Context: An increased risk of fracture in patients with primary hyperparathyroidism (PHPT) compared to the general population has been reported, but available data are controversial.
Objective: The aim of the study was to evaluate the rate of vertebral fractures (VFs) by dual-
Design and Setting: A case-
Participants: A total of 150 consecutive patients and 300 healthy women matched for age and menopausal age participated in the study.
Results: VFs were detected in 37 of 150 (24.6%) patients and 12 of 300 (4.0%) controls (P < 0.0001). The majority of VFs were mild. Stepwise multiple logistic regression analysis showed that in PHPT patients lumbar spine bone mineral density was the only variable independently associated with the prevalence of VFs (P = 0.003). The rate of fracture was higher in symptomatic (34.1%) than asymptomatic (21.1%) patients, but this difference was not statistically significant (P = 0.15). Among asymptomatic patients, fracture rate was significantly higher in those who met the criteria for parathyroidectomy (28.1%) than in those who did not (11.1%) (P = 0.03). Compared to controls, the fracture rate was significantly higher in patients with symptomatic and asymptomatic PHPT who met the criteria for surgery (P < 0.0001), but not in those who did not meet the criteria (P = 0.06).
Conclusions: VF rate is increased in postmenopausal women with PHPT compared to controls, independently of whether they are classified as symptomatic or asymptomatic. The question of whether the finding of mild morphometric VFs in the latter represents an indication for parathyroid surgery remains to be established.
Primary hyperparathyroidism is associated with an increased risk of morphometric vertebral fractures both in symptomatic and asymptomatic patients.
The common clinical presentation of primary hyperparathyroidism (PHPT) changed after the introduction of the automated serum calcium measurement from a disease that was primarily symptomatic and characterized by hypercalcemic symptoms, kidney stones, overt bone disease, and specific neuromuscular symptoms to one that is primarily asymptomatic at the time of diagnosis (1). Although PHPT occurs at all ages, the majority of patients are postmenopausal women (1). A variable degree of bone loss is commonly found, with a greater involvement of cortical sites, such as the forearm, than at trabecular sites, such as the lumbar spine (1,2). An increased risk of fracture compared with the general population has also been reported in most studies, but to what extent the risk of fracture is increased in PHPT is still controversial (3,4,5,6,7,8,9,10,11,12,13,14). Several factors, such as the retrospective nature of all studies, the selection of the patients and controls, and the methods to define vertebral fractures may account for the discrepant data. In all these studies vertebral fractures were defined on the basis of x-
Despite the preferential involvement of cortical bone in PHPT, an increased rate of vertebral fractures has been reported in most studies, some of which also included patients with asymptomatic PHPT (3,5,6,7,10,13,14). Two thirds of vertebral fractures are clinically silent, but they are associated with the same increased risk of additional vertebral and nonvertebral fractures as are clinically symptomatic vertebral fractures (15). Vertebral x-
The aim of the present study was to evaluate the presence of vertebral fractures using VFA in a series of postmenopausal women with sporadic PHPT and compare the results with an appropriate control group.
Subjects and Methods
Between January 2004 and December 2006, 230 consecutive Caucasian postmenopausal women with PHPT were evaluated at the Department of Endocrinology at the University of Pisa (Fig. 11).). The diagnosis of PHPT was based on elevated ionized [>5.3 mg/dl (>1.32 mmol/liter); normal range, 4.5–5.3 mg/dl (1.12–1.32 mmol/liter), respectively] or albumin-
Flow diagram of patient recruitment. Symptomatic patients had symptoms of hypercalcemia, nephrolithiasis, osteitis fibrosa cystica, or low-
All women underwent clinical, biochemical, and densitometric evaluations (see below). Patients with familial hypocalciuric hypercalcemia (n = 3) or identified by the screening of kindreds with PHPT (n = 1) and patients treated with antiosteoporotic drugs (n = 41), or with previous or concomitant diseases (n = 13) or therapies affecting the skeleton (n = 6), were all excluded. Of the remaining 166 women with PHPT, 150 agreed to assessment of the vertebral spine by VFA. PHPT was diagnosed in 21 (14.0%) patients because of classical manifestations of PHPT, in 22 (14.7%) in the course of an evaluation for low BMD (n = 4) or osteoporosis (n = 18), and in 107 (71.3%) in the course of a routine biochemical screening test.
