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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 4144-4148
Copyright © 1999 by The Endocrine Society

Original Studies

Skeletal Effects of Aging and Menopausal Status in Female Rhesus Macaques1

Ricki J. Colman, Joseph W. Kemnitz, Mark A. Lane, David H. Abbott and Neil Binkley

Wisconsin Regional Primate Research Center, University of Wisconsin (R.J.C., J.W.K., D.H.A., N.B.), Madison, Wisconsin 53715; the Departments of Medicine (J.W.K.) and Obstetrics and Gynecology (D.H.A.) and the Institute on Aging (N.B.), University of Wisconsin, Madison, Wisconsin 53706; and the Molecular Physiology and Genetics Section, Intramural Research Program, Gerontology Research Center, National Institute on Aging, National Institutes of Health (M.A.L.), Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Joseph W. Kemnitz, Ph.D., Wisconsin Regional Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, Wisconsin 53715-1299.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Bone mass
 Biochemical parameters
 OA
 Discussion
 References
 
To further define the nonhuman primate as a model of the adult human skeleton, we explored the impact of growth, natural menopause, and osteoarthritis on bone mass, serum markers of bone turnover (osteocalcin and C-terminal telopeptide of type I collagen) and measures of skeletal relevance (PTH, 25-hydroxyvitamin D, total alkaline phosphatase, calcium, phosphorus, creatinine, and albumin). Fifty-eight female (aged 4–30 yr) rhesus macaques were defined as growing (G; n = 12; <=10 yr old), adult premenopausal (APre; n = 30; >10 yr old; eumenorrheic, high serum estradiol and low FSH), or postmenopausal (Post; n = 16; amenorrheic for at least 1 yr, with low serum estradiol and high FSH). Total body and posterior-anterior spinal bone masses were lower in G than APre animals (P < 0.05). Post females had lower total body, distal radius, and spinal bone mass than premenopausal animals (P < 0.05). Osteocalcin was higher in Post than APre animals (P < 0.01). Other measures showed no relationship with menopausal status. In older monkeys, spinal osteoarthritis became common, causing increased dual-energy x-ray absorptiometry-measured bone mass in the lumbar spinal posterior-anterior projection. In conclusion, after natural menopause, rhesus monkeys have lower bone mass and higher skeletal turnover without alteration of the calcium-vitamin D axis. As such, they are an excellent model of human estrogen-depletion bone loss.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Bone mass
 Biochemical parameters
 OA
 Discussion
 References
 
BOTH LARGE and small animals are used to evaluate estrogen depletion bone loss. Although no animal replicates human osteoporotic fractures, nonhuman primates are excellent models in which to study both the pathogenesis and treatment of estrogen depletion bone loss (1, 2, 3, 4). Macaques and baboons reliably develop increased skeletal turnover and bone loss after surgically induced estrogen depletion (5, 6, 7, 8, 9). This is not surprising in view of their striking similarities to humans in menstrual cycle (10, 11), occurrence of natural menopause (12, 13), and bone-remodeling processes in both cancellous and cortical bone (2, 14).

Although the effects of ovariectomy on bone mass are well characterized, little information exists regarding the effects of natural menopause on bone mass and turnover in macaques. Therefore, in this study we investigated the effects of growth and subsequent natural menopause on bone mass, spinal osteoarthritis (OA) prevalence, and serum markers of bone turnover and skeletal relevance in female rhesus macaques. These data further define the rhesus monkey model of estrogen depletion and age-related bone loss.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Bone mass
 Biochemical parameters
 OA
 Discussion
 References
 
Animals

Fifty-eight female rhesus monkeys (Macaca mulatta), aged 4–30 yr, were studied. All were housed at the Wisconsin Regional Primate Research Center and had known birth dates and complete medical histories. No animal had any clinical or experimental history known to affect skeletal parameters. The protocol was carried out with approval of the University of Wisconsin-Madison Graduate School institutional animal care and use committee.

All animals were housed indoors throughout life in varied conditions ranging from single caging to social groups of 10 or more. Animal room temperature and humidity were maintained at approximately 21 C and 50–60%, respectively. A 12-h light, 12-h dark schedule was maintained; no outside light reached the rooms. Individuals were grouped in rooms with others with whom they had extensive visual and auditory contact and were exposed to a rotating panel of objects supplied to enrich their environment. All animals had 24-h access to tap water and either standard laboratory chow [Purina monkey chow #5038, Ralston Purina Co., St. Louis, MO; n = 12 growing (G), 19 adult premenopausal (APre), and 16 postmenopausal (Post)] containing approximately 0.9% calcium, approximately 0.7% phosphorus, and 6.6 IU vitamin D/g or a purified diet (Teklad #85387, Madison, WI; n = 11 APre) containing 0.8% calcium, approximately 0.5% phosphorus, and 2.2 IU vitamin D/g. These 11 animals had received this purified diet for 2.5 yr. Before this they had been fed standard chow. The 47 animals receiving standard chow had been on this diet throughout their lives.

