FD/MAS: An important research project that was published this year were the results of a randomized placebo-controlled study of the bisphosphonate, alendronate, for the treatment of FD. The objective was to determine the efficacy of alendronate in the treatment of FD. The design was a two-year, randomized, double-blind, placebo-controlled study. It was a single center study conducted at the NIH Clinical Center in Bethesda, MD. The study included forty subjects with polyostotic FD (24 adults, and 16 children). Subjects were stratified by age, and randomized to drug or placebo. Study drug (alendronate) was administered over a 24 month period in 6 month cycles (6 months on, 6 months off). The dose was stratified-adjusted in the following manner: 40 mg daily for subjects >50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg. The primary endpoint was 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. Clinical data was collected on 35 subjects who completed the study. Results showed 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, i.e. not affected by FD, at the lumbar spine (P =0.006), and in predetermined regions (sentinel lesions) of FD (P < .001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups in response to treatment. In summary, 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. The conclusion was that the orally-administered bisphosphonate alendronate was not an effective treatment for most of the clinically relevant aspects of FD. Based on the results of uncontrolled reports and the trend seen in this study, more potent intravenous bisphosphonates may be an effective treatment. Better medical treatment is needed for the treatment of FD. An important review published this year in Gene Reviews reflects a summary of the > 15 years of our work in studying and treating FD/MAS. The diagnosis of FD/MAS is based on the finding of two or more typical clinical features. In individuals whose only clinical finding is monostotic fibrous dysplasia, identification of a somatic activating mutation of GNAS is required to establish the diagnosis. Mutation detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Management of FD/MAS is most effectively accomplished by a multidisciplinary team of specialists. In regard to FD, no medical therapies are available; management focuses on optimizing function and minimizing morbidity related to fractures and deformity (including scoliosis). For precocious puberty, the goal of treatment is to prevent bone age advancement and not compromise adult height. For girls, options include the aromatase inhibitor letrozole and/or the estrogen receptor modulator tamoxifen; for boys, treatment options are less well established. For thyroid disease, methimazole effectively manages hyperthyroidism; however, because hyperthyroidism is persistent, the need for thyroidectomy is common. In the treatment of GH excess medical therapy is the preferred first-line treatment; options include (alone or in combination) octreotide and the growth hormone receptor antagonist pegvisomant. For neonatal cortisol excess, treatment varies by the presentation of neonatal Cushing syndrome. All persons with FD/MAS should be monitored: Infants for clinical signs of hypercortisolism; children for growth acceleration and other clinical signs of precocious puberty and/or growth hormone excess; thyroid function tests routinely in children age <5 years; males for testicular lesions with physical examination and testicular ultrasound. In persons with FD, periodic radiographs to monitor existing FD and development of new lesions; phosphorus levels to monitor for the development of hypophosphatemia. Craniofacial FD: yearly vision and hearing evaluations; periodic skull CT. Spine FD: close monitoring for progressive scoliosis. In children with thyroid abnormalities on ultrasound examination but normal thyroid function, monitor thyroid function periodically. In general, in most cases, it is wise to counsel against contact sports and other high-risk activities (when skeletal involvement is significant). Prophylactic optic nerve decompression (in patients with craniofacial FD) is contraindicated, as is surgical removal of ovarian cysts, and radiation therapy for treatment of FD, which carries a risk for malignancy. This review article includes a detailed set of treatment algorithms that will prove invaluable for clinicians caring for patients with FD/MAS. Mineral Homeostasis: An important study published this year in the area of mineral homeostasis was the finding of an increase in the requirement for calcium and active vitamin D replacement after the discontinuation of PTH in the treatment of 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, subsequent subjects were slowly weaned from hPTH 1-34 over several weeks. At the time when PTH was discontinued, subjects were requiring two to three times their 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 those before starting PTH. 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.

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Berglund, J A; Gafni, R I; Wodajo, F et al. (2018) Tumor-induced osteomalacia in association with PTEN-negative Cowden syndrome. Osteoporos Int 29:993-997
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