Parathyroid Hormone in the Pathophysiology of Osteoporosis

C H A P T E R

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Parathyroid Hormone in the Pathophysiology of Osteoporosis Sundeep Khosla Endocrine Research Unit and Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA

INTRODUCTION The potential role of parathyroid hormone (PTH) in the pathogenesis of osteoporosis has received considerable attention over the past several decades. While it is now well established that intermittent PTH treatment is anabolic for bone,1 sustained increases in PTH secretion, as seen in primary hyperparathyroidism, generally have detrimental skeletal effects, particularly in cortical bone.2,3 The potential role of parathyroid hormone in contributing to the pathogenesis of osteoporotic fractures has gained new traction in light of recent studies using high resolution peripheral quantitative computed tomography (HRpQCT) showing that with aging, cortical bone loss predominates,4 and that cortical bone plays a major role in determining bone strength5,6 and by inference, fracture risk. This may be true even at the vertebrae, where the thin cortical shell appears to be fairly important in determining vertebral bone strength.5 This chapter reviews the alterations in PTH secretion and action following the menopause in women and with advancing age in both sexes, followed by a discussion of the evidence that PTH may be influencing fracture risk, particularly in the elderly, through its potentially detrimental effects on cortical bone.

EARLY POSTMENOPAUSAL BONE LOSS Recent cross-sectional and longitudinal studies using QCT have demonstrated that trabecular bone loss at multiple sites begins in young adult life (in the third decade), whereas cortical bone mass remains relatively stable until the menopause and declines subsequently.7 Nonetheless, trabecular bone loss also accelerates during the menopausal transition. This is accompanied by

The Parathyroids, Third Edition http://dx.doi.org/10.1016/B978-0-12-397166-1.00058-8

a reproducible increase in the incidence of osteoporotic fractures following the menopause, with continued increases in fracture risk later in life.8 The primary driver for early (within 10 years) menopausal bone loss is clearly estrogen deficiency,9 rather than PTH. A number of mouse and human studies have now identified the potential mechanisms by which estrogen deficiency leads to accelerated bone loss. A major mechanism is the loss of the direct effects of estrogen on osteoclast development and apoptosis,10,11 leading to enhanced bone resorption. However, estrogen deficiency is also associated with increased RANK ligand (RANKL) production by skeletal12 and hematopoietic12,13 cells in the bone microenvironment, leading to a further increase in bone resorption. In addition, there is a relative deficit in bone formation, which appears to be due to increased osteoblast apoptosis,14 NFκB activation,15 and possibly to increased skeletal production of sclerostin.16,17 The increased bone resorption in the setting of estrogen deficiency leads to a flux of calcium from the skeleton and, based on the normal homeostatic regulation of PTH, would be expected to lower serum PTH concentrations. Likely due to the relatively small, physiological changes involved, this has been difficult to demonstrate in cross-sectional studies and is most evident following acute estrogen deprivation or replacement. Thus, Fiore et al.18 found that 3 months following oophorectomy, serum calcium concentrations increased modestly, accompanied by a fall in circulating PTH and a rise in urine calcium excretion (Ca/Cr ratio) (Table 58.1). Conversely, McKane and colleagues19 demonstrated that 6 months following estrogen treatment of early postmenopausal women, serum calcium values declined, accompanied by an increase in serum PTH and a fall in 24-hour urine calcium excretion (Table 58.1). Thus, in the early menopausal period of bone loss, PTH appears to be

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58.  PARATHYROID HORMONE IN THE PATHOPHYSIOLOGY OF OSTEOPOROSIS

responding to, rather than driving, the increase in bone resorption. While not the principal driver of early menopausal bone loss, PTH could still be modulating the effects of estrogen deficiency on bone and contribute to the variable rates of bone loss observed in postmenopausal women, thereby accounting for the fact that only a subset of these women develop accelerated bone loss and what has been referred to as “type I” osteoporosis.9 Thus, as shown in Figure 58.1A, estrogen treatment of postmenopausal women blunts the effects of a PTH infusion on increasing bone resorption, suggesting that estrogen may alter skeletal sensitivity to the pro-resorptive effects of PTH.20 In addition, estrogen also appears to reduce TABLE 58.1  Effects of Oophorectomy (Top Panel) or Estrogen Treatment (ET, Lower Panel) on Serum Calcium, PTH, and Urine Calcium in Women Basal Values

