Parathyroid hormone response to severe vitamin D deficiency is sex associated: An observational study of 571 hip fracture inpatients

Abstract

Objectives

To investigate the association between sex and parathyroid hormone response to severe vitamin D deficiency after hip fracture.

Design

Cross-sectional study.

Setting

Rehabilitation hospital in Italy.

Participants

571 consecutive inpatients with hip fracture and severe vitamin D deficiency (serum 25-hydroxyvitamin D < 12ng/ml), without hypercalcemia or estimated glomerular filtration rate (GFR) < 15ml/min.

Measurements

In each patient we assessed PTH (by two-site chemiluminescent enzyme-labelled immunometric assay), 25-hydroxyvitamin D (by immunoenzymatic assay), albumin-adjusted total calcium, phosphate, magnesium, and creatinine 21.3 ± 6.1 (mean ± SD) days after fracture occurrence. Functional level was assessed using the Barthel index. PTH response to vitamin D deficiency was classified as either secondary hyperparathyroidism (serum PTH >75pg/ml) or functional hypoparathyroidism, i.e., inappropriate normal levels of PTH (≤75pg/ml).

Results

Among the 571 patients, 336 (59%) had functional hypoparathyroidism, whereas 235 (41%) had secondary hyperparathyroidism. PTH status was significantly different between sexes (p=0.003): we found functional hypoparathyroidism in 61% of women and 43% of men (secondary hyperparathyroidism in 39% of women and 57% of men). The significance of the between-sex difference was maintained after adjustment for age, estimated GFR, phosphate, albumin-adjusted total calcium, albumin, Barthel index scores, 25-hydroxyvitamin D, and hip fracture type (either cervical or trochanteric). The adjusted odds ratio was 1.85 (95%CI from 1.09 to 3.13; p=0.023).

Conclusions

Data shows that PTH response to vitamin D deficiency was sex-associated following a fracture of the hip. The higher prevalence of secondary hyperparathyroidism may play a role in the known prognostic disadvantage found in hip-fracture men.

Introduction

A secondary increase in parathyroid hormone (PTH) is often found in aged people and has been attributed to several factors, including vitamin D deficiency, impaired renal function, inadequate calcium intake, and estrogen depletion (1). Unsurprisingly, secondary hyperparathyroidism is highly prevalent among hip-fracture patients (2., 3., 4., 5., 6.) who are aged, deficient in vitamin D, poorly nourished, and affected by relevant comorbidity including impaired renal function with progressive multisystem decline and loss of physiologic reserve (7., 8., 9.). However, PTH elevation is not always found in vitamin D depletion: several hip-fracture patients with severe vitamin D deficiency do not have PTH excess, as firstly shown by Sahota et al. (10) and confirmed by several recent reports (11., 12., 13.). The condition of having inappropriately normal levels of PTH has been named “functional hypoparathyroidism” (10). At now, it is not clear the reasons why vitamin D depletion leads to either secondary hyperparathyroidism or functional hypoparathyroidsim in individual subjects (10., 11., 12., 13.).

Hip fractures represent the most severe consequence of bone fragility, because they result in a 8% to 36% excess mortality within one year (14) and approximately 20% of hip fracture survivors require long-term nursing home care, whereas only 40% fully regain their pre-injury level of independence (15).

On the whole, the burden of hip fractures can be estimated as disability-adjusted life-years lost and represents a challenge for the healthcare systems in a lot of countries throughout the world (16).

A sustained elevation of PTH levels exerts catabolic effects on bone and has been implicated in the genesis of bone fragility and hip fractures (1, 17, 18). Furthermore, PTH excess may lead to an unfavorable outcome following hip fracture occurrence (5, 6, 19). Several other factors are associated with adverse prognosis. Among them, male sex plays a relevant role because it has been consistently associated with high risk of complications, high mortality rates, and increased risk of institutionalization (14, 20., 21., 22.). However, no studies investigated the association between sex and prevalence of secondary hyperparathyroidism in vitamin D depleted patients with a fragility fracture of the hip. We hypothesized that functional hypoparathyroidsm (and its inverse condition secondary hyperparathyroidism) may be sex associated in hip fracture patients.