Bone densitometry

Dual-energy x-ray absorptiometry (DXA; model DPX-L, Lunar Corp., Madison, WI) was used to measure bone mass at one time point for each animal. After an overnight fast, animals were sedated with ketamine HCl (10 mg/kg, im) and weighed. Those animals under 20 yr of age were further administered a mixture of ketamine HCl and xylazine (7 and 0.6 mg/kg xylazine, respectively, im) for additional muscle relaxation and anesthesia maintenance. For animals over 20 yr of age, an endotracheal tube was placed for maintenance on inhalant halothane (1.5% in 2 l 02/min), and atropine (0.27 mg, sc) was administered to control secretions. The endotracheal tubing was scanned and found to have no effect on bone mineral content (BMC) or bone mineral density (BMD) measurements.

All scans and analyses were performed by one operator over a 4-month span. Scans of the total body, radius, and posterior-anterior (PA) lumbar spine were performed as previously reported (15). Lateral lumbar spinal scans were performed with the animal in left lateral recumbency. BMC and BMD coefficients of variation were less than 2.5% for all sites evaluated.

Total body and spinal scans were acquired and analyzed using Lunar pediatric software (version 1.5e). Total body scans required no region of interest placement. Two analyses, standard (S PA) and central region of interest (CROI PA), of the PA lumbar spine were performed. S PA lumbar spine was localized to vertebrae 2–4. CROI analysis involved centering a 0.92-cm2 diamond-shaped region of interest within the endplates and edges of vertebrae 2–4 as previously described (16). Lateral spine analysis required manual placement of edges surrounding the bodies of vertebrae 3 and 4. Radius scans were acquired and analyzed using Lunar small animal software (version 1.0d). Two radius regions of interest, distal and proximal, were defined. The distal was 2 mm tall by 15 mm wide and encompassed the region 10–12 mm from the distal end of the radius. The proximal was 5 mm tall by 15 mm wide and encompassed the region 47.5–52.5 mm from the distal end of the radius. The sites were chosen to mimic the clinical ultradistal" and one third sites (15).

Radiographs

Immediately after DXA scanning, conventional radiographs of the lumbar spine in lateral and anterior-posterior projection were obtained for all animals. Film speed (100 or 400), kilovolts (56–70), and milliamperes (100 or 300) varied depending upon animal size. All films were reviewed by a single individual blinded to the animals’ age and DXA results. Lumbar spine degenerative changes were evaluated in both projections and graded as previously reported (17). Radiographic criteria included disc space narrowing, sclerosis or osteophytes at the sites of vertebral endplates, spinous processes, and facet joints. Overall OA severity was graded as 0 (no involvement), 1 (minimal involvement), or 2 (moderate/severe involvement).

Menstrual status

All female rhesus macaques at the Wisconsin Regional Primate Research Center were monitored daily by one individual for menstrual bleeding and estradiol (E2)-dependent changes in perineal skin color (18, 19). Animals were classified as premenopausal if they were undergoing menstrual cycles as determined by menstrual bleeding and characteristic color changes in the estrogen-sensitive skin. Those animals with E2 levels below 25 pg/mL and FSH levels above 2.3 ng/mL, no menstrual bleeding, and absence of menstrual cycles, based on color data, were considered postmenopausal.

Biochemical parameters

All animals were fasted overnight before phlebotomy. Premenopausal animals were sampled on days 4–10 of the menstrual cycle; postmenopausal specimens were obtained randomly. Blood was drawn into Vacutainers (BD, Franklin Lakes, NJ) from the saphenous or femoral vein between 0700–0900 h and allowed to clot for approximately 30 min. Samples were then centrifuged, and serum was aliquoted into separate vials for each analyte and frozen at -20 C until analysis. The following parameters were measured (numbers represent inter- and intraassay coefficients of variation, respectively): osteocalcin (RIA, Diagnostic Systems Laboratories, Inc., Webster, TX; 8.28%, 4.90%), carboxyl-terminal telopeptide of type I collagen (ICTP; RIA, INCSTAR Corp., Stillwater, MN; 6.75%, 3.08%), PTH (immunoradiometric assay, Diagnostic Products, Los Angeles, CA; 10.38%, 9.45%), 25-hydroxyvitamin D (25OHD; RIA, INCSTAR Corp.; 8.57%, 5.97%), FSH (RIA, in-house; 7.89%, 3.65%), E2 (RIA, in-house; 8.88%, 3.78%), total alkaline phosphatase (spectrophotometry, General Medical Laboratories, Madison, WI; 4.63%, 1.69%), calcium (spectrophotometry, General Medical Laboratories, Madison, WI; 1.26%, 0.52%), and phosphorus (spectrophotometry, General Medical Laboratories; 3.72%, 4.51%). All assays were fully validated for use in rhesus monkeys by parallelism and spike recovery.

