Pamidronate (Aredia)

Number: 0672


Aetna considers pamidronate (Aredia) medically necessary for treatment of any of the following indications:

  • Bone metastases or bone pain from cancer; or
  • Chronic nonbacterial osteomyelitis; or
  • Chronic recurrent multifocal osteomyelitis (CRMO) in SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis); or
  • Complex regional pain syndrome refractory to other treatments; or
  • Cystic fibrosis osteoporosis; or
  • Hypercalcemia of malignancy; or
  • Low bone mass or osteoporotic fractures following organ transplantation; or
  • Metastatic breast cancer -

    • for post-menopausal women receiving adjuvant therapy along with calcium and vitamin D supplementation to maintain or improve bone mineral density and reduce risk of fractures; or
    • used with calcium and vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastasis in persons with expected survival of ≥3 months and adequate renal function; or

  • Multiple myeloma - in combination with myeloma primary therapy; or
  • Osteogenesis imperfecta, severe cases presenting with bone pain and repeated fractures; or
  • Osteopenia in quadriplegic cerebral palsy; or
  • Osteoporosis due to immobilization in children, treatment; or
  • Paget's disease (osteitis deformans), symptomatic and characterized by abnormal and accelerated bone metabolism in 1 or more bones, where oral bisphosphonates have been ineffective.  (Signs and symptoms may include bone pain, deformity, and/or fractures; increased concentrations of serum alkaline phosphatase and/or urinary hydroxyproline; neurologic disorders associated with skull lesions and spinal deformities; and elevated cardiac output and other vascular disorders associated with increased vascularity of bones); or
  • Polyostotic fibrous dysplasia bone pain; or
  • Refractory immobilization hypercalcemia; or
  • Systemic mastocytosis associated osteopenia or osteoporosis; or
  • Thalassemia-associated osteoporosis.

Aetna considers pamidronate experimental and investigational for all other indications, including any of the following because its effectiveness for these indications has not been established:

  • Acute back pain associated with vertebral crush fracture, treatment; or
  • Androgen deprevation therapy for prostate cancer, reduction of fracture risk in men undergoing treatment; or
  • Avascular necrosis, treatment; or
  • Bacterial osteomyelitis, treatment; or
  • Bone graft in maxilla-facial reconstruction (management); or 
  • Calcinosis in juvenile dermatomyositis; or
  • Charcot arthropathy, treatment; or
  • Chondrodystrophy, treatment; or
  • Chronic inflammatory joint disease not treated by glucocorticoids, treatment; or
  • Chronic low back pain, treatment; or
  • Fanconi Bickel syndrome, treatment; or
  • Gaucher's disease, treatment; or
  • Glucocorticoid-induced osteoporosis, treatment; or
  • Hepatic osteodystrophy; or
  • Hypercalcemia associated with hyperparathyroidism or other nontumor-related conditions other than immobilization, treatment; or
  • Lumbar spinal stenosis, treatment; or
  • Osseointegration enhancement, or
  • Osteoarthropathy, treatment; or
  • Osteoblastic lesions in prostate cancer, treatment; or
  • Osteoporosis or osteopenia associated with androgen deprivation therapy for prostate cancer, treatment; or
  • Osteoporosis associated with paralysis (immobilization), prevention; or
  • Osteoporosis associated with paralysis (immobilization) in adults, treatment; or
  • Post-menopausal osteoporosis, treatment; or
  • Spinal giant cell tumors; or
  • Spinal muscular atrophy; treatment; or
  • Spondyloarthropathy, treatment; or
  • Stiff man/stiff person syndrome, treatment.

See also CPB 0524 - Zoledronic Acid and CPB 0666 - Teriparatide (Forteo).


Bisphosphonates have been shown to be effective in the treatment of osteoporosis.  Alendronate (Fosamax) and risedronate (Actonel) have been the most extensively studied bisphosphonates under clinical trials conditions.  Both drugs can lower the risk of vertebral and hip fractures by 25 to 50 %.  However, oral bisphosphonates exhibit gastro-intestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory.  Pamidronate (Aredia), an intravenous (IV) bisphosphonate, is a much more potent inhibitor of bone resorption than etidronate.  Pamidronate is a bisphosphonate that is administered by injection because it is poorly tolerated orally. 

Pamidronate is approved by the FDA for use in hypercalcemia of malignancy, Paget's disease of the bone, osteolytic bone metastases from breast cancer and osteolytic lesions of multiple myeloma.  Newer more potent bisphosphonates, such as oral ibandronate and intravenous zoledronic acid (Zometa), which will allow much less frequent administration, are currently being investigated (Reid et al, 2002).  Moreover, bone-forming agents (e.g., teriparatide) provide another therapeutic option for the treatment of severe osteoporosis.

The National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2019) recommends pamidronate for the following indications:

  • Breast Cancer - Invasive - Used with calcium and vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastasis in patients with expected survival of ≥3 months and adequate renal function
  • Breast cancer - Consider in postmenopausal (natural or induced) patients receiving adjuvant therapy along with calcium and vitamin D supplementation to maintain or improve bone mineral density and reduce risk of fractures
  • Kidney cancer - Used as a component of best supportive care for bony metastases
  • Multiple myeloma - Used in combination with primary myeloma therapy
  • Non-small cell lung cancer - Consider for supportive therapy in patients with bone metastases
  • Systemic mastocytosis - Treatment for osteopenia/osteoporosis
  • Thyroid Carcinoma - Anaplastic Carcinoma, Follicular Carcinoma, Hürthle Cell Carcinoma, Medullary Carcinoma, Papillary Carcinoma - Consider for bone metastases.  

Hypercalcemia of malignancy is a potentially life-threatening complication of cancer resulting from increased bone resorption by osteoclasts.  Management of patients with cancer-related hypercalcemia primarily consists of rehydration therapy as well as the use of a variety of available drugs that inhibit bone resorption.  One of the drugs used for this purpose is IV bisphosphonate, which has been demonstrated to lower serum calcium levels by interfering with osteoclast activity and stimulating osteoclast apoptosis.  In fact, bisphosphonates are now considered the standard treatment for cancer-related hypercalcemia (Berenson, 2002; Hurtado and Esbrit, 2002; Body and Mancini, 2002).

Paget's disease of bone, also known as osteitis deformans, is a non-malignant metabolic disease of unknown etiology, with the spine being involved in over 50 % of cases.  It is one of the most common diseases to affect bone, yet it is rare before the age of 50.  Moreover, Paget's disease of bone affects up to 2 to 3 % of the population over the age of 60 years.  This metabolic bone disorder is characterized by abnormalities of bone turnover, structure and architecture.  Bisphosphonates are the first-choice treatment option for patients with active disease (Schneider et al, 2002; Keen, 2003).

The American Society of Clinical Oncology (ASCO) convened an expert multi-disciplinary panel to determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition.  The panel recommended IV pamidronate for patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy (Hillner et al, 2000).  A Cochrane evidence review of randomized controlled clinical trials of bisphosphonates in breast cancer concluded that IV pamidronate has been demonstrated to be effective in improving metastatic bone pain (Pavlakis et al, 2005).

The ASCO also convened an expert multi-disciplinary panel to determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of lytic bone disease in multiple myeloma (MM) and to determine their respective role relative to other conventional therapies for this condition (Berenson et al, 2002).  The available evidence indicates that oral clodronate, IV pamidronate, and IV zoledronic acid are superior to placebo in reducing skeletal complications.  A reduction in vertebral fractures has consistently been observed across all studies.  No agent has shown a definitive survival benefit.  Intravenous zoledronic acid has recently been shown to be as effective as IV pamidronate.  Because there are no direct comparisons between clodronate and pamidronate or zoledronic acid, the superiority of one agent can not be definitively established.  However, the panel recommended only IV pamidronate or zoledronic acid in light of the use of the time to first skeletal event as the primary end point and more complete assessment of bony complications in studies evaluating it.  Additionally, clodronate is not available in the United States.  The choice between pamidronate and zoledronic acid will depend on choosing between the higher drug cost of zoledronic acid, with its shorter, more convenient infusion time (15 mins), versus the less expensive drug, pamidronate, with its longer infusion time (2 hrs).  The panel concluded that bisphosphonates provide a meaningful supportive benefit to MM patients with lytic bone disease.

A Cochrane evidence review of clinical trials concluded that adding bisphosphonates to the treatment of myeloma reduces pathological vertebral fractures and pain but -- from the published evidence -- not mortality (Djulbegovic et al, 2002).  The review stated that, based upon current evidence, clodronate or pamidronate may be the preferred agents for this indication.

Mayo Clinic's consensus statement on the use of bisphosphonates (e.g., pamidronate and zoledronic acid) in MM (Lacy et al, 2006) recommended discontinuing bisphosphonates after 2 years of therapy for patients who achieve complete response and/or plateau phase.  For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be decreased to every 3 months.

Both pamidronate and zoledronic acid have been shown to reduce bone loss in men undergoing androgen deprivation therapy in prostate cancer.  However, zoledronic acid has also been shown to increase bone mineral density in these patients (Smith, 2003).  In addition, zoledronic acid has been shown in randomized controlled clinical studies to reduce the incidence of skeletal-related events in men undergoing androgen-deprivation therapy.  In addition, zoledronic acid has been shown in clinical trials to reduce the incidence of skeletal events in men with osteoblastic bone metastases from prostate cancer.  By contrast, a clinical study comparing pamidronate to placebo control in men with bone metastases due to prostate cancer found no significant differences in incidence of skeletal events between the 2 groups (Lipton et al, 2002).

