Non-Invasive Assessment of Skeletal Microstructure and Estimated Bone Strength in Hypoparathyroidism

Abstract

In hypoparathyroidism, areal bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) is above average and skeletal indices by bone biopsy are abnormal. We used high resolution peripheral quantitative computed tomography (HRpQCT) and finite element analysis (FEA) to further investigate skeletal microstructure and estimated bone strength. We studied 60 hypoparathyroid subjects on conventional therapy using DXA, HRpQCT and FEA of the distal radius and tibia compared to normative controls from the Canadian Multicentre Osteoporosis Study. In hypoparathyroid women and men, areal BMD was above average at the lumbar spine and hip sites by DXA; radial BMD was also above average in hypoparathyroid women. Using HRpQCT, cortical volumetric BMD was increased in the hypoparathyroid cohort compared to controls at both the radius and tibia. Cortical porosity was reduced at both sites in pre- and postmenopausal women and at the tibia in young men with a downward trend at the radius in men. At the tibia, trabecular number was increased in premenopausal women and men and trabecular thickness was lower in women. Ultimate stress and failure load at both sites for the hypoparathyroid subjects were similar to controls. Using a linear regression model, at both radius and tibia, each increment in age decreased ultimate stress and failure load while each increment in duration of hypoparathyroidism increased these same indices. These results provide additional evidence for the critical role of parathyroid hormone in regulating skeletal microstructure. Longer disease duration may mitigate the adverse effects of age on estimated bone strength in hypoparathyroidism.

Introduction

Hypoparathyroidism is a disorder characterized by deficient parathyroid hormone (PTH) and hypocalcemia and is associated with abnormal structural and dynamic skeletal parameters. ^(1,2) Areal bone mineral density (BMD) is often above average.^(3–5) Structural abnormalities by histomorphometric analysis of iliac crest bone biopsies show increased cortical and trabecular width and cancellous bone volume⁽²⁾ as well as markedly reduced dynamic skeletal indices.^(1,2) While areal BMD in hypoparathyroid patients is generally increased, the effect on fracture risk remains unclear. A small cohort study showed an increase in morphometric vertebral fractures in patients with postsurgical hypoparathyroidism⁽⁶⁾ although two registry studies showed no difference in overall fractures between controls and hypoparathyroid patients.^(7,8) Bone geometry, microarchitecture and strength have not yet been studied in hypoparathyroid subjects using high resolution peripheral quantitative computed tomography (HRpQCT) and finite element analysis (FEA). This report provides, for the first time, results of the application of these technologies to a cohort of subjects with hypoparathyroidism.

Materials and Methods

Hypoparathyroid subjects

The diagnosis of hypoparathyroidism was established by the requirement for supplemental calcium and/or active vitamin D to maintain serum calcium in the low-normal range along with an undetectable or insufficient PTH concentration. Hypoparathyroidism was reported to have been present for at least 1 year to establish a chronic hypoparathyroid state. Subjects were excluded if they had ever been treated with PTH(1-34) or PTH(1-84).

Patients were recruited from the Metabolic Bone Diseases Unit of Columbia University Medical Center (CUMC) and from the Hypoparathyroidism Association. The study was approved by the Institutional Review Board of CUMC. All subjects gave written informed consent.

Biochemical evaluation

The average of one to three serum calcium values was used for the baseline calcium value. Biochemical indices were measured by automated techniques. The normal ranges for all assays are provided in Table 2.

Table 2.

Biochemistries of the hypoparathyroid cohort.

	Mean ± SD (N=60)	Normal range
Serum calcium (mg/dL)a	8.6 ± 0.8	8.6–10.2
PTH (pg/mL)	1.3 ± 3.1	10–65
Creatinine (mg/dL)	0.93 ± 0.20	0.50–1.30
Phosphate (mg/dL)	4.3 ± 0.7	2.5–4.5
Total alkaline phosphatase activity (U/L)	62 ± 14	33–96
Urinary calcium excretion (mg/day)	254 ± 120	50–250b
25-hydroxyvitamin D (ng/mL)	51 ± 75	30–100
1,25-dihydroxyvitamin D (pg/mL)	35 ± 22	15–60
TSH (mIU/L)c	1.63 [0.50, 2.57]	0.40–4.50

^aSerum calcium concentration was typically normal as a result of calcium and vitamin D supplementation

^bFor men, 50–300 mg/day

^cMedian [Interquartile range]

