phosphate and calcitriol, but the phosphate is often poorly tolerated and leads to diarrhea. Because PTH also promotes phosphaturia, and patients with hypoparathyroidism are hyperphosphatemic in the setting of elevated serum FGF-23, we postulated that the calcium-sensing receptor agonist, cinacalcet, which can induce hypoparathyroidism, would be an effective adjuvant in the treatment of TIO. MATERIALS AND METHODS: Two subjects with presumed TIO in whom the tumor was not located after extensive testing and who did not tolerate medical therapy with phosphorus and calcitriol were treated with cinacalcet. RESULTS: Neither treatment with phosphorus nor combined treatment with phosphorus and calcitriol had an effect on serum FGF-23 levels. Treatment with cinacalcet resulted in increased renal phosphate reabsorption and serum phosphorus and allowed for a decrease in phosphate supplementation to a dose that was tolerated. On this regimen, one patient showed significant bone healing as shown by resolution of activity on bone scan and lack of osteomalacia as assessed by histomorphometry. CONCLUSIONS: These data show that medically induced hypoparathyroidism with cinacalcet is a therapeutic option for disorders of FGF-23-mediated hypophosphatemia and that, in the absence of PTH, the phosphaturic effect of FGF-23 is decreased.

Determination of the elimination half-life of fibroblast growth factor-23.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disease caused by mesenchymal tumors that secrete fibroblast growth factor-23 (FGF-23), a newly-described vitamin D and phosphate-regulating hormone. Surgical removal of the tumor, the ectopic source of circulating FGF-23, offers the opportunity to determine the elimination half-life of FGF-23. OBJECTIVE: The aim of the study was to determine the elimination half-life of FGF-23. PATIENTS/METHODS: The tumors were removed from three patients with TIO, and serum samples were taken every 30 min for up to 72 h after the operation. FGF-23 was measured by both a C-terminal/intact assay and an intact assay, and the elimination half-life was determined by one phase exponential decay methodology. SETTING: The Mark O. Hatfield Clinical Research Center of the National Institutes of Health, a tertiary referral clinical research center, was the setting for the study. RESULTS: The elimination life of FGF-23 as determined by C-terminal/intact and intact assays was 46 +/- 12 and 58 +/- 34 min, respectively. CONCLUSIONS: The plasma half-life of serum FGF-23 is in the range of 46-58 min.

Long-term outcome of optic nerve encasement and optic nerve decompression in patients with fibrous dysplasia: risk factors for blindness and safety of observation.

OBJECTIVE: Fibrous dysplasia (FD) of bone may occur solely as a skeletal condition or it may occur in association with extraskeletal manifestations, including growth hormone (GH) excess. Uncertainty exists as to the management of FD involving the optic nerves. In an effort to clarify management, the authors studied a large population of patients. METHODS: One hundred four patients underwent an evaluation that included review of records, endocrine testing, cranial computed tomography, and neuro-ophthalmological examination. RESULTS: Ninety-one of 104 patients had craniofacial FD; complete records were available for 87 patients (174 nerves). Seventeen percent of the optic nerves were less than 50% encased, 22% were 50 to 99% encased, and 61% were 100% encased. Twelve percent of the nerves that were 100% encased showed evidence of optic neuropathy, but 88% did not. The group with optic neuropathy was not older than the group without. Patients with GH excess were significantly more likely to have nerves that were 100% encased (relative risk, 4.1; 95% confidence interval, 1.5-11.1; P = 0.0017) and to have optic neuropathy (relative risk, 3.8; 95% confidence interval, 2.0-7.1; P = 0.0019). Six prophylactic optic nerve decompressions were performed; in five patients, vision was stable after surgery, and one patient was blind after surgery. Thirteen interventional optic nerve decompression procedures were performed; six of the 13 patients showed some improvement and seven of the 13 showed no improvement or worsened vision. CONCLUSION: The vast majority of optic nerves encased with FD do not exhibit symptoms of optic neuropathy and seem to be stable over time. GH excess is associated with increased risk of nerve encasement and optic neuropathy. Patients with craniofacial FD should be screened for GH excess, and optic nerve decompression should be performed only when there is objective evidence of progressive optic neuropathy.

Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome.