Methods

Patients

We retrospectively evaluated 981 white people with hip fracture admitted consecutively to our Physical Medicine and Rehabilitation division. We focused on white patients because few non-white, elderly people live in our country. Our hospital is in a city with about one million inhabitants and the patients came from various orthopedic wards. All the patients were referred for acute inpatient rehabilitation by the consultant physiatrists of the orthopedic wards. A total of 52 of the 981 subjects were excluded from the study, because their hip fracture was caused by either major trauma or cancer affecting the bone. The remaining 929 people suffered from fractures that either were spontaneous or caused by minimal trauma (trauma equal to or less than a fall from a standing position). A total of 11 of the 929 people were excluded from the study because of either albumin-adjusted serum levels of calcium exceeding 11mg/dl or low estimated glomerular filtration rate (GFR <15ml/min). Nine patients were excluded because of missing data. The 909 remaining patients included 788 women (87%) and 121 men. Among these 909, we focused on the 571 patients (492 women = 86% and 79 men) with serum levels of 25-hydroxyvitamin D below 12ng/ml. Nine of the 571 patients (two men and seven women) had an estimated GFR between 15 ml/min and 30 ml/min. They were included in the final sample. However, we repeated statistical analyses after excluding them from the study, because a relevant decrease in 1,25dihydroxyvitamin D synthesis in these patients may be a pivotal factor in affecting the relationship between 25-hydroxyvitamin D and PTH. Institution Revision Board approval was obtained for the study protocol.

Outcome Measures

A blood sample was collected during the first three days of hospitalization, 21.3 ± 6.1 days (mean ± SD) after fracture occurrence, in the morning after an overnight fasting. In each subject, we evaluated 25-hydroxyvitamin D by an immunoenzymatic assay (coefficient of variation intrassay <8%; interassay <10%) (IDS Inc., Fountain Hills, AZ, USA), pTH by two-site chemiluminescent enzyme-labelled immunometric assay (coefficient of variation intraassay 5.7%, interassay 8.8%) (DPC Inc., Los Angeles, CA, USA), total calcium (by a photometric color test), phosphate, albumin, magnesium, and creatinine. GFR was estimated by the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation (23).

Body weight and height were measured in each subject, and body mass index (BMI) was calculated as weight/height2. To assess the degree of functional recovery, skilled physiatrists performed the Barthel Index (original version, unchanged) (24). The functional index assesses basic activities of daily living; its score ranges from 0 (total dependence) to 1 00 (total independence). Each fracture was classified as either cervical or trochanteric on the basis of radiological and surgical findings.

Data Analysis

preliminary comparisons between men and women were performed by a Mann-Whitney U test for both the continuous variables (i.e., age, PTH, 25-hydroxyvitamin D, albumin, albumin-adjusted total calcium, phosphate, GFR estimate, and magnesium) that were all non-normally distributed at a Shapiro-Wilk test and for the ordinal variable (Barthel index score). The relationship between sex and either normal (≤ 75pg/ml) or high PTH levels (>75pg/ml), and between sex and hip fracture type were investigated by a x2 test for independence with Yates continuity correction. A binary logistic regression test was used to adjust the association between sex and PTH category (either normal or elevated) for the potential confounders listed in Table 1. At a preliminary step, we investigated for each of the ten potential confounders the univariate relationship with both sex and PTH category. For eight of the ten variables (i.e., age, phosphate, albumin-adjusted calcium, 25-hydroxyvitamin D, estimated GFR, albumin, Barthel index score, and hip fracture type) a Mann-Whitney U test (for hip fracture type a x2 test for independence with Yates continuity correction) showed a p value below 0.2 for either the between-sex or the between PTH-category comparisons or for both of them. We included the eight variables together with sex in the binary logistic regression model as independent variables (the dependent variable was PTH category, classified as either normal or elevated).

Table 1.

Comparisons between the 492 women and the 79 men included in the study

Variable	Women (N=492)	Men (N=79)	P
Age (years)	82 (from 76 to 86)	82 (from 76 to 86)	0.889
PTH (pg/ml)	66.5 (from 43 to 93)	80 (from 53 to 106)	0.018
Phosphate (mg/dl)	3.6 (from 3.2 to 4.0)	3.4 (from 3.0 to 3.7)	0.001
Albumin-adjusted calcium (mg/dl)	8.9 (from 7.8 to 9.5)	8.9 (from 7.5 to 9.4)	0.194
25-hydroxyvitamin D (ng/ml	7 (from 4 to 9)	7.5 (from 4.9 to 9.6)	0.064
Estimated GFR (ml/min)	73.0 (from 59.3 to 86.0)	76.8 (from 60.6 to 98.4)	0.278
Magnesium (mg/dl)	2.0 (from 1.9 to 2.1)	2.0 (from 2.0 to 2.1)	0.170
Albumin (g/l)	31 (from 28 to 34)	30 (from 26 to 32)	0.058
Body mass index (kg/m2)	23.2 (from 20.4 to 25.0)	23.2 (from 21.3 to 25.3)	0.390
Barthel index score	45 (from 30 to 55)	30 (from 20 to 50)	0.001
Hip fracture type
(trochanteric/cervical) %	51.7 / 48.3	63.3 / 36.7	0.064

Data is shown as median and interquartile range where not otherwise stated.