Control subjects

We used previously published normative data from the Calgary, Alberta cohort of the Canadian Multicentre Osteoporosis Study (CaMos).⁽⁹⁾ CaMos is a 10-year prospective population-based study of over 9000 men and women living within 50 km of nine Canadian cities, originally recruited between 1997 and 1998 using a stratified random-sampling technique.⁽¹⁰⁾ At the 10-year follow-up visit, subjects were invited to participate in an HRpQCT substudy. Subjects from the Calgary CaMos youth cohort⁽¹¹⁾ and additional sampling strategies were utilized for a population-based HRpQCT study as previously described.⁽⁹⁾ For this analysis, we used the published data from the 20–29 year-old age strata for women (n=58) and men (n=28).⁽⁹⁾ In addition, we compared cortical parameters in our postmenopausal hypoparathyroid subjects to previously published data from a cohort of postmenopausal women from CaMos with normal areal BMD (n=87).⁽¹²⁾ We chose to compare our population to CaMos as this study provides a population-based North American cohort with data from both the radius and tibia, including estimates of bone strength.

Imaging evaluation

Areal BMD

Areal BMD was measured at the lumbar spine, L1-L4; total hip; femoral neck; and distal one third radius by dual X-ray absorptiometry (DXA; Hologic QDR4500, Waltham, MA). Subjects were measured on the same densitometer, using the same software, scan speed, and technologist, certified by the International Society of Clinical Densitometry. Measurements were performed twice at baseline for most subjects, and the average value of the two BMD measurements was used for the baseline value. Short-term in vivo precision error (root-mean-square standard deviation) was 0.026 g/cm² for L1-L4 (1.1%), 0.041 g/cm² for the femoral neck (2.4%), and 0.033 g/cm² (1.8%) for the forearm.

Volumetric BMD and microarchitecture

The nondominant distal radius and tibia were measured using HRpQCT (Xtreme CT; Scanco Medical AG, Brüttisellen, Switzerland) using a standard protocol (60 kVp, 900 μA, and 100-ms integration time) with a nominal isotropic resolution of 82 μm.⁽¹³⁾ The region of interest was defined by an antero-posterior scout view and a reference line was manually placed at the end plate of the radius and tibia. The first of 110 parallel CT slices was acquired 9.5 mm proximal to the reference line at the radius and 22.5 mm proximal to the reference line at the tibia. Attenuation data were converted to equivalent hydroxyapatite (HA) densities. The manufacturer phantom was scanned daily for quality control.

The protocol for image analysis has been previously described and validated.^(9,13–16) Briefly, a threshold-based algorithm was used to automatically separate the volume of interest into cortical and trabecular compartments. Measurements of total and trabecular bone densities (Tt.BMD, Tb.BMD, mg HA/cm³) were obtained. Trabecular bone volume (BV/TV, %) was derived from Tb.BMD assuming that fully mineralized bone has a density of 1,200 mg HA/cm³ [BV/TV %= 100 × (Tb.BMD/1200)]. Trabecular number (Tb.N, 1/mm) was defined as the inverse of the mean spacing of the mid-axes. Trabecular thickness (Tb.Th, mm) and trabecular separation (Tb.Sp, mm) were derived from BV/TV and Tb.N using standard morphologic relationships [Tb.Th=(BV/TV)/Tb.N, Tb.Sp=(BV/TV)/Tb.N]. Short-term in vivo precision error is 0.7–1.5% for total and trabecular densities and 2.5–4.4% for trabecular architecture at our facility.

In addition to the standard morphologic analysis above, an automated segmentation algorithm [Image Processing Language (IPL, Version 5.08b, Scanco Medical)] was used to measure total and cortical bone cross-sectional areas (Tt.Ar, Ct.Ar, mm²), cortical porosity (Ct.Po, %), cortical thickness (Ct.Th, mm) and cortical density (Ct.BMD, mm HA/cm³). Ct.Po was determined by the number of void voxels in each thresholded cortex image divided by the total number of cortical voxels. Ct.Th was calculated using a distance transform after removing the intracortical pores. Ct.BMD was defined by the average mineral density in the region demarcated by the autosegmentation cortical bone mask. The precision error for the automated segmentation algorithm is <1.5%.⁽¹⁷⁾ The analyses for cortical and trabecular microarchitecture are identical to those used for the previously published CaMos data using the same model machine.⁽⁹⁾

All HRpQCT images were scored for motion artifact on a scale of 0 (no artifact) to 5 (significant blurring of the periosteum, cortical discontinuities, soft tissue streaking). We excluded grade 5 images.

