2.4. Osteoporosis

2.4.1. Peak bone mass

Peak bone mass is the highest level of bone mass each individual has attained as a result of normal growth (Burckhardt & Michel 1989). In humans, it is achieved during the first two to three decades of life (Bonjour et al. 1991). The peak bone mass has been shown to be regulated mostly by genetic factors, but nutritional, behavioral, environmental and mechanical loading factors are also of importance (for review see Chesnut 1991). Twin studies have suggested that genetic factors account for up to 80% of the bone mineral density variance in young adults (for review see Ralston 1997). However, the relative contribution of these factors to the peak bone mass in comparison to other determinants is largely unknown (Chesnut 1991). A number of possible genes has been suggested for being responsible for the low bone density, including genes influencing the metabolism of osteocalcin (Kelly et al. 1991) and type 1 collagen (Tokita et al. 1994), as well as polymorphism associated with the vitamin D receptor gene (Eisman 1995), and with the estrogen receptor gene (Kobayashi et al. 1996).

Of the nutritional factors involved, a sufficient calcium intake is of greatest importance. Adequate calcium nutrition is essential for the development and maintenance of a normal skeleton (Consensus development conference 1993). Furthermore, calcium supplementation to levels above habitual intake has been shown to increase peak bone mass in children and adolescents (Consensus development conference 1993). However, calcium deficiency is assumed to exist in the majority of adolescent females, most likely throughout the world (Chesnut 1991). The recommended dietary allowance for females between the ages 11 and 18 in the USA is 1200 mg daily (Commitee on Dietary Allowances, Food and Nutritional Board, National Research Council 1989). However, many recent clinical trials (Johnston et al. 1992, Lloyd et al. 1992) have shown that this recommended allowance is not high enough to sustain maximal skeletal accumulation (for review see Heaney & Matkovic 1995). In recent consensus conferences, daily allowances of calcium between 1400 to 1500 mg/d have been recommended (NIH Consensus Conference 1994, Heaney 1998). In addition to an adequate calcium intake, good general nutrition, including adequate intakes of e.g. vitamin D, vitamin B₆, vitamin B₁₂ and vitamin K, is important for attaining the optimal peak bone mass. (Consensus development conference 1993).

Sufficient practise of physical exercise has been associated with increased bone density values among adolescents (Block et al. 1986, Recker et al. 1992). Furthermore, bone density values of the dominant arm or leg in different groups of adolescent athletes have been found to be increased (Nilsson & Westlin 1971, for review see Heaney & Matkovic 1995). On the other hand, excessive exercise, which leads to reduced body weight and impaired ovarian function in young women, may actually reduce bone mass (Drinkwater et al. 1984). Normal skeletal growth requires a normal endocrine status, including pituitary, adrenal, thyroid and gonadal functions (for review see Lam et al. 1988, Heaney & Matkovic 1995). Nowadays, a particular problem in many western countries is an acquired gonadal hormone deficiency found in many young women associated with eating disorders (Davies et al. 1990). Some life-style factors, like smoking (Välimäki et al. 1994) and alcohol abuse (Klein 1997) may also decrease peak bone mass (for review see Riggs & Melton 1986, Consensus development conference 1991). Systemic diseases, like hyperthyroidism and primary hyperparathyroidism, as well as medication, e.g. excessive exposure to glucocorticoids, can also be reasons for an inadequate peak bone mass (Consensus development conference 1991).