Although there is evidence that pamidronate increases bone mass, there are no clinical trials demonstrating that intravenous pamidronate decreases fracture rate in post-menopausal osteoporosis or glucocorticoid-induced osteoporosis.  As the experience with etidronate has shown, increases in bone mass may not translate into a reduction in fracture incidence; the quality of the bone that is formed is also important.  Solomon (2002) suggested that the notion that an IV dose of a bisphosphonates once-yearly or even less often can be used for the treatment of post-menopausal osteoporosis is encouraging.  However, before this treatment can be recommended for routine use, more research is needed to ascertain if the risk of fractures is actually lowered and to determine the safety of long-term use of this treatment.  This is in accordance with the report by Crandall (2002) who stated that the combination of bisphosphonates (alendronate) with estrogen can increase bone mass density (BMD) more so than each medication given singly in post-menopausal osteoporotic women; however, the utility of these combinations rests on whether bone density changes will translate into decreased fracture rates.

Guidelines on treatment of glucocorticoid-induced osteoporosis from the American College of Rheumatology state that “[b]oth alendronate and risedronate are recommended for the prevention and treatment of glucocorticoid-induced bone loss” and to “[c]onsider calcitonin as second-line agent if patient has contraindication to or does not tolerate bisphosphonate therapy.”  An evidence-based assessment conducted by the Royal College of Physicians (2002) noted that while pamidronate and a number of other bisphosphonates have been shown in clinical studies to reduce glucocorticoid-induced bone loss, only the bisphosphonates risedronate, alendronate, and etidronate have been shown to reduce the incidence of fractures.

Rapid bone loss following organ transplantation has been attributed to numerous factors, including hypogonadism, cyclosporine, and glucocorticoids.  Clinical studies have demonstrated the effectiveness of intravenous pamidronate in reducing the rate of bone loss following organ transplantation (ICSI, 2002).  In addition, there is limited evidence that pamidronate reduces the incidence of fractures following organ transplantation (Hodsman, 2001; Cahill et al, 2001; Aris et al, 2000; Trombetti et al, 2000; Fan et al, 2000; Reeves et al, 1998).

Orcel and Beaudreuil (2002) noted that the available evidence does not support the use of bisphosphonates in the management of patients with reflex sympathetic dystrophy, acute back pain after a vertebral crush fracture, and chronic inflammatory joint disease not treated by glucocorticoids.  Although pamidronate has been shown to increase bone mass in post-menopausal osteoporosis and glucocorticoid-induced osteoporosis, there are no published prospective randomized controlled clinical trials of the effectiveness of IV pamidronate in reducing fracture risk in these conditions.

Saad and Schulman (2004) recently reviewed the evidence regarding the role of bisphosphonates in prostate cancer.  These investigators concluded that pamidronate has been shown to prevent bone loss, whereas zoledronic acid has been shown to increase bone mass in men undergoing androgen deprivation therapy.  Finally, zoledronic acid is the only bisphosphonate that has demonstrated efficacy in reducing objectively measurable skeletal complications in patients with bone metastases secondary to prostate cancer.  This is in agreement with the findings of Small et al (2003) as well as Rosen (2004).  Rosen stated that clinical trials addressing the treatment of bone metastases related to prostate cancer have shown zoledronic acid to be the only bisphosphonate to have a significant positive effect on skeletal-related events.

Small and colleagues (2003) performed a combined analysis of 2 multi-center, randomized, placebo-controlled studies of pamidronate for men with metastatic prostate cancer.  The authors concluded that pamidronate failed to demonstrate a significant overall treatment benefit compared with placebo in the palliation of bone pain or reduction of skeletal-related events (defined as pathologic fracture, radiation or surgery to bone, spinal cord compression, or hypercalcemia).  In an editorial that accompanied the article by Small et al, Kelly and Steineck (2003) stated that “the cumulative data on bisphosphonates in patients with castrate metastatic prostate cancer to date have not shown substantial clinical benefits to patients .... until this evidence is provided, routine administration of bisphosphonates in castrate metastatic prostate cancer can not be recommended”.

A review of the evidence for the use of pamidronate for ankylosing spondylitis and spondyloarthropathies concluded that results of preliminary studies have yielded promising results, but that “[f]urther studies are required to confirm these preliminary data and to better determine the optimal regimen (dosage and rhythm) of administration” (Toussirot and Wendling, 2005).

There is limited evidence from case reports and uncontrolled case series of the effectiveness of pamidronate in the treatment of hypercalcemia associated with immobilization.  Massagli and Cardenas (1999) reported on the results of pamidronate treatment of patients with acute spinal cord injury (SCI) who developed immobilization hypercalcemia.  A total of 9 patients (7 men, 2 women), aged 15 to 41 years, with SCI (8 tetraplegia, 1 paraplegia) were treated using pamidronate between 1994 and 1998.  A single dose of 60 mg of pamidronate resolved the hypercalcemia or its symptoms in 7 (78 %) patients within days.  One patient required a 2nd dose (90 mg) and 1 patient required 3 additional doses (the 4th at 90 mg) to achieve resolution of the hypercalcemia or symptoms.  These investigators reported that side effects were mild, and included drug-related fever in 1 patient and transient asymptomatic hypocalcemia in 4 patients.  They reported that pamidronate was effective in treating immobilization hypercalcemia caused by SCI.  These investigators commented that the advantages of pamidronate include its effectiveness, the duration of treatment, ease of administration, and elimination of the need for long-term intravenous saline or daily medications.

There is, however, insufficient evidence of the effectiveness of pamidronate in preventing bone loss from immobility.  In a prospective placebo-controlled study (n = 11), Bauman et al (2005) examined the effectiveness of pamidronate in reducing bone loss in persons with acute SCI.  Pamidronate (treatment) or normal saline (placebo) was administered intravenously at baseline (22 to 65 days after injury) and sequentially over 12 months, with follow-up at 18 and 24 months.  Regional BMD was lost over time, regardless of group.  In the treatment group compared with the placebo group, these investigators noted a mild early reduction in loss of total leg BMD.  Significant bone loss from baseline occurred earlier in the placebo group at the regional sites than in the treatment group.  However, by the end of the treatment and follow-up phases, both groups demonstrated a similar percent bone loss from baseline.  The authors concluded that despite an early reduction in bone loss, pamidronate failed to prevent major, long-term bone loss in persons with acute neurologically complete SCI.

Chronic nonbacterial osteomyelitis (CNO) is a sterile inflammatory bone disorder of unknown etiology. CNO is currently thought to be in the spectrum of autoimmune and autoinflammatory disorders. Non-infectious inflammatory lesions of the mandible occur in chronic recurrent multi-focal osteomyelitis (CRMO).  Diffuse sclerosing osteomyelitis of the mandible (DSOM) is a condition thought to be a localized form of CRMO. Treatment of CNO has been directed at reducing pain and inflammation, with the intent of halting bone destruction and disease progression. Bisphosphonate therapy, especially intravenous pamidronate, has been proposed as a treatment for patients with both CRMO and DSOM who do not improve with non-steroidal anti-inflammatory drug (NSAID) treatment. A review of CNO published in Pediatrics (Borzutzky, et al., 2012) states that, due to the low prevalence of this disease, most treatment reports involve small series or individual cases. The review article explains that NSAIDS are generally used as first-line therapy, but frequently patients require additional treatments. The review states that small series have reported successful treatment of CNO with bisphosphonates. The article cites several studies involving use of pamidronate for this indication.

Yamazaki and colleagues (2007) reported a juvenile case of DSOM that showed a favorable response to pamidronate.  Although conventional treatments had been ineffective for 5 years, pamidronate administration resulted in conspicuous improvement both clinically and radiographically.  Severe adverse reaction was not found except for low-grade fever and lassitude on the day following administration.  During the course of the treatment, however, non-suppurative osteomyelitis of the right humerus also occurred, leading to the established diagnosis of chronic recurrent multi-focal osteomyelitis.  Pamidronate therapy was again performed successfully with near disappearance of clinical symptoms.  Both bone-specific alkaline phosphatase (bone formation marker) and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (bone resorption marker) showed a marked decrease with pamidronate therapy, suggesting that pamidronate is useful for the treatment of chronic recurrent multi-focal osteomyelitis with inhibitory effect on bone turnover.

Olivieri et al (2006) stated that the SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome (SaS) includes different skeletal manifestations such as recurrent multi-focal osteomyelitis, osteitis and arthritis, which are frequently associated with different forms of skin pustulosis (palmoplantar pustulosis, pustular psoriasis and severe acne).  This syndrome is strictly related to the spondyloarthopathies (particularly to psoriatic arthritis) and many SaS cases fulfill the classification criteria for the spondyloarthopathies.  Because SaS is an uncommon disease, current knowledge regarding its therapy is based on limited experiences gained by treating mainly small groups of patients.  As a consequence, its treatment is still empiric.  Several drugs (including NSAIDs, corticosteroids, sulfasalazine, methotrexate, cyclosporine, leflunomide, and calcitonin) have been administered and obtained conflicting results.  The use of antibiotics, due to the isolation of Propionibacterium acnes from the bone biopsies of several subjects with SaS, has not represented a turning point in therapy, although some patients are responsive to this treatment.  Initial reports concerning the administration of bisphosphonates (pamidronate and zoledronic acid) and of an anti-TNF-alpha agent (infliximab) are very promising for the future.  In any case, larger, multi-center, controlled, double-blind studies are needed to emerge from the present pioneering phase.

