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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 22  |  Issue : 2  |  Page : 97-102

Bone markers and renal functional status in healthy Nigeria adults


1 Endocrinology, Diabetes and Metabolism Unit, Department of Medicine, Obafemi Awolowo College of Health Sciences, Olabisi Onabanjo University Teaching Hospital, Sagamu Campus, Ogun State, Nigeria
2 Nephrology unit, Alimosho General Hospital, Igando, Lagos State, Nigeria
3 Nephrology Unit, Department of Medicine, Department of Medicine, Olabisi Onabanjo University Teaching Hospital Sagamu, Ogun State, Nigeria

Date of Submission06-Dec-2021
Date of Acceptance27-Jan-2022
Date of Web Publication19-May-2022

Correspondence Address:
Dr. Ayotunde Oladunni Ale
Department of Medicine, Obafemi Awolowo College of Health Sciences, Olabisi Onabanjo University, 1 Hospital Road, Sagamu, Sagamu Campus, Ogun State, 23401
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_40_21

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  Abstract 


Background There is a dearth of reports on the relationship between bone metabolism and renal function in Nigeria. This study determined the association between bone-turnover markers and renal functional status in healthy Nigerian adults.
Patients and methods This exploratory observational study consisted of 80 apparently healthy participants aged 22–50 years without known risk factors for renal impairment. Fasting samples were analyzed for biochemical bone-turnover markers, including serum osteocalcin, total alkaline phosphatase, 24-h urine-calcium excretion, parathyroid hormone (PTH), and 25-hydroxyvitamin D [25(OH)D]; and calcium, phosphate, and creatinine. The estimated glomerular-filtration rate (GFR) was calculated using the Cockcroft–Gault formula. Bone mineral density (BMD) was measured by Dual-energy X-ray Absorptiometry scan (DXA scan). Statistical analysis was carried out and P level less than 0.05 was regarded as significant.
Results The mean age of study participants was 32.1±5.8 years with a mean GFR of 98.15±9.02 ml/min, mean serum 25(OH)D 51.53±15.45 mmol/l, and mean BMD/Z score 0.54±0.07)/0.20±1.02. None of the participants had osteoporosis or vitamin-D deficiency. There is a significant correlation between bone marker − osteocalcin and BMD, and PTH with BMD and GFR (P<0.05). Also, a nonsignificant trend was observed between calcium excretion, 25(OH)D, and estimated GFR (P=0.07, P=0.08).
Conclusion PTH may be an early marker of bone loss in renal dysfunction.

Keywords: bone mineral density, bone markers, parathyroid hormone, renal function


How to cite this article:
Ale AO, Bakare JC, Oyebisi OO, Adeyemo OL. Bone markers and renal functional status in healthy Nigeria adults. J Egypt Soc Nephrol Transplant 2022;22:97-102

How to cite this URL:
Ale AO, Bakare JC, Oyebisi OO, Adeyemo OL. Bone markers and renal functional status in healthy Nigeria adults. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2022 Jul 5];22:97-102. Available from: http://www.jesnt.eg.net/text.asp?2022/22/2/97/345441




  Introduction Top


Bone, parathyroid gland, and kidney are endocrine organs that act in synergy through a tightly regulated process via intrinsic or circulating factors that are generally referred to as bone-turnover markers (BTMs), and thus maintain bone metabolism, calcium homeostasis, and kidney function. A classic negative feedback loops these processes by an inverse relationship between circulating concentrations of bone markers and the kidney, thus establishing a parathyroid–bone–kidney-axis set point.

BTMs are generally classified as circulating factors that affect bone turnover, like parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D]; and intrinsic factors that reflect bone-cell number and/or activity, which are generally subdivided into two categories: markers of bone formation and markers of bone resorption. Bone-formation markers derive from the osteoblastic activity. Osteocalcin, bone alkaline phosphatase, and the N-terminal propeptide of type-I procollagen are the most frequently used markers of bone formation [1]. The markers of bone resorption include degradation products of the type-I collagen such as the C-terminal cross-linking telopeptide of type-I collagen, osteoclast enzymes, such as type-5b tartrate-resistant acid phosphatase, and calcium excretion [1].