Finite element analysis

The image analysis has been previously described and validated.^(9,18,19) Whole-bone and trabecular HRpQCT images of the radius and tibia were converted into finite-element models (FAIM, Version 6.0, Numerics88, Calgary, Canada) to estimate whole-bone stiffness (N/mm), calculated as the reaction force determined by the model at 1% strain divided by the average cross-sectional area from the morphological analysis. Apparent bone strength (ultimate stress, MPa) was estimated from the stiffness value. The in vivo precision error for the stiffness measure is <3.5%.⁽²⁰⁾ Failure load (N) was calculated using the Pistoia criterion.⁽²¹⁾ The analyses for ultimate stress and failure load are identical to those used for the previously published CaMos data.⁽⁹⁾

Statistical analysis

Descriptive characteristics of study subjects were tabulated for continuous variables by means, medians and standard deviations. Women and men were grouped by age for analysis of skeletal parameters. Women were grouped into 3 categories: <40 years (premenopausal), ≥40 and <55 years (perimenopausal) and ≥55 years (postmenopausal); men were grouped into 2 categories: <50 years (younger) and ≥50 years (older). We compared the hypoparathyroid subjects to age- and sex-matched Z-scores for DXA and to the previously published HRpQCT and FEA data for the CaMos 20–29 year-old age strata for women and men.⁽⁹⁾ In addition, we compared cortical parameters in our postmenopausal hypoparathyroid subjects to a cohort of postmenopausal women from CaMos with normal areal BMD.⁽¹²⁾ Comparisons of means between hypoparathyroid subjects and controls in HRpQCT and FEA measurements were calculated and then assessed by two-sided Student’s t-test. To assess the contribution of sex, age, etiology of hypoparathyroidism and disease duration to HRpQCT variables and estimated bone strength in our hypoparathyroid subjects, we used linear regression and investigated age as both a linear and quadratic term based on results from prior studies.⁽⁹⁾ Interaction between age and sex was also evaluated. All statistical tests were performed at the level of significance of 0.05. Statistical analysis was performed using SAS, version 9.4 (SAS Institute, Inc., Cary, NC, USA).

Results

Baseline characteristics

The mean age of the hypoparathyroid subjects was 46 ± 12 years (range 26–72) and 80% were women, consistent with the demographics of the disease (Table 1). Four of the postsurgical peri- and postmenopausal women had a prior diagnosis of primary hyperparathyroidism and had experienced at least 3 years of hypoparathyroidism following parathyroid resection. The two major etiologies of hypoparathyroidism were surgical and idiopathic. The average known duration of hypoparathyroidism was 11 ± 11 years (range 1–45 years, median 6 years). The mean age and median disease duration by sex and age group are shown in Table 3.

Table 1.

Characteristics of the hypoparathyroid cohort.

	Mean ± SD (N=60)	Range (Median)
Age (years)	46 ± 12	26–72 (45)
Sex (n)
Female	48
Male	12
Etiology (n)
Postoperative	35a
Idiopathic	24
DiGeorge	1
Duration of hypoparathyroidism (years)	11 ± 11	1–45 (6)
Body mass index (kg/m2)	29.0 ± 6.3	17.0–48.4 (28.6)
Elemental calcium supplement dose (g/d)	2.60 ± 2.14	0–11.00 (1.84)
Calcitriol supplement dose (μg/d)	0.72 ± 0.57	0–3.00 (0.50)
Daily parent vitamin D dose (IU/d)	4808 ± 15831	0–100,000 (400)

^aFour subjects had surgery for primary hyperparathyroidism; 19 for thyroid cancer; 12 for benign thyroid disease

Table 3.

Bone mineral density results for the hypoparathyroid women and men.

	Women			Men
	<40 years	≥40 and <55 years	≥55 years	<50 years	>50 years
Number of subjects	18	17	13	7	5
Age in years (range)	33 ± 5 (26–39)	45 ± 4 (40–52)	61 ± 4 (55–72)	40 ± 9 (26–48)	64 ± 6 (56–72)
Duration in yearsa (range)	5 [3, 8] (1–29)	10 [4, 17] (2–32)	5 [3, 8] (3–43)	10 [5, 18] (3–20)	40 [17, 41] (6–45)
Lumbar spine BMD (g/cm2)	1.19 ± 0.15	1.22 ± 0.17	1.02 ± 0.16	1.28 ± 0.16	1.29 ± 0.23
Lumbar spine Z-score	+1.37 ± 1.42‡	+2.02 ± 1.60‡	+1.26 ± 1.31†	+1.88 ± 1.44*	+2.54 ± 1.94*
Femoral neck BMD (g/cm2)	0.98 ± 0.17	0.94 ± 0.16	0.78 ± 0.17	1.05 ± 0.08	0.95 ± 0.18
Femoral neck Z-score	+1.26 ± 1.53‡	+1.30 ± 1.53†	+0.68 ± 1.5	+1.36 ± 0.74†	+1.18 ± 1.22
Total hip BMD (g/cm2)	1.09 ± 0.16	1.06 ± 0.16	0.94 ± 0.18	1.20 ± 0.12	1.14 ± 0.20
Total hip Z-score	+1.26 ± 1.35†	+1.24 ± 1.33†	+0.94 ± 1.5*	+1.27 ± 0.85*	+1.21 ± 1.23
One-third radius BMD (g/cm2)	0.72 ± 0.05	0.72 ± 0.05	0.69 ± 0.05	0.81 ± 0.06	0.83 ± 0.06
One-third radius Z-score	+0.56 ± 0.85*	+1.02 ± 0.88‡	+1.11 ± 0.89‡	+0.07 ± 1.16	+1.31 ± 1.11
Ultradistal radius BMD (g/cm2)	0.47 ± 0.04	0.46 ± 0.06	0.42 ± 0.05	0.54 ± 0.04	0.58 ± 0.05
Ultradistal radius Z-score	+0.55 ± 0.80†	+0.72 ± 1.04*	+0.52 ± 0.82*	+0.15 ± 0.79	+1.67 ± 0.81*