Kerrison et al (2004) reported their clinical experience with pamidronate in childhood SAPHO syndrome.  The standard dosing regime for pamidronate was 1 mg/kg to a maximum of 30 mg, administered daily for 3 consecutive days, repeated thrice-monthly as required.  Response to treatment was determined by clinical observation, patient subjective response and reduction in other treatments.  A total of 7 girls were treated, with a median (range) age at diagnosis of 11 years (9 to 15 years).  All patients demonstrated a beneficial clinical response, with relief of pain, increased activity and improved well-being.  Subsequent courses of pamidronate were used in all patients.  Other medications including corticosteroids and methotrexate could subsequently be stopped.  Transient symptoms were associated with the initial course of pamidronate in some patients.  No serious adverse events were reported.  The authors concluded that pamidronate was associated with a marked improvement in function and well-being, and a reduction of pain and use of other medications in all patients, with no significant adverse effects.  However, this study represented preliminary clinical data.  The authors stated that a prospective multi-center study is needed to evaluate the role and long-term safety of pamidronate in the management of childhood SAPHO syndrome.

An OrphaNet review of SAPHO syndrome (Shilling, 2004) stated that bisphosphonates have replaced calcitonin for the treatment of refractory cases of chronic recurrent multifocal osteomyelitis (CRMO). These are administered by mouth (alendronate) or intravenously (pamidronate). The review states that patients respond well to these treatments. Rukavina (2015) explained that bisphosphonates act by reducing bone turnover, but have no effect on the skin lesions of SAPHO syndrome.

Gaucher's disease, the most prevalent lysosomal storage disorder, is characterized by an autosomal recessive inheritance of a deficiency of lysosomal acid glucocerebrosidase.  Three clinical phenotypes are recognized:
  1. type 1 (non-neuronopathic),
  2. type 2 (acute neuronopathic), and
  3. type 3 (subacute neuronopathic).
Bone lesions are associated with type 1 and type 3 Gaucher's disease.  Skeletal involvement is secondary to the progressive accumulation of histiocytes and macrophages laden with glucosylceramide in bone marrow.  Pamidronate has been employed in treating patients with Gaucher's disease; however, there is insufficient evidence to support the effectiveness of this approach.

Ciana et al (1997) reported their findings of 5 patients (3 women and 2 men; age range of 24 to 60 years) who had type 1 Gaucher's disease and severe skeletal involvement (as defined by a combination of osteopenia, osteonecrosis-osteosclerosis, and severe chronic bone pain) who were treated with pamidronate.  The drug was given intravenously (45 mg once every 3 weeks for 3 to 5 months); patients were also given 500 mg of elemental calcium daily.  The bone pain decreased rapidly in each patient.  The treatment was accompanied by decreases in markers of both bone resorption (urinary hydroxyproline and total deoxypyridinoline [p = 0.08 for both] and urinary calcium [p = 0.04]) and bone formation (serum osteocalcin, p = 0.04).  At the end of the treatment period, the mean (+/- SD) BMD of the lumbar spine, as determined by dual-energy x-ray absorptiometry, increased from 0.79 +/- 0.07 to 0.84 +/- 0.05 g per square centimeter (p = 0.04).

Fibrous dysplasia (FD) of bone, a rare disease caused by osteoblastic lineage differentiation defects, is associated with bone pain, fracture, and bone deformity, but few therapeutic options are available.  Chapurlat (2006) stated that in open studies, bisphosphonate therapy (pamidronate, alendronate) reduced bone pain associated with FD of bone and was associated to some radiological improvement.  Calcium, vitamin D, and phosphorus supplements may be useful in patients with deficiency.  The author reviewed published data on the treatment of FD with bisphosphonates, calcium, vitamin D, and phosphorus; and presented new results on FD therapy with a more potent bisphosphonate, zoledronic acid, given intravenously at the dose of 4 mg every 6 months.  Pamidronate therapy, given intravenously every 6 months at a dose of 180 mg in adults, relieved bone pain, decreased bone resorption, and improved the radiological aspect (filling of lytic lesions and/or thickening of cortices) in approximately 50 % of patients.  Bone mass density in affected sites was also significantly increased after pamidronate treatment.  Those results have been obtained only in open studies, without controls, by several research groups. In a series of 9 patients on long-term pamidronate treatment, but resisting to this medication and switched to IV zoledronic acid, no substantial improvement was observed.  There is some biological rationale supporting the use of calcium and vitamin D in patients with deficiency to improve FD lesions by limiting secondary hyper-parathyroidism.  Phosphorus supplementation may prevent mineralization defects in those patients who have both FD and renal phosphate wasting.  However, there is a lack of clinical evidence for the effectiveness of such supplements.  The author concluded that bisphosphonate treatment reduces increased osteoclastic activity in FD and probably improves bone pain, but their use should be better studied in randomized controlled trials.

Plotkin et al (2003) described the effects of pamidronate therapy in 18 children and adolescents (age at start of therapy, 6.2 to 17.5 years; 8 girls and 10 boys) with polyostotic FD, who received pamidronate for 1.2 to 9.1 years (median of 3.8 years).  Treatment cycles with pamidronate (1 to 1.5 mg/kg/day on 3 consecutive days) were given every 4 months.  Levels of serum alkaline phosphatase and urinary collagen type I N-telopeptide were elevated at baseline and decreased continuously during the first 3 years of therapy.  There was no radiographical evidence of filling of lytic lesions or thickening of the bone cortex surrounding the lesions in any patient.  Histo-morphometrical results in dysplastic bone tissue of patients receiving pamidronate (n = 7; time of therapy, 1.4 to 4.8 years) were similar to those of patients without medical therapy (n = 9).  No serious side effects were noted.  The authors concluded that pamidronate therapy appears to be safe in children and adolescents with polyostotic FD.  However, these researchers found no clear evidence that pamidronate has an effect on dysplastic lesions in such patients.

Chan and Zacharin (2006) did not find bisphosphonate treatment to be effective in treating children with McCune-Albright syndrome (MAS); one of the main features of MAS is FD.  These investigators examined outcomes of pamidronate treatment on FD in 3 children with MAS. Radiological evidence of FD progress was reviewed in these patients who were treated with pamidronate from age 2.5 to 5 years, for 8 to 10.5 years.  Despite minimal pain and a low fracture rate in long bones, except where gross deformity exists, all dysplastic lesions present in long bones continued to undergo uncontrolled expansion.  In contrast, there were no major new changes in facial configuration, no clinically obvious expansion of sphenoid wing lesions and no encroachment on optic foramina or visual field restriction in any patient.  The authors concluded that despite previous reports of limitation or reduction in size of FD lesions in adults and children, it is the authors' experience that bisphosphonate treatment of polyostotic FD in children with MAS does not arrest the expanding nature of these lesions.  Furthermore, Chapurlat and Orcel (2008) stated that bisphosphonates have been used in the treatment of FD to relieve bone pain and improve lytic lesions, but they are still under clinical evaluation.

The International Osteoporosis Foundation (Chapurlat, 2015) states "when common pain killers are not effective, bisphosphonates can be proposed to reduce bone pain. Intravenous pamidronate has been the most widely tested, only in open studies. Data for other compounds is lacking." The National Organization for Rare Disorders (2014) reports "Individuals with FD have been treated with drugs known as bisphosphonates such as pamidronate or alendronate. These drugs reduce bone turnover by inhibiting bone resorption. Calcium and vitamin D may be given along with the drug. Some affected individuals respond favorably to such therapy with the main benefit being decreased bone pain. Other affected individuals do not respond to therapy with bisphosphonates or relapse after an initial period of improvement. Relapse of bone pain is more common in individuals with polyostotic FD. Stronger bisphosphonate medications such as zoledronic acid may be used in such cases and may be most effective in improving bone pain."

Patients with chronic kidney disease have significant abnormalities of bone remodeling and mineral homeostasis and are at increased risk of fracture.  The fracture risk for kidney transplant recipients is 4 times that of the general population and higher than for patients on dialysis.  Ebeling (2007) noted that organ transplant candidates should be assessed and pre-transplantation bone disease should be treated.  Preventive therapy initiated in the immediate post-transplantation period is indicated in patients with osteopenia or osteoporosis, as further bone loss will occur in the first several months following transplantation.  Long-term organ transplant recipients should also have bone mass measurement and treatment of osteoporosis.  Bisphosphonates are the most promising approach for the management of transplantation osteoporosis.  Active vitamin D metabolites may have additional benefits in reducing hyperparathyroidism, particularly after kidney transplantation.  The author stated that large, multi-center treatment trials with oral or parenteral bisphosphonates and calcitriol are needed.

In a Cochrane review, Palmer et al (2007) assessed the use of interventions for treating bone disease following kidney transplantation.  Randomized controlled trials (RCTs) and quasi-RCTs comparing different treatments for kidney transplant recipients of any age were selected.  All other transplant recipients, including kidney-pancreas transplant recipients were excluded.  Two authors independently evaluated trial quality and extracted data.  Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95 % confidence intervals (CI) for dichotomous variables and mean difference (MD) for continuous outcomes.  A total of 24 trials (n = 1,299) were included.  No individual intervention (bisphosphonates, vitamin D sterol or calcitonin) was associated with a reduction in fracture risk compared with placebo.  Combining results for all active interventions against placebo demonstrated any treatment of bone disease was associated with a reduction in the RR of fracture (RR 0.51, 95 % CI: 0.27 to 0.99).  Bisphosphonates (any route), vitamin D sterol, and calcitonin all had a beneficial effect on the BMD at the lumbar spine.  Bisphosphonates and vitamin D sterol also had a beneficial effect on the BMD at the femoral neck.  Bisphosphonates were more effective in preventing BMD loss when compared head-to-head with vitamin D sterols.  Few or no data were available for combined hormone replacement, testosterone, selective estrogen receptor modulators, fluoride or anabolic steroids.  Other outcomes including all-cause mortality and drug-related toxicity were reported infrequently.  The authors concluded that treatment with bisphosphonates, vitamin D sterol or calcitonin after kidney transplantation may protect against immunosuppression-induced reductions in BMD and prevent fracture.  However, they stated that adequately powered clinical studies are needed to ascertain if bisphosphonates are better than vitamin D sterols for fracture prevention in this population.  Moreover, the optimal route, timing, and duration of administration of these interventions remains unknown.

