Clinical studies of skeletal diseases

Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

Fibrous Dysplsia/McCune-Albright Syndrome:[unreadable] [unreadable] In the study by Hart el al, as part of our efforts to characterize the natural history of FD, we determined the onset, progression and plateau of skeletal lesions in FD, and how the extent of disease correlated with functional outcomes. We evaluated 109 subjects with FD who had been studied at the NIH for up to 32 years. We found that 90% of the skeletal disease burden was established by age 15. Disease was established in a region-specific pattern: 90% of the lesions were established in the craniofacial region by 3.4 years, in the extremities by age 13.7, and in the axial skeleton by age 15.5. Twenty-five out of 103 subjects eventually required ambulatory aids. The median age at which assistance was required was 7 (range 1-43). The median bone scan score for subjects requiring assistance was 64.3 (range 18.6-75) compared to 23.1 (range 0.5-63.5) in the unassisted subjects (p<0.0001). Amongst subjects requiring assistance with ambulation, 92% demonstrated this need by 17 yr. This study established that the majority of skeletal lesions and the associated functional disability in FD occur within the first decade of life. The implication is that the window of time for preventative therapies is narrow. These findings have implications for prognosis, the timing and type of therapy, and the development of trials of new therapies and their interpretation.[unreadable] [unreadable] An earlier observation that arose out of the natural history study was that surgical decompression of the optic nerves, a highly morbid procedure that was the standard of care at the time, was not indicated. Earlier work also suggested that it was the subgroup of patients with growth hormone (GH) excess that were at risk for disease-associated craniofacial morbidity (blindness, deafness, and macrocephaly). We tested this hypothesis by studying 104 patients with FD, and found that 17% of the optic nerves were <50% encased, 22% were 50-99% encased, and 61% were 100% encased. Only 12% of the nerves that were 100% encased showed evidence of optic neuropathy, while 88% of the 100% encased nerves did not. The group with optic neuropathy was not older than the group without, confirming that the disease was not progressive (in the absence of GH excess). Patients with GH excess were significantly more likely to have nerves that were 100% encased, and to have optic neuropathy. Six prophylactic optic nerve decompressions were performed; in 5 patients vision was stable postoperatively, and 1 patient was blind. There were 13 interventional (prophylactic) optic nerve decompression procedures; 6/13 showed some improvement and 7/13 showed no improvement or worsened vision. From these data, we concluded that the vast majority of optic nerves encased with FD do not exhibit symptoms of optic neuropathy and appear 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 only be performed when there is objective evidence of progressive optic neuropathy. [unreadable] [unreadable] One of the most pressing clinical issues for some patients with FD is pain. While pain was known to be associated with FD in some patients, it was not known which patients suffered from pain, what the severity of their pain was, which skeletal sites were more likely to be painful, what the natural history of the pain was, and what treatments were effective/ineffective. To answer these questions, we conducted a cross sectional, retrospective review of the NIH cohort of patients with FD. We studied 35 children and 43 adults. We found that pain at sites of FD was common, reporteed by 67% of the population. Pain was more common and severe in adults than in children (81% and 49%, respectively p<0.005, severity 4.1/10, and 2.8/10, respectively, p<0.01). Surpprisingly, there was no correlation between pain severity and skeletal disease burden. A disturbing, but unfortunately typical finding was that children were more likely than adults to be untreated for pain (44% vs. 26%). We concluded that pain, which was sometimes severe, was common in FD and was often under-treated, especially in children. The prevalence and severity of pain was greater in adults, but was unrelated to the burden of FD. The increase in pain is neither due to more fractures, which are more common in children, nor to the development of new FD lesions, which was not a significant feature of aging.[unreadable] [unreadable] The treatment of precocious puberty has been one of the most vexing problems in the care of patients with MAS. Our objective was to assess the efficacy of the potent, third generation aromatase inhibitor letrozole in decreasing pubertal progression, and the response of indices of bone turnover associated with FD in girls with MAS. Nine girls, 3-8 years of age were evaluated at baseline, and every 6 mo for 12-36 months while on treatment with letrozole at a dose of 1.5-2.0 mg/M2/d. We found that girls had decreased rates of linear growth (p=0.01) and bone age advance (p=0.004). There was cessation or slowing in the rates of bleeding over 12-36 mo of therapy. Ovarian volume, serum estradiol levels, and indices of bone metabolism fell after 6 months (p=0.05), but tended to rise by 24-36 months. Uterine volumes did not change. We concluded that letrozole can be effective therapy for precocious puberty in many girls with gonadotropin-independent precocious puberty. With 36 months of follow-up, this study represents the longest study of girls with MAS treated with modern drugs.[unreadable] [unreadable] Disorders of mineral metabolism:[unreadable] [unreadable] An important question to answer in the study of any hormone is what its biological half life is. To answer this question we studied a group of patients with FGF-23-producing tumors, TIO. Surgical removal of the tumor offered the opportunity to determine the elimination half life of FGF-23. The tumors were removed from three patients with TIO and serum samples were taken every 30 minutes for up to 72 hours after the operation. The elimination half life was determined by one phase exponential decay methodology. The elimination life of FGF-23 as determined by C-terminal/intact and intact assays was found to be 46 +/- 12 and 58 +/- 34 min., respectively. Therefore, the plasma half life of serum FGF-23 is in the range of 46 - 58 min. This is important information for future studies of FGF-23 action, and in determining the biology of FGF-23 in disease states such as renal failure, where there are very high levels of C-terminus, but not intact FGF-23.[unreadable] [unreadable] We previously showed that patients with hypoparathyroidism, who have high serum phosphorus also have high serum FGF-23, indicating that in the absence of PTH, FGF-23, which acts to lower serum phosphate by action at the proximal renal tubule, is an ineffective phosphaturic agent. This suggests that the phosphaturic effect of FGF-23 is PTH-dependent. To test this hypothesis, we treated two patients with TIO with the drug cinacalcet. Cinacalcet renders patients hypoparathyroid by its action at the parathyroid gland to decrease PTH secretion. We studied two subjects with TIO with cinacalcet and found that cinacalcet-induced hypoparathyroidism, resulted in an increase in renal phosphate reabsorption and serum phosphorus, and allowed for a decrease in phosphate supplementation to a dose that was tolerated. These data demonstrated two important findings: 1) medically-induced hypoparathyroidism with cinacalcet is a therapeutic option for TIO, and likely the whole class of disorders caused by over production of FGF-23, 2) that the phosphaturic action of FGF-23 is PTH-dependent.