Clin Rheumatol (2011) 30:639–645 DOI 10.1007/s10067-010-1587-z
ORIGINAL ARTICLE
Osteomalacia revisited A report on 28 cases Laia Gifre & Pilar Peris & Ana Monegal & Maria Jesús Martinez de Osaba & Luisa Alvarez & Núria Guañabens
Received: 2 June 2010 / Revised: 15 September 2010 / Accepted: 28 September 2010 / Published online: 15 October 2010 # Clinical Rheumatology 2010
Abstract The aim of this study was to analyse the clinical manifestations and the most frequent causes of osteomalacia (OM) in a group of 28 patients diagnosed with this disorder during a 20-year period. OM was diagnosed by bone biopsy and/or by Bingham and Fitzpatrick criteria (two of the following: low calcium, low phosphate, elevated total alkaline phosphatase [total AP] or suggestive radiographs). Of these patients, 13 had vitamin D deficiency OM (VD-OM), 14 hypophosphatemic OM (HypoP-OM) and
*
Gifre and Peris contributed equally to this work.
L. Gifre (*) Metabolic Bone Diseases Unit, Service of Rheumatology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain e-mail:
[email protected] P. Peris : A. Monegal : N. Guañabens Metabolic Bone Diseases Unit, Service of Rheumatology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Villarroel 170, 08036 Barcelona, Spain
one had OM-associated hypophosphatasia. Deficient sun exposure and celiac disease were the most frequent etiologies of VD-OM, whereas most HypoP-OM were hereditary forms. The main clinical symptoms were polyarthralgias (89%), frequently associated with fractures (75%). Fifty seven percent had densitometric criteria of osteoporosis. Patients with VD-OM showed significantly higher total AP and PTH serum values, but lower vitamin D, serum calcium, calciuria and bone mass than patients with HypoP-OM. Conversely, HypoP-OM patients had significantly lower serum phosphate and higher phosphaturia than patients with VD-OM. Briefly, high total AP, low serum calcium and low serum phosphate were observed in 85%, 65% and 15%, respectively, of patients with VD-OM, being observed in 64%, 14% and 100%, respectively, of HypoP-OM patients. Nearly 50% of these latter showed increased FGF23 levels. In conclusion, in this study, the frequencies of HypoP-OM and VD-OM were similar. The most frequent laboratory abnormalities were increased total AP and decreased serum phosphate. A urinary calcium loss of less than 50 mg/dl was highly discriminatory for VD-OM and a serum phosphate less than 2.3 mg/dl was also high discriminatory for HypoP-OM. Low densitometric values and fractures were frequent among these patients.
P. Peris : A. Monegal : N. Guañabens CIBERehd, Barcelona, Spain
Keywords Hypophosphatemia . Hypovitaminosis D . Osteomalacia . Pseudofractures
M. J. Martinez de Osaba Hormone Laboratory, Hospital Clínic, Barcelona, Spain
Introduction
L. Alvarez Department of Biochemistry and Molecular Genetics, Hospital Clínic, Barcelona, Spain
Osteomalacia (OM) is a metabolic bone disorder characterised by an alteration in bone mineralisation, frequently caused by disorders in vitamin D or phosphate metabolism, or by other processes which can also interfere with bone
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mineralisation. Clinical manifestations are nonspecific and include skeletal fractures, generalised or localised bone pain, polyarthralgias and/or proximal muscular weakness. Symptoms can be confused with other conditions such as polymyalgia rheumatica, polymyositis, fibromyalgia, diffuse idiopathic skeletal hyperostosis, metastatic bone disease, multiple myeloma, myeloproliferative problems and, especially, with osteoporosis [1, 2]. Biochemical and radiological alterations in OM are well described. However, they are not totally specific and they can also differ depending on the etiology of this process. Therefore, for diagnosing OM, awareness of this entity and knowledge of the most common findings associated with the different forms of OM are essential. Whereas in vitamin D deficiency OM (VD-OM), a deficiency of this vitamin is indeed the main factor associated with the development of this disorder, in the case of hypophosphatemic diseases [e.g. hypophosphatemic OM (HypoPOM)], a putative humoral phosphaturic factor, initially referred to as phosphatonin, has been suggested to be the principal causative factor. At present, fibroblast growth factor 23 (FGF23) is regarded as the most appropriate candidate for phosphatonin and is even considered as a hormone regulator of the phosphate metabolism [3]. Interestingly, recent investigations have shown increased serum values of this factor in different HypoP-OMassociated conditions [4]. Thus, whereas mutations in the gene encoding FGF32 or in the phosphate endopeptidase called PHEX have been reported in hereditary forms of HypoP-OM [3], in the case of oncogenic OM, the tumour overexpresses this protein [2, 3]. In addition, it should be pointed out that there are other forms of OM, such as those related to hypophosphatasia, with subtle findings in some adult patients that can easily be misdiagnosed as osteoporosis. In these cases a decrease in total alkaline phosphatase (total AP) may be the only noticeable laboratory finding in the general biochemical profile. Therefore, in order to aid in the diagnosis of this not uncommon condition, the aim of the present study was to analyse the clinical characteristics, the laboratory abnormalities and the most frequent causes of OM in a group of 28 patients attended in a Metabolic Bone Diseases Unit of a Rheumatology Department.
Material and methods We reviewed the reports of patients with OM who have been visited in our department over the last 20 years (from 1989 to 2009). This department has a Metabolic Bone Diseases Unit highly experienced in treating these medical conditions. Clinical data were obtained from a detailed review of medical records, which included a careful history
Clin Rheumatol (2011) 30:639–645
and physical examination, laboratory, radiologic, scintigraphic, densitometric and bone biopsy results. Patients without OM criteria were not included in the study. Automated biochemical profile, total AP and 24-h urinary calcium and phosphate excretion were obtained in all patients, as were vitamin D metabolites and parathormone (PTH). Biochemical markers of bone turnover were measured in 15 patients and FGF23 was determined in eight patients. The diagnosis of OM was established by compatible bone biopsy and/or by Bingham and Fitzpatrick criteria [5], the latter including at least two of the following abnormalities: low serum calcium and/or phosphate, elevated total AP or a radiographic finding suggestive of OM. Laboratory determinations Automated biochemical profile (including serum calcium and phosphate), complete blood cell count, total AP, serum proteins and 24-h urine calcium and phosphate were measured by standard procedures. Serum 25-hydroxyvitamin D (25OHD) and 1,25 dihydroxyvitamin D (1–25OH2D) were determined by radioimmunoassay (RIA; DiaSorin, Stillwater, MN, USA). Serum PTH was measured by immunoradiometric assay (IRMA; Allegro Intact PTH, Nichols Institute Diagnostics). Osteocalcin (OC) was determined by IRMA (Elsa-Osteo-Cis, Gif-sur-Yvette, France). Serum bone alkaline phosphatase (bone AP) and propeptide amino-terminal of type I procollagen (PINP) were measured by an IRMA and RIA, respectively, (Hybritech, Liege, Belgium; Orion, Espoo, Finland); urinary amino-terminal telopeptide of type I collagen (NTX) was determined by enzyme immunoassay (Ostex, Seattle, WA, USA). FGF23 was measured by enzyme immunoassay (Immunotopics, San Clemente, CA, USA). This assay recognises both full-length FGF23 and Cterminal cleavage fragments of FGF23 [6]. Urinary hydroxyproline (HYP) was measured by high-performance liquid chromatography. Urine determinations were expressed as a ratio to creatinine. Hypercalciuria was defined as a urinary calcium excretion >4 mg/kg/day and hypocalciuria by calcium excretion
