Bone destruction and hypercalcemia in plasma cell myeloma. (1986)

M YELOMA is almost always associated with a marked increase in destructive osteolytic bone lesions. Bone destruction in myeloma is responsible for the most distressing clinical features of this disease, including intractable bone pain, fractures occurring either spontaneously or following trivial injury, and hypercalcemia with its attendant symptoms and signs. Eighty percent of patients present with bone pain as a predominant symptom.’ The bone lesions occur in several patterns. Occasionally, patients develop single osteolytic lesions that are associated with solitary plasmacytomas. Some patients have diffuse osteopenia, which mimics the appearance of osteoporosis, and is due to the myeloma cells being spread diffusely throughout the axial skeleton. In most patients there are multiple discrete lytic lesions occurring at the site of deposits or nests of myeloma cells. Bone scans in myeloma show very little abnormality. Isotopic bone scans are performed with labeled bisphosphonates that are taken up at sites of mineral deposition and reflect increased activity of bone forming cells. Myeloma is characterized by discrete lytic lesions with little increase in formation and this is probably the explanation for the difference in appearance between the bone scan in myeloma and the bone scan in breast cancer, where osteoblast activity is frequently increased. Similarly, serum alkaline phosphatase, which also reflects osteoblast activity, is usually not increased in patients with myeloma, unless they have coexistent pathological fractures. Most available evidence suggests that the mechanism of bone destruction in myeloma is primarily osteoclastic. This was first suggested in a study in which morphologic examination was performed on autopsy and biopsy samples of bone from a series of 37 patients with myeloma.’ In this series, active osteoclastic bone resorption was found predominantly in specimens that contained more than 20% marrow myeloma cell infiltration. In specimens of bone from myeloma patients that contained few or no myeloma cells, little osteoclast activity or evidence of active bone resorption was observed. This suggested that the myeloma cells caused the osteoclast activity that led to increased bone resorption. The association between increased osteoclasts on bone resorbing surfaces and areas of heavy myeloma cell infiltration was confirmed in a later study using the technique of quantitative bone histomorphometry on undecalcified transiliac bone biopsies from 118 patients with myeloma.3 Surprisingly, no decrease in mean trabecular bone volume was observed, but abnormalities were observed in bone formation. Bone forming surfaces were increased away from the areas of heavy myeloma cell infiltration but the osteoid seams were reduced in thickness and had a lowered calcification rate. The authors suggested that the activity of individual osteoblasts may be reduced in many patients with myeloma, accounting for these latter findings. Further evidence that the mechanism of bone resorption in myeloma is primarily osteoclastic is provided by data that show drugs that are specific inhibitors of osteoclast activity such as the bisphosphonates, mithramycin, and corticosteroids are usually very effective in lowering the serum calcium in patients with myeloma.4,“16 Not all workers have found increased osteoelastic resorption in myeloma. Schechter et al’ saw little evidence of osteoclastic activity in the patients they studied. MacDonald et al” suggested that murine myeloma cells had the capacity to destroy bone directly in vitro independent of osteoclasts, in a similar manner described earlier for human breast cancer cells.’ Whether this phenomenon has an in vivo significance is not currently known, In some patients with myeloma, osteosclerosis