Walsh et al (2009) examined the effect of pamidronate on bone loss following kidney transplantation.  Patients were randomly assigned to treatment (n = 46) or control (no treatment; n = 47) groups.  They were stratified according to parathyroid hormone (PTH) level and sex.  Those with PTH level less than 150 pg/ml were excluded.  The treatment and control groups received pamidronate, 1 mg/kg, peri-operatively and then at 1, 4, 8, and 12 months or no treatment, respectively.  All received calcium (500 mg) and vitamin D (400 units) daily.  Immunosuppression was cyclosporine and prednisolone, with no difference in dosing between the 2 groups.  Bone mineral density was evaluated by means of dual-energy x-ray absorptiometry of the lumbar spine and hip at baseline and 3, 6, 12, and 24 months, with the primary end point at 1 year of percentage of change in BMD from baseline.  Clinical fractures were recorded and also evaluated by means of spinal radiographs at baseline and 1 and 2 years.  Pamidronate protected BMD at the lumbar spine; BMD increased by 2.1 % in the treatment group and decreased by 5.7 % in the control group at 12 months (p = 0.001).  Protection was also seen in Ward's area of the hip (p = 0.002) and the total hip (p = 0.004).  There was no difference in femoral neck BMD loss between the 2 groups.  Fracture rates in the treatment and control groups were 3.3 % and 6.4 % per annum, respectively.  The authors concluded that pamidronate protects against post-transplantation bone loss at the lumbar spine and Ward's area of the hip.  The major limitation of this study was that it was not powered to detect differences in fracture rates.

It is also interesting to note that in a RCT of pamidronate in the prevention of bone loss following liver transplantation, Monegal et al (2009) reported that 90 mg of IV pamidronate within the first 2 weeks and at 3 months following liver transplantation preserve lumbar bone mass during the first year, without significant adverse events.  However, pamidronate does not reduce bone loss at the femoral neck; and furthermore it does not reduce skeletal fractures.

Osteonecrosis of the jaws is a recently described adverse effect in patients treated with bisphosphonates and, in particular, potent aminobisphosphonates.  Most of the reported cases have been in patients with multiple myeloma or metastatic cancer, though cases have also been identified in patients with osteoporosis.  In a systematic review, Woo et al (2006) found that, in almost all reported cases, patients received pamidronate or zoledronic acid.  These investigators conducted a systematic review of reported on cases of osteonecrosis of the jaws following treatment with bisphosphonates.  A total of 29 papers (n = 368) were included: 10 case series of 10 or more individuals and 19 series or case reports of fewer than 10 patients.  There were 368 reported cases of bisphosphonate-associated osteonecrosis of the jaw.  The mandible alone was affected in 65 % of cases, the maxilla alone in 26 %, and both sites in 9 %.  The most important risk factors were, according to the reviewers, type and total dose of bisphosphonate, history of trauma, dental surgery or dental infection.  Ninety-four per cent of patients received pamidronate or zoledronic acid.  Osteonecrosis occurred after having a tooth removed or other dentoalveolar surgery in 60 % of cases; the remaining cases occurred spontaneously.

Moreover, in a population-based analysis, Wilkinson et al (2007) reported that users of IV bisphosphonates (pamidronate and/or zoledronic acid) had an increased risk of inflammatory conditions, osteomyelitis, and surgical procedures of the jaw and facial bones.  The increased risk may reflect an increased risk for osteonecrosis of the jaw.

In an open, pilot study, Feld and colleagues (2009) stated that degenerative lumbar spinal stenosis, manifesting as chronic low back pain and neurogenic claudication, is an increasing chronic problem in an aging population, with limited effective conservative treatment options.  Based on previous reports on the utility of subcutaneous calcitonin and 2 anectodal cases, these researchers launched an open trial of intravenous monthly pamidronate infusions, over a course of 3 to 6 months in this condition.  Of 24 patients, 75 % reported pain improvement, with the mean visual analog scale score improved by 40 %; while composite functional improvement in walking time, activities of daily living, and sense of well being was reported by 66 %, with a mean improvement of 50 %.  The authors concluded that these findings suggested the usefulness of this modality and warrant examination in a RCT.

In a systematic review, Cardozo and colleagues (2008) examined the use of bisphosphonates in the treatment of avascular necrosis (AN).  Studies in which bisphosphonate was used for the treatment of AN were researched through the Medline databases (from 1966 to 2007) and the Cochrane Central Register of Controlled Trials and using the following terms: "avascular necrosis," "aseptic necrosis," "bisphosphonates," "alendronate," "pamidronate," "zoledronate," and "risedronate".  Only 7 articles that met the previously established criteria were obtained from MedlineE, and none was obtained from the Cochrane Central Register of Controlled Trials.  Of these 7 articles, 2 were RCTs and 5 were prospective comparative studies; 1 of them corresponded to an extension of a previous study.  The review demonstrated that there are no controlled and double-blind studies about the efficacy of bisphosphonates in the treatment of AN.  Thus, the data are still insufficient for justifying its use for this indication.  On the other hand, non-controlled studies appear to demonstrate favorable results, particularly in diminishing pain, improving mobility, and lowering the incidence of articular collapse, which justifies new studies being developed in this area.

Voskaridou and Terpos (2008) noted that osteopenia and osteoporosis cause severe problems in patients with thalassemia major (TM).  The delay in sexual maturation, the presence of diabetes and hypothyroidism, the parathyroid gland dysfunction, the accelerated hemopoiesis with progressive marrow expansion, the direct iron toxicity on osteoblasts, the iron chelators, the deficiency of growth hormone or insulin growth factors, all have been identified as major causes of osteoporosis in patients with TM.  However, despite the normalization of hemoglobin levels, adequate hormone replacement and effective iron chelation, patients continue to show an unbalanced bone turnover with an increased resorptive phase resulting in seriously diminished BMD.  During the last decade, bisphosphonates have been used for the management of osteoporosis in TM.  Alendronate, pamidronate, and zoledronic acid have shown efficacy in increasing BMD in patients with TM.  However, further trials must be conducted in order to clarify the exact role of each bisphosphonate, the long-term benefit and side-effects as well as the effects of the combination of bisphosphonates with other effective agents, such as hormonal replacement, on thalassemia-associated osteoporosis.

Gaudio and colleagues (2008) stated that TM is a common cause of skeletal morbidity, as shown by the increased fracture risk in thalassemic patients.  The pathogenesis of this bone disease is multi-factorial and culminates in a state of increased bone turnover with excessive bone resorption and remodeling.  Despite hormonal replacement therapy, calcium and vitamin D administration, effective iron chelation, and normalization of hemoglobin levels, patients with TM continue to lose bone mass.  The increased bone turnover rate observed in patients with TM justifies the use of powerful anti-resorption drugs, such as bisphosphonates.  To date, alendronate, pamidronate, and zoledronate seem to be effective in increasing BMD and normalizing bone turnover, but more trials are needed to evaluate their efficacy in reducing fracture risks in larger thalassemic populations.

Skordis et al (2008) examined  the effect of 2 bisphosphonate drugs, alendronate and pamidronate on bone mass in patients of both genders with TM.  A total of 53 (22 males and 31 females) TM patients of Greek Cypriot origin were randomly divided into 2 groups; 
  1. nbsp;29 patients in group A with a mean age of 33 years were treated with alendronate and
  2. 24 patients in group B with a mean age of 34 years received pamidronate for a period of 2 years.
The effectiveness of both drugs was estimated based on the change of BMD values of lumbar spine and femoral neck.  Bone mineral density of lumbar spine and femoral neck was measured by dual-energy X-ray absiorptiometry.  All patients were on the standard treatment protocol of Thalassaemia. Statistical analysis was performed with the SPSS program.  Following completion of treatment with pamidronate, the mean lumbar spine BMD has improved from -2.813 to -2.174 (p < 0.001) and the mean hip BMD from -2.138 to -2.078 (p = 0.018).  The change of spine BMD in patients who received alendronate was from -2.720 to -2.602 (p = 0.059) and the changes in BMD at the femoral neck from -2.035 to -2.007 (p = 0.829).  The authors concluded that these findings demonstrated the effectiveness of 2 bisphosphonate drugs in improving BMD values in patients with TM and osteoporosis.  Since the origin of bone disease in TM is multi-factorial and some of the underlying pathogenic mechanisms are still unclear, further research in this field is needed, which will allow the design of optimal therapeutic measures.

Guidelines on the clinical management of thalassemia (Cappellini, et al. 2008) state that “bisphosphonates can be used as second line therapy in TM patients (non-responders or poor responders) and those without hypogonadism (TI) with encouraging results.” The guidelines recommend pamidronate 1–2 mg/kg body weight once a month as IV infusion for 3–5 years as one option.