^aMedian [Interquartile range]; all other values mean ± SD

^*p<0.05;

^†p<0.01;

^‡p<0.001 compared to 0

Biochemical evaluation

Serum calcium concentration was typically normal as a result of supplementation with calcium and active vitamin D (Table 2). Although median TSH was in the normal range, it was reduced in 17 subjects indicating overtreatment with levothyroxine, with 13 subjects having a TSH value <0.1 mIU/L.

Imaging

DXA

Areal BMD values and Z-scores are presented in Table 3. In the hypoparathyroid premenopausal women and younger men, areal BMD was significantly above average at the lumbar spine (Z-scores +1.37 and +1.88, respectively), femoral neck (+1.26 and +1.36, respectively) and total hip (+1.26 and +1.27, respectively). For the premenopausal women, the 1/3 distal radius (+0.56) and ultradistal radius (+0.55) sites were also above average. Areal BMD was also above average for age for the perimenopausal woman at all sites; postmenopausal women at the lumbar spine, total hip, ultradistal and 1/3 radius; and men ≥50 years at the lumbar spine and ultradistal radius.

HRpQCT

We compared the HRpQCT results in our hypoparathyroid women and men with the normative CaMos cohort (Table 4 and Figure 1). Removing the subjects with TSH values <0.1 mIU/L or those with a prior history of primary hyperparathyroidism did not appreciably change the results (not shown).

Table 4.

HRpQCT parameters for hypoparathyroid women and men by age at the radius and tibia compared to normative controls.