In the bones, PTH acts on osteoblast and osteoclast [2]. It indirectly stimulates osteoclast activity that ultimately leads to resorption of the bones and calcium release. However, this osteoclast activity is preceded by the action of PTH on osteoblast. PTH directly stimulates osteoblasts, which increases their expression of RANKL, a receptor activator for nuclear-factor kappa-B ligand, allowing for the differentiation of osteoblasts into osteoclasts. PTH also inhibits the secretion of osteoprotegerin, allowing for preferential differentiation of osteoblasts into osteoclasts [2]. Osteoprotegerin normally competitively binds with RANKL diminishing the ability of osteoblasts to form osteoclasts. Osteoclasts function to remodel the bones (resorption) by degrading hydroxyapatite and other organic material, thereby releasing calcium into the blood. At the kidney, PTH increases calcium reabsorption in the nephrons while decreasing phosphate in the proximal nephrons [2].

Vitamin D maintains bone health. It regulates bone resorption by promoting osteoclast differentiation via directly acting on osteoblast or osteocytes [3]. Vitamin D stimulates intestinal absorption of calcium, regulates PTH release by the chief cells, and mediates PTH-stimulated bone reabsorption [3].

Several studies have demonstrated the beneficial effects of PTH and vitamin D in the body, including the cardiovascular, skeletal, and renal. Hyperparathyroidism and vitamin-D deficiency have been implicated in cardiovascular disorders and kidney failure [4].

Researches have reported linkages between osteoporosis and cardiovascular disease; and bone markers and cardiovascular risk factors either through common risk factors, shared pathophysiology, genetic factors, or causal links [5],[6],[7]. Directly or indirectly, these cardiovascular risk factors are also established risk factors in the etiology of renal-disease pathology. Metabolic bone disease is a well-studied complication of chronic renal disease [8], and with the rising prevalence in renal disease, especially in Nigeria, osteoporosis with other metabolic bone diseases and other comorbid conditions is expected to surge [9]. The need to research into markers of bone turnover becomes imperative to detect or screen for early bone involvement to mitigate against the morbidity associated with renal disease. Therefore, our study focused on healthy participants with no known risk factors for renal impairment nor cardiovascular diseases. This study assessed the association between BTMs and renal functional status in apparently healthy adults. Research on this interrelationship between BTMs and renal functional status in healthy adults in Nigeria is sparse. Furthermore, this research will serve as a template for further studies on BTMs and chronic renal disease.


  Patients and methods Top


This study was done in the Endocrine Unit, Lagos State University Teaching Hospital, Ikeja, Nigeria. The study was carried out in accordance with the principles of the Declaration of Helsinki. Study approval was granted by the Ethics Committee of Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria. All participants signed informed consent.

Study participants

The study population comprised healthy adult volunteers aged 22–50 years derived from hospital staff and healthy patients’ relative who visited the hospital. One hundred healthy adult participants were recruited by systematic random sampling, but only 80 consented to the research. Exclusion criteria included those with cardiovascular diseases, renal diseases, endocrinopathies, liver diseases, amenorrheic, menopausal, or any other medical disorders, alcohol use, smoking, or medication use.

Study design

This is a descriptive cross-sectional study.

Instrument

A purpose-designed interviewer-administered questionnaire was employed to capture sociodemographic information and other clinical data.

Anthropometric measures

Participants were measured for height, weight, and waist circumference using a stadiometer, digital scale, tape rule by standardized protocol, and BMI calculated by weight (kg)/height (m) [2],[10].

Laboratory analyses

Biochemical analyses: under sterile conditions, samples of fasting blood were collected to conduct clinical studies. Urine samples were obtained to assess calcium and creatinine levels. Calcium, serum albumin, phosphorus, and creatinine concentrations were determined using a timed end-point method, bromocresol green albumin assay, vanadate–molybdate method, and modified Jaffe method, respectively. The creatinine clearance was estimated for all participants using Cockcroft and Gault formula. creatinine clearance ml/min [(140–age)×weight]/(serum creatinine×72) (weight is in kg, age in years, and serum creatinine in mg/dl; in females multiplied by 0.85).

Hormonal analyses

Analyses of 25(OH)D, osteocalcin (1–43/49), and intact PTH levels were determined by an enzyme-linked immunosorbent assay method using a fasting sample under a sterile condition. The assay results were read off using a Thermo-fisher multiskan Ex microplate reader (UK) after following the manufacturer’s protocol.

Bone mineral density determination

Lunar PIXI peripheral densitometer using dual-energy X-ray absorptiometry technique was employed in the measurement of the left distal radius (lower-third) bone mineral density (BMD). BMD expressed as exact values in g/cm2 and as Z scores, which represent the BMD value normalized for age-matched and sex-matched mean. Coefficients of variation 1.0% at the distal forearm. The International Society for Clinical Densitometry criteria is used for definition of BMD, Z score less than −2 as osteoporosis and normal as more than 2 [11].