Following Oophorectomy

Ca, mg/dl

9.12 ± 0.12

9.60 ± 0.10b

PTH, pg/ml

728 ± 32

684 ± 27a

Urine Ca/Cr

0.114 ± 0.04

0.121 ± 0.03b

Basal Values

Following ET

Ca, mmol/l

2.28 ± 0.02

2.18 ± 0.02c

PTH, pmol/l

3.4 ± 0.4

4.7 ± 0.4c

Urine Ca, mmol/24 hr

3.30 ± 0.35

2.20 ± 0.25c

AGE-RELATED CHANGES IN PTH SECRETION

aP < 0.05 bP < 0.01 cP < 0.001

Soon after the introduction of assays for PTH, serum PTH concentrations were found to increase with age in both women and men.23–29 Because the initial studies used assays directed against the mid-region or carboxyterminus of PTH, some of the apparent increase with age could have been due to retention of these inactive fragments as a consequence of reduced glomerular filtration rate in the elderly. However, a number of studies using assays directed against the amino terminus or against 25

(A) (1-84) PTH (nmol/L)

Urine hydroxyproline/creatinine μmol/μmol

versus basal values. Data in the top panel are adapted from18 (n = 15, before and following oophorectomy) and the data in the lower panel are adapted from19 (n = 18 before and following ET).

0.06

the sensitivity of the parathyroid glands to induced hypocalcemia (Figure 58.1B), resulting in blunted PTH secretion for comparable reductions in serum calcium levels.21 Thus, depending on the variable responses among postmenopausal women in PTH secretion and action in the setting of estrogen deficiency, PTH could certainly modulate rates of postmenopausal bone loss and susceptibility to developing osteoporosis. Evidence against this hypothesis, however, comes from studies by Ebeling and colleagues22 who showed that acute (4 days) calcium deprivation (dietary calcium 230 mg/day and treatment with a calcium binding agent) led to similar increases in endogenous PTH secretion and in markers of bone resorption in control and osteoporotic postmenopausal women. Thus, neither parathyroid gland responsiveness nor the skeletal effects of PTH appeared to be altered in the osteoporotic women. The preponderance of evidence would indicate, therefore, that at least in the early postmenopausal period, PTH appears to be responding to the estrogen deficiency-induced changes in bone turnover rather than driving these changes.

0.04

0.02

(B)

20 15 10

*

5 EDTA Infusion

0

Basal

4

8

12

16

20

0

0 30 60 90 120

Duration of (1-34) human PTH infusion (hrs)

180

240

300

1440

Time (min)

FIGURE 58.1  (A) Urine hydroxyproline/creatinine levels in response to a PTH infusion in untreated (open circles) and estrogen-treated (closed circles) women. Hydroxyproline/creatinine levels increased significantly in both groups (P < 0.05) but rose more briskly and to a higher peak in the untreated women. An overall group difference over time was seen by ANOVA (P < 0.05). (B) Mean changes in PTH levels during and after a 2-hour EDTA infusion in untreated and estrogen-treated women. The peak change was higher in untreated women (P < 0.04) and there was an overall group difference by repeated measures ANOVA (P < 0.02). (A) Adapted from20 with permission. (B) Adapted from21 with permission.