2.4.2. Bone loss

Adult skeleton is constantly being remodeled. Normal homeostasis is a balance between bone resorption and bone formation, which is controlled mainly by hormonal and mechanical factors (for review see Rodan 1996). The purpose of remodeling is thought to be the enabling of functions such as supporting the calcium homeostasis and hematopoesis, and maintaining the load-bearing capacity of bone by preventing and repairing microscopic structural damage (Parfitt 1996). Bone remodeling is carried out by temporary anatomic structures known as basic multicellular units (Frost 1986). Remodeling (for review see Väänänen 1993) is initiated by activation of osteoclastic stem cells to differentiate into mature multinucleated osteoclasts. A resorption phase includes tight attachment of the activated osteoclasts to bone (Lakkakorpi et al. 1989), followed by actual bone absorption during which solubilization of hydroxyapatite crystals is done by acidification of resorption lacuna (Väänänen et al. 1990), followed by degradation of organic bone matrix by lysosymal hydrolases and collagenases (Blair et al. 1986, for review see Vaes 1988). During a reversal phase, mononuclear cells prepare the resorption lacunae for bone formation (Eriksen et al. 1990). Bone formation starts with the activation of preosteoblasts to differentiate into osteoblasts, which secrete bone-matrix proteins to form the organic matrix, which is later mineralized. At each remodeling site, bone resorption is coupled with bone formation, locally released growth factors and cytokines acting as mediators of this process (for review see Canalis et al. 1988, Mundy 1995). The decrease of bone mass is a consequence of an imbalance between the amount of mineral and matrix removed, and subsequently incorporated into each resorption cavity (for review see Kanis et al. 1990).

After reaching its peak, bone mass begins a gradual decline in both men and women as a natural part of the aging process (Christiansen 1992). In men and premenopausal women, bone loss is relatively slow, and primarily related to the gradual thinning of trabecular plates and cortical bone, caused by the age-related decline in the amount of matrix synthesized by the osteoblasts (Aaron et al. 1987, Mellish et al. 1989). Age-related osteoporosis has been defined as type II osteoporosis (Riggs & Melton 1983). It is characterized, in addition to the impaired bone formation, by secondary hyperparathyroidism caused by an age-related decrease in calcium absorption, and leading to increased bone turnover (Delmas et al. 1983, for review see Kassem et al. 1996). As bone formation at the cellular level is defective, increased bone turnover results in increased bone loss (Kassem et al. 1996). The impaired calcium absorption is probably caused by an age-related intestinal resistance to 1,25-dihydroxyvitamin D₃ (Eastell et al. 1991), and by a decrease in intestinal vitamin D receptor concentration with aging (Ebeling et al. 1992). Furthermore, aging is associated with a decline in the levels of growth hormone (Zadic et al. 1985, Rudman & Rao 1991) and insulin-like growth factor-1 (Quesada et al. 1992), which may also explain some of the variability in calcium homeostasis and bone turnover (for review see Blumsohn & Eastell 1995). Other factors suggested to affect bone turnover during aging include nutritional deficiencies and a low level of physical activity (for review see Blumsohn & Eastell 1995).

In women, bone loss progresses much more rapidly after the menopause. This is related to estrogen deficiency-caused increase in bone turnover, bone resorption exceeding bone formation (for review see Heaney et al. 1978, Christiansen 1992). The loss of ovarian function leads to enhanced development of both osteoclast and osteoblast progenitors in bone marrow (for review see Manolagas & Jilka 1995), to increased activation frequency of new basic multicellular units (Eriksen et al. 1990), as well as to an imbalance between bone resorption and formation at each remodeling unit, with the former exceeding the latter (Eriksen et al. 1990, Jilka et al. 1992). Because of its large surface area and relatively thin network structure, cancellous bone is especially sensitive to this kind of disturbance (for review see Parfitt 1988). As a consequence, there is complete removal of some trabecular plates, and significant disruption of the trabecular lattice, the trabeculae becoming more widely separated and trabecular connectivity reduced (Dempster 1995). Consistent with biomechanical principles, this results in reduction of bone strength that is disproportionately greater than the reduction in bone mass (Melton & Riggs 1988). Estrogen regulates bone remodeling by modulating the production of cytokines and growth factors from bone marrow and bone cells (for review see Pacifici 1996a). The bone sparing effect of estrogen seems to be due to its ability to block osteoclastogenesis and the activation of mature osteoclasts and to promote apoptotic osteoclast death (Pacifici 1996a). On the other hand, estrogen deficiency-caused increase in the levels of interleukin-1 and tumor necrosis factor are proposed as causative factors underlying the accelerated bone loss (Pacifici 1996a). Postmenopausal osteoporosis has been defined as type I osteoporosis (Riggs & Melton 1983). It is characterized by decreased parathyroid hormone secretion, decreased 1,25 hydroxyvitamin D₃ production, and, as a consequence, decreased calcium absorption (for review see Kassem et al. 1996). Postmenopausal osteoporosis is probably not a result of the menopause only, but also of additional factors that are present in some of these women, and that exacerbate and prolong the rapid phase of the bone loss induced by the estrogen deficiency (Khosla et al. 1995, Kassem et al. 1996). Such factors may include defects of osteoblasts, impairing their ability to increase bone formation in order to compensate for the increased bone resorption (Cohen-Solal et al. 1991), and genetic predisposiotion for a pattern of cytokine secretion (Pacifici et al. 1991, Jilka et al. 1992, Kassem et al. 1996).

