Table 2.

Cross-sectional studies on perimenopausal bone metabolism and bone mineral density.

Author	Title	Design	Methods	Relevant findings	Conclusion
Ebeling et al. 1996 [64]	Bone turnover markers and bone density across the menopausal transition	281 women, 45–57  years. 3 groups: 60 premenopausal 118 perimenopausal 103 postmenopausal (of these, 36 with HRT)	DXA E2, FSH, LH, inhibin on day 4–8 of menstrual cycle if applicable Bone formation: OC, BAP, PICP Bone resorption: PYD, DPD, NTX	Postmenopausal group: BMD ↓ ↓. Loss in BMD correlated with age in perimenopausal group. Perimenopausal group: LH, FSH doubled versus premenopause; E2, BAP did not differ between premenopausal and perimenopausal group. ↑ PYD, DPD, NTX, BAP, and OC in postmenopausal versus premenopausal group. perimenopausal group: Positive correlation of BMD with DPD. All women: correlation of BMD with NTX, BAP, OC, FSH	Perimenopause: increased bone resorption rate and decreased bone density. Other factors apart from E2 are involved in the development of postmenopausal osteoporosis
Khosla et al. 2005 [65]	Relationship of volumetric bone density and structural parameters at different skeletal sites to sex steroid levels in women	235 untreated women 3 groups: (i) premenopausal (20–39  years.) (ii) mixed (40–59  years.) (iii) postmenopausal (>60  years.)	QCT E2, Testosterone	Postmenopausal group: significant correlation of low bioavailable E2 and BMD (trabecular and cortical). 40–59 years: significant correlation between average rise in bioavailable E2 and loss in trabecular BMD.	Trabecular bone reacts faster to lowering E2. The threshold for estrogen deficiency in cortical bone in women appears to be lower than that in trabecular bone.
Kushida et al. 1995 [66]	Comparison of markers for bone formation and resorption in premenopausal and postmenopausal subjects, and osteoporosis patients	95 premenopausal women, 30–53  years. 66 postmenopausal women, 50–69  years 29 untreated women with osteoporosis, 55–91  years. No distinct perimenopausal group, but included in pre- and postmenopausal	No BMD measurement Bone formation: AP, OC, PICP, Bone resorption: PYD, DPD	Postmenopausal group: AP, OC, PICP, PYD, DPD significantly higher than in premenopausal group. In osteoporosis: PICP, PYD, DPD significantly higher than in postmenopausal group. Women ≥ 50  years: PYD, DPD higher than in women 30–49  years.	Markers in postmenopause higher than in premenopause. In women with osteoporosis resorption markers are higher than formation markers.
Löfman et al. 2005 [67]	Common biochemical markers of bone turnover predict future bone loss: a 5-year follow-up study	Cross sectional study (+ longitudinal) 192 women, 21–79  years. 3 groups (i) premenopausal (ii) perimenopausal (i.e., premenopausal at baseline and postmenopausal after 5  years). (iii) postmenopausal	2x DXA Bone formation: BAP, OC, AP Bone remodelling: Hpr Ca	Baseline values of markers correlated negatively with baseline BMD. AP, OC, Hpr, Ca rise at the “beginning of menopause” 15 years after menopause: OC and Hpr are still elevated.	Bone markers and current BMD could give information about coming loss of BMD.
Melton et al. 1997 [68]	Relationship of bone turnover to bone density and fractures	351 women, 20–80 years. 2 groups: 138 premenopausal 213 postmenopausal (i) 47 with HRT (ii) 166 without HRT of these, 89 cases of osteoporosis No distinct perimenopausal group	DXA Bone formation: OC, BAP, PICP Bone resorption: PYD, DPD, NTX	Premenopausal group: OC, NTX negatively correlated with BMD. Postmenopausal group: increase of markers with age. Postmenopausal group: OC, BAP, NTX, PICP negatively correlated with BMD. Osteoporosis: markers↑, BMD↓.	Combination of markers with BMD measurement is sensible for prediction of individual fracture risk. NTX is best predictor of loss in BMD.
Ravn et al. 1996 [69]	High bone turnover is associated with low bone mass in both pre- and postmenopausal women	979 women, 30–75  years. 2 groups: 334 premenopausal 645 postmenopausal 5 year-longitudinal analysis. No distinct perimenopausal group, but included in pre- and postmenopausal	DXA Bone formation: OC, AP Bone remodelling: HydroxyProline Bone resorption: CTX	Premenopausal <50  years: markers stable. Women with highest markers had significantly lower BMD. OC and CTX correlated with BMD. Postmenopausal group: CTX, OC sign. higher than in premenopausal group. 5  years. after menopause: CTX, OC stable again.	Bone metabolism is accelerated in perimenopause and early postmenopause.
Sowers et al. 2003 [70]	The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN	2336 women, multiethnic, 42–52 years. 2 groups: (i) premenopausal (ii) perimenopausal	DXA E2, FSH, T, DHEAS, SHBG (day 2-7 of menstrual cycle if applicable)	Perimenopausal group: FSH higher and BMD lower than premenopausal group. All women: negative correlation of FSH with BMD. No correlation of E2 and BMD.	Loss of BMD starts before menopause.