All statistical analyses were repeated after excluding from the study sample the nine patients (two men and seven women) whose estimated GFR was between 15 and 30 ml/min.

The statistical package used was SPSS, version 14.

Results

Preliminary comparisons between the 492 women and the 79 men with severe vitamin D-deficiency are shown in Table 1. Two-hundred thirty-five of the 571 patients (41%) had secondary hyperparathyroidism (PTH serum levels exceeding 75pg/ml), whereas the remaining 336 (59%) had functional hypoparathyroidism (normal PTH levels despite severe vitamin D deficiency). PTH status was significantly different between sexes (p=0.003): we found functional hypoparathyroidism in 61% of women and 43% of men (secondary hyperparathyroidism in 39% of women and 57% of men), as shown in Table 2. The significance of the between-sex difference was maintained after adjustment for age, estimated GFR, phosphate, albumin-adjusted total calcium, albumin, Barthel index scores, 25-hydroxyvitamin D, and hip fracture type. The adjusted odds ratio was 1.85 (95%CI from 1.09 to 3.13; p=0.023).

Table 3.

Binary logistic regression analysis. Factors associated with PTH status

	B (SE)	Odds Ratio and 95% CI	p
Age (years)	0.03 (0.01)	1.03 (from 1 to 1.06)	0.037
Sex	0.61 (0.27)	1.85 (from 1.09 to 3.13)	0.023
Phosphate (mg/dl)	-0.70 (0.17)	0.50 (from 0.36 to 0.70)	<0.001
Albumin-adjusted calcium (mg/dl)	-0.27 (0.10)	0.76 (from 0.63 to 0.93)	0.008
25-hydroxyvitamin D (ng/ml)	0.04 (0.03)	1.04 (from 0.98 to 1.10)	0.239
Estimated GFR (ml/min)	-0.018 (0.04)	0.98 (from 0.97 to 0.99)	<0.001
Albumin (g/l)	-0.01 (0.23)	0.99 (from 0.95 to 1.04)	0.664
Barthel index score	-0.01 (0.01)	0.99 (from 0.98 to 1.00)	0.072
Hip fracture type	0.01 (0.19)	1.01 (from 0.70 to 1.46)	0.95

The dependent variable was the PTH level categorized as ≤ 75 (that was conventionally attributed a value of 0) or > 75 (that was conventionally attributed a value of 1). The independent variables included in the regression model are listed in the Table. Male sex and trochanteric fracture were conventionally attributed a value of 1 (female sex and cervical fracture = 0). The full model was statistically significant (x2 = 86.9; df=9; p<0.001).

Table 2.

Count and percentages of women and men with functional hypoparathyrodism or secondary hyperparathyroidism

	Normal PTH (functional hypoparathyrodism)	PTH excess (secondary hyperparathyroidism)	total
Women	N=302	N=190	N=492
% within sex	61.4%	38.6%	100%
Men	N=34	N=45	N=79
% within sex	43.0%	57.0%	100%
Total	N=336	N=235	N=571
% of whole sample	58.8%	41.2%	100%

A Chi-square test for independence (with Yates Continuity Correction) indicated a significant association between sex and PTH status categorized as either functional hypoparathyroidism or secondary hyperparathyroidism, x2 (1, n=571) =8.72, p=0.003.

Excluding from analyses the nine patients with an estimated GFR between 15 and 30 ml/min did not materially change the results (data not shown).

Discussion

Data shows that PTH response to severe vitamin D deficiency was sex-associated in hip-fracture patients: vitamin D-deficient women had a higher prevalence of functional hypoparathyroidism (and a lower prevalence of secondary hyperparathyroidism) than men. The adjusted odds ratio was 1.85. To our knowledge, no previous studies investigated the association between sex and PTH response to vitamin D depletion following a hip fracture.

In agreement with the wider literature, vitamin D deficiency was highly prevalent in our sample of hip fracture inpatients (4, 5, 10, 25., 26., 27.). Indeed, a poor nutritional status is commonly found following a fracture of the hip (8, 28., 29., 30.). We confirm that despite vitamin D depletion, i.e., a well-known cause of secondary hyperparathyroidism (1), a substantial proportion of patients did not have PTH levels exceeding the normal range (10., 11., 12., 13.). Notably, in our study the prevalence of vitamin D deficiency was similar in men and women: PTH response to vitamin D deficiency (and not deficiency itself) differed between sexes.

