Osteomalacia with low alkaline phosphatase: a not so rare condition with important consequences

Abstract

SUMMARYHypophosphatasia is a genetic disorder, characterised by a dysfunctional tissue-non-specific isoenzyme of alkaline phosphatase that impacts bone metabolism and predisposes to osteomalacia or rickets. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease. Several forms of hypophosphatasia are recognised. We present a case of a 50-year-old woman with low impact fractures and loss of teeth at a young age. She also had a low alkaline phosphatase and was diagnosed with adult hypophosphatasia. Although the severe forms of hypophosphatasia are rather rare, the adult form is thought to occur quite frequently. As this condition is not well known by healthcare professionals, the time to diagnosis and initiation of adequate treatment is often postponed. When encountering a patient with low alkaline phosphatase, low bone density or a history of bone fractures, the possibility of hypophosphatasia should be considered. BACKGROUND

Bone histomorphometry in the evaluation of osteomalacia

“…2 A & B, for instance) obfuscates the original descriptions of the condition with its characteristic clinical, radiographic, scintigraphic, and histologic features. Furthermore, excess osteoid accumulation (surface or volume) can occur in several conditions: states of high bone turnover (primary or secondary hyperparathyroidism and hyperthyroidism) ( Silverberg et al, 1989 ; Rao et al, 1993 ; Mosekilde and Melsen, 1978 ; Moore et al, 2009 ), enzyme defects (hypophosphatasia) ( Whyte, 2016 ; Belkhouribchia et al, 2016 ), matrix disorders (fibrogenesis imperfecta ossium ( Ralphs et al, 1989 ), Paget's disease of bone ( Singer, 2016 ), and axial osteomalacia ( Demiaux-Domenech et al, 1996 ). In fact, such assumptions have led to the use of large doses of vitamin D to treat some of these disorders in the past!…”

Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening

“…While some genotype-phenotype correlations are recognized, there is significant clinical and intrafamilial variability and limited information relating enzyme activity to disease manifestations (Bianchi, 2015;Mornet et al, 2011). Mild HPP, often due to ALPL heterozygous loss of function, dominant negative or compound heterozygous variants with moderate loss of function is far more common than severe HPP associated with homozygous or compound heterozygous variants with near/ complete loss of function (Belkhouribchia et al, 2016;Bianchi, 2015;Fauvert et al, 2009;Mornet et al, 2011).…”

“…While some genotype–phenotype correlations are recognized, there is significant clinical and intrafamilial variability and limited information relating enzyme activity to disease manifestations (Bianchi, 2015; Mornet et al, 2011). Mild HPP, often due to ALPL heterozygous loss of function, dominant negative or compound heterozygous variants with moderate loss of function is far more common than severe HPP associated with homozygous or compound heterozygous variants with near/complete loss of function (Belkhouribchia et al, 2016; Bianchi, 2015; Fauvert et al, 2009; Mornet et al, 2011). Interpreting the effect of one or more ALPL variants presents a challenge for the clinician, as many of the >400 documented variants (Johannes Kepler University, n.d.) are private and uncharacterized in the literature, whereas others remain in commercial laboratory databases as proprietary information; a phenomenon that is not unique to ALPL.…”

“…AP is known to be elevated during pregnancy (Whyte et al, 1995) due to normal placental production of ALP; the lower limit for AP in gravid patients with HPP is not yet established. Making the diagnosis of HPP at any age has additional importance today because of both the recent FDA approval of enzyme replacement therapy (ERT) to treat infantile and childhood‐onset HPP as well as the contraindication of bisphosphonate treatment for bone fragility in persons with HPP (Belkhouribchia et al, 2016; Mornet, 2018; Sutton et al, 2012). Furthermore, the features of HPP may evolve over the lifespan and longitudinal re‐evaluation is crucial for those who have this diagnosis (Bianchi, 2015; Mornet et al, 2011; Mornet et al, 2021; Whyte, Madson, et al, 2016; Whyte, Rockman‐Greenberg, et al, 2016).…”

Diagnosis of Hypophosphatasia in Adults Presenting With Metatarsal Stress Fracture: Proof‐of‐Concept for a Case‐Finding Strategy

“…( 6 ) Low serum ALP concentrations, hypophosphatasemia, may be recognized retrospectively or newly discovered, and further history‐taking and medical record review may elucidate symptoms and signs consistent with HPP manifesting during childhood despite diagnosis in adulthood. ( 7‐9 )…”