A total of 148 had sporadic PHPT, and two had familial PHPT that was later diagnosed by the measurement of serum calcium and PTH in first-
Patients were grouped as symptomatic (n = 41; 27.3%), defined by the presence of symptoms of hypercalcemia, nephrolithiasis, osteitis fibrosa cystica, and low-
The control group consisted of 300 healthy postmenopausal women matched (2:1) for age (± 2 yr) and menopausal age (± 5 yr). They were selected from a series of ambulatory postmenopausal women with no diseases or therapies affecting the skeleton. They underwent a densitometric evaluation (lumbar spine and hip) during the same period of time, as a part of the menopause screening and agreed to a VFA evaluation. Routine blood tests in these control subjects were normal, including a serum calcium and PTH determination.
The study was approved by the local Institutional Review Board. Written informed consent was obtained from all patients.
Serum calcium, creatinine, and urinary calcium and creatinine clearance were determined using standard methods. Ionized calcium was measured as previously described (18). Serum PTH was measured by immunoradiometric assay (DiaSorin, Saluggia, Italy), bone-
BMD (grams per square centimeter) was measured by DXA (QDR-
For VFA, two lateral scans of the vertebrae from T4 to L4 were performed using the single-
A lateral radiograph of the thoracic and lumbar spine was obtained in the first 50 patients for internal validation of the VFA methodology.
The operator performing the VFA was blinded to the subject’s clinical status.
Vertebral fractures were defined using the Genant’s semiquantitative method (combination of morphometric and visual assessment), which is commonly used for diagnosis of vertebral fractures (22). Accordingly, fractures were classified as mild (20–25% loss of vertebral height), moderate (25–40% loss of vertebral height), and severe (greater than 40% loss of vertebral height).
Hereinafter, the abbreviation “VF” will be used to indicate a vertebral fracture detected by VFA, independently of whether it was x-
Data presentation and statistical analyses
Data are expressed as mean ± sd or prevalence, unless otherwise specified. Univariate statistical analyses were performed by unpaired t test, χ2, or odds ratios (ORs), as appropriate. Stepwise forward logistic models were used to identify potential predictors of the prevalence of VF. LS-
Demographic and biochemical data
Selected clinical and biochemical data of the 150 postmenopasual PHPT patients and controls are reported in Table 11.. There was no statistically significant difference in age, menopausal age, years since menopause, 25-
Baseline clinical, biochemical, and densitometric (mean ± sd) data of the 150 patients and 300 controls enrolled in the study
Validation of the VFA vs. x-
To validate VFA as a reliable method to detect vertebral fractures, the first 50 patients had both VFA and lateral x-
VFA in PHPT and controls
VFs were detected in 37 of 150 (24.6%) patients and 12 of 300 (4.0%) controls [χ2 = 41.9, P < 0.0001; OR = 7.86 (95% CI, 3.96–15.61)]. All VFs were asymptomatic. The prevalence of VFs in patients vs. controls was still higher even if patients referred for evaluation of clinical nonvertebral fractures (n = 2) or low BMD (n = 22) were excluded [χ2 = 34.6, P < 0.0001; OR = 6.86 (CI, 3.36–14.00)]. One VF was found in 25 patients and six controls; two or more VFs were found in 12 patients and six controls. The total number of VFs was 52 in patients and 24 in controls. In both groups, all VFs were scored as mild or moderate (39 and 13 in PHPT patients and 19 and 5 in controls, respectively); no severe VFs were observed. It has been argued that isolated, mild deformities as determined by VFA are questionable because they are not a reliable index of vertebral fractures. Indeed, only two or more mild deformities have been associated with significant incident fracture risk independent of BMD in randomized clinical trials in postmenopausal osteoporosis (23). In this regard, when cases with only one mild deformity were excluded, the fracture rate was still significantly higher in patients (20 of 150 or 13.3%) compared with controls (8 or 300 or 2.7%) [χ2 = 17.7, P < 0.0001; OR = 5.61 (95% CI, 2.41–13.08)].