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Age-Related Changes in PTH Secretion

intact PTH have noted similar age-related increases in circulating PTH in both sexes28,30,31 (Figure 58.2). Moreover, urinary nephrogenous cyclic AMP was also found to increase with age,26 consistent with an age-related increase in biologically active PTH. Though most studies have depicted the increase in serum PTH with age as a continuous relationship, more detailed analysis has revealed that the major increase in women occurs after age 70 years. Thus, Koh et al.32 analyzed serum PTH concentrations from 12,238 women aged 55–81 years from the Fracture Intervention Trial and found that the percent change in serum PTH per 10-year rise in age between ages 55 and 69 years was −1.9% [95% confidence intervals (CI), −4.2 to 0.4%]. In contrast, the change in serum PTH per 10-year rise in age between 70 and 81 years was +3.8% (95% CI, 1.0 to 6.7). Similarly, Prince et al.33 measured serum PTH levels in 655 pre- and postmenopausal women, and noted that the age-related increase in serum PTH became evident approximately 20 years after the menopause, or about age 70 years, given an average age of menopause at approximately 50 years. There are limited data at present on potential ethnic differences in the age-related changes in serum PTH concentrations. A number of studies have demonstrated

PTH, pmol/L

8 6 4 2 0

20

40

60 Age, yrs

80

100

FIGURE 58.2  Serum PTH concentrations as a function of age among an age-stratified sample of Rochester, Minnesota, men (solid lines, squares) and women (dashed lines, circles). Correlation with age was 0.30 (P < 0.001) for the men and women. Adapted from31 with permission.

higher circulating PTH values in premenopausal AfricanAmerican compared to Caucasian women.34,35 Perry et al.,36 however, compared circulating PTH in young (mean age, 36 years) and elderly (mean age, 71 years) African-American versus Caucasian women and found that, though serum PTH levels were slightly higher in the young African-American women, these differences were even greater in the elderly women (Table 58.2). Thus, age-related increases in serum PTH secretion may be even greater in African-American than in Caucasian women. Serum PTH also has a circadian rhythm, with peak concentrations in the mid-afternoon and at night.37,38 This circadian pattern is present in both young and elderly subjects, but Eastell et al.37 demonstrated that the age-related increases in serum PTH are, in fact, greatest at night. Thus, because most studies have measured PTH in the morning, they may have underestimated the magnitude of the age-related increase in PTH secretion. In order to better characterize the age-related changes in parathyroid function, Ledger et al.39 performed detailed studies assessing PTH secretory dynamics in young (age range, 27–34 years) versus elderly (range, 71–77 years) women. Using sequential infusions of calcium and EDTA, they defined the entire PTH secretory curve as a function of ionized calcium activity in the two groups (Figure 58.3). As is evident, the elderly women had an exaggerated response to induced hypocalcemia and also had a higher non-suppressible component of PTH secretion (elderly, 0.8 pmol/liter; young, 0.4 pmol/ liter; P < 0.001). Of note, the abnormal PTH secretory curve of the elderly women could be made identical to the PTH secretory curve in the young women following 1 week of 1,25-dihydroxyvitamin D3[1,25(OH)2D3] therapy. The set point or ionized calcium value at which halfmaximal PTH secretion was achieved (representing the sensitivity of each individual parathyroid cell to changes in serum ionized calcium) did not differ between the young and elderly women. These investigators interpreted their findings as demonstrating in the elderly women “functional” parathyroid hyperplasia that was reversible by short-term 1,25(OH)2D3 therapy.

TABLE 58.2  Serum PTH Concentrations in African-American and Caucasian Women African-American Women

Caucasian Women

PTHa

Premenopausal (n = 28)

Postmenopausal (n = 25)

Premenopausal (n = 20)

Postmenopausal (n = 19)

Mean ± SEM

58.3 ± 3.4b

79.3 ± 6.1c

51.2 ± 4.3b

63.3 ± 3.5

Range

21.2–98.4

21.4–127.6

24.8–90.2

34.0–81.3

aPTH

values given in picomoles/liter. significantly less than the older age group of the same ethnicity; P < 0.05. cStatistically significantly greater than the same age group of Caucasian females; P < 0.05. Adapted from36. bStatistically

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TABLE 58.3  Changes in Serum PTH and in Biochemical Markers of Bone Turnovera

16

Serum intact PTH, pmol/L

14

Spearman Correlation Coefficients

12 10 8

vs. Age

vs. PTH

54%

0.354c

1.00

BSAP

38%

0.329c

0.192d

OC

64%

0.392c

0.206d

fPYD

76%

0.505c

0.203d

NTx

86%

0.344c

0.190d

PTH

6 4 2 0

Increase with Age

Variableb

1.0

1.1

1.2

1.3

1.4

Serum ionized calcium, mmol/L

FIGURE 58.3  Fitted sigmoidal curves relating PTH to ionized calcium for young (●) and elderly (○) subjects. Solid lines are before 1,25(OH)2D3 treatment and dashed lines are after 1,25(OH)2D3 treatment. Adapted from39 with permission.

