The Bone Resorption Assessment from used in our office can improve the quality of life for women. This test:
Using
the two most specific markers of bone resorption, the Bone Resorption Assessment
measures bone loss accurately and inexpensively. By discriminating between
patients with high and low bone turnover - two subgroups which benefit from
different therapeutic approaches - health care professionals can prescribe
appropriate treatments and monitor patient compliance and treatment
effectiveness.1
The Bone Resorption Assessment is also invaluable in studying osteoporosis and the bone diseases associated with arthritis, metabolic bone disease, and cancer.
The noninvasive urine analysis assays Pyridinium (Pyd) and Deoxypyridinium (D-Pyd), two collagen crosslinks found to be more specific for bone resorption than other assays for tissue collagen metabolites, such as telopeptides.3
Background
Osteoporosis is the most common bone disorder in America.4 More than 50% of healthy American women aged 30-40 are likely to develop vertebral fractures as they age due to osteoporosis.5 Unfortunately, treatment is only partially successful (at best) once progressive bone weakening has occurred. It is important to identify women in danger and those who are currently losing bone at an accelerated rate so that effective treatment can begin when the therapeutic burden is prevention instead of reversal of bone loss.
Bone is a dynamic tissue, continually formed and resorbed. Until a woman is in her early 20s, she synthesizes more bone than is resorbed. Eventually, aging shifts this balance, and most women over age 30 slowly lose bone.
Osteoporosis results when the normal cycle of bone remodeling is interrupted. In normal remodeling, bone cells called osteoclasts carve out cavities in the bone surface, which are filled by osteoblasts to form new bone.
In bones affected with osteoporosis, new bone formation does not keep up with bone removal, leaving the bone progressively brittle. As bone is lost, the skeleton continues to have a normal composition, but it becomes porous, hyper-mineralized and more fragile.
A woman may lose 30% to 50% of her cortical bone thickness over a lifetime.6 Although both men and women slowly lose bone as they age, some women lose bone much more rapidly around menopause. It has been assumed that menopause initiates this more rapid bone loss.
Preventive measures such as exercise, diet, and nutritional supplements are known to help prevent and partially reverse the effects of osteoporosis. If preventive measures are to be initiated prior to the onset of rapid bone loss, they must be considered by young women-those in their 30s and 40s.
Impact of osteoporosis
More than 25 million Americans, primarily women, are candidates for developing osteoporosis.7 The disease leads to 1.5 million fractures per year.7 The World Health Organization has declared osteoporosis the second biggest medical problem, next to cardiovascular diseases.8
In the United States, a third of all women 60 and older have spinal compression fractures. Such fractures cause varying degrees of pain, deformed spine, and height loss and are associated with loss of appetite, heartburn, bloating and difficulty in breathing.4
Metabolic bone and joint diseases (osteo-arthritis, rheumatoid arthritis, cancer, endocrine disorders, Paget’s disease and amenorrhea) account for an additional twelve million cases of accelerated bone loss per year.
The future health and economic impact of established osteoporosis is expected to be substantial. In many Western societies, patients with hip fractures occupy more hospital beds than patients with any other disease.9 In the United States, more than 300,000 hip fractures occur each year due to osteoporosis.7 Half of the patients with hip fractures cannot walk independently afterward, frequently developing complications such as pneumonia or blood clots. Current trends forecast as many as 500,000 hip fractures annually by the year 2000.6
Excluding chronic alcoholics, fewer men than women develop osteoporosis. Men generally have greater bone mass, consume more calcium, and exercise more than comparably-aged women. Menopause dramatically increases the rate of bone loss.