	Women				Men
Radius	<40 years	≥40 and <55 years	≥55 years	CaMos 20–29 years	<50 years	>50 years	CaMos 20–29 years
Tt.Ar (mm2)	253 ± 44	256 ± 43	267 ± 41	263 ± 43	380 ± 70	339 ± 91	349 ± 56
Tt.Ar/ht (mm2/ht)	154 ± 25	156 ± 23	164 ± 25	159 ± 3	217 ± 34	198 ± 45	194 ± 6
Tt.BMD (mg HA/cm3)	352 ± 48*	348 ± 56	297 ± 52	320 ± 61	357 ± 64	430 ± 93	350 ± 11
BV/TV	0.140 ± 0.032	0.124 ± 0.045	0.111 ± 0.026	0.126 ± 0.028	0.162 ± 0.044	0.181 ± 0.041	0.169 ± 0.030
Tb.N (1/mm)	2.03 ± 0.35	1.87 ± 0.43	1.94 ± 0.32	1.95 ± 0.21	2.05 ± 0.38	2.11 ± 0.33	2.20 ± 0.25
Tb.Th (mm)	0.069 ± 0.011	0.065 ± 0.016	0.057 ± 0.008*	0.064 ± 0.011	0.079 ± 0.020	0.085 ± 0.010	0.077 ± 0.015
Tb.Sp (mm)	0.441 ± 0.109	0.517 ± 0.245	0.472 ± 0.099	0.454 ± 0.065	0.421 ± 0.086	0.397 ± 0.078	0.382 ± 0.049
Ct.Ar (mm2)	59 ± 8	61 ± 10	56 ± 7†	63 ± 10	82 ± 7	90 ± 9	87 ±15
Ct.Ar/ht (mm2/ht)	36 ± 5	37 ± 6	35 ± 5*	38 ± 1	47 ± 5	53 ± 6	48 ± 2
Ct.BMD (mg HA/cm3)	910 ± 35‡	922 ± 50‡	866 ± 70	836 ± 56	893 ± 63†	916 ± 75*	786 ± 63
Ct.Po (%)	4.3 ± 1.3‡	4.6 ± 1.6†	6.2 ± 2.3	6.2 ± 3.1	6.0 ± 2.5	6.2 ± 2.5	8.1 ± 4.3
Ct.Th (mm)	1.02 ± 0.14	1.05 ± 0.23	0.95 ± 0.14*	1.06 ± 0.19	1.12 ± 0.17	1.33 ± 0.31	1.25 ± 0.25
Ultimate Stress (MPa)	33 ± 7	32 ± 8	23 ± 7†	31 ± 9	35 ± 9	42 ± 12	35 ± 9
Failure Load (N)	2101 ± 374	2099 ± 497	1653 ± 236‡	2033 ± 352	3204 ± 565	3224 ± 295	2993 ± 574
Tibia	<40 years	≥40 and <55 years	≥55 years	CaMos 20–29 years	<50 years	>50 years	CaMos 20–29 years
Tt.Ar (mm2)	679 ± 125	701 ± 104	697 ± 66*	648 ± 11	922 ± 149	778 ± 138	856 ± 27
Tt.Ar/ht (mm2/ht)	414 ± 69	426 ± 53*	427 ± 33†	392 ± 6	527 ± 72	455 ± 66	475 ± 12
Tt.BMD (mg HA/cm3)	316 ± 35	297 ± 40*	267 ± 41‡	320 ± 50	322 ± 58	378 ± 73	331 ± 44
BV/TV	0.148 ± 0.028	0.133 ± 0.035	0.134 ± 0.025	0.148 ± 0.029	0.168 ± 0.034	0.189 ± 0.038	0.178 ± 0.025
Tb.N (1/mm)	2.02 ± 0.34*	2.00 ± 0.41	1.96 ± 0.27	1.82 ± 0.26	2.24 ± 0.10†	2.08 ± 0.36	2.06 ± 0.28
Tb.Th (mm)	0.074 ± 0.011‡	0.067 ± 0.015‡	0.068 ± 0.009‡	0.082 ± 0.014	0.075 ± 0.014	0.092 ± 0.019	0.088 ± 0.014
Tb.Sp (mm)	0.433 ± 0.078*	0.453 ± 0.116	0.452 ± 0.075	0.480 ± 0.087	0.371 ± 0.027	0.402 ± 0.084	0.407 ± 0.060
Ct.Ar (mm2)	121 ± 11‡	126 ± 16*	106 ± 14‡	136 ± 24	152 ± 17†	169 ± 31	181 ± 45
Ct.Ar/ht (mm2/ht)	74 ± 7‡	77 ± 11	65 ± 10‡	82 ± 2	87 ± 10*	99 ± 9	101 ± 5
Ct.BMD (mg HA/cm3)	897 ± 36‡	887 ± 39†	818 ± 54*	856 ± 44	883 ± 40‡	864 ± 79	785 ± 53
Ct.Po (%)	7.0 ± 1.7‡	7.8 ± 2.9	10.4 ± 2.9*	8.6 ± 3.5	8.8 ± 1.4‡	10.6 ± 3.3	12.4 ± 4.6
Ct.Th (mm)	1.38 ± 0.14‡	1.41 ± 0.22†	1.20 ± 0.17‡	1.59 ± 0.34	1.48 ± 0.21†	1.79 ± 0.39	1.89 ± 0.61
Ultimate Stress (MPa)	35 ± 6	32 ± 7*	28 ± 6‡	37 ± 8	35 ± 10	44 ± 13	38 ± 8
Failure Load (N)	5766 ± 957	5546 ± 1109	4884 ± 705†	5655 ± 890	7575 ± 870	7645 ± 1082	7579 ± 1165

Mean ± SD

^*p<0.05;

^†p<0.01;

^‡p<0.001

Figure 1.

Comparison of HRpQCT and FEA results at the distal radius and tibia in the hypoparathyroid women <40 years (n=18) and men <50 years (n=7) to the control groups. Tt.Ar/ht, total area/height; Tt.BMD, total volumetric bone mineral density; BV/TV, trabecular bone volume fraction; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; Ct.Ar/ht, cortical area/height; Ct.BMD, cortical volumetric bone mineral density; Ct.Po, cortical porosity; Ct.Th, cortical thickness

*p<0.05 compared to controls; ]+ p<0.05 radius versus tibia

Premenopausal women and young men

At both the radius and tibia, Ct.BMD was higher in the hypoparathyroid premenopausal women (radius: +8.9%, tibia +4.9%) and younger men (radius: +13.7%, tibia: +12.5%) compared to controls. Ct.Po was lower at both the radius (−30.7%) and tibia (−18.6%) in premenopausal women and at the tibia in younger men (−29.0%). At the radius, the younger men also showed a trend towards lower Ct.Po (−25.9%, p=0.061). At the tibia, but not the radius, Ct.Th was lower in premenopausal women (−13.2%) and younger men (−21.7%). Tb.Th (−13.2%) and Tb.Sp (−9.8%) were lower in premenopausal women. Tb.N was higher in premenopausal women (+11.0%) and young men (+8.7%). For both hypoparathyroid premenopausal women and younger men, there were differences between the radius and tibia in Tt.Ar, Ct.Ar, Ct.Th and Ct.Po (Figure 1).