Similar alterations in the maximal and minimal components of the PTH secretory curve were reported by Portale et al.40 in young (mean ± SEM, 39 ± 1 years) versus elderly (74 ± 2 years) men. However, in contrast to the study by Ledger et al.,39 Portale et al.40 did note a significant increase in the set point for PTH secretion in the elderly men. This difference may reflect a true gender difference in PTH secretory dynamics or possibly the use of different experimental protocols to define PTH secretory dynamics in the two studies. Overall, however, the data from both studies are consistent with functional parathyroid hyperplasia in elderly women and men, and this notion is supported by an autopsy study that found a trend toward parathyroid hyperplasia in elderly subjects.41

RELATIONSHIP OF AGE-RELATED INCREASES IN SERUM PTH TO INCREASED BONE TURNOVER AND BONE LOSS As noted earlier, age-related increases in serum PTH concentrations have been postulated to contribute to age-related bone loss in men and women, primarily by increasing bone turnover. In the setting of an agerelated impairment in osteoblast generation or function, increased bone turnover leads to bone loss. Indirect evidence for this comes from observations showing correlations between serum PTH and bone turnover markers in elderly women30,42 (Table 58.3). However, correlation does not prove causality. To test directly the hypothesis that secondary hyperparathyroidism mediated the agerelated increase in bone resorption, Ledger et al.38 used

aStudy conducted on a group of 304 women residents of Rochester, Minnesota, from the third into the tenth decade of life. bBSAP, bone specific alkaline phosphatase; OC, osteocalcin; fPYD, urinary free pyridinoline; NTx, urinary N-telopeptide of type I collagen. cP < 0.0001. dP < 0.001. Adapted from69.

a 24-hour calcium infusion to suppress PTH secretion in young (age range, 24–35 years) versus elderly (range, 71–78 years) women and then assessed the changes in bone resorption markers in the two groups. Specifically, they postulated that if bone resorption were more dependent on PTH in the elderly compared to the young women, then the decrease in bone resorption markers following suppression of PTH secretion by an intravenous calcium infusion should be greater in the elderly women. Figure 58.4 shows the changes in the bone resorption marker, urinary N-telopeptide of type I collagen (NTx), in the young and elderly women. As is evident, suppression of PTH secretion eliminated the differences in NTx excretion between the two groups, and the mean decrement in NTx excretion following PTH suppression in the elderly women (7.5  ±  1.9  nmol/mmol Cr) was significantly greater than that in the young women (4.1 ± 1.5 nmol/ mmol Cr; P < 0.05). These experiments, therefore, provide a causal link between age-related increases in PTH secretion and the corresponding increases in bone resorption. Consistent with these data, several43–49 but not all50 studies have also found associations between the agerelated increases in serum PTH and changes in bone density in elderly subjects. Some of the conflicting data may relate to the fact that PTH likely has preferential effects in causing cortical bone loss with minimal (or perhaps even protective) effects on cancellous bone.51 Thus, studies using standard dual-energy X-ray absorptiometry (DXA), which provides an integrated measure of cancellous and cortical bone at the various skeletal sites, are unable to dissect these differing effects of PTH on bone. To address this issue, Boonen et al.45 used peripheral quantitative computed tomography (pQCT), which allows the separate determination of cortical and cancellous bone mineral density (BMD)

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Relationship of Age-Related Increases in Serum PTH to Increased Bone Turnover and Bone Loss

(A)

(B)

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FIGURE 58.4  Urinary N-telopeptide of type I collagen (NTx) excretion in young women (A) and elderly women (B) on the baseline day (○) and on the calcium infusion day (●). Adapted from38 with permission.