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Causes of osteoporosis Osteoporosis is a complex disease with genetic and environmental factors . Genetic traits such as Caucasian or Asian ancestry or a family history of osteoporosis dramatically increase the potential for developing osteoporosis. Gender is important, as women are four times more likely than men to develop the disease. Fair-skinned, slender, and small-boned women who have a close relative with the disease have the greatest potential. The extent to which genetic influences on peak bone mass can be modified by lifestyle changes remains an important question for research studies.4,10-13
Markers of bone loss and turnover
Measurements of bone mass assess the short-term likelihood of fractures. Few tools have been available to assist health care professionals in identifying bone resorption before it has become excessive. Static markers of bone mass, such as photon absorptiometry, do not provide information on the dynamics of bone formation and resorption. Bone biopsies provide this information but are too invasive for routine use. Photon absorptiometry Bone loss can be estimated by photon absorptiometry.10 A single measurement is employed to determine bone mass; two or more measurements over time are required to determine bone loss rates. Because of the relatively small changes in bone mass and the precision of the bone mass measurement methods, serial bone mass measurements may take an unacceptably long period of time.9 Photon absorptiometry is static and does not reflect the activity of the bone remodeling cycle.15 Photon absorptiometry provides an excellent tool for identifying women who are in immediate danger of developing fractures. It has limited value, however, in predicting those who will lose bone, develop osteoporosis, or are more likely to suffer fractures in the future. A woman already undergoing accelerated bone loss may have a normal bone scan if, for example, she started with a higher than normal bone mass due to increased calcium intake and exercise. For years, researchers have looked for biochemical methods to determine bone loss rates associated with the development of osteoporosis.16 We have found a few labs that specialize in these methods and focus its efforts on two collagen crosslinks with greater specificity for bone resorption, particularly D-pyd, than other assays for tissue collagen metabolites, such as telopeptides.3 Biochemical markers Biochemical markers are dynamic measures of bone turnover, providing information on the pathogenesis of bone diseases and on the rate of bone turnover. Various assays (bone alkaline phosphatase, osteocalcin, and procollagen peptide) have been developed during the past decade to measure bone formation. Bone resorption has been evaluated by a number of urinary excretion assays, including hydroxyproline, galactosyl hydroxylysine, pyridinoline, and deoxypyridinoline. Of these, the pyridinium crosslinks have been found to be more accurate and show a higher discrimination power than other assays.17 Pyridinium crosslinks are products of a unique series of reactions during the maturation of collagen fibrils, leading to the formation of pyridinium and deoxypyridinium. Bone collagen contains both Pyd and D-Pyd. Release of these components from bone undergoing resorption constitutes the main source of both crosslinks in urine.2 Both Pyd and D-Pyd occur only in extracellular collagen. Pyd is a major cross-link in the collagen of bone as well as connective tissues (tendon and cartilage, but not skin), while D-Pyd is located primarily in bone and serves as a specific marker of this tissue. Research supports these indicators as excellent, sensitive and specific indicators of bone loss due to osteoporosis.18,19 Presence in the urine of higher than normal amounts of Pyd and D-Pyd indicate a rapid rate of bone loss.20-22 The markers are also highly useful in treatment monitoring as biochemical markers such as Pyd and D-Pyd have a beneficial ratio between change/precision when compared with bone mass measurement.9 The ability to measure urine crosslinks led to their application in clinical studies. The good correlations between pyridinium crosslink excretion and bone turnover rates measured by radioisotope methods or histomorphometry provide direct validation of the urinary markers.2 Pyridinium crosslinks appear to be independent of diet.2 Both Pyd and D-Pyd are specific markers of bone resorption in various bone-related disorders. Crosslink excretion is greatly increased in patients with Paget’s disease, primary hyperpara- thyroidism, osteomalacia, and osteoporosis, and these assays are especially useful in monitoring therapy.2,23 A high rate of bone turnover in an untreated postmenopausal woman indicates that bone loss is likely to be rapid. Nearly all women will show high bone turnover in the first few years after menopause, but about a third will continue to have high turnover 10-20 years after menopause. Many clinicians believe such women are destined to suffer extensive bone loss and should be targeted for aggressive therapy to block bone resorption.24
Relationship of biochemical markers to osteoporosis Many studies have investigated the relationship of pyridinium markers to osteoporosis. In one, the urinary excretion of Pyd crosslinks was compared with iliac crest biopsy in a group of elderly women with untreated osteoporosis.21 The crosslinks relative to creatinine correlated closely with bone resorption with osteocalcin, a specific marker of bone formation and osteoporosis.