Statistical analysis

Study animals were separated into 3 groups. Sixteen animals were postmenopausal (Post) by criteria described above (and as defined in humans). The 42 premenopausal animals were arbitrarily classified as G (n = 12) or APre (n = 30) based on published age of peak bone mass (15, 20).

All analyses were carried out using JMP statistical software (SAS Institute, Inc., Cary, NC). Comparisons between groups were made by ANOVA with post-hoc t tests. {chi}2 analysis was used to test for differences in OA prevalence by group. Spearman rank correlations were used to explore the relationship between radiograph scores and age. The effect of OA on DXA-measured BMD was explored by ANOVA with post-hoc t tests. Significance was determined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Bone mass
 Biochemical parameters
 OA
 Discussion
 References
 
Group descriptions

Animal descriptive data are presented in Table 1Go. There was no overlap between premenopausal (G and APre groups) and Post animals in circulating E2 or FSH concentrations. Within the APre group, those receiving Teklad chow (n = 11) had lower (P < 0.01) mean serum 25OHD concentrations (63.8 ± 7.2 vs. 128.7 ± 9.1 ng/mL) and distal radial BMD (0.237 ± 0.014 vs. 0.284 ± 0.009). No other parameters differed by diet.


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  		Table 1. Group characteristics

 

   Bone mass
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Bone mass
Biochemical parameters
 OA
 Discussion
 References
 
BMC and BMD data are presented in Tables 2Go and 3Go, respectively. As BMC and BMD results were similar, only BMD is reported below.


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  		Table 2. BMC (grams) in growing, adult, and postmenopausal animals

 

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  		Table 3. BMD (grams per cm2) in growing, adult, and postmenopausal animals

 
G vs. APre. Total body and S PA spine BMD were lower in G than APre animals (Table 3Go). CROI PA spine, lateral spine, and radius BMD did not differ (Table 3Go).

Post vs. APre. Lumbar spine (S PA, CROI PA, and lateral) and proximal radius BMD were lower in Post than APre animals (Table 3Go). Total body and distal radius BMD did not differ (Table 3Go).


   Biochemical parameters
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Bone mass
 Biochemical parameters
OA
 Discussion
 References
 
G vs. APre. Serum osteocalcin, ICTP (Fig. 1Go), and albumin (Table 4Go) levels were higher in G than APre animals. PTH, 25OHD, total alkaline phosphatase, calcium, phosphorus, and creatinine did not differ (Table 4Go).



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  		Figure 1. Midfollicular fasted serum osteocalcin and ICTP in G, APre, and Post animals. Data represent group means with SEs. Different markers above bars represent groups that are significantly different by ANOVA with post-hoc Student’s t test (P < 0.05).

 

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  		Table 4. Markers of skeletal relevance in growing, adult, and postmenopausal animals

 
Post vs. APre. Serum osteocalcin (Fig. 1Go) was higher, and creatinine (Table 4Go) was lower in Post than APre animals. ICTP (Fig. 1Go), PTH, 25OHD, total alkaline phosphatase, calcium, phosphorus, and albumin (Table 4Go) did not differ.


   OA
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Bone mass
 Biochemical parameters
 OA
Discussion
 References
 
OA prevalence differed (P < 0.0001) by group. No (0 of 12) G animals had radiographically demonstrable evidence of OA, whereas 40% (12 of 30) of APre and 81% (13 of 16) of Post animals had evidence (score of 1 or 2) of OA (Table 5Go).


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  		Table 5. Lumbar spine osteoarthritis score by group

 
Lumbar spine OA scores increased with age. The mean age of those with no OA was 12.8 and 22.7 yr for animals with moderate/severe OA (Table 6Go). Furthermore, OA was present in only 3.2% (1 of 31) of animals under 18 yr of age, but in 77.8% (21 of 27) of those over 18 yr.


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  		Table 6. Group characteristics and BMD (grams per cm2) values by index of lumbar spine osteoarthritis

 
Within the APre group, those with moderate/severe OA (score of 2) had higher PA spine BMD (S PA and CROI PA) than animals with no or minimal OA (score of 0 or 1; P < 0.05). BMD at other sites was not related to OA score. The effect of OA on BMD was not evaluated in G or Post animals due to a lack of individuals with evidence of OA or no OA, respectively.

