The thesis tests the idea that renal metabolic acidosis contributes to bone
disease, rather than being an epiphenomenon.
Data from fifty patients with varying degrees of chronic renal failure,
non-dialysis dependent, were collected. There were eleven cases with
clinical osteomalacia, supported by radiological changes, raised serum
alkaline phosphatase, and wide osteoid seams on bone histology.
Investigative techniques that were used were: standard blood and urine
biochemistry (always simultaneous and fasting); biochemistry of
twenty-four hour urine collections; radio calcium absorption test;
metabolic balance combined with isotopic bone formation rates;
quantitative radiology of the 2nd metacarpal cortex; quantitative bone
histology of iliac crest.
Data gathered were: Plasma calcium, phosphorus, creatinine, alkaline phosphatase,
GFR, fasting urine Ca/Cr ratio, calcium excretion
per unit GF (CaE), P/Cr, PE, TMP; urine calcium, phosphorus,
creatinine, hydroxyproline per 24 hours. Radio-calcium absorption was fraction of
dose per hour. Mineralisation rate per day (m) was estimated by the
expanding pool method, using radio-calcium, resorption by the
difference of m from the balance. The ratio of cortical to total cross
sectional area at the mid point of the second metacarpal, and cortical
width, allowed estimation of the state of cortical bone.
Undecalcified iliac crest biopsies allowed estimation of forming surfaces, osteoid
seam thickness, and trabecular bone mass. Iliac crest cortical bone was
also examined. The relation between serum alkaline phosphatase and
osteoid and resorbing surfaces was tested.

Overall, the degree of bony abnormality was strongly associated with raised
alkaline phosphatase, lower plasma calcium, lower plasma bicarbonate
but independent of GFR. Acidosis was strongly associated with
thinner metacarpal cortex, greater trabecular osteoid surface, and
higher osteoid mass. In balance studies, calcium balance and
mineralisation rate increased when acidosis was corrected but plasma
calcium did change significantly. In vitamin D deficient rats with normal
renal function but made acidotic with acid loading, rickets was more
severe compared to non-acidotic animals, and healing was
delayed after administration of 25-OH cholecalciferol.
Taken together, the data suggested that acidosis was a directly
causative factor of bone disease defined by raised alkaline
phosphatase, excess osteoid and thin cortices. Hypocalcemia could be
explained by a renal tubular leak even in the presence of reduced GFR.
It was not explained by net mineralisation which was equaled by
resorption nor by malabsorption of calcium. However,
hypocalcaemia itself was not a direct cause of the observed bony changes.
Administration of vitamin D to hypocalcemic patients corrected the
plasma calcium by increasing renal tubular reabsorption of calcium in
all cases, though in some, calcium was also delivered from elsewhere,
bone or diet. Total plasma phosphate did not appear to influence the
development of bone disease, but this neglects the possible role of ionised species.

Concepts put forward: in chronic renal failure, bone disease,
particularly osteomalacia, is driven by acidosis. Cortical bone
undergoes endosteal resorption and trabecular bone density increases.
There is a net transfer of mineral from cortical bone to trabecular
bone. Overall, the skeleton remains in balance.
Hypocalcemia correlates with bone disease but cannot explain it.
Acidosis inhibits mineralisation.
However, overall, mineralisation rate is increased implying that slow
mineralisation is taking place over a greatly increased surface.
Inhibition of mineralisation at individual sites by acidosis might be
explained
1) By a shift in the phosphate species away from trivalent
phosphate. This species is biochemically the most reactive with
calcium, and is very sensitive to pH change, so CaP association would
be diminished.
2) Inhibition of activity of alkaline phosphatase, the
concentration of which paralleled the rate of bone formation, or amount
of osteoid surface. Alkaline phosphatase activity is highly sensitive to pH (literature data) in
the range seen among the patients in this study. To invoke the role of
alkaline phosphatase as causative implies that it must play a role in
promoting mineralisation (as has long been suggested).
3) If mineralisation is dependent on seeding of calcification sites by matrix
vesicles, and acidosis inhibits calcium uptake by vesicles (literature
data), this would explain the association between acidosis and local
mineralisation failure documented here.
4) Acidosis might directly inhibit the action of vitamin D in some way, but there are no
convincing data to support this.