Relationship to other disorders affecting bone Arthritis Several studies support collagen crosslinks as valuable markers of arthritic disease activity.25-27 Seibel studied the excretion of collagen crosslinks in patients with rheumatoid arthritis, with osteoarthritis, and in normal controls.27 The levels of Pyd and D-Pyd relative to creatinine increased significantly in both groups of patients, an indication of increased bone resorption. Patients with advanced osteoarthritic disease had higher levels of Pyd than those with less pronounced joint damage. Gough found significantly increased excretion rates of Pyd and D-Pyd with disease activity and bone loss in patients with rheumatoid arthritis, concluding that these collagen crosslinks may be useful markers of bone and cartilage turnover in patients with rheumatoid arthritis.25
Metabolic bone disease
Uebelhart measured the urinary excretion of Pyd crosslinks in normal adults and in patients with metabolic bone disease.20 There was a three-fold increase in patients with primary hyperparathyroidism and a twelve-fold increase in patients with Paget’s disease compared to controls. Excretion increased two to three times as much, due to menopause. When Paget’s disease was treated with bisphosphonates to inhibit bone resorption without altering bone formation over a short time span, the level of crosslinks declined to the normal range. The data indicate that urinary D-pyd crosslinks reflect specifically collagen degradation during bone resorption. Robins also analyzed urinary concentrations of Pyd and D-Pyd relative to creatinine in patients with metabolic bone disorders and reported significantly elevated values in patients with Paget’s disease of the bone, primary hyperparathyroidism, and osteomalacia.28 Furthermore, there was a significant correlation between the concentrations of crosslinks and urinary hydroxyproline, although the variations in the latter were large. Alvarez found that biochemical markers of bone turnover were increased when Paget’s disease activity is high. This study suggested that urinary Pyd measurement would improve the detection of Paget’s disease during low periods of zdisease activity.23
Cancer
Metastatic disease in bone is of concern to patients with a history of cancer, including breast carcinoma. In a preliminary study, urinary collagen crosslinks were measured in groups of patients with breast cancer, patients with bone metastases, and controls with no evidence of metastatic disease.29 Values for both Pyd and D-Pyd were significantly greater in the group with metastases than in healthy volunteers. Excretion of the crosslinks correlated with elevated serum levels of phosphatase activity as well.
Alcoholic bone disease
Chronic alcohol consumption leads to various bone pathologies, possibly due to decreased consumption of calcium and Vitamin D, reduced osteoblastic function, and increased bone turnover. Preedy found that chronic ethanol feeding in rats led to decreased excretion of D-Pyd but not Pyd, thus increasing the ratio of Pyd/D-Pyd.30 The research implicates a reduction of the absolute rate of bone resorption and the inhibition of mature crosslinks with chronic consumption of ethanol. Clinical therapeutics Conventional treatment of osteoporosis includes estrogen replacement therapy (ERT), calcium supplements, and weight-bearing exercise. Drugs such as calcitonin and bisphosphonates have also been used. ERT inhibits bone resorption in postmenopausal women and has been shown to reduce the incidence of osteoporotic fractures by about 50%. Although the conventional approach reduces the incidence of osteoporosis, many women cannot or will not use ERT because of the risks and side effects associated with it. A number of different vitamins and minerals in addition to calcium play a role in maintaining healthy bones, but unfortunately, Americans often consume inadequate amounts of these nutrients. Additionally, hormone therapy may be more effective when ovarian hormones other than estrogen are taken into consideration. Vitamins and minerals affect bone loss Calcium Calcium has been known for its ability to positively impact bone formation. Now, evidence suggests it also slows down bone resorption.32-34 Research indicates a calcium-rich supplement containing Microcrystalline Hydroxyapatite Concentrate has been useful in preventing bone thinning and increasing cortical bone thickness.35 The Bone Resorption Assessment, through its analysis of pyridinium and deoxypyridinium crosslinks, can monitor the effectiveness of a calcium treatment