Idiopathic Osteoporosis—Is the Osteoblast To Blame?

Sundeep Khosla

Mayo Clinic and Foundation Rochester, Minnesota 55905

Address correspondence and requests for reprints to: Sundeep Khosla, Endocrine Research Unit, Mayo Clinic, West Joseph 5–164, Rochester, Minnesota 55905.


    Introduction
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 Introduction
 References
 
Tremendous progress has been made in recent years towards our understanding of the pathogenesis of involutional osteoporosis. After exclusion of individuals with clearly identifiable secondary causes of osteoporosis, estrogen deficiency and aging are the two major factors responsible for the development of osteoporosis in most patients. Despite ongoing areas of controversy, we now know many of the potential mediators of estrogen action on the skeleton (1, 2) and of the role of age-related factors, such as secondary hyperparathryoidism (3) and impaired osteoblast function (4) in the pathogenesis of age-related bone loss. In spite of these advances, however, any classification of osteoporosis continues to have a troublesome "idiopathic" category that creates a sense of insecurity for practicing clinicians.

Like most other disorders of bone and mineral metabolism, idiopathic osteoporosis was first described by Fuller Albright in 1944 (5). This group of patients consists of either premenopausal women or men with intact gonadal function who have no identifiable secondary cause for osteoporosis. To avoid overlap with "senile" osteoporosis, most definitions of this disorder have included men only up to the age of 65–70 yr. The condition is relatively uncommon, with an estimated annual incidence rate of 0.4 cases per 100,000 (6). In contrast to involutional osteoporosis, which has a female preponderance, idiopathic osteoporosis occurs with equal frequency in women and men. There is a wide clinical spectrum (6, 7, 8), perhaps because more than one disorder is involved. In some patients, the disease runs a mild course and is clinically manifested by a single or only a few vertebral fractures, even in the absence of treatment. Moreover, with the increasing use of bone densitometry, a number of relatively young individuals with low bone mass are likely to be recognized, and it is probable that many of these individuals simply failed to achieve adequate peak bone mass because of genetic or environmental factors. The usual clinical presentation, however, is the occurrence of multiple vertebral fractures over a period of 5–10 yr, with an associated loss of height. Fractures of the ribs and metatarsals are also common. In severely affected individuals, unilateral or bilateral hip fractures may occur. At the extreme end of the spectrum, patients may become incapacitated as the disease progresses and, rarely, may even die from respiratory failure.

As with involutional osteoporosis, serum values for calcium, phosphorus, and alkaline phosphatase are normal in idiopathic osteoporosis. Some (9) but not all (6) reports have noted elevated urinary calcium values. Bone histomorphometric analysis has generally revealed, as expected, the presence of both cancellous osteopenia as well as a reduction in cortical width. Bone turnover, as assessed by bone formation rates and various (albeit imprecise) histomorphometric indices of bone resorption, has been heterogeneous in these individuals.

A consistent finding in several studies, however, has been a reduction in mean wall thickness in bone biopsies from these patients (6, 10). To understand the significance of this parameter, it is helpful to review briefly the process of normal bone remodeling. This is initiated by the activation of osteoclast precursors to form osteoclasts, which then begin to excavate a cavity. A cavity of about 0.05 mm3 is excavated, followed by the activation of osteoblast precursors, which line the resorption cavity and lay down newly synthesized osteoid, which is subsequently mineralized. This coupled process of bone resorption and formation occurs at a large number of bone remodeling units in the skeleton, and the wall thickness is the distance from the base of the resorption cavity, previously excavated by the osteoclasts, to the end of the osteoid surface laid down by the osteoblasts. It thus represents an index of the amount of work done by the osteoblasts in refilling the resorption cavity. A reduction in mean wall thickness, then, implies that the osteoblasts have failed to do their work. The importance of this defect was first demonstrated by Lips et al. (4), who showed that mean wall thickness declined significantly with age in normal individuals. This forms the basis for the now widely held belief that osteoblast function decreases with age, thereby contributing to age-related bone loss. Thus, while overall bone turnover at the skeletal level increases with age, largely the result of the age-related increase in serum parathyroid hormone levels (3), the osteoblasts in elderly individuals are unable to keep up with the osteoclasts at each bone remodeling unit, resulting in bone loss. The mechanism(s) responsible for this age-related defect in osteoblast function, however, remain to be defined.

In this issue of The Journal of Clinical Endocrinology and Metabolism, Johansson et al. (11) (see page 2795) and Kurland et al. (12) (see page 2799) provide additional insights into the impairment in osteoblast function in at least a subset of male patients with idiopathic osteoporosis. As previously shown (6, 10), Johansson et al. (11) demonstrate that, as a group, these patients have a significant reduction in mean wall thickness. These investigators also assessed histomorphometric indices of bone resorption, which are painfully tedious to determine (13). By doing so, however, they were able to demonstrate that the reduction in mean wall thickness in these patients resulted, in turn, in a net negative bone balance between bone formation and resorption at each bone remodeling unit, thus leading to bone loss.

