Sunshine and vitamin D once defined the field of bone and mineral research. However, our field has progressed greatly over the past decade, in great measure from significant advances in biotechnology. Happily, these research advances have brought forth the promise of more precise diagnosis and more targeted therapeutics. One important technology that has rapidly advanced our field is genomics. Genome wide association studies have shed light on the genes that influence vitamin D homeostasis and bone mass. More recently, high–throughput DNA sequencing technologies have been used to address an increasingly diverse range of disorders of bone and mineral metabolism, both common and arcane. The scale and efficiency of next-generation sequencing allows rapid interrogation of genetic material, and can rapidly generate an unbiased encyclopedia of a patient’s exome, genome or transcriptome. Whole-exome sequencing is both less costly and less technically demanding than whole-genome sequencing as only the protein-coding regions (∼1% of the genome) are analyzed. Study of only a small number of patients is necessary to identify a disease-causing gene. Significant wins in our field using the application of whole-exome sequencing are represented by the recent identification of CYP24A1 as a cause of idiopathic infantile hypercalcemia (1), GNA11 as a novel cause of familial hypocalciuric hypercalcemia (2) and hypoparathyroidism (2-4), and FAM20c as an unsuspected cause of hypophosphatemic rickets (5) . It is certain that these techniques will soon disclose the genetic basis for additional disorders of bone and mineral metabolism. And the complementary techniques to analyze the epigenome, metabolome, and microbiome will likely shed further light (pun intended!) on bone disease.
Pari passu with these successes in biotechnology come new strategies for treating bone disease that are based on recombinant proteins and monoclonal technology. Our patients have benefited greatly from PTH peptides for treatment of osteoporosis (6) and more recently hormone replacement in hypoparathyroidism (7), the last major endocrine disorder to be treated by replacement of a missing hormone. More exciting still is the recent availability of enzyme replacement for life-threatening hypophosphatasia (8). We have gained experience using humanized monoclonal antibodies that react with and neutralize RANKL to treat osteoporosis, and await approval of monoclonal antibodies that bind and inhibit sclerostin, a glycoprotein inhibitor of osteoblast Wnt signaling, and provide a new anabolic option for treating osteoporosis (9). And recent early clinical trials of an antibody against FGF23 in patients with deforming X-linked hypophosphatemic rickets suggest that this approach may provide a more effective and safer treatment than conventional therapy with phosphorus and calcitriol (10, 11).
Lastly, but by no means least exciting, are the many new technologies for assessment of bone strength and fracture risk that are now under development and will soon be applied widely in our clinics. These techniques include finite element analysis, high resolution peripheral quantitative computed tomography (HR-pQCT), and trabecular bone score (TBS), a gray-level textural metric that can be extracted from the two-dimensional lumbar spine dual-energy X-ray absorptiometry (DXA) image. The TBS provides important information about bone microarchitecture and extends the utility of standard bone mineral density measurement to identify patients with increased bone fragility due to reduced bone mass or bone quality (12).
Overall, these advances will extend our ability to diagnose common and uncommon disorders of bone and mineral metabolism and to provide new and more effective therapeutic options for our patients. Indeed, the forecast is sunny days ahead for a field once limited to recommendation of a sunshine vitamin!
Michael A. Levine, MD, FAAP, FACP, FACE, Associate Editor, The Journal of Clinical Endocrinology & Metabolism
Paul Robertson, MD, Editor-in-Chief, The Journal of Clinical Endocrinology & Metabolism
- Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, Misselwitz J, Klaus G, Kuwertz-Broking E, Fehrenbach H, Wingen AM, Guran T, Hoenderop JG, Bindels RJ, Prosser DE, Jones G, Konrad M 2011 Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N. Engl. J. Med. 365:410-421
- Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H, 3rd, Thakker RV 2013 Mutations affecting G-protein subunit alpha11 in hypercalcemia and hypocalcemia. N. Engl. J. Med. 368:2476-2486
- Li D, Opas EE, Tuluc F, Metzger DL, Hou C, Hakonarson H, Levine MA 2014 Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization. J. Clin. Endocrinol. Metab. 99:E1774-1783
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- Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, Bjerknes R 2013 Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J. Bone Miner. Res. 28:1378-1385
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- Mannstadt M, Clarke BL, Vokes T, Brandi ML, Ranganath L, Fraser WD, Lakatos P, Bajnok L, Garceau R, Mosekilde L, Lagast H, Shoback D, Bilezikian JP 2013 Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. The lancet. Diabetes & endocrinology 1:275-283
- Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H 2012 Enzyme-replacement therapy in life-threatening hypophosphatasia. N. Engl. J. Med. 366:904-913
- McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster JY, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang YC, Libanati C, Bone HG 2014 Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370:412-420
- Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, Kawakami T, Ito T, Zhang X, Humphrey J, Insogna KL, Peacock M 2014 Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J. Clin. Invest. 124:1587-1597
- Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, Vergeire M, Humphrey JS, Glorieux FH, Portale AA, Insogna K, Peacock M, Carpenter TO 2015 Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23. J. Clin. Endocrinol. Metab. 100:2565-2573
- Silva BC, Leslie WD, Resch H, Lamy O, Lesnyak O, Binkley N, McCloskey EV, Kanis JA, Bilezikian JP 2014 Trabecular bone score: a noninvasive analytical method based upon the DXA image. J. Bone Miner. Res. 29:518-530