program. Magnesium The typical American diet often contains less than two-thirds of the RDA for magnesium. Deficiency is common in women with osteoporosis and appears to be associated with abnormal bone mineral crystal formation. Magnesium is necessary for the absorption of calcium and plays a part in the conversion of vitamin D to its active form. A two-year study found nearly 75 percent of 31 women taking 250-750 mg of oral magnesium showed bone density increases of one percent to eight percent.36 Vitamin K Vitamin K is a cofactor in the synthesis of osteocalcin, a unique bone protein which attracts calcium to bone tissue. Inadequate vitamin K levels impair normal bone mineralization. Serum vitamin K levels in individuals with osteoporosis were found to be 74 percent lower compared to a healthy control group.37 Age-related dietary changes, reduced efficiency of absorption, and use of antibiotics that destroy vitamin K-producing intestinal flora may all contribute to vitamin K deficiency. Boron Evidence suggests that boron may promote synthesis of compounds related to bone health, including estrogen, testosterone, DHEA, and vitamin D, and play an important role in maintaining bone mass. One study showed that three milligrams of boron per day decreased urinary calcium excretion by 44 percent and increased levels of estradiol (the most biologically active form of estrogen in the body) to that found in women receiving estrogen replacement therapy.38 Manganese In a study of 14 women with osteo- porosis, blood levels of manganese were 75 percent lower than those of age-matched controls.39 Manganese deficiency has also been found to produce osteoporosis in animals. Studies suggest that manganese is a necessary mineral for bone mineralization. Vitamin D In many patients with osteoporosis there is an impairment in renal conversion of vitamin D to its most active form. This may result from deficiencies in estrogen, magnesium, or boron. Folic acid Folate is important in the metabolism of homocysteine, a metabolic intermediate that may affect osteoporosis by interfering with collagen crosslinking, resulting in a defective bone matrix. Increased levels of homocysteine have been found in postmenopausal women. The beneficial effect of folic acid appears to occur even in women who have no apparent deficiency of the vitamin.40 Other nutrients Additional studies suggest that vitamin B6, vitamin C, zinc, copper, silicon, and strontium play roles in maintaining bone mass. Due to poor food choice and processed food, many of these nutrients are lacking in the American diet. A comprehensive nutritional supplement program which provides all of the vitamins and minerals involved in bone health may be valuable in preventing and treating osteoporosis. Exercise Exercise plays an important role in prevention and treatment of osteoporosis. Weight-bearing exercise strengthens bones, increases bone mass, and increases a person’s reaction time and stability, thus decreasing the likelihood of a bone-breaking fall. Walking, running, tennis, aerobics, and weightlifting are effective at building and maintaining bone mass. Swimming may increase bone density while strengthening the cardiovascular system. Hormonal therapy Estrogen Estrogen replacement therapy inhibits bone resorption and reduces the incidence of osteoporotic fractures. However, ERT also increases the risk of certain forms of cancer. While the increased risk of endometrial cancer is prevented by the concomitant use of a progestogen, there is evidence that ERT may also cause breast cancer. However, it has been shown that one of three naturally occurring forms of estrogen, known as estriol, may actually prevent breast cancer.41 A combination estrogen medication called Tri-estrogen (containing 80% estriol, 10% estrone, and 10% estradiol) may present a safer alternative to standard ERT in the management of postmenopausal osteoporosis.
Progesterone
Progestogens have been shown to reduce bone loss. Natural progesterone may be significantly safer and more effective than progestogens. One study of postmenopausal women receiving progesterone demonstrated increased bone density in all subjects. Over several years, average bone mass increased by 15.4 percent. Height loss was stabilized, and no new osteoporotic fractures occurred.42 Progesterone appears to enhance new bone formation in contrast to estrogen, which merely inhibits resorption of old bone. Unlike estrogen, progesterone is not carcinogenic, and there is evidence that progesterone actually prevents certain female cancers.
