Holick made discoveries in the field of vitamin D that have led to novel therapies for metabolic bone diseases, hypocalcemic disorders, and psoriasis. He is author of more than 400 publications about the biochemistry, physiology, metabolism and photobiology of vitamin D and the pathophysiology of vitamin D deficiency.[8]
His scientific work increased awareness in the pediatric and medical communities regarding vitamin D deficiency,[9] and its role in causing not only metabolic bone disease, and osteoporosis in adults, but increasing risk of children and adults developing common deadly cancers, autoimmune diseases, including type 1 diabetes, multiple sclerosis and heart disease,[10] as discussed in his review article.[10]
As a graduate student, he identified the major circulating form of vitamin D, 25-hydroxyvitamin D3,[20] which is the vitamin D metabolite that is measured by physicians worldwide to determine a patient's vitamin D status.[21] He also identified the active form of vitamin D, 1,25-dihydroxyvitamin D3,[22] as well as other metabolites including 24,25-dihydroxyvitamin D3,[23] 1,24,25-trihydroxyvitamin D3[24] and 25,26-dihydroxyvitamin D3.[25]
As a fellow, he participated in the first chemical synthesis of 1,25-dihydroxyvitamin D3[26] and 1α-hydroxyvitamin D3[27] to treat renal osteodystrophy,[28]hypoparathyroidism,[29][30] vitamin D dependent rickets type I,[31] and osteoporosis.[32] Furthermore, he elucidated the pathophysiology of hereditary vitamin D-dependent rickets which involves defective vitamin D metabolism,[33] and the pathophysiological mechanisms of X-linked hypophosphatemic rickets.[34]
Holick helped develop the first clinical assays for 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D,[35] determined how vitamin D3 is made in the skin from sun exposure,[36] and established how season,[37] time of day,[38] skin pigmentation,[39] sunscreen use,[40] and latitude[37] influenced this vital cutaneous process.
He established that the skin was not only the organ responsible for making vitamin D3[36] but was also a target tissue for its active form, 1,25-dihydroxyvitamin D3.[41] He determined the extremely inhibitory effects of 1,25-dihydroxyvitamin D3 on keratinocyte proliferation and the promoting effects on differentiation,[41] and translated these seminal observations by demonstrating that the topical application of 1,25-dihydroxyvitamin D3 and several of its analogs were effective for the treatment of psoriasis.[42]
He demonstrated that macrophages[43] and prostate cells[44] have the enzymatic machinery to produce 1,25-dihydroxyvitamin D3, and established that the extrarenal production of 1,25-dihydroxyvitamin D3 may play a crucial role not only in cancer prevention but also in regulating the immune system.[45]
He developed a vitamin D absorption test[46] and demonstrated that vitamin D was bioavailable in orange juice, leading to fortification of juice products in the United States.[47] He also used the test to demonstrate the major cause of vitamin D deficiency in obesity is sequestration of vitamin D in the fat.[48]
He helped perform dose escalation studies establishing how much vitamin D is required to maintain blood levels of 25-hydroxyvitamin D in the sufficient range for adults. These studies also demonstrated that up to 10,000 IU of vitamin D a day for 5 months did not cause toxicity.[49]
Controversies
Holick has been involved in several medical controversies. While at Boston University, he was asked to leave the Division of Dermatology because of his promoting the medical benefits of sun exposure. He accepted research funding for this work from a non-profit tanning bed company, considered by many to be an important potential bias. Barbara Gilchrest, then head of the department at Boston University, called Holick's book "shlock science" and Holick "a poster boy for the tanning industry".[50]
Holick received nearly $163,000 from 2013 to 2017 from pharmaceutical companies, according to Medicare’s Open Payments database, which tracks payments from drug and device manufacturers. The companies paying him included Sanofi-Aventis, which markets vitamin D supplements; Shire, which makes drugs for hormonal disorders that are given with vitamin D; Amgen, which makes an osteoporosis treatment; and Roche Diagnostics and Quidel Corp., which both make vitamin D tests.[51]
Holick has also been criticized by other physicians because of his testimony, defending accused child abusers by asserting that Ehlers–Danlos syndrome is a cause of non-traumatic fractures in infancy (rather than abuse).[52] In one case of a child who had suffered broken bones in which Holick defended the accused parent, the child later went on to suffer severe brain injury, for which the parent, named Robert Marvin Ray, has been indicted.[50][53][54][55]
Since May 2017, Holick has been barred from evaluating or treating children by Boston Medical Center, which subsequently reported him to the Massachusetts Board of Registration in Medicine for "health care facility discipline",[54] but is still allowed to evaluate children who are participating in his research project.[55] Boston University has defended Holick's right to testify in courts, as part of his academic freedom.[55]
Holick has speculated that the dinosaurs may have died of rickets and osteomalacia caused by a lack of vitamin D in reduced sunlight.[56]
A paper on Vitamin D to treat COVID19 has been retracted.[57]
Awards
Holick has been awarded for his contributions to the field of vitamin D research with prizes,[58] including:
^Holick, MF (2011). The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems. Plume 1st edition. ISBN978-0452296886.
^Holick, MF; Deluca, HF; Avioli, LV (1972). "Isolation and identification of 25-hydroxycholecalciferol from human plasma". Archives of Internal Medicine. 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID4332591.