CONTEXT: GH excess affects approximately 20% of the patients with McCune-Albright syndrome (MAS). MAS is caused by sporadic, postzygotic, activating mutations in the GNAS gene, which codes for the cAMP-regulating protein, G(s)alpha (gsp oncogene). These same mutations are found in approximately one third of the sporadic cases of acromegaly. OBJECTIVE: We examined efficacy of the GH receptor antagonist, pegvisomant, in controlling gsp oncogene-mediated GH excess and skeletal disease (fibrous dysplasia of bone) associated with MAS. SETTING AND PATIENTS: Five MAS patients with GH excess were treated with 20 mg/d sc injection of pegvisomant for 12 wk in a randomized, double-blind, placebo-controlled crossover study at the National Institutes of Health. MAIN OUTCOME MEASURES: The primary measure of efficacy was normalization of IGF-I. Secondary outcome measures were reduction in serum IGF binding protein-3 (IGFBP-3), improvement of fatigue and sweating, and reduction in markers of bone metabolism and bone pain. RESULTS: Combined mean changes in serum IGF-I at 6 and 12 wk were -236.4 ng/ml (53%, P < 0.005) and -329.8 ng/ml (62%, P < 0.001), respectively. IGFBP-3 decreased by 0.8 mg/liter (24%, P < 0.01) and 2.9 mg/liter (37%, P < 0.005), respectively. There were no significant changes in signs and symptoms of acromegaly or markers of bone metabolism and bone pain, nor was there a significant change in pituitary size. Retrospective comparison of the degree of control achieved with pegvisomant vs. other medications (long-acting octreotide +/- dopamine agonist) in the same group showed that the two regimens were similarly effective. CONCLUSIONS: Pegvisomant effectively reduced IGF-I and IGFBP-3 levels in gsp-mediated GH excess but had no effect on fibrous dysplasia.

The correlation of specific orthopaedic features of polyostotic fibrous dysplasia with functional outcome scores in children.

BACKGROUND: Polyostotic fibrous dysplasia has a wide clinical spectrum, with substantial variation between patients in terms of orthopaedic manifestations, including the number of fractures, the degree of deformity of the limbs, and the presence of scoliosis. Data from bone scans, skeletal surveys, and records were correlated with the Pediatric Outcomes Data Collection Instrument scales to examine whether any specific facet of orthopaedic involvement could be related to functional abilities. METHODS: All patients who were sixteen years of age or younger and who were part of an ongoing natural history study of polyostotic fibrous dysplasia (including McCune-Albright syndrome) were sent an age-appropriate Pediatric Outcomes Data Collection Instrument outcomes tool. The medical records and radiographs of the patients who returned forms were reviewed. Radiographic measurements of scoliosis, the femoral neck-shaft angle, and limb deformities were then performed. The extent of skeletal involvement with polyostotic fibrous dysplasia (disease burden) was assessed on bone scans with use of a validated tool. A chart review was performed to determine the fracture rate, the use of bisphosphonates, and the endocrine status. These measurements were correlated with the Pediatric Outcomes Data Collection Instrument scores. RESULTS: The outcomes tool was sent to twenty-seven patients and the completed instrument was returned by twenty patients, for a response rate of 74%. The parent-child form was filled out for twelve patients and the parent-adolescent form was filled out for eight patients. The mean standardized Pediatric Outcomes Data Collection Instrument scores for all twenty patients were lowest for sports (62; range, 14 to 100) and happiness (72; range, 25 to 100). Adolescents and parents disagreed with regard to sports (with adolescent scores being higher than parental scores) and pain (with parental scores being higher than adolescent scores). However, the overall global scores correlated well between the parents and the adolescents (r = 0.78, p = 0.03). The femoral neck-shaft angle correlated strongly with the Pediatric Outcomes Data Collection Instrument score for sports (r = 0.46, p = 0.03) but not for transfers. The bone scan scores for the lower extremity disease burden correlated with both the transfer scale (r = 0.76, p = 0.03) and the sports scale (r = 0.77, p = 0.02). Deformity of the limbs, the presence of scoliosis, the prevalence of endocrine dysfunction, and the number of fractures did not correlate with the Pediatric Outcomes Data Collection Instrument scores. CONCLUSIONS: In patients with polyostotic fibrous dysplasia, the loss of the normal femoral neck-shaft angle and the disease burden in the lower extremities appear to have the greatest effect on functional activity as measured with the Pediatric Outcomes Data Collection Instrument tool.

Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D.