Peri- and postmenopausal women and older men

Results for perimenopausal hypoparathyroid women were similar to those for premenopausal women, with a trend towards increased Tt.BMD at the radius (p=0.052) and increased Ct.BMD at both the radius and tibia. Ct.Th and Tb.Th decreased at the tibia alone. Ct.Po in the perimenopausal women was significantly decreased at the radius alone (Table 4). In postmenopausal hypoparathyroid women compared to postmenopausal controls, Ct.BMD was higher and Ct.Po was lower at both the radius and tibia (Table 5). Ct.Th was frankly lower at the tibia and trended lower at the radius. In older men, Ct.BMD was increased at the radius compared to young controls, while other cortical and trabecular parameters were not significantly different.

Table 5.

Cortical HRpQCT parameters for hypoparathyroid postmenopausal women ≥55 years compared to normative postmenopausal controls.

	Postmenopausal women
	Hypoparathyroid	Control	p
n	13	87
Age	61 ± 4	65 ± 10	0.159
Radius
Ct.BMD (mg HA/cm3)	866 ± 70	822 ± 71	0.039
Ct.Po (%)	6.2 ± 2.3	8.5 ± 3.6	0.028
Ct.Th (mm)	0.95 ± 0.14	1.06 ± 0.20	0.059
Tibia
Ct.BMD (mg HA/cm3)	818 ± 54	774 ± 72	0.037
Ct.Po (%)	10.4 ± 2.9	13.7 ± 4.7	0.016
Ct.Th (mm)	1.20 ± 0.17	1.52 ± 0.25	<0.0001

Mean ± SD

Linear regression analysis of HRpQCT parameters in all hypoparathyroid subjects

The results of the linear regression analysis in the hypoparathyroid cohort are presented in Table 6. Etiology was not a significant predictor and the final model included age, sex and disease duration. Sex was a significant predictor of Tt.Ar, BV/TV, Ct.Ar and Ct.Th at both the radius and tibia, Tb.Th at the radius and Tt.BMD at the tibia, adjusting for the other variables in the model. Using age as a quadratic term did not appreciably change the results and data are presented with age as a linear term. Age was the only significant predictor of Ct.Po at both the radius and tibia. Every 10-year increment in age was associated with an increase in Ct.Po by 0.5% at the radius and 1.2% at the tibia. At the radius, each 10-year increment in age was associated with a reduction in BV/TV (−0.009) and Tb.Th (−0.003 mm). In contrast, each 10-year increment in duration of hypoparathyroidism increased BV/TV (+0.012) and Tb.Th (+0.003 mm). Longer disease duration was also associated with increased Tt.BMD and Ct.Ar at the radius. In addition, at the tibia, each 10-year increment in age was associated with a reduction in Tt.BMD (−12 mg HA/cm³) and Ct.BMD (−25 mg HA/cm³) while each 10-year increment in disease duration increased these parameters (Tt.BMD: +22 mg HA/cm³; Ct.BMD: +15 mg HA/cm³). Longer disease duration also increased BV/TV, Tb.Th, Tb.Sp, Ct.Ar and Ct.Th at the tibia. There were no significant interactions between age and disease duration.

Table 6.

Results of linear regression model with age, sex and disease duration on HRpQCT and FEA parameters in all hypoparathyroid subjects. The top panels give the results for the radius and the bottom panels the results for the tibia.

Radius	Tt.Ar	Tt.Ar/ht	Tt.BMD	BV/TV	Tb.N	Tb.Th	Tb.Sp	Ct.Ar	Ct.Ar/ht	Ct.BMD	Ct.Po	Ct.Th	Ultimate Stress	Failure Load
Agea	-	-	-	-0.009*	-	−0.003*	-	-	-	-	0.5*	-	−3†	−142†
Sexb	108‡	53‡	-	0.036†	-	0.016‡	-	24‡	12‡	-	-	0.16*	6*	1169‡
Disease durationa	-	-	20†	0.012†	-	0.003*	-	2*	13*	-	-	-	3†	144†
Tibia	Tt.Ar	Tt.Ar/ht	Tt.BMD	BV/TV	Tb.N	Tb.Th	Tb.Sp	Ct.Ar	Ct.Ar/ht	Ct.BMD	Ct.Po	Ct.Th	Ultimate Stress	Failure Load
Agea	-	-	−12*	-	-	-	-	-	-	−25‡	1.2‡	-	−2†	−322†
Sexb	188‡	84‡	34*	0.029†	-	-	-	37‡	17‡	-	-	0.21†	-	1944‡
Disease durationa	-	-	22‡	0.012†	-	0.004*	−0.021*	5*	3*	15†	-	0.07†	4‡	383‡

