To address the natural history of Williams syndrome (WS), we performed multisystem assessments on 20 adults with WS over 30 years of age and documented a high frequency of problems in multiple organ systems. The most striking and consistent findings were: abnormal body habitus; mild-moderate high frequency sensorineural hearing loss; cardiovascular disease and hypertension; gastrointestinal symptoms including diverticular disease; diabetes and abnormal glucose tolerance on standard oral glucose tolerance testing; subclinical hypothyroidism; decreased bone mineral density on DEXA scanning; and a high frequency of psychiatric symptoms, most notably anxiety, often requiring multimodal therapy. Review of brain MRI scans did not demonstrate consistent pathology. The adults in our cohort were not living independently and the vast majority were not competitively employed. Our preliminary findings raise concern about the occurrence of mild accelerated aging, which may additionally complicate the long-term natural history of older adults with WS. We provide monitoring guidelines to assist in the comprehensive care of adults with WS.

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n ¼ 68) or placebo (n ¼ 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean AE standard error [SE] difference, -8.1 AE 3.24; p ¼ 0.012). Reductions in WOMAC physical function subscale (-4.9 AE 2.48; p ¼ 0.048) and Brief Pain Inventory worst pain (-0.5 AE 0.28; p ¼ 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared 1383with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.

Osteoporosis is the most common metabolic bone disease in the USA and the world. It is a subclinical condition until complicated by fracture(s). These fractures place an enormous medical and personal burden on individuals who suffer from them and take a significant economic toll. Any new fracture in an adult aged 50 years or older signifies imminent elevated risk for subsequent fractures, particularly in the year following the initial fracture. What a patient perceives as an unfortunate accident may be seen as a sentinel event indicative of bone fragility and increased future fracture risk even when the result of considerable trauma. Clinical or subclinical vertebral fractures, the most common type of osteoporotic fractures, are associated with a 5-fold increased risk for additional vertebral fractures and a 2-to 3-fold increased risk for fractures at other sites. Untreated osteoporosis can lead to a vicious cycle of recurrent fracture(s), often resulting in disability and premature death. In appropriate patients, treatment with effective antifracture medication prevents fractures and improves outcomes. Primary care providers and medical specialists are critical gatekeepers who can identify fractures and initiate proven osteoporosis interventions. Osteoporosis detection, diagnosis, and treatment should be routine practice in all adult healthcare settings. The Bone Health and Osteoporosis Foundation (BHOF)formerly the National Osteoporosis Foundationfirst published the Clinician's Guide in 1999 to provide accurate information on osteoporosis prevention and treatment. Since that time, significant improvements have been made in diagnostic technologies and treatments for osteoporosis. Despite these advances, a disturbing gap persists in patient care. At-risk patients are often not screened to establish fracture probability and not educated about fracture prevention. Most concerning, the majority of highest risk women and men who have a fracture(s) are not diagnosed and do not receive effective, FDA-approved therapies. Even those prescribed appropriate therapy are unlikely to take the medication as prescribed. The Clinician's Guide offers concise recommendations regarding prevention, risk assessment, diagnosis, and treatment of osteoporosis in postmenopausal women and men aged 50 years and older. It includes indications for bone densitometry as well as fracture risk thresholds for pharmacologic intervention. Current medications build bone and/or decrease bone breakdown and dramatically reduce incident fractures. All antifracture therapeutics treat but do not cure the disease. Skeletal deterioration resumes sooner or later when a medication is discontinued-sooner for nonbisphosphonates and later for bisphosphonates. Even if normal BMD is achieved, osteoporosis and elevated risk for fracture are still present. The diagnosis of osteoporosis persists even if subsequent DXA T-scores * M. S. LeBoff