UNLABELLED: Serum FGF-23 regulation was studied in patients with hypoparathyroidism or pseudohypoparathyroidism treated with calcitriol. Serum FGF-23 levels changed in parallel in response to changes in serum 1,25-D, suggesting that FGF-23 may be regulated by 1,25-D. In addition, the phosphaturic effect of FGF-23 may be diminished in the absence of PTH action on the kidney. INTRODUCTION: Fibroblast growth factor (FGF)-23 is a recently described hormone that has been shown to be involved in the regulation of phosphate and vitamin D metabolism. The physiologic role of FGF-23 in mineral metabolism and how serum FGF-23 levels are regulated have yet to be elucidated. Three patients with mineral metabolism defects that allowed for the investigation of the regulation of FGF-23 were studied. MATERIALS AND METHODS: Patient 1 had postsurgical hypoparathyroidism and Munchausen's syndrome and consumed a pharmacologic dose of calcitriol. Patient 2 had postsurgical hypoparathyroidism and fibrous dysplasia of bone. She was treated with increasing doses of calcitriol followed by synthetic PTH(1-34). Patient 3 had pseudohypoparathyroidism type 1B and tertiary hyperparathyroidism. She underwent parathyroidectomy, which was followed by the development of hungry bone syndrome and hypocalcemia, requiring treatment with calcitriol. Serum FGF-23 and serum and urine levels of mineral metabolites were measured in all three patients. RESULTS: Patient 1 had an acute and marked increase in serum FGF-23 (70 to 670 RU/ml; normal range, 18-108 RU/ml) within 24 h in response to high-dose calcitriol administration. Patient 2 showed stepwise increases in serum FGF-23 from 117 to 824 RU/ml in response to increasing serum levels of 1alpha,25-dihydroxyvitamin D (1,25-D). Finally, before parathyroidectomy, while hypercalcemic, euphosphatemic, with low levels of 1,25-D (10 pg/ml; normal range, 22-67 pg/ml), and with very high serum PTH (863.7 pg/ml; normal range, 6.0-40.0 pg/ml), patient 3 had high serum FGF-23 levels (217 RU/ml). After surgery, while hypocalcemic, euphosphatemic, and with high serum levels of serum 1,25-D (140 pg/ml), FGF-23 levels were higher than preoperative levels (305 RU/ml). It seemed that the phosphaturic effect of FGF-23 was diminished in the absence of PTH or a PTH effect. CONCLUSIONS: Serum FGF-23 may be regulated by serum 1,25-D, and its phosphaturic effect may be less in the absence of PTH.

Physical function is impaired but quality of life preserved in patients with fibrous dysplasia of bone.

Fibrous dysplasia of bone (FD) is a congenital, non-heritable skeletal disorder that is associated with multiple skeletal complications, including repeated fractures, limb length discrepancy, and bone pain. The disease-specific impact of FD on quality of life outcomes is unknown. We sought to understand the impact of the scope and extent of the skeletal disease on quality of life in adults and children with FD. The health-related quality of life was quantified in a population of adults (n = 56) and children (n = 22) with FD using validated health assessment questionnaires, the Medical Outcomes Study 36 Item Short-Form Health Survey, volume 2 (SF36) (adults) and the Child Health Questionnaire Parent Form 50 (CHQ-PF50) (children). Clinical demographic data and skeletal disease burden scores (SDBS, amount of skeleton involved with FD) were measured, and correlations with health-related quality of life were sought. The SF36 and CHQ-PF50 revealed lower Physical Function Summary scores in FD patients compared to the U.S. population norms (adult 41 vs. 50, Z score < -5.0, pediatric 39 vs. 50, Z score < -5.0). However, the SF36 and CHQ-PF50 Mental/Psychological summary scores were not different from those of U.S. population norms (adult 50 vs. 50, Z score = 0, pediatric 48 vs. 50 Z score = -0.9). The score on the Physical Function Domain of both tools was strongly negatively associated with the SDBS (adult Spearman rho = -0.43, P = 0.009, pediatric Spearman rho = -0.72, P = 0.005). The groups of adult and pediatric patients with SDBS > 30 had decreased Physical Function Domain scores when compared to those with scores < 30 (adult 35 vs. 45, P = 0.002, pediatric 57 vs. 78, P = 0.04, respectively). One of the largest effects was seen in the parents of children with FD, who had significantly lower Parental Emotional scores than those of the parents of healthy norms (54 vs. 88, Z score < -5.0), suggesting a high degree of emotional morbidity in the parents of children with FD. Despite measurable functional limitations in adults and children, and significant parental emotional impairment, patients with FD achieve a high level of social and emotional function. These data are important for prognosis and parental reassurance.

An instrument to measure skeletal burden and predict functional outcome in fibrous dysplasia of bone.