^aβ coefficient represents 10-year change in age and disease duration

^bReference is female sex

-p=NS,

^*p<0.05,

^†p<0.01,

^‡p<0.001

FEA

Ultimate stress and failure load were similar for premenopausal women and young and older men compared to the normative controls at both sites. In postmenopausal women, ultimate stress and failure load were significantly decreased at both the radius and tibia compared to the normative young female CaMos data. Ultimate stress was decreased in perimenopausal women at the tibia alone.

Linear regression analysis of FEA parameters in all hypoparathyroid subjects

In the linear regression model, at both radius and tibia, each 10-year increment in age decreased ultimate stress (−3 and −2 MPa, respectively) and failure load (−142 and −322 N, respectively) while each 10-year increment in disease duration increased these parameters (ultimate stress: +3 and +4 MPa, respectively; failure load: +144 and +383 N, respectively), adjusting for the other variables in the model. There were no significant interactions between age and disease duration.

Discussion

Increased areal BMD by DXA at the spine and hip has been a consistent finding across several hypoparathyroid cohorts.^(22–25) The current study adds to our knowledge of the skeleton in hypoparathyroidism, beyond DXA, by applying the non-invasive technology of HRpQCT to subjects completely deficient in parathyroid hormone. We have demonstrated microarchitectural changes in both the cortical and trabecular compartments of bone. Ct.BMD was higher and Ct.Po lower at the radius and tibia in women and men with hypoparathyroidism compared to healthy controls. There were site-specific differences noted between the radius and tibia. Estimated bone strength in our younger hypoparathyroid subjects was not different from controls.

The increase in Ct.BMD is consistent with increased areal BMD at the distal radius and hip. It is unlikely to account, however, for the increase in areal BMD of the lumbar spine because that site is comprised primarily of trabecular bone. Tt.BMD was increased at the radius in premenopausal women but unchanged at the tibia and no significant differences in Tt.BMD were noted in men. Thus, the compartmental analysis of BMD by HRpQCT cannot fully account for the increase in areal BMD by DXA. Importantly, however, we did not measure skeletal mineralization. In a study of hypoparathyroid subjects, including some subjects from this cohort, bone mineralization density distribution (BMDD) measured by quantitative backscattered electron imaging of specimens from the iliac crest was increased compared to controls.⁽²⁶⁾ BMDD has been found to be associated with the extent of bone remodeling activity.⁽²⁷⁾ Since bone remodeling activity is classically low in hypoparathyroidism,^(2,28,29) increased mineralization could conceivably account for increased areal BMD in this disease. This would also be consistent with the lack of any significant differences in BV/TV.

Chen and colleagues⁽³⁰⁾ studied skeletal microstructure using peripheral quantitative computed tomography of the forearm in 9 postmenopausal women with postsurgical or idiopathic hypothyroidism of at least 3 years duration. Hypoparathyroid subjects were compared to postmenopausal women with primary hyperparathyroidism and healthy controls. Ct.BMD at the 20% site was higher in the hypoparathyroid subjects compared to controls and hyperparathyroid women. Ct.Ar and Ct.Th were greater in the hypoparathyroid women at both the 4 and 20% sites compared to the controls and hyperparathyroid subjects.