To identify whether risk factor relationships for VFs among PHPT patients differed from those of controls, a stepwise logistic regression analysis was performed, using the variables that were available in both groups (age, menopausal age, years since menopause, BMI, total serum calcium, PTH, 25-
ROC curves were constructed to further evaluate the relationship between LS-
Fracture distribution was also evaluated in patients and controls according to LS-
Correlates of VF prevalence in PHPT patients
In the following analyses, variables that were available only in PHPT patients and not in controls were also included.
As shown in Table 33,, patients who had fractures were significantly older, had menopause earlier, and had been in the menopausal state for a longer period of time. Moreover, BMD at all sites was significantly lower in those who had sustained a fracture in comparison to those who had not.
When patients were classified as osteoporotic (n = 82) or nonosteoporotic (n = 68) on the basis of T-
Fourteen variables (age, BMI, menopausal age, years since menopause, LS-
VFA in PHPT according to severity of the disease
As indicated in Fig. 33,, left panel, the rate of VFs was higher in patients with symptomatic PHPT (34.1%) compared with the rate of fracture in asymptomatic subjects (21.1%), but this difference was not statistically significant [OR = 1.94 (95% CI, 0.88–4.28); P = 0.15]. When the same analysis was performed in asymptomatic patients classified according to whether they met or did not meet criteria for parathyroidectomy, the VF rate was significantly higher in the former (28.1%) compared with the latter (11.1%) [OR = 3.1 (95% CI, 1.06–9.19); P = 0.032; Fig. 33,, right panel]. The fracture rate in patients with symptomatic PHPT and in those with asymptomatic PHPT who met the criteria for surgery was significantly higher than in controls (4.0%) [OR = 12.4 (95% CI, 5.23–25.59), P < 0.0001; and OR = 9.39 (95% CI, 4.25–20.78), P < 0.0001]. But when asymptomatic subjects who did not meet criteria for surgery were compared with controls, there was no significant difference in fracture rate [OR = 3.0 (95% CI, 1.00–8.96); P = 0.06].
Rate of VF in patients and controls. Left, Symptomatic and asymptomatic patients and controls. Right, Asymptomatic patients, grouped according to whether they met or did not meet the criteria for surgery established by the 2002 Workshop on Asymptomatic ...
In the present study, the number of morphometric VFs was evaluated in a series of patients with PHPT diagnosed between 2004 and 2006. This series mostly included patients with asymptomatic PHPT (72.7%) and therefore generally reflects the current most common presentation of the disease.
Vertebral fractures were evaluated using the Genant semiquantitative method, which is the current technique of choice for diagnosis of vertebral fractures by VFA (24). As demonstrated by the validation study in 50 patients in whom VFA and standard spine radiographs were compared, concordant results were obtained in the majority of cases (92%), even among cases with mild deformities (83.3%). It can be argued that sensitivity to detect vertebral fractures by VFA is lower than that of standard radiography. Moreover, accuracy of VFA may be influenced by scoliosis and disc space osteoarthritis. Thus, the use of a follow-
Several lines of evidence indicate that cancellous bone mass is relatively preserved in postmenopausal women with mild PHPT (26), suggesting that the hyperparathyroid state affords relative protection against the cancellous bone loss associated with the menopause. This has been recently confirmed by micro-
Several studies have dealt with the risk of vertebral fractures in patients with untreated PHPT (3,5,6,7,10,13,14) and, with few exceptions (4,12), an increased rate of vertebral fractures compared with controls was demonstrated. However, all previous studies were retrospective and mostly included patients with either symptomatic or asymptomatic PHPT in whom the rate of vertebral fractures was not evaluated separately. The wide range of fracture rates reported in PHPT patients [from 1.7% (Ref. 12) to 46.9% (Ref. 3)] is likely due to differences in patient selection, ethnicity, and methods used for the definition of vertebral fractures.
