Osteoporosis, a unitary hypothesis of collagen loss in skin and bone

Summary

Progress in osteoporosis has been stultified by repetitive, statistic-driven studies and catechistic reviews; in the absence of concept and hypothesis research is aimless, and the trivial associations it continually reveals, has led to the cul-de-sac of multifactorialism. A return to hypothesis-led research which seeks major causal defects and the conclusive therapies that arise from them is essential.

The hypothesis proposed evolved from research into the mechanism of senile purpura. This predicted a causal loss of skin collagen that was contrary to contemporary opinion, but was confirmed when collagen was expressed absolutely, instead as a percentage or ratio: women have less collagen than men and it decreases by 1% a year in exposed and unexposed skin. Corticosteroids (which also produce shear purpura) reduce skin collagen and androgen and virilism increase it; growth hormone produces the greatest increase, and there is a decrease in hypopituitarism. All these changes in skin collagen correspond to changes in bone density, and the circumstances are too various for coincidence. This led to the hypothesis that the changes found in skin collagen also occur in bone collagen, leading to the associated changes in bone density; thus a loss of collagen in skin and bones with aging is the causal counterpart to loss of bone density in senile osteoporosis.

If this is correct then, as with aging, androgen and virilisation, corticosteroids, growth hormone and hypopituitarism, changes in bone density should correspond to systemic changes in skin collagen. This correspondence is found to occur in osteogenesis imperfecta and Ehlers-Danlos syndrome, two genetically discrete families of disordered collagen production, and other situations, e.g., scurvy and homocystinuria. A primary loss of collagen in osteoporotic bones is an essential prediction of the hypothesis; in fact this loss is well established but, inexplicably, it has been assumed to be secondary to the bone loss.

Because of the comparable changes in skin and bones, the hypothesis implies that skin collagen could be used to predict the state of the bones and their response to treatment. It also implies androgen should be an effective treatment of osteoporosis, and growth hormone even more effective (likewise, of course, skin aging). More importantly, skin collagen and the production of collagen by skin fibroblasts could be used for the assay and industrial development of more potent, if not less toxic treatments and prevention of loss of bone (and skin) substance.

Introduction

The prevalence of osteoporosis has increased more than our understanding of its cause and treatment. Why? An outsider may see problems which have become too familiar to be noticed by workers in the field. I therefore present a hypothesis to explain lack of progress before presenting a different approach.

With a few, mostly recent, exceptions publications since 1960 have revolved in a slow spiral of fashion round the same interacting themes, periodically fortified by “reviews”, the mind-closing, repetitive effect of which is to encourage the finding of new evidence that fits into the framework of old beliefs, and to tame and incorporate whatever does not. The underlying themes are too well known to require yet another repetition and, like the reviews that promote them, carry little of interest to the critical reader. Indeed, one of the Lancet’s last series of reviews on osteoporosis [1], [2], [3], [4], which provided yet another consolidatory exposition of the osteoporotic theme park, finally admitted the absence of solid aetiological evidence yet, curiously, found itself able to conclude “osteoporosis… has no single cause” and, worse still, is “likely to have a heterogenous cause [2]”! Unfortunately that unthinking assumption is now commonplace (e.g. [5]).

Reviews are rarely intellectually neutral, and the packages of pre-conceptualised information they provide can mat the mind with cliché. And, sadly, they have helped mire osteoporosis in the morass of multifactorial causation, a contemporary belief destructive to research and understanding. In part, this belief relates to the contemporary muddle about the meaning of “the cause” of disease and the related absurdities of “holism” and stochastic chaos [5] – ideas which mate so well with relativist compromise; science does not dice with relativism. More prosaically, but equally dangerously, it also relates to the suffocation of research by a popular form of statistical epidemiology, which in turn elevates the inevitable finding of trivial associations into the lazy concept of multifactorial aetiology, that last resort of the intellectually destitute. Now it is not the time for a discussion of this muddle, or the reason for my certainty that, by contrast, all diseases that can be controlled (and we should maintain of interest, albeit of a different type in any that, perhaps, cannot) will be found to have single points of effective attack, notwithstanding the inevitable multiplicity of impinging influences. The role of the clinical scientist is to escape from the web of those impinging influences, those inevitable but minor “factors” that can always be found and promoted, and where possible to fly away on the wings of a therapeutic missile. The search for Erhlich’s sublime bullets is still what the clinical researcher should aim at; they are devastatingly effective, and like discreteness of disease, make a lethal counter to the soggy multifactorial concept.