There was no linear relationship between body weight and OA. Although not significant, body weight was lowest in animals with minimal OA and highest in animals with moderate/severe OA (Table 6Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Bone mass
 Biochemical parameters
 OA
 Discussion
References
 
Female macaques are excellent models of human estrogen depletion bone loss after ovariectomy, reliably showing decreased bone mass and increased bone turnover (1, 2, 3, 4, 5, 6, 7, 8, 9). This study documents similar findings after natural menopause, defined as amenorrhea for at least 1 yr combined with low serum E2 and high FSH levels. Thus, estrogen depletion, whether surgical or natural, leads to similar skeletal effects in rhesus monkeys.

Loss of estrogen at menopause plays a central role in osteoporosis development, as its deficiency is associated with a period of high bone turnover and accelerated bone loss (21, 22, 23). Mimicking the human condition, postmenopausal rhesus monkeys in this study had lower bone mass (total body, spine, and radius) and higher bone turnover (as determined by osteocalcin) than APre animals. We propose that naturally postmenopausal rhesus macaques are a suitable model for the evaluation of E2 depletion bone loss as well.

Bone turnover is elevated during growth and development in humans (24), an observation replicated in this study, with elevated serum osteocalcin and ICTP levels in growing animals. Also consistent with human (24, 25, 26) and ovariectomized nonhuman primate (2, 7) data, bone turnover, as measured by serum osteocalcin, was elevated after natural menopause. The stability of ICTP and total alkaline phosphatase after menopause may reflect their lack of skeletal specificity.

No differences were observed in 25OHD or PTH between postmenopausal and younger animals, i.e. age-related hypovitaminosis D and associated secondary hyperparathyroidism were not observed. By contrast, vitamin D insufficiency is extremely common in older humans (27, 28) and can result from inadequate sunlight exposure or dietary inadequacy. That this does not occur in older monkeys probably reflects the high vitamin D content of laboratory chow. Furthermore, the mean serum 25OHD concentration of postmenopausal rhesus monkeys (137 ng/mL) was more than 2-fold higher than the normal range upper limit in humans (65 ng/mL) (29). Even the lower vitamin D intake provided by a purified diet (33% of standard laboratory chow) produced 25OHD levels at the upper normal limit in humans. Skeletal aging researchers should be cognizant of this diet-related difference between laboratory-housed macaques and humans. Furthermore, nonhuman primates appear to be appropriate for the study of bone loss not confounded by vitamin D insufficiency and elucidation of the role this insufficiency plays in age-related bone loss.

Lumbar spine OA becomes extremely common with advancing age in humans, affecting up to 80% of elderly people (30). In accordance with these findings, OA prevalence and severity increase with age in baboons (31) and cynomolgus (32) and rhesus macaques (33). Based upon our data, rhesus monkeys below age 18 yr are unlikely to have lumbar spine OA. However, in older individuals, OA falsely elevates DXA quantification of bone mass by adding to the total measured mineral content in the affected area (17, 34, 35, 36). In this study, DXA-measured BMC and BMD of the PA lumbar spine were higher with increasing degree of OA. By contrast, DXA-measured BMC and BMD of the lumbar spine in the lateral projection did not increase with the presence of OA. This illustrates the need for a method of spinal bone loss analysis, such as lateral DXA (and potentially CROI or quantitative computed tomography) to reduce the confounding effect of OA.

In conclusion, this study documents that natural menopause in rhesus macaques results in decreased bone mass and increased skeletal turnover (as measured by osteocalcin) mimicking the human condition. Thus, rhesus macaques appear to be an excellent model for estrogen depletion bone loss in women after either ovariectomy or natural menopause; however, appropriate methods need to be used to minimize OA effects. Further studies of a longitudinal design are needed to improve characterization of bone physiology after natural menopause in rhesus macaques.


   Acknowledgments
 
The authors gratefully acknowledge the excellent technical assistance provided by S. T. Baum, K. M. Gari, G. Scheffler, F. H. Wegner, S. G. Eisele, T. S. Frost, and the Animal Care and Veterinary Staff of the Wisconsin Regional Primate Research Center.


   Footnotes
 
1 This work was supported by NIH Grants PO1-AG-11915, P51-RR-00167, and K08-AG-00801. This is Publication 39-011 of the Wisconsin Regional Primate Research Center. Back

Received January 14, 1999.

Revised July 13, 1999.

Accepted August 10, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Bone mass
 Biochemical parameters
 OA
 Discussion
 References
 

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