UNLABELLED: An instrument to measure skeletal burden in fibrous dysplasia was developed. Biological and clinical relevance was shown by correlating skeletal burden scores with bone markers, quality of life, and ambulatory status. Childhood scores predict adult ambulatory status, and scores were unaffected when bone markers decreased with bisphosphonate treatment or aging. INTRODUCTION: Fibrous dysplasia (FD) is a skeletal disease with a broad clinical expression. There is no objective method to assess the extent of skeletal involvement or predict outcome. We developed an instrument to measure skeletal burden that correlates with physical function, health-related quality of life (HRQL), and ambulatory status. MATERIALS AND METHODS: Seventy-nine patients with FD underwent bone scintigraphy. The skeletal burden score was derived from a weighted score based on the regional measurement using bone scintigraphy to estimate the amount of FD in anatomical segments. Six readers scored 20 scans twice to determine the inter- and intrareader agreement. To assess biological significance, scores were correlated with bone markers. To assess functional outcome, scores on the SF-36 (adults) or CHQ-PF50 (children) were correlated with skeletal burden scores. In a group of patients who had bone scans as children and adults (n = 6), the ability to predict ambulatory status was tested. Skeletal burden scores were assessed in patients before and after treatment with pamidronate (n = 5). RESULTS: The inter- and intrareader agreement of burden scores were r = 0.96, and 0.98, respectively (p < 0.001 for both). The scores correlated with markers of bone metabolism and HRQL (Spearman rho, 0.54-0.67 p < 0.001 and -0.43, p = 0.001, respectively). The mean score of patients who ambulated unassisted was significantly lower than those requiring assistance (p < 0.001 unassisted versus crutch and/or wheelchair). In unassisted ambulators, younger patients had higher scores, suggesting high childhood scores may predict adulthood impairment. In six patients with childhood and adulthood scans, childhood scores >30 predicted assisted ambulation in adulthood. There was a negative correlation between bone markers and age (Spearman rho, -0.42 to -0.70; p < 0.001), but not age and skeletal burden score. Pamidronate treatment decreased serum alkaline phosphatase but had no effect on the skeletal burden score. CONCLUSIONS: This is a validated and reliable instrument for the measurement of skeletal burden of FD and is able to predict functional outcome.

Fracture incidence in polyostotic fibrous dysplasia and the McCune-Albright syndrome.

UNLABELLED: In patients with polyostotic fibrous dysplasia of bone, the peak incidence of fractures is during the first decade of life, followed by a decrease thereafter. Phosphaturia is associated with an earlier incidence and increased frequency of fractures. INTRODUCTION: Fibrous dysplasia (FD) is a disorder involving either one (monostotic) or several bones (polyostotic FD [PFD] and sometimes is associated with cafe-au-lait hyperpigmentation of the skin and one or more hyperfunctioning endocrinopathies (McCune-Albright syndrome [MAS]). Both PFD and MAS are often associated with phosphaturia. Although fractures occur frequently in PFD/MAS, fracture incidence and the effect of age and co-existing metabolic abnormalities (endocrinopathy and/or phosphaturia) on fractures are ill defined. MATERIALS AND METHODS: We reviewed the medical records and examined the endocrine and phosphorus metabolism of 35 patients with PFD/MAS. We report on the age at which extremity fractures occurred and their location and treatment. The results of endocrine and phosphorus metabolism testing and associations between age of first fractures, number of fractures, fracture rate, and metabolic abnormalities were noted. RESULTS: The average follow-up was 14.2 years (range, 2-39 years), during which 172 fractures occurred. The number and sites of fractures were 103 femoral, 25 tibial, 33 humeral, and 11 forearm. Twenty-seven patients had PFD with one or more endocrinopathies and/or phosphaturia, and eight had PFD alone. The endocrinopathies included precocious puberty (n = 19), hyperthyroidism (n = 9), growth hormone excess (n = 6), and one patient each with Cushing syndrome and primary hyperparathyroidism. Twelve patients had phosphaturia. The peak rate of fractures occurred between 6 and 10 years of age and decreased thereafter. Patients with metabolic abnormalities sustained their first fracture at an earlier age (6.9 versus 16.6 years, p < 0.005) and had a higher lifetime rate of fractures (0.29 versus 0.08 fractures/year), relative to patients with PFD alone. Phosphaturia was the single metabolic dysfunction associated with both an earlier age of first fracture (5.1 versus 16.6 years, p < 0.05) and a greater lifetime fracture rate (0.35 versus 0.08 fractures/year, p < 0.05). CONCLUSIONS: The occurrence of extremity fractures in FD peaks between 6 and 10 years of age and declines thereafter. Fractures occur earlier and more frequently in the presence of phosphaturia. These data have implications for long-term prognosis, clinical management, and interpretation of therapeutic interventions.