Slobodin et al (2009) reviewed the available published data regarding the potential use of pamidronate in rheumatology practice.  Methods include the review of relevant articles retrieved by a PubMed search utilizing the index term "pamidronate".  All available RCTs, open trials, and case series as well as properly reported case studies evaluating usage of pamidronate in rheumatic disorders were included in the literature review.  The efficacy of pamidronate in patients with spondyloarthropathies; SAPHO syndrome; hypertrophic osteoarthropathy; osteoporotic vertebral fractures; chronic back pain due to disk disease or spinal stenosis; Charcot arthropathy; transient osteoporosis; and complex regional pain syndrome-type 1, has been demonstrated in more than 40 reports, the majority of which, however, were not controlled studies.  In some of reviewed conditions, aside from providing analgesic relief, pamidronate may also have disease-modifying properties.  While used in different doses in a variety of rheumatic disorders, pamidronate was generally reported to be well-tolerated with an overall good safety profile.  Pamidronate may represent an effective and safe choice for a spectrum of rheumatic patients, suffering from intractable musculoskeletal pain, unresponsive to traditionally recommended therapies.  The authors stated that large RCTs examining the efficacy of pamidronate in the rheumatic conditions are urgently needed.

De La Mata and co-workers (2011) examined the effectiveness of available drugs in undifferentiated spondyloarthritis (u-SpA).  Systematic review of studies were retrieved from Medline (1961 to July 2009), Embase (1961 to July 2009), and Cochrane Library (up to July 2009).  A complementary hand search was also performed.  The selection criteria were as follows: (population) u-SpA patients; (intervention) non-steroidal anti-inflammatory agents, disease-modifying anti-rheumatic drugs, anti-tumor necrosis factor-alpha, anakinra, abatacept, biphosphonates, or thalidomide; (outcome) pain, function, structural damage and quality of life; (study design) RCT, cohort studies, and case reports; (level of evidence) according to The Oxford Centre for Evidence-based Medicine (update 2009).  An additional narrative review was performed to analyze the effects of drug therapies in patients with spondyloarthritis according new Assessment of Spondyloarthritis International Society criteria.  A total of 7 studies were included in this review: 2 RCTs, 1 cohort study, and 4 case reports, which included 117 patients with u-SpA (mostly young men).  No evidence related to the effect of non-steroidal anti-inflammatory agents or disease-modifying anti-rheumatic drugs on u-SpA patients was found.  Infliximab and etanercept showed some benefit regarding clinical outcomes, function, and quality of life.  Two RCTs reported important benefit of infliximab and adalimumab also in patients with predominantly axial spondyloarthritis.  Rifampicin plus doxycycline improved some clinical outcomes but ciprofloxacin had no benefit.  Anecdotal positive evidence was reported with pamidronate.  No serious adverse events were reported in the retrieved studies.  The authors concluded that low-quality evidence suggested a benefit of tumor necrosis factor-alpha blockers in u-SpA and good-quality evidence in predominantly axial spondyloarthritis.  The use of antibiotics remains controversial.  High-quality trials are needed to definitively assess the effect of available drugs in these patients.

Soriano and colleagues (2012) stated that little data are available for the use of disease-modifying anti-rheumatic drugs in ankylosing spondylitis.  Sulfasalazine has been the best studied.  These researchers examined efficacy data for individual agents (including pamidronate) and combinations of agents.  Intriguingly, these agents continue to be used with some frequency, even in the absence of efficacy data.  To answer these questions, additional systematic studies of these agents in ankylosing spondylitis are needed and will likely need to be done by interested collaborative groups such as SPARTAN.

The ASCO executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer (Van Poznak et al, 2011) stated that bone-modifying agent therapy is only recommended for patients with breast cancer with evidence of bone metastases; subcutaneous denosumab 120 mg every 4 weeks, IV pamidronate 90 mg over no less than 2 hours, or IV zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks is recommended.  There is insufficient evidence to show greater efficacy of one bone-modifying agent over another.  In patients with a calculated serum creatinine clearance of more than 60 mg/min, no change in dosage, infusion time, or interval of bisphosphonate administration is required.  Serum creatinine should be monitored before each dose.  All patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health.  Furthermore, the guideline noted that the use of biochemical markers to monitor bone-modifying agent use is not recommended.

In a Cochrane review, Conwell and Chang (2012) evaluated the effects of bisphosphonates on the frequency of fractures, BMD, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis (CF).  These investigators searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on February 15, 2012.  Additional searches of PubMed were performed on May 14 2011.  Randomized controlled trials of at least 6 months duration studying bisphosphonates in people with cystic fibrosis were included.  Two authors independently selected trials and extracted data.  Trial investigators were contacted to obtain missing data.  A total of 9 trials were identified and 7 (with a total of 237 adult participants) were included.  Data were combined (when available) from 6 included studies in participants without a lung transplant.  Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95 % CI: 0.13 to 3.80).  No fractures were reported in studies with follow-up at 24 months.  However, in patients taking bisphosphonates after 6 months the percentage change in BMD increased at the lumbar spine, mean difference 4.61 (95 % CI: 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95 % CI: 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95 % CI: -2.42 to 1.45).  In patients taking bisphosphonates, at 12 months the percentage change in BMD increased at the lumbar spine, mean difference 6.10 (95 % CI: 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95 % CI: 2.99 to 5.70).  At 24 months, in patients treated with bisphosphonates the percentage change in BMD also increased at the lumbar spine, mean difference 5.49 (95 % CI: 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95 % CI: 3.74 to 8.36).  There was clinical heterogeneity between studies and not all studies reported all outcomes.  Bone pain was the most common adverse event with intravenous agents.  Flu-like symptoms were also increased in those taking bisphosphonates.  In participants with a lung transplant (1 study), intravenous pamidronate did not change the number of new fractures.  At axial sites, BMD increased with treatment compared to controls: percentage change in BMD at lumbar spine, mean difference 6.20 (95 % CI: 4.28 to 8.12); and femur mean difference 7.90 (95 % CI: 5.78 to 10.02).  The authors concluded that oral and intravenous bisphosphonates increase BMD in people with CF.  Severe bone pain and flu-like symptoms may occur with intravenous agents.  They stated that additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events.  Furthermore, they noted that additional trials are also required to further assess gastro-intestinal adverse effects associated with oral bisphosphonates.  Trials in larger populations are needed to determine effects on fracture rate and survival.

A Consensus Statement on bone health in cystic fibrosis (Aris, et al., 2005) stated that “small RCTs support a role for bisphosphonates in adult patients with very low BMD or after lung transplantation. Broader use of bisphosphonates or treatment with newer anabolic agents cannot be endorsed without additional testing.”  The consensus guideline explained that “bisphosphonates have been used in several uncontrolled observational and in three randomized controlled (RCT) trials in adults with CF. Trials of these drugs in CF children have not been conducted to date. Pamidronate (30 mg, iv, every 3 months) was the first bisphosphonate used in adults with CF, because it circumvented the potential problems related to malabsorption of an oral bisphosphonate. In an RCT [citing Haworth, et al., 1998], pamidronate resulted in significant gains in lumbar spine (mean difference between arms, 5.8%; P < 0.001) and total hip (mean difference, 3.0%; P < 0.05) BMD after 6 months. Unfortunately, significant adverse events occurred with pamidronate use. These included moderate to severe bone pain, fever, and phlebitis in almost 75% of the patients, a number of whom required hospitalization. None of the patients taking oral corticosteroids at the time of the pamidronate infusion developed bone pain, suggesting that prednisone therapy had a protective effect. Thus, a 3- to 5-d course of prednisone may be useful before pamidronate infusions.”

Ward and colleagues (2007) stated that children with chronic illnesses are at increased risk for reductions in bone strength and subsequent fractures (osteoporosis), either due to the impact of the underlying condition on skeletal development or due to the osteotoxic effect of medications (e.g., glucocorticoids) used to treat the chronic illness.  Bisphosphonates are being administered with increasing frequency to children with secondary osteoporosis; however, the efficacy and harm of these agents remains unclear.  In a Cochrane review, these investigators examined the effectiveness and harm of bisphosphonate therapy in the treatment and prevention of secondary osteoporosis in children and adolescents.  They searched the Cochrane Central Register of Controlled Trials (Issue 4, 2006), MEDLINE, EMBASE, CINAHL and ISI Web of Science (inception to December 2006).  Further literature was identified through expert contact, key author searches, scanning reference lists of included studies, and contacting bisphosphonate manufacturers.  Randomized, quasi-randomized, controlled clinical trials, cohort, and case controls of bisphosphonate(s) in children 0 to 18 years of age with at least 1 low-trauma fracture event or reductions BMD in the context of secondary osteoporosis were selected for analysis.  Two reviewers independently extracted data and assessed quality.  Case series were used for supplemental harms-related data.  A total of 6 RCTs, 2 controlled clinical trials (CCTs), and 1 prospective cohort (n = 281 children) were included and classified into osteoporosis due to:
  1. neuromuscular conditions (1 RCT) and
  2. chronic illness (5 RCTs, 2 CCTs, 1 cohort).
Bisphosphonates examined were oral alendronate, clodronate, and IV pamidronate.  Study quality varied.  Harms data from 23 case series (n = 241 children) were used.  Heterogeneity precluded statistically combining the results.  Percent change or Z-score change in lumbar spine areal BMD from baseline were consistently reported.  Two studies carried out between-group analyses; 1 showed no significant difference (using oral alendronate in anorexia nervosa) while the other demonstrated a treatment effect on lumbar spine with IV pamidronate in burn patients.  Frequently reported harms included the acute phase reaction, followed by gastro-intestinal complaints, and bone/muscle pain.  The authors concluded that the findings of this study justified further evaluation of bisphosphonates among children with secondary osteoporosis.  However, the evidence does not support bisphosphonates as standard therapy.  Short-term (3 years or less) bisphosphonate use appears to be well-tolerated.  An accepted criterion for osteoporosis in children, a standardized approach to BMD reporting, and examining functional bone health outcomes (e.g., fracture rates) will allow for appropriate comparisons across studies.

