Endocrine abnormalities and bone loss in women

Early acceleratedphase

This phase begins at menopause, can be prevented by oestrogen replacement, and almost certainly results from the cessation of ovarian function. Oestrogen acts through high affinity oestrogen receptors in osteoblasts and osteoclasts to restrain bone turnover, and when this restraint is lost at menopause, overall bone turnover increases and resorption increases more than formation. In addition, the increased activity of osteoclasts and their prolonged lifespan lead to trabecular plate perforation and to loss of structural elements, thus weakening bone out of proportion to the loss of bone density. The high rate of bone resorption increases skeletal calcium outflow, which leads to a partial suppression of parathyroid hormone (PTH) secretion and compensatory increases in urinary calcium excretion (Riggs et al 1998). The reason for the cessation of the rapid phase of

0 90

1 80

I 70

yenopause WOMEN

MEN

\\

V

\ Xs.

S SX.

\

\

N.

•s»

•N,

Age, years

90 50 60 70 80

Age, years

90 Q

70 I

FIG. 1. Schematic representation of changes in bone mass over life in cancellous (broken line) and cortical (solid line) bone in women (left panel) and men (right panel) from age 50 onward. Note that men have only one phase of continuous bone loss but women have two — an early accelerated phase and a late slow phase. Note also that the accelerated phase, but not the slow phase, involves disproportionate loss of cancellous bone. (With permission from Riggs et al 1998.)

bone loss is unclear but may relate to the activation of biomechanical forces that limit the rate of further bone loss when the amount of cancellous bone falls below some critical level.

Late slow phase

As the rapid bone loss phase subsides, serum levels of PTH increase progressively throughout the remainder of life. Markers for bone turnover also increase and these increases are directly correlated with the increase in serum PTH (Table 2). Suppression of PTH secretion by intravenous calcium infusion abolishes the differences in bone resorption markers between young and elderly women (Ledger et al 1994), strongly suggesting that the increase in bone resorption in ageing women is PTH-dependent. Also, a chronic, high calcium intake will also reduce elevated values for serum PTH in elderly women into the premenopausal range (McKane et al 1995). Thus, a considerable body of data implicates secondary hyperparathyroidism as the cause of the late slow phase of bone loss in elderly women. The secondary hyperparathyroidism has traditionally been assumed to be secondary to age-related factors that impair calcium absorption and renal Ca2+ homeostasis. However, the recent findings that the increases in both serum PTH and bone resorption in late postmenopausal women can be normalized by oestrogen replacement suggests that oestrogen deficiency may play a causal role (McKane et al 1997, Khosla et al 1998; Table 3).

TABLE 2 Changes in serum PTH and in biochemical markers for bone turnover in 304 women residents of Rochester, MN from the third into the tenth decade of life

Spearman correlation coefficients

TABLE 2 Changes in serum PTH and in biochemical markers for bone turnover in 304 women residents of Rochester, MN from the third into the tenth decade of life

Spearman correlation coefficients

Variable

Increase with D (%)

vs. age

vs. PTH

PTH

54%

0.354**

1.000

BSAP

38%

0.329**

0.192*

OC

64%

0.392**

0.206*

fPYD

76%

0.505%**

0.203*

NTx

86%

0.344**

0.190*

Samples are age-stratified and population-based. Postmenopausal women receiving oestrogen replacement are not included. There are age-related increases in serum PTH and in markers for bone formation (serum bone specific alkaline phosphatase [BSAP] and osteocalcin [OC]) and bone resorption (urine free pyridinoline [fPYD], and cross-linked N-terminal telopeptide of type I collagen [NTx]). Furthermore, the increases in biochemical markers are directly correlated with the increases in serum PTH. (Data are from re-analysis of study of Khosla et al 1997.) *P<0.0001, **P< 0.001.

Samples are age-stratified and population-based. Postmenopausal women receiving oestrogen replacement are not included. There are age-related increases in serum PTH and in markers for bone formation (serum bone specific alkaline phosphatase [BSAP] and osteocalcin [OC]) and bone resorption (urine free pyridinoline [fPYD], and cross-linked N-terminal telopeptide of type I collagen [NTx]). Furthermore, the increases in biochemical markers are directly correlated with the increases in serum PTH. (Data are from re-analysis of study of Khosla et al 1997.) *P<0.0001, **P< 0.001.