Multivariate analysis showed that age and LS-
VF rate was increased independently of whether patients were classified as symptomatic or asymptomatic, although VFs occurred more frequently in the former than in the latter group. An important observation related to those who did not meet criteria for surgery. Presumably, these patients, also with asymptomatic PHPT, do not present the same risk for fracture as do those who do meet criteria for surgery. The rate of VFs was not increased in asymptomatic patients who did not meet the criteria for parathyroidectomy. Thus, these results help to validate the criteria upon which recommendations are made for surgery in asymptomatic PHPT.
Based on these considerations, the routine assessment of vertebral fractures by VFA might be appropriate in the evaluation of patients with asymptomatic PHPT. The question of whether the finding of a mild morphometric vertebral fracture represents an indication for parathyroid surgery in patients with mild asymptomatic PHPT remains to be established.
We thank Maria Laura Manca (Department of Neuroscience, University of Pisa, Pisa, Italy) for statistical analysis assistance.
This work was partly supported by grants from MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica) Rome, Italy (to C.M.) and by grants from the University of Pisa (Fondi di Ateneo per la Ricerca; to C.M.).
Disclosure Summary: The authors have nothing to disclose.
First Published Online April 28, 2009
Abbreviations: BMD, Bone mineral density; BMI, body mass index; BSAP, bone-
Silverberg SJ, Bilezikian JP 2001 Clinical presentation of primary hyperparathyroidism in the United States. In: Bilezikian JP, Markus R, Levine MA, eds. The parathyroids. 2nd ed. London: Academic Press; 349–360.
Silverberg SJ, Shane E, de la Cruz L, Dempster DW, Feldman F, Seldin D, Jacobs TP, Siris ES, Cafferty M, Parisien MV, Lindsay R, Clements TL, Bilezikian JP 1989 Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 4:283–291. [PubMed]
De Geronimo S, Romagnoli E, Diacinti D, D'Erasmo E, Minisola S 2006 The risk of fractures in postmenopausal women with primary hyperparathyroidism. Eur J Endocrinol 155:415–420. [PubMed]
Kaji H, Yamauchi M, Chihara K, Sugimoto T 2005 The threshold of bone mineral density for vertebral fractures in female patients with primary hyperparathyroidism. Eur J Endocrinol 153:373–378. [PubMed]
Vestergaard P, Mosekilde L 2003 Fractures in patients with primary hyperparathyroidism: nationwide follow-
Vestergaard P, Mollerup CL, Frøkjaer VG, Christiansen P, Blichert-
Khosla S, Melton 3rd LJ, Wermers RA, Crowson CS, O'Fallon W, Riggs B 1999 Primary hyperparathyroidism and the risk fracture: a population-
Kenny AM, MacGillivray DC, Pilbeam CC, Crombie HD, Raisz LG 1995 Fracture incidence in postmenopausal women with primary hyperparathyroidism. Surgery 118:109–114. [PubMed]
Melton 3rd LJ, Atkinson EJ, O'Fallon WM, Heath 3rd H 1992 Risk of age-
Wishart J, Horowitz M, Need A, Nordin BE 1990 Relationship between forearm and vertebral mineral density in postmenopausal women with primary hyperparathyroidism. Arch Intern Med 150:1329–1331. [PubMed]
Larsson K, Lindh E, Lind L, Persson I, Ljunghall S 1989 Increased fracture risk in hypercalcemia. Acta Orthop Scand 60:268–270. [PubMed]
Wilson RJ, Rao S, Ellis B, Kleerekoper M, Parfitt AM 1988 Mild asymptomatic primary hyperparathyroidism is not a risk factor for vertebral fractures. Ann Intern Med 109:959–962. [PubMed]