Bryant et al (2009) evaluated the safety and effectiveness of various treatment options for osteopenia and osteoporosis secondary to cancer treatment in pediatric patients undergoing cancer therapy.  A systematic search of PubMed (1949 to November 2008) and International Pharmaceutical Abstracts (to November 2008) was conducted using the following search terms: osteoporosis, osteopenia, pediatrics, cancer, neoplasms, chemotherapy, bisphosphonates, calcium, vitamin D, calcitonin, and physical therapy.  All prospective studies that evaluated various osteoporosis treatment options in pediatric patients undergoing chemotherapy were included.  Results from studies evaluating bisphosphonates and other treatments in children with osteoporosis due to other causes were also included if important safety and effectiveness data were provided.  Most commonly reported primary effectiveness end-points included comparisons of bone density parameters measured before and after treatment.  A total of 4 clinical studies and 2 case reports describing treatment with bisphosphonates, specifically alendronate and pamidronate, for osteoporosis or osteopenia in pediatric cancer patients were identified.  Results from the trials showed that these medications were effective in reducing BMD loss during cancer therapy and were well-tolerated in this special population.  Primary effectiveness end-points included improvements in Z-scores measured by dual-energy X-ray absorptiometry scans.  The most commonly reported adverse effects included hypocalcemia, mild stomach upset, and infusion-related hyperpyrexia.  Four additional clinical trials involving the treatment of osteoporosis or osteopenia in children and adolescents who developed bone degeneration after chronic steroid therapy were also included.  In these trials, treatment options such as calcitonin, and calcium and vitamin D supplementation were also shown to be beneficial.  The authors concluded that the clinical trials published to date were limited to only a few conducted in small populations of patients diagnosed with lymphoblastic leukemia or non-Hodgkin's lymphoma.  However, alendronate and pamidronate both appeared to be effective options in improving BMD scores with minimal adverse effects.

Lee and associates (2013) stated that reduced BMD is a significant sequelae in children receiving chemotherapy for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL).  Reduced BMD is associated with an increased risk for fractures.  Pamidronate has been used to treat osteoporosis in children.  This study evaluated the safety and effectiveness of pamidronate in children with low BMD during and after chemotherapy for ALL and NHL.  Between April 2007 and October 2011, a total of 24 children with ALL and NHL were treated with pamidronate.  The indication was a decreased BMD Z-score less than -2.0 or bone pain with a BMD Z-score less than 0.  Pamidronate was infused at 1 mg/kg/day for 3 days at 1- to 4-month intervals (pamidronate group, cases).  The BMD Z-scores of the cases were compared with those of 10 untreated patients (control group).  Lumbar spine BMDs were measured every 6 cycles using dual energy X-ray absorptiometry and Z-scores were calculated.  Bone turnover parameters (25-hydroxyvitamin D, alkaline phosphatase, parathyroid hormone, osteocalcin, and type I collagen c-terminal telopeptide) were analyzed.  The median cycle of pamidronate treatment was 12.  Increases in BMD Z-scores were significantly higher in the pamidronate group than in the control group (p < 0.001).  Bone mineral density (mg/cm(2)) increased in all pamidronate-treated cases; 20 patients who complained of bone pain reported pain relief after therapy.  The treatment was well-tolerated.  The authors concluded that pamidronate appears to be safe and effective for the treatment of children with low BMD during and after chemotherapy for ALL and NHL.

Baroncelli et al (2013) noted that although spontaneous remission occurs in patients with idiopathic juvenile osteoporosis (IJO), permanent bone deformities may occur.  These researchers examined the effects of long-term pamidronate treatment on clinical findings, bone mineral status, and fracture rate in patients with IJO.  A total of 9 subjects (age 9.8 ± 1.1 years, 7 males) were randomized to IV pamidronate (0.8 ± 0.1 mg/kg per day for 3 days; cycles per year 2.0 ± 0.1; duration 7.3 ± 1.1 years; n = 5) or no treatment (n = 4).  Fracture rate, phalangeal quantitative ultrasound, and lumbar BMD by dual energy X-ray absorptiometry at entry and during follow-up (range of 6.3 to 9.4 years) were assessed.  Bone pain improved in treated patients.  Difficulty walking continued for 3 to 5 years in untreated patients, and vertebral collapses occurred in 3 of them.  During follow-up, phalangeal amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and lumbar BMD area and BMD volume progressively increased in treated patients (p < 0.05 to p < 0.0001).  In untreated patients AD-SoS and BTT decreased during the first 2 to 4 years of follow-up (p < 0.05 to p < 0.01); lumbar BMD area increased after 6 years (p < 0.001) whereas BTT and lumbar BMD volume increased after 7 years of follow-up (p < 0.05 and p < 0.001, respectively).  At the end of follow-up, AD-SoS, BTT, lumbar BMD area, and BMD volume Z-scores were lower in untreated patients than in treated patients (-2.2 ± 0.3 and -0.5 ± 0.2; -1.9 ± 0.2 and -0.6 ± 0.2; -2.3 ± 0.3 and -0.7 ± 0.3; -2.4 ± 0.2 and -0.7 ± 0.3, p < 0.0001, respectively).  Fracture rate was higher in untreated patients than in treated patients during the first 3 years of follow-up (p < 0.02).  The authors concluded that the findings of this study showed that spontaneous recovery of bone mineral status is unsatisfactory in patients with IJO.  Pamidronate treatment stimulated the onset of recovery phase reducing fracture rate and permanent disabilities without evidence of side-effects.

Makitie et al (2013) stated that osteoporosis is an important pediatric disorder that involves almost all pediatric subspecialties.  Osteogenesis imperfecta is the most common form of childhood-onset primary osteoporosis, but several other forms are also known.  Secondary osteoporosis is caused by an underlying chronic illness or its treatment.  The most common causes of secondary osteoporosis include chronic systemic inflammation, glucocorticoid use and neuromuscular disabilities.  The skeletal sequelae can present in childhood as low-energy peripheral and vertebral fractures, or become evident in adulthood as low bone mass and an increased propensity to develop osteoporosis.  Management should aim at prevention, as interventions to treat symptomatic osteoporosis in the pediatric age group are scarce.  Bisphosphonates are the principal pharmacological agents that can be used in this setting, but data on their safety and effectiveness in pediatric populations remain inadequate, especially in patients with secondary osteoporosis.  Consequently, it is important to understand the potential skeletal effects of pediatric illnesses and their therapies in order to institute effective and timely prevention of skeletal complications.

A review of the treatment of mastocytosis-associated osteoporosis (Pardanani et al, 2013) reported that bisphosphonate therapy is effective in increasing vertebral bone mineral density and preventing osteoporotic fractures, but has considerably less efficacy in increasing hip and femoral neck BMD. The NCCN Drugs & Biologics Compendium (2018) has a 2A recommendation for pamidronate for treatment of osteopenia/osteoporosis associated with systemic mastocytosis.

Bone Graft in Maxillo-Facial Reconstruction (Management)

Bayat and colleagues (2017) stated that although bone grafts are commonly used in reconstructive surgeries, they are sensitive to local perfusion and are thus prone to severe resorption.  Bisphosphonates can inactivate osteoclasts and can be used to control the undesirable bone resorption.  In a randomized clinical trial, these researchers examined the effect of administration of bisphosphonates on bone resorption.  A total of 20 patients with bony defects who were candidates for free autogenous grafts were randomized into "pamidronate" and "control" groups.  Bone segments were soaked in either pamidronate solution or normal saline and were inserted into the area of the surgery.  Bone densities were measured post-surgery and in 6-month follow-up.  Data were obtained via Digora software and analyzed.  The mean ± SD bone density in pamidronate group changed from 93.4 ± 14.6 to 93.6 ± 17.5 (p < 0.05); in the control group the density decreased from 89.7 ± 13.2 to 78.9 ± 11.4 (p < 0.05).  The mean difference of bone density in anterior areas of the jaws showed higher dual-energy X-ray absorptiometry (DXA, previously DEXA) in comparison to posterior regions (p = 0.002).  The authors concluded that locally administered pamidronate affected reduction in bone resorption.  Moreover, they stated that further studies are needed to further study the routine administration of local pamidronate in grafts, especially with respect to graft’s mechanical strength.

Hepatic Osteodystrophy

Spirlandeli and colleagues (2017) examined the bone phenotypes and mechanisms involved in bone disorders associated with hepatic osteo-dystrophy (HOD).  Hepatocellular disease was induced by carbon tetrachloride (CCl4).  In addition, the effects of disodium pamidronate on bone tissue were evaluated.  The study included 4 groups of 15 mice:
  1. C = mice subjected to vehicle injections;
  2. C+P = mice subjected to vehicle and pamidronate injections;
  3. CCl4+V = mice subjected to CCl4 and vehicle injections; and
  4. CCl4+P = mice subjected to CCl4 and pamidronate injections.
CCl4 or vehicle was administered for 8 weeks, while pamidronate or vehicle was injected at the end of the 4rth week.  Bone histomorphometry and biomechanical analysis were performed in tibiae, while femora were used for micro-computed tomography and gene expression.  CCl4 mice exhibited decreased bone volume/trabecular volume and trabecular numbers, as well as increased trabecular separation, as determined by bone histomorphometry and micro-computed tomography, but these changes were not detected in the group treated with pamidronate.  CCl4 mice showed increased numbers of osteoclasts and resorption surface.  High serum levels of receptor activator of nuclear factor-κB ligand and the increased expression of tartrate-resistant acid phosphatase in the bones of CCl4 mice supported the enhancement of bone resorption in these mice.  The authors concluded that these findings suggested that bone resorption is the main mechanism of bone loss in chronic hepatocellular disease in mice.  They stated that the present study encourages further studies to address the mechanism of action of disodium pamidronate in HOD.  This study’s drawback was that the dynamic parameters of bone histomorphometry were not evaluated.  However, the present findings are important preliminary data for a more comprehensive study examining alterations in bone remodeling, namely, increased bone resorption as the main mechanism of bone loss in cirrhosis predominantly due to hepatocyte disorders.

