{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:46:28Z","timestamp":1792125988684,"version":"4.4.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":90,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Alkaline phosphatase (ALP) plays an essential role in skeletal mineralization and bone metabolism. While elevated ALP levels are commonly investigated in clinical practice, persistently low ALP values are often overlooked despite their potential association with hypophosphatasia (HPP), a rare metabolic bone disorder caused by pathogenic variants in the\n                      <jats:italic>ALPL<\/jats:italic>\n                      gene. This study aimed to determine the prevalence and clinical characteristics of adults with persistently low ALP in a large tertiary care hospital.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a retrospective review of adult patients who underwent serum ALP testing at King Abdulaziz Medical City, Riyadh, between January 2017 and December 2024. Patients with \u2265\u20092 ALP measurements\u2009&lt;\u200940 IU\/L separated by at least 30 days were identified. Secondary causes of low ALP were excluded through review of clinical history, laboratory data, and medication records. Demographic, clinical, biochemical, and imaging data were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 243,362 adults with 928,403 ALP measurements, 7,307 patients (3.0%) had at least one ALP value\u2009&lt;\u200940 IU\/L. A total of 179 patients had\u2009\u2265\u20092 ALP measurements\u2009&lt;\u200940 IU\/L. After excluding 154 patients with secondary causes or incomplete data, 25 patients were identified with unexplained persistently low ALP (0.01% of the total tested population). The mean age was 52.2 years (range 18\u201392), and 68% were female. The mean nadir ALP was 30.2 IU\/L. Musculoskeletal (MSK) symptoms (92%) and fatigue (79%) were the most common clinical manifestations, followed by dental abnormalities (50%), anxiety (33%), and depression (29%). Fractures were reported in 46% of patients, most commonly affecting the vertebrae, hips, and metatarsals. In subgroup analysis, patients with MSK symptoms had significantly lower nadir ALP levels (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.021). Familial clustering of persistently low ALP was observed in 25% of patients. Notably, none of the reviewed electronic medical records documented recognition of persistently low ALP or consideration of hypophosphatasia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Persistently low ALP is uncommon but clinically relevant. Many affected patients demonstrated clinical features compatible with possible adult hypophosphatasia, and familial clustering suggests a possible genetic contribution. Greater awareness of this biochemical finding may improve recognition of potential HPP, prevent inappropriate antiresorptive therapy, and facilitate earlier diagnostic evaluation, including biochemical and genetic testing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04493-1","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T16:25:08Z","timestamp":1784391908000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Persistently low serum alkaline phosphatase in adults: prevalence and clinical characteristics in a large tertiary care hospital"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7673-2975","authenticated-orcid":false,"given":"Fahad","family":"Alshahrani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Alsuliman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reema","family":"Alkalefah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaden","family":"Almutairi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Aleidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Almohaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"4493_CR1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.bone.2017.02.011","volume":"102","author":"MP Whyte","year":"2017","unstructured":"Whyte MP. Hypophosphatasia: An overview For 2017. Bone. 2017;102:15\u201325.","journal-title":"Bone"},{"key":"4493_CR2","doi-asserted-by":"crossref","unstructured":"Khan AA, Brandi ML, Rush ET, Ali DS, Al-Alwani H, Almonaei K, et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2024;35(3):431\u20138.","DOI":"10.1007\/s00198-023-06844-1"},{"issue":"1","key":"4493_CR3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.bone.2013.01.024","volume":"54","author":"KE Berkseth","year":"2013","unstructured":"Berkseth KE, Tebben PJ, Drake MT, Hefferan TE, Jewison DE, Wermers RA. Clinical spectrum of hypophosphatasia diagnosed in adults. 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J bone mineral research: official J Am Soc Bone Mineral Res. 2014;29(7):1651\u201360.","journal-title":"J bone mineral research: official J Am Soc Bone Mineral Res"},{"key":"4493_CR8","doi-asserted-by":"crossref","unstructured":"Maman E, Borderie D, Roux C, Briot K. Absence of recognition of low alkaline phosphatase level in a tertiary care hospital. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2016;27(3):1251\u20134.","DOI":"10.1007\/s00198-015-3346-0"},{"issue":"3","key":"4493_CR9","first-page":"289","volume":"65","author":"LHR Vieira","year":"2021","unstructured":"Vieira LHR, Peixoto KC, Fl\u00f3si CL, de Farias MLF, Madeira M. Active search of adult patients with persistently low serum alkaline phosphatase levels for the diagnosis of hypophosphatasia. 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Osteoporos international: J established as result cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA. 2021;32(2):377\u201385.","journal-title":"Osteoporos international: J established as result cooperation between Eur Foundation Osteoporos Natl Osteoporos Foundation USA"},{"key":"4493_CR13","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/1750-1172-2-40","volume":"2","author":"E Mornet","year":"2007","unstructured":"Mornet E, Hypophosphatasia. Orphanet J Rare Dis. 2007;2:40.","journal-title":"Orphanet J Rare Dis"},{"issue":"3","key":"4493_CR14","doi-asserted-by":"publisher","first-page":"109046","DOI":"10.1016\/j.ymgme.2025.109046","volume":"144","author":"ET Rush","year":"2025","unstructured":"Rush ET, Del Angel G, Dong J, Bates T, Steiner RD, Cox A. Genetic characterization of a large cohort of individuals with a clinical suspicion of hypophosphatasia in the United States. 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Clin Chem Lab Med. 2024;62(1):128\u201337.","journal-title":"Clin Chem Lab Med"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04493-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04493-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04493-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:10:05Z","timestamp":1792123805000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04493-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,18]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4493"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04493-1","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,18]]},"assertion":[{"value":"17 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was approved by the Institutional Review Board of King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was waived by the Institutional Review Board due to the retrospective nature of the study and the use of de-identified clinical data.","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"359"}}