Marilyn H. Kelly

Fracture Incidence in Polyostotic Fibrous Dysplasia and the McCune‐Albright Syndrome

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.

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 (Gsα). 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.

Cinacalcet in the management of tumor-induced osteomalacia.

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.

Fibroblast Growth Factor‐23 Is Regulated by 1α,25‐Dihydroxyvitamin D

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.

An Instrument to Measure Skeletal Burden and Predict Functional Outcome in Fibrous Dysplasia of Bone

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.

Selective Venous Catheterization for the Localization of Phosphaturic Mesenchymal Tumors

Tumor‐induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D3 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.

Onset, Progression, and Plateau of Skeletal Lesions in Fibrous Dysplasia and the Relationship to Functional Outcome†

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.

Pathophysiology and medical treatment of pain in fibrous dysplasia of bone

One of the most common complications of fibrous dysplasia of bone (FD) is bone pain. Usual pain killers are often of inadequate efficacy to control this bone pain. The mechanism of bone pain in FD remains uncertain, but by analogy with bone tumors one may consider that ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers also occur in the dysplastic skeleton. Bone pain has been reported in up to 81% of adults and 49% of children. It affects predominantly the lower limbs and the spine. The degree of pain is highly variable and adults reports more pain than children. Bisphosphonates have been shown to reduce bone pain in uncontrolled studies. Their influence on bone strength remains unknown. In a randomized trial testing alendronate, bone pain was not significantly improved. Another trial assessing the effect of risedronate is ongoing. Possible future therapies include tocilizumab, denosumab and drugs targeting nerve growth factor and its receptor TrkA.

LONG-TERM OUTCOME OF OPTIC NERVE ENCASEMENT AND OPTIC NERVE DECOMPRESSION IN PATIENTS WITH FIBROUS DYSPLASIA: RISK FACTORS FOR BLINDNESS AND SAFETY OF OBSERVATION

OBJECTIVEFibrous 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. METHODSOne hundred four patients underwent an evaluation that includedreview of records, endocrine testing, cranial computed tomography, and neuro-ophthalmological examination. RESULTSNinety-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. CONCLUSIONThe 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.

Tumor localization and biochemical response to cure in tumor-induced osteomalacia

Tumor‐induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor‐23 (FGF23)‐secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with 111Indium‐octreotide with single photon emission computed tomography (octreo‐SPECT or SPECT/CT), and 18fluorodeoxyglucose positron emission tomography/CT (FDG‐PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo‐SPECT imaging, and 16 of 20 FDG‐PET/CT imaging. Eighteen of 19 (95%) were positive on octreo‐SPECT, and 14 of 16 (88%) on FDG‐PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo‐SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG‐PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease‐free at last follow‐up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C‐terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25‐dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo‐SPECT was more sensitive and specific, but in many cases FDG‐PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.