Spinal Giant Cell Tumors

Luksanapruksa et al (2016) noted that spinal giant cell tumors (SGCT) remain challenging tumors to treat. Although advancements in surgical techniques and adjuvant therapies have provided new options for treatment, evidence-based algorithms are lacking.  These investigators reviewed the peer-reviewed literature that addresses current treatment options and management of SGCT to produce an evidence-based treatment algorithm.  Articles published between January 1, 1970 and March 31, 2015 were selected from PubMed and EMBASE searches using keywords "giant cell tumor" and "spine" and "treatment".  Relevant articles were selected by the authors and reviewed.  A total of 515 studies were identified, of which 81 studies were included.  Complete surgical resections of SCGT resulted in the lowest recurrence rates.  However, morbidity of en bloc resections is high and in some cases, surgery is not possible.  Intra-lesional resection can be coupled with adjuvant therapies, but evidence-based algorithms for use of adjuvants remain elusive.  Several recent advancements in adjuvant therapy may hold promise for decreasing SGCT recurrence, specifically stereotactic radiotherapy, selective arterial embolization, and medical therapy using denosumab and interferon.  The authors concluded that complete surgical resection of SGCT should be the goal when possible, particularly if neurologic impairment is present.  They stated that denosumab holds promise as an adjuvant and perhaps stand-alone therapy for SGCT.  These researchers also noted that there is emerging evidence that bisphosphonates also have anti-tumoral effects as adjuvant therapy for GCT; however, the best level of evidence for this indication is “IV”.

An UpToDate review on “Giant cell tumor of bone” (Thomas and Desai, 2017) states that “Bisphosphonates -- In vitro studies suggest that bisphosphonates may be effective in killing the stromal and osteoclast-like cells of GCTB.  A few clinical reports note symptomatic benefit and local disease control, sometimes for prolonged periods.  However, eradication of tumor giant cells has not been observed following preoperative treatment, and the role of bisphosphonates in the clinical care of patients with GCTB remains to be clearly defined”.

Chronic Low Back Pain

Pappagallo and colleagues (2014) noted that intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget's disease of bone, metastatic bone disease, and MM.  Based on positive findings from a prior case series, these researchers conducted a randomized, placebo-controlled study to evaluate the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine.  Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90-mg infusions).  Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months post-infusion using electronic diaries.  Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function.  There were no pamidronate-related serious adverse events (SAEs) or other significant safety findings.  A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180-mg pamidronate group.  Least squares mean changes in daily average pain score were -1.39 (SE = 0.43) for placebo, and -1.53 (0.71), -1.26 (0.81), -1.42 (0.65), and -4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (p = 0.012 for pamidronate 180-mg versus placebo).  The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180-mg compared with placebo.  The authors concluded that  i.v. pamidronate, administered as two 90-mg infusions, decreased pain intensity for 6 months in subjects with CLBP.  Moreover, they stated that while these results were promising, they emphasized this was a pilot study with limited numbers of highly selected subjects, and results should not be generalized.  They stated that further studies are needed to confirm these findings and assess the overall risks/benefits in this population before any medical recommendation can be made for use of pamidronate in the medical therapy of CLBP.

The authors noted that this pilot study had several drawbacks.  A large number of exclusion criteria were employed to identify eligible subjects and to ensure a diagnosis of CLBP, including MRI evidence of degenerative disease of the spine; this could affect the generalizability of these findings.  Subjects in the first 2 dose levels were recruited at a different institution than the last 2 dose levels; although the same inclusion and exclusion criteria were used, this may have unpredictably affected the efficacy findings.  Subjects who developed flu-like symptoms could have interpreted these symptoms as induced by the study drug and developed expectations of benefit of treatment.  However, only about 30 % of subjects in the highest 2 dose levels correctly guessed their treatment assignment (pamidronate or placebo), and the remaining subjects were unsure or guessed incorrectly.  Finally, this pilot, dose-finding study consisted of small groups of subjects (n = 11 in each of the 4 groups) at each dose level and combined placebo-treated subjects for the statistical analysis.

Metastatic Breast Cancer

Van Poznak and colleagues (2017) updated an ASCO and Cancer Care Ontario (CCO) guideline on the role of bone-modifying agents (BMAs) in metastatic breast cancer.  This focused update addressed the new data on intervals between dosing and the role of BMAs in control of bone pain.  A joint ASCO-CCO Update Committee conducted targeted systematic literature reviews to identify relevant studies.  The Update Committee reviewed 3 phase-III non-inferiority clinical trials of dosing intervals, 1 systematic review and meta-analysis of studies of de-escalation of BMAs, and 2 randomized trials of BMAs in control of pain secondary to bone metastases.  Patients with breast cancer who have evidence of bone metastases should be treated with BMAs.  Options include denosumab, 120 mg subcutaneously, every 4 weeks; pamidronate, 90 mg intravenously, every 3 to 4 weeks; or zoledronic acid, 4 mg intravenously every 12 weeks or every 3 to 4 weeks.  The analgesic effects of BMAs are modest, and they should not be used alone for bone pain.  The Update Committee recommended that the current standard of care for supportive care and pain management-analgesia, adjunct therapies, radiotherapy, surgery, systemic anticancer therapy, and referral to supportive care and pain management-be applied.  Evidence is insufficient to support the use of one BMA over another.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) lists invasive breast cancer as a recommended indication of pamidronate:

  • Post-menopausal (natural or induced) patients receiving adjuvant therapy along with calcium and vitamin D supplementation to maintain or improve bone mineral density and reduce risk of fractures (2A Recommendation)
  • Used with calcium and vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastasis in patients with expected survival of greater than or equal to 3 months and adequate renal function (1 Recommendation).

Osseointegration Enhancement

Kellesarian and colleagues (2018) noted that this present study is the first one to systematically review the influence of local delivery of pamidronate (PAM) and/or ibandronate (IBA) on osseointegration enhancement.  These researchers evaluated the efficacy of IBA and/or PAM local delivery (topically or coating on implants surfaces) in promoting osseointegration.  To address the focused question, "Does local IBA and/or PAM delivery enhances osseointegration?", indexed databases were searched without time or language restrictions up to and including May 2016 using various combinations of the following keywords: "pamidronate", "ibandronate" ,"bisphosphonates", "osseointegration" and "topical administration".  Letters to the Editor, historic reviews, commentaries, case series, and case reports were excluded.  A total of 15 studies were included; 14 were performed in animals and 2 were clinical trials; 1 study reported an experimental model and a clinical trial in the same publication.  Results from 12 experimental studies and 2 clinical studies reported improved biomechanical properties and/or osseointegration around implants with PAM and/or IBA; 2 experimental studies showed that PAM and/or IBA did not improve osseointegration.  The authors concluded hat on experimental grounds, local IBA and/or PAM delivery appeared to enhance osseointegration; however, from a clinical perspective, further RCTs are needed to evaluate the effectiveness of IBA and PAM in promoting osseointegration around dental implants.

Spinal Muscular Atrophy

An UpToDate review on “Spinal muscular atrophy” (Bodamer, 2018) does not list pamidronate as a therapeutic option.

Calcinosis in Juvenile Dermatomyositis

Marco Puche and colleagues (2010) noted that calcinosis is a frequent finding in up to 40 % of children with juvenile dermatomyositis (JDM).  Different treatments (aluminum hydroxide, diltiazem, probenecid, alendronate, etc.) have been used in an attempt to clear calcinosis and to avoid the onset of new calcium deposition, but none has been clearly effective.  Pamidronate is a nitrogen-containing bisphosphonate with a potent inhibiting bone resorption effect that has been used to treat osteoporosis in children.  These investigators reported 3 children with JDM who developed calcinosis and who received intravenous (IV) pamidronate with good results.  All 3 patients met the Bohan and Peter diagnostic criteria for JDM.  Intravenous pamidronate was given at 1 mg/kg/day on 3 consecutive days every 3 months according to the protocol established by Glorieux et al. for osteoporosis treatment in osteogenesis imperfecta.  The calcinosis which developed in all 3 patients improved.  No important adverse events (AEs) were observed.  The authors concluded that in all 3 cases, calcinosis significantly decreased, and even totally cleared in patient 1.  Total clearance of pre-existing calcinosis in JDM with pamidronate therapy has not been previously described with any of the afore-mentioned treatments.  The advantage of treatment with pamidronate compared to treatment with alendronate is that IV administration does not produce esophagitis, the most frequent AE when orally administering bisphosphonates.  These researchers stated that these findings suggested that therapy with IV pamidronate in conjunction with good disease control with DMARD therapy is an apparently safe and effective treatment for calcinosis management in JDM.

Hoeltzel and associates (2014) stated that calcinosis is one of the hallmark sequelae of JDM, and despite recent progress in the therapy of JDM, dystrophic calcification still occurs in approximately 1/3 of patients.  This review discussed the current, albeit limited, understanding of risk factors for the development of calcinosis in JDM, as well as approaches to assessment, and current views on its pathogenesis.  Anecdotal approaches to treating calcinosis associated with JDM, including both anti-inflammatory therapies and agents aimed at inhibiting the deposition of calcium hydroxyapatite, were reviewed.  An improved understanding of the pathogenesis of calcinosis, the establishment of standardized measurement tools to assess calcinosis, and randomized controlled trials (RCTs) employing more sensitive outcome measures are needed to develop effective therapies for this often disabling complication.

