Humoral hypercalcemia of malignancy is a common complication of lung and certain other cancers. The hypercalcemia results from the actions of tumor factors on bone and kidney. We report here the isolation of full-length complementary DNA clones of a putative hypercalcemia factor, and the expression from the cloned DNA of the active protein in mammalian cells. The clones encode a prepro peptide of 36 amino acids and a mature protein of 141 amino acids that has significant homology with parathyroid hormone in the amino-terminal region. This previously unrecognized hormone may be important in normal as well as abnormal calcium metabolism.

https://science.sciencemag.org/content/sci/237/4817/893.full.pdf

A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression

I. Introduction II. Chemistry III. Effects in Vivo A. Inhibition of calcification B. Inhibition of bone resorption C. Effects on bone formation D. Effects on noncalcified tissues IV. Mechanisms of Action A. Calcification B. Bone resorption C. Other effects V. Pharmacokinetics VI. Animal Toxicology and Human Adverse Events A. Animal toxicology B. Human adverse events VII. Conclusion

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Bisphosphonates: Mechanisms of Action

Because of its failure to act when given orally and its rapid hydrolysis when given parenterally, pyrophosphate was used therapeutically only in scintigraphy and against dental calculus. This prompted us to search for analogs that showed similar physicochemical activity but resisted enzymatic hydrolysis and, therefore, would not be degraded metabolically. The bisphosphonates fulfilled these conditions. This review will deal with the mechanisms of action of these compounds. In vitro results, as well as results both in animals and humans, will be integrated in an attempt to deduce the current state of the art. Various reviews have been published recently on bisphosphonates and may be consulted also for information on other aspects (8 ‐14). Since the literature in this field is plentiful, selective citation was necessary. Priority is given to papers dealing with the mechanisms of action. Since many papers often deal with the same finding, in most cases only the first ones are quoted. Subsequent papers are quoted only if they convey new knowledge.

/pdf/bisphosphonates-mechanisms-of-action-2dti1bc2gx.pdf

Bisphosphonates: mechanisms of action.

Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone. In vitro alendronate bound to bone particles with a Kd of approximately 1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 x 10(-3) fmol/microns 2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts.

/pdf/bisphosphonate-action-alendronate-localization-in-rat-bone-c7rn2hyeqf.pdf

Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.

Background Despite its association with disability, death, and increased medical costs, osteoporosis in men has been relatively neglected as a subject of study There have been no large, controlled trials of treatment in men Methods In a two-year double-blind trial, we studied the effect of 10 mg of alendronate or placebo, given daily, on bone mineral density in 241 men (age, 31 to 87 years; mean, 63) with osteoporosis Approximately one third had low serum free testosterone concentrations at base line; the rest had normal concentrations Men with other secondary causes of osteoporosis were excluded All the men received calcium and vitamin D supplements The main outcome measures were the percent changes in lumbar-spine, hip, and total-body bone mineral density Results The men who received alendronate had a mean (±SE) increase in bone mineral density of 71±03 percent at the lumbar spine, 25±04 percent at the femoral neck, and 20±02 percent for the total body (P<0001 for all comparisons with base

Alendronate for the treatment of osteoporosis in men

Focal osteomalacia due to low-dose diphosphonate therapy in paget's disease

Comparison of three intravenous bisphosphonates in cancer-associated hypercalcaemia.

Although osteoporosis is generally regarded as a disease of women, up to 30% of hip fractures and 20% of vertebral fractures occur in men. Risk factors for osteoporotic fractures in men include low body mass index, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, diseases that predispose to low bone mass, and conditions increasing the risk of falls. The key drugs and diseases that definitely produce a decrease in bone mineral density (BMD) and/or an increase in fracture rate in men are long-term corticosteroid use, hypogonadism, alcoholism and transplantation. Age-related bone loss may be a result of declining renal function, vitamin D deficiency, increased parathyroid hormone levels, low serum testosterone levels, low calcium intake and absorption. Osteoporosis can be diagnosed on the basis of radiological assessments of bone mass, or clinically when it becomes symptomatic. Various biochemical markers have been related to bone loss in healthy and osteoporotic men. Their use as diagnostic tools, however, needs further investigation. A practical approach would be to consider a bone density more than one SD below the age-matched mean value (Z < -1) as an indication for therapy. The treatment options for men with osteoporosis include agents to influence bone resorption or formation and specific therapy for any underlying pathological condition. Testosterone treatment increases BMD in hypogonadal men, and is most effective in those whose epiphyses have not closed completely. Bisphosphonates are the treatment of choice in idiopathic osteoporosis, with sodium fluoride and anabolic steroids to be used as alternatives.

/pdf/management-of-male-osteoporosis-report-of-the-uk-consensus-1ik0gr937s.pdf

S. H. Ralston

Papers

Focal osteomalacia due to low-dose diphosphonate therapy in paget's disease

Comparison of three intravenous bisphosphonates in cancer-associated hypercalcaemia.

Management of male osteoporosis: report of the UK Consensus Group.

Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroidsicalcitonin in treatment of cancer-associated hypercalcaemia

Mineralisation defects with pamidronate therapy for Paget's disease