FD/MAS: To evaluate the long-term survival of bone-grafting procedures in subjects with polyostotic fibrous dysplasia, we reviewed the operative reports and radiographs of the NIH cohort of patients with FD. Twenty-three subjects (mean age 13 y range, 2-40) with fifty-two bone-grafting procedures had a mean follow-up time of 19.6 y (range, 29-47 y). Kaplan-Meier life table estimates, Cox proportional hazard models, and T-tests comparing means were performed to assess various aspects of graft survival. The results showed a 50% estimate of survival of 14.5 years. Cox proportional hazards models showed no advantage comparing allograft with autograft or structural with nonstructural graft materials. The mean age of the patients was significantly greater (p < 0.001) in the subgroup of subjects in whom grafts were maintained over time (20.9 y) compared with the subgroup of patients whose grafts were resorbed (9.8 y). From these findings we concluded that bone-grafting is of limited value in treating FD. The expectations of patients and surgeons should include the high probability of graft resorption over time, particularly in younger patients. This suggests the maintenance of normal bone mechanics with implant support should be the priority of surgical intervention. The indications for surgery in craniofacial FD, the best techniques, and the efficacy of various approaches are poorly understood, particularly in polyostotic disease and MAS. To assess this, we examined the surgical indications and risk factors for recurrence in the NIH cohort. One hundred thirty-three subjects with craniofacial FD were evaluated. Radiographic studies, operative reports, and clinical records were reviewed. Thirty-six subjects underwent 103 craniofacial procedures (mean, 2.8 operations per subject), with 13.5 10.5-year follow-up (range, 0 to 39 y). The most common indication was craniofacial deformity (n = 61 operations), including 36 initial operations (59%) and 26 reoperations (41%). Mean time to reoperation was 3.4 +/- 3.2 y (range, 0.3 to 13.3 y). Regrowth occurred after 42 operations (68%), and was more frequent after operations in subjects with MAS with growth hormone excess, 22 of 25 operations (88%), than without growth hormone excess 15 of 36 operations (58%); p = 0.02. Of 11 subjects with growth hormone excess, nine (82%) were undiagnosed at the time of their initial operation. Regrowth was more frequent after debulking procedures, 31 of 38 (82%), than after more aggressive reconstructions 9 of 20 (45%); p = 0.007. Eleven subjects underwent treatment for aneurysmal bone cysts, with recurrence in one subject. Eleven subjects underwent biopsies without complications or regrowth. We concluded that regrowth and reoperation are common, particularly after debulking procedures. Outcomes are favorable for aneurysmal bone cysts and biopsies. In MAS growth hormone excess is a risk factor for regrowth, and may be underdiagnosed. Surgeons should be aware of appropriate screening for endocrinopathies in FD. These findings highlight the importance of a multidisciplinary approach to craniofacial FD, and individualized care with long-term follow-up. Osteonecrosis of the jaw (ONJ) is an established side effect of bisphosphonates. Although frequently prescribed for patients with FD, there are no reports of ONJ in the literature. This has led some to conclude that patients with FD are at low risk for the development of bisphosphonate-related ONJ. We reviewed the NIH cohort to determine the prevalence and risk factors for the development of ONJ in patients with FD. Of the 76 patients with FD in the NIH cohort who were treated with bisphosphonates, 4 developed ONJ (5.4%). Three patients developed ONJ in areas of FD-affected bone and 1 in an area of normal bone. All 4 patients had features known to be associated with ONJ in the general population, including long-term high-dose intravenous bisphosphonate treatment, periodontal and endodontic infections, and dentoalveolar surgical procedures. These cases establish ONJ as a potential complication of bisphosphonate treatment in patients with FD. The presence of established risk factors for ONJ in this group of patients with FD suggests that high-risk patients could be identified before the development of ONJ. Clinicians should use caution in prescribing bisphosphonates to patients with FD and should do so only for established indications. Mineral Homeostasis: The effects of temperature, handling, length of storage, and freeze-thaw cycles on FGF23 levels are unknown. To answer this we studied samples from our cohorts of patients with FGF23 excess. Serum and plasma FGF23 were measured using three commercially-available ELISA assays, two measuring iFGF23 and one measuring cFGF23. Samples from subjects with known FGF23 disorders were stored at 4, 22, and 37 C and analyzed at different intervals up to 48 hours (h). A subset of samples underwent repeated freeze-thaw cycles, and samples frozen at -80 C for up to 60 months were reanalyzed. The effect of adding a furin convertase inhibitor on FGF23 degradation was investigated. Plasma FGF23 levels were stable when stored at 4 and 22 C for 48 h. Both plasma and serum FGF23 levels demonstrated relative stability after five freeze-thaw cycles. Long-term storage at -80 C for 60 months induced variability in FGF23 levels. The addition of a furin inhibitor did not affect FGF23 degradation. Intact FGF23 levels showed good correlation only at the upper end of the assay range when comparing the two assays. From these data we determined that the sample type, handling, and choice of assay are factors that affect FGF23 levels and should be considered when measuring this hormone. The effect of PTH discontinuation on mineral metabolism and bone in hypoparathyroidism is unknown. To understand this we studied PTH discontinuation in 9 subjects with hypoparathyroidism who had been receiving hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries, bone turnover markers, 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 required 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 turnover markers 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. These data demonstrate that 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.
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