Both the early accelerated and the late slow phases of bone loss in women are associated with low levels of serum oestrogen, and oestrogen treatment is effective in preventing further bone loss in both phases (McKane et al 1997, Ettinger et al 1985). However, in the early phase of bone loss there is a trend to decreased serum PTH and these levels increase following oestrogen treatment. By

TABLE 3 Comparative e^cts of age and oestrogen status in women as described by McKane et al (1997)

Postmenopausal Postmenopausal

Variable Premenopausal untreated treated

TABLE 3 Comparative e^cts of age and oestrogen status in women as described by McKane et al (1997)

N

30

30

30

Age (years)

32.0

0.5

74.2

0.6

73.8

0.6

Serum:

PTH (pmol/l)

2.7

0.2

3.6

0.3*

2.5

0.2

Urine:

NTx (nmol/mmol Cr)

28.8

2.3

42.9

3.5**

24.6

2.3

PYD (nmol/mmol Cr)

45.6

1.6

61.2

3.2**

40.7

1.6

DPD (nmol/mmol Cr)

11.9

0.5

16.2

1.0**

9.4

0.5

Serum 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. For difference from premenopausal groups: *P < 0.05, **P < 0.005.

Serum 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. For difference from premenopausal groups: *P < 0.05, **P < 0.005.

contrast, serum PTH levels increase progressively in the late slow phase of bone loss and are decreased by oestrogen treatment. We have attempted to resolve this paradox by hypothesizing that oestrogen has two major effects on bone — a direct action on bone cells and an action on external calcium homeostasis that increases PTH secretion and indirectly increases bone loss (Riggs et al 1998). The loss of the direct effect of oestrogen on bone cells is responsible for the early rapid phase of bone loss. This direct effect is initiated by the large and relatively rapid fall in serum oestrogen levels at menopause, and it becomes less important after the rapid accelerated phase of bone loss subsides. In the late slow phase, the indirect effect of oestrogen deficiency on extra-skeletal calcium metabolism leads to the secondary hyperparathyroidism that is the major cause of the bone loss.

The indirect effect is initiated by loss of oestrogen action on the intestine and kidney (Riggs et al 1998). The intestine contains oestrogen receptors and oestrogen stimulates calcium absorption (Gennari et al 1990). Oestrogen also increases renal calcium conservation (McKane et al 1995) through a PTH-independent enhancement of tubular reabsorption of calcium. During oestrogen deficiency, the loss of the intestinal and renal actions of oestrogen leads to external losses of calcium and negative calcium balance. Unless these losses of calcium are offset by large increases in dietary calcium (McKane et al 1996), they will lead to secondary hyperparathyroidism and continued bone loss.

Decreasedbone formation

Both the early accelerated and the late slow phases of bone loss are associated with an absolute increase in bone resorption and a relative decrease in bone formation. Normally, there is a tight coupling of bone formation to bone resorption. During oestrogen deficiency, however, there is a failure of a compensatory increase in bone formation to offset the increase in bone resorption and this leads to continued bone loss. This abnormality is demonstrable soon after menopause suggesting that it is caused by oestrogen deficiency. Oestrogen has been shown to increase collagen synthesis in skin fibroblasts and to increase production of insulin-like growth factor (IGF)1 (Ernst et al 1989) and transforming growth factor (TGF)b (Ashcroft et al 1997), growth factors that are anabolic for osteoblasts. Also, oestrogen prolongs the lifespan of mature osteoblasts by decreasing apoptosis (Manolagas 2000). Oestrogen deficiency could also account for the impaired osteoblastic function in older women, although it is possible that age-related abnormalities in hormones or growth factors regulating osteoblast function also contribute.

The probable mechanisms by which oestrogen deficiency produces bone loss in ageing women are shown in Fig. 2A.

FIG. 2. Schematic representation of unitary model for bone loss in postmenopausal women (A) and in ageing men (B). See text for details. (With permission from Riggs et al 1998.)
From PMS To PPD

From PMS To PPD

The Stages Of A Woman’s Life Are No Longer A Mystery. Get Instant Access To Valuable Information On All The Phases Of The Female Body From Menstruation To Menopause And Everything In Between.

Get My Free Ebook


Post a comment