Convincing explanations for low PTH levels in vitamin D depletion are still lacking. Bjorkman et al. hypothesized that reduced mobility may be the cause of blunted PTH response in many subjects due to increased bone resorption from the unloaded skeleton resulting in a non-PTH mediated release of calcium (11). Besides mobility level, serum calcium is affected by several factors and is known as a major determinant of PTH (1). Aging itself may be associated with an increased PTH secretion (31, 32), and may modulate PTH response in vitamin D deficiency. Chronic kidney disease is accompanied by mineral metabolism disturbances including early PTH elevation together with a decrease in both serum 1,25-dihydroxyvitamin D and urine phosphate excretion (33, 34). One strength of our study is that the association we found between sex and PTH status was independent of functional recovery, age, albumin-adjusted serum calcium, estimated GFR, and phosphate.

Magnesium depletion is associated with blunted PTH secretion (35), besides resistance to PTH action (36). However, in our sample we found no associations between serum magnesium and PTH status. Intracellular magnesium may be a stronger predictor of PTH levels, because enzymes which mediate PTH synthesis and its cellular response (adenylate cyclase and phospholipase C) are known to be highly magnesium dependent (37). Unfortunately, serum magnesium does not accurately reflect intracellular magnesium concentrations (38), several patients with normal circulating magnesium are magnesium depleted (39), and magnesium deficiency (shown by a loading test) was shown as an important factor contributing to blunted PTH response to vitamin D deficiency in osteoporotic patients (39). Sahota et al. hypothesized other potential explanations to justify the blunted PTH response in vitamin D depletion (40). Dysfunction of the parathyroid glands may be a potential cause and may include abnormalities of the parathyroid calcium sensing receptor, abnormalities of the serum 1,25-dihydroxyvitamin D receptor, or rarer causes such as abnormal expression of growth repressing genes within the gland (41), but these plausible hypotheses need support by data. Clearly, further studies are needed to investigate the mechanisms underlying the type of PTH response to vitamin D deficiency and its association with sex.

The clinical meaning of our result rests on the linkage between secondary hyperparathyroidism and an unfavorable outcome following hip fracture. Fisher et al. found a significant association between PTH excess and both peri-operative myocardial injury and in-hospital all-cause mortality in 238 consecutive patients with hip fracture (5). The same group confirmed the association between PTH excess and peri-operative myocardial infarction and in-hospital mortality in 287 patients (6). Furthermore, they showed a prolonged length of stay and an increased risk of being discharged to institutional care in the patients with secondary hyperparathyroidism (6). Di Monaco et al studied 456 hip fracture patients consecutively admitted to a rehabilitation facility: they showed an inverse association between PTH serum levels and recovery of ability to function in activities of daily living (19). Very recently, Madsen et al found a significant association between secondary hyperparathyroidism and one-year mortality in 565 hip fracture patients admitted to a university hospital (42). Interestingly, secondary hyperparathyroidism affected prognosis independently of vitamin D deficiency (5, 6, 19, 42), that is per se associated with reduced performance and adverse outcome (19, 25, 27, 43), although inconsistencies exist in the literature on vitamin D and function in older people (44). The negative prognostic role of secondary hyperparathyroidism after hip fracture is consistent with data in other groups of patients affected by various diseases, and even in the general aged population (45., 46., 47., 48.).

Because male sex is significantly associated with unfavorable outcomes after hip fracture (14, 20., 21., 22.), we hypothesize that the higher prevalence of secondary hyperparathyroidism we describe in our current study may contribute to explain the prognostic disadvantage in men. Large prospective studies are needed to test this hypothesis.

Elevated PTH levels may contribute to an unfavorable prognosis by several mechanisms (5, 6, 19, 41, 45., 46., 47., 48.), although a cause and effect relationship has not been proven and a simple role of bystander or marker of frailty cannot be excluded (42, 49).

Our study has limitations. We evaluated one sample of white people, who were surgically operated on and were referred for inpatient rehabilitation. As a consequence, our results are not generalizable to the overall population of hip fracture patients. We did not collect data on some factors that could alter PTH levels, including dietary calcium intake (1) and use of loop diuretics (50) or corticosteroids. Seasonal variations in 25-hydroxyvitamin D levels were not investigated. Blood samples for laboratory assessment were collected around three weeks after fracture occurrence, so a role of hospitalization in worsening the deficiency of vitamin D and modulating PTH response cannot be excluded. Finally, the cross-sectional design does not prove causal inference.

Despite limitations, our results show that PTH response to vitamin D deficiency was sex-associated following a fracture of the hip. The higher prevalence of secondary hyperparathyroidism may play a role in the known prognostic disadvantage found in hip-fracture men. Proper intervention trials are needed to confirm the hypothesis of improved outcome due to prevention or early treatment of secondary hyperparathyroidism following a fracture of the hip.

Disclosure

all the authors have no conflict of interest.