The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication.

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.

Paternally inherited inactivating GNAS1 mutations cause POH. This finding extends the range of phenotypes derived from haplo insufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that Gsalpha is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

Upon secretion, transforming growth factor (TGF) β is maintained in a sequestered state in extracellular matrix as a latent form. The latent TGFβ is considered as a molecular sensor that releases active TGFβ in response to the perturbations of the extracellular matrix at the situations of mechanical stress, wound repair, tissue injury, and inflammation. The biological implication of the temporal discontinuity of TGFβ storage in the matrix and its activation is obscure. Here, using several animal models in which latent TGFβ is activated in vascular matrix in response to injury of arteries, we show that active TGFβ controls the mobilization and recruitment of (messenchymal stem cells) MSCs to participate in tissue repair and remodeling. MSCs were mobilized into the peripheral blood in response to vascular injury and recruited to the injured sites where they gave rise to both endothelial cells for reendothelialization and myofibroblastic cells to form thick neointima. TGFβ were activated in the vascular matrix in both rat and mouse models of mechanical injury of arteries. Importantly, the active TGFβ released from the injured vessels is essential to induce the migration of MSCs, and cascade expression of monocyte chemotactic protein-1 (MCP-1) stimulated by TGFβ amplifies the signal for migration. Moreover, sustained high levels of active TGFβ were observed in peripheral blood, and at the same time points following injury, Sca1+CD29+CD11b−CD45− MSCs, in which 91% are nestin+ cells, were mobilized to peripheral blood and recruited to the remodeling arteries. Intravenously injection of recombinant active TGFβ1 in uninjured mice rapidly mobilized MSCs into circulation. Further, inhibitor of TGFβ type I receptor (TβRI) blocked the mobilization and recruitment of MSCs to the injured arteries. Thus, TGFβ is an injury-activated messenger essential for the mobilization and recruitment of MSCs to participate in tissue repair/remodeling.