2.4.3. Prevention and treatment of bone loss

Sufficient intake of dietary calcium (1500 mg/day), along with sufficient supply of vitamin D to optimize calcium absorption, are among the most important factors in the prevention of osteoporosis at the population level (for review see Johnston 1996, Masi & Bilezikian 1997). Malabsorption of calcium is a common disorder in osteoporotic subjects, and thus treatment with calcium supplements alone is often ineffective (Horowitz et al. 1987). Malabsorption can be corrected to some extent by the addition of 1,25 dihydroxyvitamin D₃ to the calcium regimen (Need et al. 1985). On the other hand, reduced calcium absorption efficiency has also been linked with a heritable polymorphism at the vitamin D receptor genotype, being conductive especially during low calcium intake levels (Dawson-Hughes et al. 1995). Other helpful modes of preventive action at the population level include maintaining an adequate rate of weight-bearing physical activity (Dalsky et al. 1988, Stevenson et al. 1989, for review see Stevenson et al. 1990), avoiding smoking and abuse of alcohol (Riggs & Khosla 1995), as well as paying attention to such efforts that minimize the likelihood of an individual to fall, e.g. concerning balance, eyesight and environmental factors (Masi & Bilezikian 1997).

Pharmacological intervention to decrease postmenopausal and age-related bone loss should be undertaken in persons who, because of low bone density, are deemed to be at increased risk for osteoporosis (Riggs & Khosla 1995). Hormone replacement therapy has been the most widely used form of therapy for the prevention of postmenopausal osteoporosis since the early 1990s (Eriksen et al. 1996), with current consensus recommendations indicating that this is the treatment of choice (Rozenbaum & Birkhäuser 1996). Estrogen intervention in postmenopausal women reduces accelerated bone remodeling and subsequent bone loss (for review see Lindsay 1995, Christiansen 1996). This is mainly related to the ability of estrogen to retard bone resorption (Riggs & Melton 1986, Pacifici 1996b), although stimulation of bone formation is likely to play a contributory role (Chow et al. 1992, Bain et al. 1993). The effects of estrogen therapy continue for as long as estrogens are given, but discontinuation of the therapy results in a bone loss rate comparable to that in the early postmenopausal years (Lindsay et al. 1978). On the other hand, increased age is not a contraindication to this therapy (Quigley et al. 1987, for review see Lindsay 1995). However, in older women, side effects, such as breast tenderness and recurrence of menstrual bleeding may be poorly tolerated (Prestwood et al. 1995), and in fact, no more than one third of women accept long-term hormone replacement therapy even in those countries where it is most widely used (Consensus development conference 1993). Estrogen therapy accelerates intestinal absorption of calcium either directly (Heaney et al. 1978), or indirectly by increasing the supply of 1,25-dihydroxyvitamin D₃ (Cosman et al. 1990). Progestins are usually given along with estrogen for endometrial protection in nonhysterectomized women, because of the estrogen-related increased risk of endometrial hyperplasia and cancer (Whitehead et al. 1981, for review see Agarwal & Judd 1995). Long term use of estrogens is also associated with an increased risk of developing breast cancer in postmenopausal women (for review see Bergkvist & Persson 1996). The risk is assumed to increase by 30% after 10 years" use, and by 50% after 20 years" use (Brinton et al. 1986). On the other hand, estrogen therapy has been associated with protective effects against cardiovascular diseases (for review see Bergkvist & Persson 1996). This effect stems mainly from favorable alterations in plasma lipid concentrations, and from direct effects on arteries (Limacher 1998).

