Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?

Osteonecrosis of the jaw (ONJ) is a serious event that uncommonly complicates the natural history of bone metastatic patients treated with bisphosphonates [1]. The pathogenesis of this adverse event is unknown and probably multifactorial [2, 3]. The mechanisms by which bisphosphonates may cause ONJ are unclear. It is commonly believed that bone turnover disruption and angiogenesis reduction in local bone microenvironment induced by these drugs could affect the quality of jaw bone during growth and healing, promoting the development of a non-healing wound and osteonecrosis [1]. Bishosphonates are able to induce hypocalcaemia and hyperparathyroidism [4]; this condition could potentially be contributory. Secondary hyperparahyroidism, in fact, is a major factor responsible for renal osteodystrophy [5]. This condition favours the onset of spontaneous osteonecrosis usually observed in the femoral head region. The possible contributing effect of secondary hyperparathyroidism after bisphosphonate administration to ONJ development has never been addressed. From 2002 to 2005 ONJ has been observed in 13 breast cancer patients (aged between 42 and 75 years) with metastatic bone disease, submitted to zoledronic acid therapy (4 mg i.v. every 4 weeks) plus specific antineoplastic therapies in two Italian Oncology Institutions. All patients also received a 500 mg calcium supplement and 400 IU of vitamin D daily. Median time elapsed from starting zoledronic acid to the ONJ onset was 14 months (range 3–44). Circulating serum calcium was measured every month in all patients and values were corrected for serum albumin. Serum parathyroid hormone (PTH) levels were concomitantly evaluated in the six patients followed in one institution. Calcium and PTH values obtained at baseline conditions before starting zoledronate and in the 4 months preceding ONJ were compared with those obtained at baseline and from the 12th to 14th month of zoledronate treatment in 40 consecutive breast cancer patients followed in one institution who did not develop ONJ over the subsequent 18 months. As outlined in Table 1, at baseline conditions no difference in serum calcium levels between the two groups was observed; contrast patients destined to develop ONJ had higher PTH levels than controls. ONJ patients showed lower calcium levels and higher PTH values during zoledronate treatment than controls at all time points considered. Many of the differences attained statistical significance. In the randomised registrative study of zoledronic acid in bone metastatic breast cancer patients [5], increased PTH was observed in the first treatment months, showing a progressive decrease in the subsequent months. This pattern has been confirmed in our control patients, since, after 12 months of zoledronate treatment, serum calcium was normal and serum PTH was only slightly elevated. Patients developing ONJ showed a clear persistence of a condition of relative hypocalcaemia and secondary hyperparathyroidism in the time period preceding this adverse event. These results suggest that persistent hyperparathyroidism may be involved in the complex pathogenesis of ONJ associated with bisphosphonate treatment. Tailoring calcium and vitamin D consumption to each patient, on the basis of serum calcium and serum PTH, could potentially limit the onset of ONJ. letters to the editor Annals of Oncology