FIGURE 58.5  (A) Cortical and trabecular bone loss in the distal radius in different age groups. Error bars show SDs. * P < 0.0001; (B) Panel A: Micrograph of a specimen from a 29-year-old woman. Pores are regular in shape and evenly distributed in the cortex; Panel B: Micrograph of a specimen from a 67-year-old woman. Pores are large, irregularly shaped, and have coalesced in the cortex adjacent to the marrow producing cortical remnants; Panel C: Micrograph of a specimen from a 90-year-old women. Most of the cortex is trabecularized by large and coalesced pores. Micrographs are of anterior subtrochanteric specimens. Adapted from4 with permission.

in the peripheral skeleton, to test the relationship between compartmental BMD and a number of variables, including serum PTH, in 129 women aged 70–87 years. By multiple regression analysis, they found that serum PTH was a negative predictor of cortical, but not cancellous, BMD at the wrist. Conversely, Shukla et al.52 found that hypoparathyroid subjects (mean age, 57 years) had little or no change in vertebral cancellous BMD compared to age-matched controls as assessed by vertebral computed tomography (z scores, +0.5 to +1.8), but they had marked increases in combined cancellous and cortical BMD as assessed by dualphoton absorptiometry (z scores, +1.4 to +6.2). These findings regarding the relationship of the agerelated increases in PTH secretion to cortical bone loss have gained increasing relevance in light of recent work by Zebaze and colleagues4 who used HRpQCT and a novel

analysis of cortical porosity along with scanning electron microscopy to demonstrate that, with aging, there are marked decreases in cortical bone mass (Figure 58.5A) and increases in cortical porosity (Figure 58.5B). Given the evidence that PTH also increases cortical porosity,53–55 a logical question is whether, with aging, PTH drives the increase in cortical porosity. Furthermore, since it is now clear that cortical bone is perhaps the dominant structural determinant of bone strength,5,6 the PTH-induced increases in cortical porosity may also be important in contributing to age-related fractures, although at least with PTH therapy, the increased cortical porosity appears to be on the endocortical surface, which has minimal adverse biomechanical effects.53 Thus, further studies examining the potential role of PTH in mediating the age-related changes in cortical bone and fracture risk are clearly warranted.

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ETIOLOGY OF THE SECONDARY HYPERPARATHYROIDISM OF AGING A number of factors have been postulated to contribute to the age-related increase in circulating PTH.9 Chief among these are vitamin D deficiency, impaired renal 1,25(OH)2D production or action, and, more recently, estrogen deficiency. There is no doubt that vitamin D deficiency leads to secondary hyperparathyroidism.56 However, serum PTH concentrations have been shown to increase in populations in which there have been no age-related changes in 25-hydroxyvitamin D status.57 Though vitamin D deficiency may contribute in certain populations to secondary hyperparathyroidism, the latter is clearly present even in populations in which there is no evidence for vitamin D deficiency. Thus, other primary factors must be involved. A subset of elderly persons also has a decline in renal 1α-hydroxylase activity associated with a reduction in glomerular filtration rate.58 This results in low circulating 1,25(OH)2D concentrations, which, in turn, leads to impaired intestinal calcium absorption as well as a potential loss of feedback suppression of PTH secretion by 1,25(OH)2D, thus causing secondary hyperparathyroidism. However, Eastell et al.30 found that in a population of relatively healthy women, serum PTH concentrations increased despite an age-related increase (rather than decrease) in circulating 1,25(OH)2D. In contrast, intestinal calcium absorption did not change with age. Based on these data, Eastell et al. postulated that intestinal resistance to 1,25(OH)2D action accounted for the increase in serum 1,25(OH)2D concentrations with aging, which in turn were maintained by elevated circulating PTH. Consistent with this hypothesis, Ebeling et al.59 found a decrease in intestinal vitamin D receptor concentrations in elderly women, although this issue remains controversial.60 Finally, Pattanaungkul et al.61 used an in vivo dose response to 1,25(OH)2D in young versus elderly women to show that the slope of the relationship between intestinal calcium absorption and the molar ratio of 1,25(OH)2D to vitamin D-binding protein [the “free” 1,25(OH)2D index], representing intestinal sensitivity to 1,25(OH)2D, was significantly greater in the young compared to the elderly women. Thus, though vitamin D deficiency or impaired renal function leading to deficient 1α-hydroxylase activity may contribute to secondary hyperparathyroidism in some elderly individuals, the age-related increase in serum PTH is present even in the absence of both abnormalities. Overall, the data are consistent with impaired intestinal calcium absorption resulting from intestinal resistance to 1,25(OH)2D action as being a significant contributing factor to age-related secondary hyperparathyroidism. Finally, aging may also be associated with impaired renal calcium conservation, which would also contribute