In adults with X‐linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25‐dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023‐CL304 is an ongoing, open‐label, single‐arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia‐related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, –54%, osteoid thickness, –32%, osteoid surface/bone surface, –26%, [median] mineralization lag time, –83%). Mean serum phosphorus concentration averaged across the mid‐point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment‐emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure‐related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Increasing dietary protein results in an increase in urinary calcium. Despite over 80 y of research, the source of the additional urinary calcium remains unclear. Because most calcium balance studies found little effect of dietary protein on intestinal calcium absorption, it was assumed that the skeleton was the source of the calcium. The hypothesis was that the high endogenous acid load generated by a protein-rich diet would increase bone resorption and skeletal fracture. However, there are no definitive nutrition intervention studies that show a detrimental effect of a high protein diet on the skeleton and the hypothesis remains unproven. Recent studies from our laboratory demonstrate that dietary protein affects intestinal calcium absorption. We conducted a series of short-term nutrition intervention trials in healthy adults where dietary protein was adjusted to either low, medium or high. The highest protein diet resulted in hypercalciuria with no change in serum parathyroid hormone. Surprisingly, within 4 d, the low protein diet induced secondary hyperparathyroidism that persisted for 2 wk. The secondary hyperparathyroidism induced by the low protein diet was attributed to a reduction in intestinal calcium absorption (as assessed by dual stable calcium isotopes). The long-term consequences of these low protein-induced changes in calcium metabolism are not known, but they could be detrimental to skeletal health. Several recent epidemiological studies demonstrate reduced bone density and increased rates of bone loss in individuals habitually consuming low protein diets. Therefore, studies are needed to determine whether low protein intakes directly affect rates of bone resorption, bone formation or both.

High dietary protein intakes are known to increase urinary calcium excretion and, if maintained, will result in sustained hypercalciuria. To date, the majority of calcium balance studies in humans have not detected an effect of dietary protein on intestinal calcium absorption or serum parathyroid hormone. Therefore, it is commonly concluded that the source of the excess urinary calcium is increased bone resorption. Recent studies from our laboratory indicate that alterations in dietary protein can, in fact, profoundly affect intestinal calcium absorption. In short-term dietary trials in healthy adults, we fixed calcium intake at 20 mmol/d while dietary protein was increased from 0.7 to 2.1 g/kg. Increasing dietary protein induced hypercalciuria in 20 women [from 3.4 ± 0.3 (x -± SE) during the low-protein to 5.4 ± 0.4 mmol/d during the high-protein diet]. The increased dietary protein was accompanied by a significant increase in intestinal calcium absorption from 18.4 ± 1.3% to 26.3 ± 1.5% (as determined by dual stable isotopic methodology). Dietary protein intakes at and below 0.8 g/kg were associated with a probable reduction in intestinal calcium absorption sufficient to cause secondary hyperparathyroidism. The long-term consequences of these low-protein diet-induced changes in mineral metabolism are not known, but the diet could be detrimental to skeletal health. Of concern are several recent epidemiologic studies that demonstrate reduced bone density and increased rates of bone loss in individuals habitually consuming low-protein diets. Studies are needed to determine whether low protein intakes directly affect rates of bone resorption, bone formation, or both.Am J Clin Nutr 2003;78(suppl):584S-92S. KEY WORDSDietary protein, urinary calcium, parathyroid hormone, vitamin D, hypercalciuria, bone, soy INTRODUCTIONAlmost 30 million Americans are affected by osteoporosis, and women are 4 times more likely to suffer from this disease than men (1). The health problem is reaching near-epidemic proportions in the United States and worldwide. Nutrition plays an important role in both the prevention and the pathogenesis of many chronic diseases, including osteoporosis. Numerous studies have established that dietary calcium and vitamin D are critical nutrients for both accruing and maintaining skeletal mass. In contrast, our understanding of how other dietary components, such as protein, affect calcium homeostasis and skeletal metabolism is limited.

Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24-48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.

These data provide evidence that depressed intestinal calcium absorption explains, in part, low-protein-induced secondary hyperparathyroidism.