Testosterone and DHEA
Although testosterone and dehydroepiandrosterone (DHEA) are considered male hormones, they are produced in substantial amounts by the ovaries. Each of these hormones has been shown to enhance new bone formation. Ovariectomized women as well as some women with intact ovaries may develop testosterone deficiency. In such cases, testosterone therapy may be of benefit. Serum levels of DHEA tend to decline around the time of menopause. A further fall in levels occurs around age 70, as the adrenal gland loses its capacity to produce the hormone. Administration of DHEA may help to prevent or reverse osteoporosis. Other considerations The physician should rule out gastrointestinal problems such as hypochlorhydria, dysbiosis, and malabsorption, which can compromise nutritional status, especially of minerals and fat-soluble nutrients such as vitamin K. Individuals should avoid exposure to toxic metals, especially aluminum, which can bind to phosphorus in the intestine, leading to phosphorus depletion and fecal calcium excretion. Magnesium deficiency enhances the absorption of aluminum. Certain medications such as gluco- corticoids, anticonvulsants, anticoagulants, and some diuretics may result in a loss of bone tissue. Patients using these medications should be monitored for bone loss 1 Delmas PB. Osteo Int 1993;Suppl 1:S81-86. 2 The Lancet 1992;340:278-9. 3 Robins SP. Acta Orthop Scand 1995; (Suppl 266)66:171-5. 4 Riffee JM. Amer Pharm 1992;Vol NS32; 8:61-72. 5 Prior JC et al. N Eng J Med 1990;323:1221-7. 6 Riggs BL. N Eng J Med 1992;(Aug 27):620-7. 7 Stand UP to Osteoporosis. National Osteo- porosis Foundation, 1994. Washington, D.C. 8 Holbrook TL et al. Amer Acad Orthopedic Surg 1984. 9 Riis BJ. Am J Med 1993;95(5A):17-21S. 10 Wark JD. Bailliere’s Clin Endocrinol Metab 1993;7:151-81. 11 Lufkin EG. Comp Therapy 1992;18(12):14-17. 12 Compston JE. Clin Endocrin 1990;33:653-82. 13 Albers MM. Health Care for Women Inter 1990; 11:11-19. 14 Avioli LV. Orthopaedic Rev 1992;(Sept):1126-9. 15 Notelovitz M. Fertility and Sterility 1993;59(4):707-25. 16 Azria M. Calcif Tissue Int.1989;45:7-11. 17 Bettica P et al. Clin Chem 1992;38(11):2313-8. 18 Hassager C et al. Clin Endocrinology 1992; 37:45-50. 19 Delmas PD. Bone 1992;13:S17-21. 20 Uebelhart D et al. Bone Miner 1990; 8:87-96. 21 Delmas PD et al. J Bone Min Res 1991; 6(6):639-44. 22 McLaren AM et al. Ann Rheum Dis 1992; 51:648-51. 23 Alvarez L et al. J Bone Min Res 1995; 10(3):458-65. 24 Ettinger B. Current Opinion OB GYN 1993; 5:396-403. 25 Gough AKS et al. Ann Rheum Dis 1994; 53:14-17. 26 Seibel MJ et al. J Rheumatol 1989;16:964-70. 27 MacDonald AG et al. Brit J Rheum 1994; 33:16-19. 28 Robins SP et al. Eur J Clin Invest 199 1;21:310-15. 29 Paterson CR et al. Br J Cancer 1991;64:884-6. 30 Preedy VR et al. Alcohol and Alcoholism 1991; 26(2):191-8. 31 Seibel MJ et al. J Bone Min Res 1993;8:881-9. 32 Shapses SA et al. J Nutr 1995;125:2814-21. 33 Horowitz M et al. Am J Clin Nutr 1994; 60:965-8. 34 Blumsohn A et al. J Clin Endocrinol Metab 1994;79:730-5. 35 Epstein O et al. Am J Clin Nutr 1982; 36:426-30. 36 Vikhanski L. Med Tribune July 22, 1993. 37 Hart JP et al. J Clin Endocrinol Metab 1985; 60:1268-9. 38 Nielsen FH. Nutr Today 1988;(Jan-Feb):4-7. 39 Raloff J. Science News 1986;130:199. 40 Brattstrom LE. Metabolism 1985;34:1073-7. 41 Follingstad AH. JAMA 1978;239:29-30. 42 Lee JR. Med Hypotheses 1991;35:316-18.
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© 2001 Ronald J. Grisanti
D.C., D.A.B.C.O
NOTICE: This information is provided for educational
purposes. Any medical procedures, dietary changes, or nutritional supplements
discussed herein should only be undertaken on the advice of a qualified
physician.
Ronald J. Grisanti, D.C.,
D.A.B.C.O
The Grisanti Alternative Medicine Center
4200 East North Street, Suite 14 • Greenville, SC 29615
(864) 292-0226 • FAX: (864) 268-7022
Significantly,
lifestyle choices affect bone health for all women. These modifiable
factors include diet and nutrition, physical activity, excessive alcohol
consumption, and cigarette smoking. Physiologic states and disease
comprise a third category of factors
.
In
another study, elderly women with femoral fractures associated with
osteoporosis were compared with age-matched controls.22 Women
with fractures and osteoporosis excreted higher levels of crosslinks.
The molar ratio of Pyd to D-Pyd did not differ appreciably among the
three groups. Patients with recent fractures showed higher excretion of
both markers than those without recent fractures, indicating that
accidental bone fractures also increase crosslink excretion.