Definition of terms

  1. Vitamin-D deficiency defined by 25(OH)D by less than 25 nmol/l (≤10 ng/ml) [12].
  2. Elevated PTH defined by more than 6.9 pmol/l [13].
  3. Osteoporosis defined by International Society for Clinical Densitometry criteria as Z scores less than −2 [11].


Data analysis

Statistical analysis was conducted using a software package SPSS, version 21.0, IBM. The results were represented as mean, SDs, and proportions. Pearson’s correlation was used to examine the relationship between PTH, bone markers, BMD, and creatinine clearance.


  Results Top


The studied participants’ characteristics

The mean age of the participants was 35.10±0.5.8 years with a mean of glomerular-filtration rate (GFR) 98.15±9.02 ml/min/1.73 m2 and mean BMD of 0.567 (0.07) with Z score 0.20 (1.05). No participants had vitamin-D deficiency or osteoporosis. The mean GFR (ml/min/1.73 m2) of the males was significantly greater than the females (mean of male=108.57±12.39 vs. female=92.53±7.20, P=0.04). The other characteristics of the studied participants are as seen in [Table 1].
Table 1 Clinical and biochemical characteristics of the studied participants

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Correlation studies

Demography

The mean age of the studied participants 32.10 (5.8) correlates with GFR (r=−0.31, P=0.02).

Correlation between biochemical bone markers

No significant correlation was found between bone-formation marker and resorption markers, serum osteocalcin and calcium excretion (r=0.85, P=0.6), and between serum osteocalcin and PTH (r=−0.13, P=0.42) as seen in [Table 2].
Table 2 Correlation between biochemical bone markers, bone mineral density, and estimated glomerular-filtration rate

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Serum parathyroid hormone, 25-hydroxyvitamin D, calcium metabolism

A nonsignificant trend was observed between PTH and corrected calcium (r=0.3, P=0.09) and serum phosphorus (r=−0.3, P=0.069), but PTH showed no correlation with serum 25(OH)D (r=−0.03, P=0.98).

There was no significant correlation between 25(OH)D and serum calcium or serum phosphorus (r=0.056, P=0.73 or r=0.24, P=0.14). However, correlation existed between serum 25(OH)D with serum calcium–phosphorus product (r=−0.23, P=0.015), urinary phosphorus (r=−0.35, P=0.029), urinary calcium–phosphorus product (r=−0.36, P=0.021), and calcium excretion (r=−0.33, P=0.041).

Biochemical bone markers and bone mineral density

The bone-formation marker − osteocalcin − correlates with BMD/Z score (r=−0.46, P=0.002), Z score (r=−0.6, P=0.000). However, neither alkaline phosphatase nor 25(OH)D or calcium excretion correlated with BMD (r=0.26, P=0.11, r=−0.24, P=0.143, r=−0.029, P=0.86), respectively. PTH correlates with BMD (r=−0.448, P=0.002) and Z score (r=−0.5, P=0.000).

Bone markers and renal function

Among all the biochemical bone markers, only the resorption marker − PTH showed a significant inverse correlation with renal function [PTH-correlated estimated glomerular-filtration rate (eGFR) r=−0.4, P=0.011], with a nonsignificant trend observed between eGFR and calcium excretion (r=−0.29, P=0.07); and 25(OH)D (r=0.28, P=0.08). While none of the bone-formation markers − osteocalcin or alkaline phosphatase showed correlation with eGFR (r=−0.13, P=0.430; r=−0.028, P=0.87), respectively. Also, no significant correlation was observed between BMD and eGFR (r=0.06, P=0.7) as shown in [Table 2].


  Discussion Top


This exploratory observational study investigates the relationship between BTMs and renal function in healthy adults. age range 22–50 who had attained skeletal maturity and peak bone mass without known cardiovascular risk factors and a normal renal function as defined by creatinine clearance 88–128 ml/min for women and 97–137 ml/min for men, none of the participants had impaired renal function.

Neither vitamin-D deficiency nor hyperparathyroidism were observed among participants.

The Dual-energy X-ray Absorptiometry scan (DXA scan) showed that none of participants had osteoporosis defined as a Z score less than −2 by the International Densitometry Society [11].