to secondary hyperparathyroidism. Thus, Ledger et al.38 found that elderly women had a significantly higher fractional excretion of calcium, despite higher PTH values than young women. Collectively, then, the data are consistent with agerelated alterations in intestinal calcium absorption and in renal calcium handling as the proximate causes of the secondary hyperparathyroidism in elderly persons. Thus, the elderly must consume more dietary calcium to prevent negative calcium balance. By combined calcium balance and kinetic methods, Heaney et al.62 found that premenopausal women required 1000 mg/day, whereas postmenopausal women required 1500 mg/day to maintain calcium balance. This figure considerably exceeds the average calcium intake of most postmenopausal women in the United States.63 To test directly for these differences in calcium requirement, McKane et al.64 performed intensive metabolic studies in a group of young adult premenopausal women on their usual calcium intake, a group of elderly women on their usual calcium intake, and a group of elderly women who had received a high-calcium supplement for 3 years (Table 58.4). As shown in the table, the unsupplemented elderly women had the expected increases in serum PTH and in bone resorption markers, whereas the calcium-supplemented women had values for serum PTH and bone resorption markers that were indistinguishable from the (unsupplemented) young women. These data support the hypothesis that a failure of elderly women to increase their calcium intake to a level high enough to offset the TABLE 58.4  Comparative Effects of Age and Calcium Intake in Womena Elderly Womenc Variableb

Young Women

Usual Ca Diet

High-Ca Diet

Number in group

12

15

13

Age, years

30.1 ± 1.3

71.0 ± 0.7

68.3 ± 0.6

Dietary Ca, mg/day

918 ± 56

815 ± 75

2414 ± 72*

Serum PTH, pmol/liter

2.01 ± 0.16

3.41 ± 0.27*

2.18 ± 0.17

43.7 ± 1.8

51.7 ± 3.0†

43.1 ± 2.6

10.9 ± 0.4

14.2 ± 0.9*

10.7 ± 0.7

Urine   PYD, nmol/

mmol Cr   DPD, nmol/

mmol Cr aData

from64. intact PTH is a 24-hour integral of samples obtained every 2 hours. Urine pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by fluorometric detection after high-performance liquid chromatography and were expressed as a ratio to creatinine (Cr). All results are mean ± SEM. cFor difference from the young group: *P < 0.05; †P < 0.005. Adapted from69. bSerum

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References

age-related increase in net calcium loss contributes substantially to their development of secondary hyperparathyroidism and increased bone resorption; however, the number of subjects in this study was relatively small, and these findings need to be confirmed in a larger sample of comparable subjects. Somewhat surprisingly, evidence indicates that longterm estrogen deficiency may be a key permissive factor for the development of the age-related changes in calcium homeostasis and the ensuing secondary hyperparathyroidism. Thus, McKane et al.65 studied three groups of women to assess the relative contributions of “aging” versus estrogen deficiency toward the secondary hyperparathyroidism and increased bone resorption in elderly women: young adult premenopausal women (Group A); untreated elderly women (Group B); and elderly women who were receiving long-term estrogen replacement therapy (Group C). Because Groups B and C were of comparable age, but differed in estrogen status, and Groups A and C were comparable with respect to estrogen status, but differed in age, the effect of age and estrogen deficiency could be dissociated. As shown in Table 58.5, after estrogen deficiency was corrected, there were no effects on serum PTH and bone resorption levels that could be attributed to aging per se. While these data need to be confirmed in a larger study, consistent with these observations, Khosla et al.66 also found, in a population study, that serum PTH and bone turnover increased progressively in untreated postmenopausal women, whereas there were no age-related increases in TABLE 58.5  Comparative Effects of Age and Estrogen Status in Womena Groupc Variableb