Kochersberger G, Buckley NJ, Leight GS, Martinez S, Studenski S, Vogler J, Lyles KW 1987 What is the clinical significance of bone loss in primary hyperparathyroidism. Arch Intern Med 147:1951–1953. [PubMed]
Dauphine RT, Riggs BL, Scholz DA 1975 Back pain and vertebral crush fractures: an unemphasized mode of presentation for primary hyperparathyroidism. Ann Intern Med 83:365–367. [PubMed]
Ross PD, Davis JW, Epstein RS, Wasnich RD 1991 Pre-
Lewiecki EM, Laster AJ 2006 Clinical review: clinical applications of vertebral fracture assessment by dual-
Bilezikian JP, Potts Jr JT, Fuleihan Gel-
Cetani F, Pardi E, Borsari S, Tonacchera M, Pinchera A, Marcocci C 2003 Two Italian kindreds with familial hypocalciuric hypercalcemia caused by loss-
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D 1999 A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470. [PubMed]
Ambrogini E, Cetani F, Cianferotti L, Vignali E, Banti C, Viccica G, Oppo A, Miccoli P, Berti P, Bilezikian JP, Pinchera A, Marcocci C 2007 Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trials. J Clin Endocrinol Metab 92:3114–3121. [PubMed]
WHO Study Group on Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis 1994 Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO study group. Geneva: World Health Organization; 1–129. [PubMed]
Genant HK, Wu CY, van Kuijk C, Nevitt MC 1993 Vertebral fracture assessment using a SQ technique. J Bone Miner Res 8:1137–1148. [PubMed]
Siris ES, Genant HK, Laster AJ, Chen P, Misurski DA, Krege JH 2007 Enhanced prediction of fracture risk combining vertebral fracture status and BMD. Osteoporos Int 18:761–770. [PubMed]
Schousboe JT, Vokes T, Broy SB, Ferrar L, McKiernan F, Roux C, Binkley N 2008 Vertebral fracture assessment: the 2007 ISCD official positions. J Clin Densitom 11:92–108. [PubMed]
Schousboe JT, Debold CR 2006 Reliability and accuracy of vertebral fracture assessment with densitometry compared to radiography in clinical practice. Osteoporos Int 17:281–289. [PubMed]
Dempster DW, Parisien M, Silverberg SJ, Liang XG, Schnitzer M, Shen V, Shane E, Kimmel DB, Recker R, Lindsay R, Bilezikian JP 1999 On the mechanism of cancellous bone preservation in postmenopausal women with mild primary hyperparathyroidism. J Clin Endocrinol Metab 84:1562–1566. [PubMed]
Parisien M, Mellish RW, Silverberg SJ, Shane E, Lindsay R, Bilezikian JP, Dempster DW 1992 Maintenance of cancellous bone connectivity in primary hyperparathyroidism: trabecular strut analysis. J Bone Miner Res 7:913–919. [PubMed]
O'Neill TW, Felsenberg D, Varlow J, Cooper C, Kanis JA, Silman AJ 1996 The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study. J Bone Miner Res 11:1010–1018. [PubMed]
Siris ES, Miller PD, Barrett-
Dempster DW, Müller R, Zhou H, Kohler T, Shane E, Parisien M, Silverberg SJ, Bilezikian JP 2007 Preserved three-
Roschger P, Dempster DW, Zhou H, Paschalis EP, Silverberg SJ, Shane E, Bilezikian JP, Klaushofer K 2007 New observations on bone quality in mild primary hyperparathyroidism as determined by quantitative backscattered electron imaging. J Bone Miner Res 22:717–723. [PubMed]
Montagnani A, Gonnelli S, Cepollaro C, Bruni D, Franci MB, Lucani B, Gennari C 2002 Graphic trace analysis of ultrasound at the phalanges may differentiate between subjects with primary hyperparathyroidism and with osteoporosis: a pilot study. Osteoporos Int 13:222–227. [PubMed]