Bone-turnover markers

Among all the BTMs, only PTH and osteocalcin showed inverse correlation to BMD. This is in keeping with studies in Caucasians and Asians [14],[15],[16] The bone is a dynamic tissue that undergoes continuous remodeling throughout life by renewal and repairs in adulthood through a coordinated normal physiologic process of coupling of bone formation and resorption activities with net favor of bone formation [17]. Uncoupling of these bone activities will result in bone disease. Osteocalcin is a hormone product of osteoblast and measures osteoblastic activity [18], and PTH plays critical roles in bone and calcium metabolism, and kidney function. In its bone-resorption role, it acts by directly increasing resorption action via osteoclast activity or by facilitating osteoblastic differentiation to osteoclasts, thereby increasing calcium release from the bones [19]. This may further suggest that biochemical changes in osteocalcin and PTH level reflect bone metabolism with no net bone loss. Furthermore, the urinary calcium excretion, a product of bone degradation, showed no correlation with BMD alluding to steady state of normal bone metabolism.

Our findings showed that mean BMD/Z score do not correlate with eGRF in healthy participants, in addition, osteoporosis, hyperparathyroidism, and osteomalacia were not observed among the participants, suggesting that metabolic bone disease is not a feature of normal kidney function or early phase of renal disease, but rather that of late disease. Furthermore, there was correlation between GFR and age. Age is a determinant of renal function, as age increases, there is proportionate reduction in renal function [20],[21]. Also, the GFR in males was higher than those of females in this study, which is consistent with other studies [21],[22].

Bone markers, calcium, and renal function: None of the bone-cell number or activity − formation marker − osteocalcin showed a direct correlation with GFR but to BMD, suggesting that there was no uncoupling of bone phases with normal renal function. However, PTH showed an inverse relationship with GFR and BMD; 25(OH)D showed a trend with eGFR. A tightly controlled feedback-loop mechanism regulates PTH and vitamin-D levels; PTH stimulates vitamin-D synthesis in the kidneys, and vitamin D regulates secretion of PTH via the negative-feedback loop [23]. PTH acts by increasing the circulating levels of calcium and decreasing phosphate, whereas vitamin D exerts a stimulatory effect on both calcium and phosphate. The kidney plays an important role by converting 25(OH)D to active forms in the body to 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D. A study reported a direct correlation between 25(OH)D and 24,25 dihydrovitamin D in a general Korean population [24] and 25-hydroxyvitamin D serves as the best indicator of body supply of vitamin D [24]. Another study in postmenopausal women reported a similar finding between 1,25 dihydrovitamin D and 25(OH)D [25].

In this study, no correlation was observed between PTH, 25(OH)D, and other biochemical bone markers. This confirmed the previous report of dissociation of these parameters in blacks compared with the Caucasians. This was explained by the fact that in blacks, the threshold at which 25(OH)D stimulates secretion of PTH and other bone markers is lower and sufficient for metabolism [26].

Summarily from the above findings, PTH inversely correlated with BMD and renal function, and this may be an early indicator of bone loss and renal dysfunction. Previous studies have reported the association between cardiovascular risk factors − age, adiposity, glycemic indices, blood pressure and BTMs, and cardiovascular disease [6],[7]. These factors are also implicated in the etiology of chronic renal disease through similar pathophysiology/mechanism. Similarly, the effects of PTH and vitamin D on cardiovascular system have been reported. Hyperparathyroidism and vitamin-D deficiency have been implicated in cardiovascular disorders and kidney failure. Therefore, we can reliably adduce from the outcome of this study that PTH is an early biomarker to consider when screening for bone and/or kidney dysfunction.

The present study has one main limitation, the sample size. A larger sample may be considered more representative of a general young healthy population.


  Conclusion Top


Our results provided a reliable link between bone markers and renal function. PTH may serve as an early biomarker and screen for metabolic bone disease in renal health or vice versa in Nigerians.

Notably, PTH is very expensive and not easily accessible because a limited number of laboratories assay the hormone. Nonetheless, it is our hope that this study will stimulate interest in this area of research, and consequently expand the use of PTH in medical clinics in Nigeria to screen for metabolic bone disease in patients with chronic kidney disease.


  Acknowledgements Top


Author contributions: concept/design: O.A.A. Definition of intellectual content: O.A.A.. Literature: O.A.A., C.B.J., O.O.O., and L.A.O. Clinical studies/experimental studies: O.A.A. and C.B.J.. Data acquisition/analysis and statistical analysis: O.A.A. and L.A.O.. Paper preparation: O.A.A., C.B.J., O.O.O., and L.A.O.. Paper editing and review: O.A.A., C.B.J., O.O.O., and L.A.O.. Paper approval: O.A.A., C.B.J., O.O.O., and L.A.O.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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