Our data in hypoparathyroid postmenopausal women compared to normative postmenopausal controls confirms the increase in Ct.BMD at both sites; however, we found a trend towards a decrease in Ct.Th at the radius and a significant decline in Ct.Th at the tibia. Ct.BMD is inversely proportional to Ct.Po and proportional to its degree of mineralization.⁽³¹⁾ Ct.Po is known to be associated with the degree of bone remodeling. The reductions we noted in Ct.Po at both the radius and tibia may account for the increase in Ct.BMD in our hypoparathyroid subjects. The etiology for the decreased Ct.Th in our hypoparathyroid cohort is unclear. A number of subjects in our cohort demonstrated over-replacement with thyroid hormone and five had a prior diagnosis of primary hyperparathyroidism. Both thyrotoxicosis and primary hyperparathyroidism are known to adversely affect cortical bone and can result in cortical thinning.^(32,33) However, excluding subjects with low TSH values or a prior diagnosis of primary hyperparathyroidism did not appreciably change our results. In addition, etiology of hypoparathyroidism was not associated with Ct.Th in our cohort. The advanced segmentation algorithm we used has been previously validated and shown to be robust in characterizing cortical features from HRpQCT images in healthy subjects.⁽¹²⁾ However, there may be undetected disease-specific effects that are complicating the measurement of Ct.Th in our hypoparathyroid subjects. In addition, weight-bearing exercise has been demonstrated to play an important role in skeletal microarchitecture, including Ct.Th.⁽³⁴⁾ While not measured as part of this study, our hypoparathyroid subjects appeared to be less active after their diagnosis and a relative lack of weight-bearing exercise may have contributed to the microarchitectural findings at the tibia. We also cannot exclude site-specific scanner differences that are usually higher for microstructural parameters than BMD.⁽³⁵⁾

Skeletal microstructure has also been studied in hypoparathyroid subjects using histomorphometric analysis of iliac crest bone biopsy specimens. A study of 33 hypoparathyroid subjects with age- and gender-matched controls showed greater cancellous bone volume in hypoparathyroid subjects due to an increase in trabecular width.⁽²⁾ Trabecular number and trabecular separation were similar to controls. Cortical width was also greater in the hypoparathyroid subjects and there was a non-significant decrease of 17% in cortical porosity. Bone formation rate was greatly reduced, most profoundly in the cancellous envelope. Further analysis of these specimens using micro-computed tomography⁽³⁶⁾ showed increased cancellous bone volume, Tb.Th and Tb.N in hypoparathyroid subjects. Our results show an increase in Tb.N at the tibia but not the radius in younger women and men, and a decrease in Tb.Th at the tibia in women. There were no differences in BV/TV in our cohort compared to controls. A study comparing HRpQCT with bone biopsy showed only modest correlations between microarchitectural measures.⁽³⁶⁾ Relationships between areal BMD of the spine and hip with HRpQCT measures were stronger however, indicating that the iliac crest may not necessarily be most representative of other skeletal sites. There is precedent for discrepancies to be appreciated when measurements at the iliac crest are compared to those by HRpQCT. For example, using histomorphometric analysis of bone biopsy specimens of the iliac crest, trabecular microarchitecture in patients with primary hyperparathyroidism is maintained,^(37,38) despite evidence showing that fracture risk, particularly at the vertebral spine, is increased.⁽³⁹⁾ Using HRpQCT, postmenopausal women with primary hyperparathyroidism were shown to have abnormal trabecular microarchitecture.⁽³³⁾ The disparities between our HRpQCT results and those from bone biopsy may be attributed to these previously reported differences between the iliac crest and other sites.

There are limited fracture data for hypoparathyroid patients. One small cohort study showed an increase in morphometric vertebral fractures in 16 postmenopausal women with postsurgical hypoparathyroidism,⁽⁶⁾ although registry studies with hundreds of subjects showed no difference in vertebral or overall fracture risk between hypoparathyroid subjects and controls.^(7,8) In the registry studies, postsurgical patients were at lower risk for upper extremity fractures ⁽⁷⁾ and non-surgical patients at higher risk for upper extremity fractures.⁽⁸⁾ Prior studies have indicated that the relationship between Ct.Po and bone strength is exponential, with small changes in Ct.Po resulting in much larger declines in bone strength.^(31,40,41) Despite reduced Ct.Po, estimated bone strength in our study was unchanged, although this may have been due to the decrease in Ct.Th. In addition, the FEA models we used did not account for differences in tissue mineralization.

As per prior studies, we noted significant relationships between age and sex with cortical and trabecular microarchitectural parameters and estimated bone strength.^(9,15,42) We also noted positive relationships with longer disease duration, mitigating the adverse effects of increasing age on ultimate stress and failure load. Factoring the aging process into this analysis provides the opportunity to appreciate that in hypoparathyroidism, there are duration-related abnormalities that one would have expected, such as in Tt.BMD, Ct.BMD, Ct.Th, Ct.Ar, BV/TV, Tb.Th and Tb.Sp.

The strengths of this investigation include the large cohort of hypoparathyroid subjects studied using noninvasive imaging technologies not previously extended to this population. We compared our results to a well-characterized population-based cohort, not a convenience sample. The limitations include the cross-sectional design and relatively small numbers of hypoparathyroid subjects per age and gender group. Longitudinal studies are needed to confirm our findings.

Using noninvasive high resolution imaging, we have demonstrated abnormal microarchitecture in hypoparathyroid subjects, giving additional evidence for the critical role of parathyroid hormone in establishing and maintaining bone quality.