Delayed Diagnosis of Osteoporosis

Fig. 31.1

(A) Bone loss at the lumbar spine in enrollees of the Study of Women’s Health Across the Nations over 4 years of follow-up. Upon entry into the trial, these women were classified as premenopausal (purple), early perimenopausal (green), late perimenopausal (red) and early postmenopausal (blue). Drawn from data in [2]. (B) Activation frequency in iliac crest bone biopsy specimens from women premenopausal women and women at 1 and 13 years postmenopause. Redrawn from [3]. (C) Estradiol and FSH levels in women of different races (blue: Hispanics; red: Caucasians; dark green: African Americans; pink: Japanese; light green: Chinese) across the menopausal transition. Of note is that estrogen levels can be normal during the late perimenopause, while FSH levels have risen by about threefold. Redrawn from [4]. (D) Urinary N-telopeptide/creatinine ratio (grey) and serum osteocalcein (black) in enrollees of the Study of Women Across Nations (SWAN) plotted as a function of quartiles of serum FSH, a marker of the menopause. Redrawn from [5]. (E) Representative iliac crest bone biopsy of a woman taken before and after menopause subject to 2D histomorphometry. From [6]. (F) Iliac crest bone biopsy of a woman taken before and after menopause subject to 3-D μ-CT. This sensitive technology yielded significant decrements in structural parameters, such as bone volume and trabecular thickness and number, across the menopausal transition. From [6]. (G) Simulated loss of bone from a trabeculum. (a) Mild bone loss might result in trabecular thinning (left panel), whereas more aggressive bone loss associated with high remodeling results in complete removal of the trabeculum (right panel). (b) The latter severely decreases bone strength. Trabecular thinning will cause a 17 % loss in strength if 10 % of the bone tissue is lost. The same loss in bone tissue will result in a 50 % loss in bone strength if the trabeculae are removed. From [7], adapted with permission

Concordant with the rapidity of the bone loss across the menopausal transition, histology and high resolution μCT of bone biopsies show evidence of trabecular perforation and loss. Perforation is far more detrimental to bone strength than thinning. Perforation reduces strength by two- to fivefold more than does thinning. Consequently, a woman undergoing rapid bone loss may also be losing bone strength due to trabecular perforation, even if her BMD has not decreased substantially. Of particular importance is the irreversibility of this process. Once lost, trabeculae are not rebuilt, so the lost bone strength occurring across menopausal transition is most likely permanent.

BMD measurements cannot quantify the rate of bone loss. Neither can they capture trabecular perforation and thinning. Bone turnover markers can be valuable point estimates of the rate of loss [8]. Unlike two BMD determinations, which provide an interval estimate of “lost bone,” the single measurement of a remodeling marker will positively predict the risk of ongoing “bone loss.” [9] Hence, elevated marker levels can be clinically useful during early menopause. Studies show strikingly positive correlations of bone loss and urinary N-telopeptide levels. Urinary N-telopeptide levels are 19 % higher in perimenopausal than post-menopausal women. An increase of 1 SD in N-telopeptide and osteocalcin levels increased the odds of losing spinal BMD, the most affected site during the early menopause, by 2.1 % and 1.6 %, respectively. SWAN showed cross-sectional correlations between urinary N-telopeptide and serum FSH levels; the latter, in turn, predicted bone loss over 4 years. With further validation, bone remodeling markers will likely be utilized increasingly to predict early bone loss across the menopausal transition (Table 31.1). Our patient’s elevated N-telopeptide level was consistent with the decline in BMD noted during her treatment-free interval.

Table 31.1

Bone remodeling markers

Bone formation markers

Serum osteocalcin

Serum bone-specific alkaline phosphatase

Serum intact N-terminal propeptide of type 1 procollagen (PINP)

Serum intact C-terminal propeptide of type 1 procollagen (PICP)

Fragments of osteocalcin (experimental)

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