^Hollis, BW (1996). "Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it". Calcif Tissue Int. 58 (1): 4–5. doi:10.1007/BF02509538. PMID8825231. S2CID35887181.
^Holick, MF; Schnoes, HK; Deluca, HF; Suda, T; Cousins, RJ (1971). "Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine". Biochemistry. 10 (14): 2799–804. doi:10.1021/bi00790a023. PMID4326883.
^Holick, MF; Schnoes, HK; Deluca, HF; Gray, RW; Boyle, IT; Suda, T (1972). "Isolation and identification of 24,25-dihydroxycholecalciferol, a metabolite of vitamin D made in the kidney". Biochemistry. 11 (23): 4251–5. doi:10.1021/bi00773a009. PMID4342902.
^Holick, M.; Holick, S.; Tavela, T; Gallagher, B; Schnoes, H.; Deluca, H. (1975). "Synthesis of (6-3H)-1alpha-hydroxyvitamin D3 and its metabolism in vivo to (3H)-1alpha,25-dihydroxyvitamin D3". Science. 190 (4214): 576–8. doi:10.1126/science.1188356. PMID1188356. S2CID21530294.
^Kooh, Sang Whay; Fraser, Donald; Deluca, Hector F.; Holick, Michael F.; Belsey, Richard E.; Clark, Mary B.; Murray, Timothy M. (1975). "Treatment of Hypoparathyroidism and Pseudohypoparathyroidism with Metabolites of Vitamin D: Evidence for Impaired Conversion of 25-Hydroxyvitamin D to 1α,25-Dihydroxyvitamin D". New England Journal of Medicine. 293 (17): 840–4. doi:10.1056/NEJM197510232931702. PMID170516.
^Neer, R.M.; Holick, M.F.; Deluca, H.F.; Potts, J.T. (1975). "Effects of 1α-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 on calcium and phosphorus metabolism in hypoparathyroidism". Metabolism. 24 (12): 1403–13. doi:10.1016/0026-0495(75)90055-4. PMID1196134.
^Fraser, Donald; Kooh, Sang Whay; Kind, H. Peter; Holick, Michael F.; Tanaka, Yoko; Deluca, Hector F. (1973). "Pathogenesis of Hereditary Vitamin-D-Dependent Rickets". New England Journal of Medicine. 289 (16): 817–22. doi:10.1056/NEJM197310182891601. PMID4357855.
^Clemens, TL; Adams, JS; Nolan, JM; Holick, MF (1982). "Measurement of circulating vitamin D in man". Clinica Chimica Acta. 121 (3): 301–8. doi:10.1016/0009-8981(82)90239-X. PMID6286167.
^ abHolick, MF; MacLaughlin, JA; Clark, MB; Holick, SA; Potts, JT junior; Anderson, RR; Blank, IH; Parrish, JA; et al. (1980). "Photosynthesis of previtamin D3 in human skin and the physiologic consequences". Science. 210 (4466): 203–205. Bibcode:1980Sci...210..203H. doi:10.1126/science.6251551. PMID6251551.
^ abWebb, AR; Kline, L; Holick, MF; Nielsen, CT; Price, PA; Christiansen, C; Skakkebaek, NE (1988). "Influence of season and latitude on the cutaneous synthesis of vitamin D3: Exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin". J Clin Endocrinol Metab. 67 (2): 273–8. doi:10.1210/jcem-67-2-373. PMID2839537.
^Lu, Z; Chen, TC; Holick, MF (1992). Influence of season and time of day on the synthesis of vitamin D3. In: Holick MF, Kligman A, eds. Proceedings of the Biologic Effects of Light Symposium. pp. 53–6. {{cite book}}: |work= ignored (help)
^Clemens, TL; Adams, JS; Henderson, SL; Holick, MF (1982). "Increased skin pigment reduces the capacity of the skin to synthesize vitamin D". Lancet. 1 (8263): 74–6. doi:10.1016/S0140-6736(82)90214-8. PMID6119494. S2CID41818974.
^ abSmith, EL; Walworth, NC; Holick, MF (1986). "Effect of 1 alpha,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions". J. Invest. Dermatol. 86 (6): 709–14. doi:10.1111/1523-1747.ep12276343. PMID2423618.
^Pèrez, A; Chen, TC; Turner, A; Raab, R; Bhawan, J; Poche, P; Holick, MF (1996). "Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin d3) for the treatment of psoriasis". Br J Dermatol. 134 (2): 238–46. doi:10.1111/j.1365-2133.1996.tb07608.x. PMID8746336. S2CID24213908.
^Adams, JS; Singer, FR; Dacad, MA; Sharma, OP; Hayes, MJ; Vouros, P; Holick, MF (1985). "Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis". J Clin Endocrinol Metab. 60 (5): 960–6. doi:10.1210/jcem-60-5-960. PMID2984238.
^Farraye, FA; Nimitphong, H; Stucchi, A; Dendrinos, K; Boulanger, A; Vijjeswarapu, A; Tanennbaum, A; Biancuzzo, R; et al. (2011). "Use of a novel vitamin D bioavailability test demonstrates that vitamin D absorption is decreased in patients with quiescent Crohn's disease". Inflamm Bowel Dis. 17 (10): 2116–21. doi:10.1002/ibd.21595. PMID21910173. S2CID4940789.