Postmenopausal Postmenopausal Premenopausal Untreated Treated

Number in group

30

30

30

Serum PTH, pmol/liter

2.7 ± 0.2

3.6 ± 0.3*

2.5 ± 0.2

42.9 ± 3.5†

24.6 ± 2.3

61.2 ± 3.2†

40.7 ± 1.6

16.2 ± 1.0†

9.4 ± 0.5

Urine   NTx, nmol/ 28.8 ± 2.3

mmol Cr   PYD, nmol/ 45.6 ± 1.6

postmenopausal women who had been on long-term estrogen therapy. The most plausible explanation for the ability of estrogen to prevent the age-related increase in serum PTH levels is the potential effect of estrogen on extra-skeletal calcium homeostasis, namely, on intestinal calcium absorption,67 renal calcium handling,19,68 and possibly directly on PTH secretion.21 Aging men also have increases in serum PTH concentrations that are very similar to those seen in women,31 despite the absence of menopause. It is possible that the age-related decreases in bioavailable (or non-sex-hormone binding globulin bound) estrogen and/or testosterone that have been observed31 lead to alterations in calcium homeostasis in aging men similar to those found in elderly women, resulting in the eventual development of secondary hyperparathyroidism.

SUMMARY AND CONCLUSIONS Serum PTH concentrations clearly increase with age in a parallel manner in women and in men. At a functional and anatomic level, this is due to some degree of parathyroid hyperplasia in elderly persons. Indirect and direct evidence implicates the age-related increase in serum PTH in mediating at least part of the agerelated increase in bone turnover and bone loss. Moreover, recent evidence indicates that cortical bone loss and increases in cortical porosity are important features of age-related bone loss. Given the known detrimental effects of PTH on cortical bone and porosity, this leads to the plausible hypothesis that the age-related increases in PTH are responsible, in large part, for the cortical bone changes with aging. Though vitamin D deficiency and impaired renal 1α-hydroxylase activity resulting in deficient 1,25(OH)2D production may contribute to the secondary hyperparathyroidism in some elderly individuals, age-associated changes in calcium homeostasis, related perhaps to long-term sequelae of sex steroid deficiency, may also be an important cause of the secondary hyperparathyroidism of aging. Further studies are needed to better define the extra-skeletal effects of sex steroids on calcium homeostasis in women and in men, and the contribution of increased PTH concentrations toward cortical bone loss in the elderly.

mmol Cr   DPD, nmol/ 11.9 ± 0.5

mmol Cr aData

from.65 intact PTH was fasting morning value. Bone resorption markers were measured by ELISA kit for N-telopeptide of type I collagen (NTx) and by fluorometric detection after HPLC for pyridinoline (PYD) and deoxypyridinoline (DPD). All results are mean ± SEM. cFor difference from premenopausal group: *P, 0.05; †P < 0.005. Adapted from69.

bSerum

References 1.  Cipriani C, Irani D, Bilezikian JP. Safety of osteoanabolic therapy: a decade of experience. J Bone Miner Res 2012;27:2419–28. 2.  Bilezikian JP, Silverberg SJ. Asymptomatic primary hyperparathyroidism. N Engl J Med 2004;350:1746–51. 3.  Vu TD, Wang XF, Wang Q, Cusano NE, Irani D, Silva BC, et al. New insights into the effects of primary hyperparathyroidism on the coritcal and trabecular compartments of bone. Bone 2013;55:57–63.

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VI.   THE PARATHYROIDS AND OSTEOPOROSIS