While mean wall thickness is, on average, reduced in patients with idiopathic osteoporosis, all the studies have found significant overlap in this parameter between the patients and control subjects. Indeed, in an earlier study, Marie et al. (14) noted a similar variability in histomorphometric indices in these patients and, to address this issue, separated their patients into those who appeared to have a clear impairment in osteoblast function (as assessed by the fraction of the trabecular surface covered in vivo with a double tetracycline label) versus those who appeared to have normal osteoblast function. As might be expected, the former group had a significant reduction in mean wall thickness, whereas the latter group did not. Moreover, these investigators also demonstrated that cultured osteoblastic cells from the subgroup of patients with reduced tetracycline labeled double surface and reduced mean wall thickness also had impaired proliferative capacity in vitro. In contrast, osteoblastic cells from the patients with a normal tetracycline-labeled double surface and normal mean wall thickness had in vitro proliferation indices similar to the control subjects. Thus, it appears that patients with idiopathic osteoporosis are not only heterogeneous clinically but are likely also to be heterogeneous in the specific abnormality in skeletal turnover that results in bone loss. A significant proportion, however, clearly have an impairment in osteoblast function, resulting in a net negative balance between bone formation and resorption.

As in the case of the osteoblast defect in aging, the mechanism(s) responsible for impaired osteoblast function in idiopathic osteoporosis remain unclear. To attempt to address this issue, Johansson et al. (11) and Kurland et al. (12) hypothesize that changes in the insulin-like growth factor (IGF) system might be responsible, at least in part, for the osteoblast defect in this disorder. Both IGF-I and -II are important skeletal growth factors that have potent stimulatory effects on osteoblast proliferation and differentiation in vitro. Thus, defects in this system could certainly be responsible for an impairment of osteoblast function. For the clinical investigator, however, the IGF system poses almost insurmountable hurdles. These hurdles consist principally of the IGF binding proteins (IGFBPs). The IGFBPs, six of which have been characterized to date (15), modulate the activities of the IGFs both systemically and locally. The IGFBPs are structurally homologous yet functionally distinct (15), and they serve a number of important roles, including transport of IGFs in the circulation, delivery of IGFs to target tissues, and modulation of cell responses to IGFs (15). Ninety-five percent of IGFs in the circulation are tightly bound to IGFBP-3 with an acid labile subunit (ALS) in a ternary complex of approximately 150 kDa. This complex is restricted to the vascular space and serves to limit bioavailability of IGFs to target tissues (16). Approximately 5% of IGFs circulate bound to IGFBP-1, -2, and -4 in binary complexes of approximately 50 kDa, which can cross the capillary barrier and gain access to specific tissues (16). Only an extremely small percentage of the total IGFs in the circulation are present in the unbound or free form.

Given the complexity of this system, measurement of total serum IGF-I or -II levels may or may not provide meaningful information on the actual levels of these growth factors available to a particular tissue. Moreover, since the IGFs clearly have both local and systemic effects, circulating levels of IGF-I or -II may not necessarily accurately reflect changes in the microenvironment of a particular tissue, such as bone. These problems notwithstanding, clinical investigators continue to courageously measure circulating IGF-I and -II levels in various disorders. In this issue, Kurland et al. (12) show that, as a group, male patients with idiopathic osteoporosis have lower total circulating IGF-I levels compared with age-matched controls. This reduction, while significant, is modest: the average reduction is approximately 0.75 standard deviation units. These findings are similar to previous results of Ljunghall et al. (17), although the paper from the same group by Johansson et al. (11) in this issue did not find differences in IGF-I levels between patients and controls. They did, however, note lower IGFBP-3 levels, the significance of which remains unclear.

The reason(s) for the low circulating IGF-I levels in a subset of patients with idiopathic osteoporosis remain unclear. Growth hormone is the major physiologic regulator of IGF-I production by the liver, and impaired growth hormone secretion could result in low circulating IGF-I levels. However, previous studies of growth hormone secretion in these patients have failed to identify any significant abnormalities (17). Moreover, while it is generally believed that the liver is the principle source of circulating IGFs, bone is also a major reservoir of both IGF-I and -II (15), and it is possible that the skeletal contribution to circulating IGF-I is decreased in these patients. Clearly, more studies are needed to address these important unresolved issues.

Where does this leave us with regard to the defect in osteoblast function in patients with idiopathic osteoporosis? First, it is clear that this group of patients is clinically and pathogenetically heterogeneous. Nonetheless, there is accumulating evidence that the osteoblast is clearly to blame in a significant subset of these patients, in whom it simply does not do the work it is supposed to do, resulting in a net negative balance between bone formation and resorption and thus, bone loss. Second, it does appear that circulating IGF-I levels are low, again at least in a subset of these patients. While one can envision plausible links between this finding and an impairment in osteoblast function, as Kurland et al. (12) appropriately speculate, the relationship between low or low-normal serum IGF-I levels and the development of idiopathic osteoporosis remains to be clearly defined. Thus, although studies on circulating IGF levels may provide important indirect evidence to support the hypothesis that abnormalities of this system result in impaired osteoblast function in patients with idiopathic osteoporosis, proof of this hypothesis must await the development of better techniques to assess the abnormalities in the IGFs, as well as in other growth factors, in the bone microenvironment of patients with idiopathic and other forms of osteoporosis.

Received July 3, 1997.

Accepted July 8, 1997.


    References
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 Introduction
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