In order to utilize the beneficial effects of estrogen on bone metabolism, but to avoid the undesirable side effects, selective estrogen receptor modulators (SERMs) have been the focus of many recent studies. The most promising of these preparates so far is raloxifene. It seems to have estrogen agonist effects on bone and cholesterol metabolism, and estrogen antagonist effects on uterine and mammary tissue (Delmas et al. 1997). The antagonist activity is probably mediated via classical pharmacological competition for estrogen receptor binding, and the agonist activity appears to involve novel post-receptor pathways and non-classical estrogen response elements which are activated by SERMs (Bryant & Dere 1998). However, these findings are only preliminary, and large clinical trials are currently in progress.

Intranasal administration of salmon calcitonin has also been shown to inhibit osteoclastic bone resorption. It is used to some extent by postmenopausal women unable or unwilling to tolerate long-term hormone replacement therapy. A problem in its use, in addition to its expensiveness, is an occurance of resistance, associated with formation of neutralizing antibodies (Muff et al. 1991), downregulation at receptor sites (Gruber et al. 1984), or counterregulatory mechanisms (Singer et al. 1980). However, it has only slight side effects, like transient facial flushing, nausea, rare vomiting and diarrhea, which should not necessiate drug discontinuation. Thus, calcitonin is considered perhaps the safest of all currently available pharmacological therapies for osteoporosis (for review see Chesnut 1995). Calcium supplements are often given along with calcitonin to prevent induction of secondary hyperparathyroidism (Riggs & Khosla 1995).

Bisphosphonates are used increasingly to treat bone diseases characterized by increased bone resorption. They attenuate bone turnover by suppressing the activity of osteoclasts. The most common adverse events include abdominal pain, nausea, dyspepsia, constipation and diarrhea. More alarming have been the reports of some patients developing esophageal ulceration, although as a result of unrecommended administration of the second-generation bisphosphonates (for review see Jeal et al. 1997). Long-term high-dose treatment with a first-generation bisphosphonate, etidronate, has been associated with defects in mineralization (Canfield et al. 1977). A hypothetical concern regarding the long-term use of agents such as bisphosphonates that suppress bone remodelation, is a decreased ability of bone to respond to microfractures, which might then lead to progression of macrofractures (Chesnut 1995). However, no increase in fracture rates has been detected following bisphosphonate therapy so far (Harris et al. 1993).

Fluoride has the potential to increase skeletal mass. However, it has been shown to affect the crystalline structure of bone, and thus to increase its fragility (Hedlund & Gallagher 1989, for review see Riggs & Khosla 1995). This has been explained by toxic actions of fluoride ion on skeletal mineralization, impairment of the normal processes of bone resorption, and fluoride-induced decrease in strength per unit of bone (for review see Kleerekoper 1996). Other problems concerning the use of fluoride include gastrointestinal effects and a peripherial bone pain (Consensus development conference 1993). The problems in the use of fluoride stems also partly from its narrow therapeutical window, and with strict dosing, also favorable effects on fracture rates have been achieved (Reginster et al. 1998). Insulin-like growth factor and transforming growth factor are also substances that increase bone formation, but their possible usefulness in the therapy of osteoporosis is still under clinical investigation (Boonen et al. 1997).

As seen from the above, the drugs that are used for the prevention of osteoporosis are obviously effective against the progression of the disease. On the other hand, their use is not unproblematic, because of the many side effects they have expressed. Thus, developing more physiological preparations for the prevention of osteoporosis is still a challenging task.