Giri and co-workers (2020) noted that JDM is a rare systemic autoimmune disease with calcinosis as its hallmark sequelae.  These investigators reported 3 JDM patients with calcinosis, who were treated with pamidronate.  There was complete clearance of calcinosis in 1 child.

Furthermore, an UpToDate review on “Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis” (Hutchinson and Feldman, 2020) states that “A number of therapies have been reported to be effective in case reports, but none are consistently successful.  Thus, we do not use them.  These therapies include probenecid, diltiazem, aluminum hydroxide, alendronate, pamidronate, intralesional glucocorticoids, and sodium thiosulfate”.


Dosing recommendations

Pamidronate is available as Aredia in 30mg, 60mg and 90mg vials for intravenous infusion.

Hypercalcemia of malignancy

  • Moderate Hypercalcemia: The recommended dose of Aredia in moderate hypercalcemia (corrected serum calciumFootnotes for Albumin-corrected serum calcium* of approximately 12-13.5 mg/dL) is 60 to 90 mg. The 60-mg dose is given as an initial, SINGLE-DOSE, intravenous infusion over at least 4 hours. The 90-mg dose must be given by an initial, SINGLEDOSE, intravenous infusion over 24 hours.
  • Severe Hypercalcemia: The recommended dose of Aredia in severe hypercalcemia (corrected serum calciumFootnotes for Albumin-corrected serum calcium*>13.5 mg/dL) is 90 mg. The 90-mg dose must be given by an initial, SINGLE-DOSE, intravenous infusion over 24 hours.

Footnotes for Albumin-corrected serum calcium* Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).

Paget's Disease

The recommended dose of Aredia in patients with moderate to severe Paget's disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.

Osteolytic Bone Lesions of Multiple Myeloma

The recommended dose of Aredia in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.

Osteolytic Bone Metastases of Breast Cancer

The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3-4 weeks.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

96360 - 96368 Intravenous infusion
96374 - 96379 Therapeutic, prophylactic, or diagnostic injection; intravenous push

HCPCS codes covered if selection criteria are met:

J2430 Injection, pamidronate disodium, per 30 mg

ICD-10 codes covered if selection criteria are met:

C00.0 - C43.9
C44.0 - C7a.8
C76.0 - C86.6
C88.2 - C94.32
C94.8 - C96.4
C96.a - C96.9
D00.0 - D09.9
Malignant neoplasm
C79.51 - C79.52 Secondary malignant neoplasm of bone and bone marrow
D47.02 Systemic mastocytosis
E83.52 Hypercalcemia [of malignancy or immobilization]
G80.0 Spastic quadriplegic cerebral palsy
G90.50 - G90.59 Complex regional pain syndrome I
M80.00 - M81.8 Osteoporosis
M86.30 - M86.69 Chronic osteomyelitis [nonbacterial] [chronic recurrent multifocal osteomyelitis (CRMO)]
M88.0 - M88.9 Osteitis deformans w/o mention of bone tumor [symptomatic Paget's disease]
Q78.0 Osteogenesis imperfecta [severe]
Q78.1 Polyostotic fibrous dysplasia
Z94.0 - Z94.9 Transplanted organ and tissue status

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

A02.24 Salmonella osteomyelitis
C61 Malignant neoplasm of prostate [treatment of osteoblastic lesions in prostate cancer]
C64.1 - C64.9 Malignant neoplasm of kidney, except renal pelvis
C79.82 Secondary malignant neoplasm of genital organs [treatment of osteoblastic lesions in prostate cancer]
D07.5 Carcinoma in situ of prostate [treatment of osteoblastic lesions in prostate cancer]
D48.0 Neoplasm of uncertain behavior of bone and articular cartilage [spinal giant cell tumors]
D57.40 - D57.419 Sickle-cell thalassemia
E20.8 - E21.5
Disorders of parathyroid gland
E72.00 Disturbances of amino-acid transport [Fanconi Bickel syndrome]
E75.22 Gaucher disease
G12.0 - G12.9 Spinal muscular atrophy and related syndromes
G25.82 Stiff-man syndrome
L70.0 - L70.9
M00.00 - M08.09
M08.20 - M08.99
M11.00 - M12.19
M12.50 - M19.93
Arthropathy associated with infections, crystal arthropathies, arthropathy associated with other disorders classified elsewhere, rheumatoid arthritis and other inflammatory polyarthropathies, osteoarthrosis and allied disorders, and other and unspecified arthropathies
M45.0 - M46.1
M46.50 - M47.9
M48.10 - M48.38
M48.8x1 - M49.89
Ankylosing spondylitis and other inflammatory spondylopathies and spondylosis and allied disorders
M12.20 - M12.29 Villonodular synovitis (pigmented)
M27.2 - M27.3 Inflammatory conditions of jaws
M27.61 Osseointegration failure of dental implant
M27.8 Other specified diseases of the jaws [fibrous dysplasia of jaw(s)]
M33.00 - M33.09 Juvenile dermatomyositis [calcinosis in juvenile dermatomyositis]
M48.061 - M48.07 Spinal stenosis of lumbar region
M54.5 Low back pain
M54.9 Dorsalgia, unspecified
M61.40 - M61.49 Other calcification of muscle [calcinosis in juvenile dermatomyositis]
M65.9 Synovitis and tenosynovitis, unspecified
M85.00 - M85.09 Fibrous dysplasia [monostotic]
M85.2 Hyperostosis of skull
M85.30 - M85.39 Osteitis condensans
M85.80 - M85.9 Other specified disorders of bone density and structure [osteopenia]
Disorder of bone and cartilage, unspecified
M86.00 - M86.29
M86.8X0 - M86.9
M89.60 - M89.69
M90.80 - M90.89
Osteomyelitis, periostitis, and other infections involving bone
M87.00 - M87.9
M90.50 - M90.59
N25.81 Secondary hyperparathyroidism of renal origin
Q77.0 - Q77.1
Q77.4 - Q77.5
Q78.8 Other specified osteochondrodysplasias [hepatic osteodystrophy]
S12.000+ - S12.691+, S22.000+ - S22.089+, S32.000 - S32.2xx+ Fracture of vertebral column
Numerous options Late effect of fracture of spine and trunk without mention of spinal cord lesion
S14.0xxS - S14.159S, S24.0xxS - S24.9xxS, S34.01xS - S34.139S Late effect of spinal cord injury

The above policy is based on the following references:

  1. Akerkar SM, Bichile LS. Pamidronate -- a promising new candidate for the management of spondyloarthropathy. Indian J Med Sci. 2005;59(4):165-170.
  2. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum. 2001;44(7):1496-1503.
  3. American Hospital Formulary Service. AHFS Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists; 2003.
  4. Aris RM, Lester GE, Renner JB, et al. Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation. Am J Respir Crit Care Med. 2000;162(3 Pt 1):941-946.
  5. Aris RM, Merkel PA, Bachrach LK, et al. Guide to bone health and disease in cystic fibrosis. J Clin Endocrinol Metab. 2005;90(3):1888-1896.
  6. Baroncelli GI, Vierucci F, Bertelloni S, et al. Pamidronate treatment stimulates the onset of recovery phase reducing fracture rate and skeletal deformities in patients with idiopathic juvenile osteoporosis: Comparison with untreated patients. J Bone Miner Metab. 2013;31(5):533-543.
  7. Bauman WA, Wecht JM, Kirshblum S, et al. Effect of pamidronate administration on bone in patients with acute spinal cord injury. J Rehabil Res Dev. 2005;42(3):305-313.
  8. Bayat M, Garajei A, Afshari Pour E, et al. The effect of locally administered pamidronate on autogenous bone graft in maxillofacial reconstruction: A randomized clinical trial. Int J Organ Transplant Med. 2017;8(1):43-47.
  9. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20(17):3719-3736.
  10. Berenson JR. Treatment of hypercalcemia of malignancy with bisphosphonates. Semin Oncol. 2002;29(6 Suppl 21):12-18.
  11. Berry S, Waldron T, Winquist E, Lukka H; Genitourinary Cancer Disease Site Group. The use of bisphosphonates in men with hormone-refractory prostate cancer. Practice Guideline Report #3-14. Cancer Care Ontario Practice Guidelines Initiative 2005. Toronto, ON: Cancer Care Ontario; 2005. 
  12. Blair MM, Carson DS, Barrington R. Bisphosphonates in the prevention and treatment of glucocorticoid-induced osteoporosis. J Fam Pract. 2000;49(9):839-848.
  13. Bodamer OA. Spinal muscular atrophy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed May 2018.
  14. Body JJ, Coleman R, Clezardin P, et al; International Society of Geriatric Oncology. International Society of Geriatric Oncology (SIOG) clinical practice recommendations for the use of bisphosphonates in elderly patients. Eur J Cancer. 2007;43(5):852-858.
  15. Body JJ, Mancini I. Bisphosphonates for cancer patients: Why, how, and when? Support Care Cancer. 2002;10(5):399-407.
  16. Body JJ, Mancini I. Treatment of tumor-induced hypercalcemia: A solved problem? Expert Rev Anticancer Ther. 2003;3(2):241-246.
  17. Borzutzky A, Stern S, Reiff A, et al. Pediatric chronic nonbacterial osteomyelitis. Pediatrics. 2012;130(5):e1190-e1197.
  18. Boulos P, Dougados M, Macleod SM, Hunsche E. Pharmacological treatment of ankylosing spondylitis: A systematic review. Drugs. 2005;65(15):2111-2127.
  19. Brenckmann C, Papaioannou A. Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2001;(4):CD002010.
  20. Bryant ML, Worthington MA, Parsons K. Treatment of osteoporosis/osteopenia in pediatric leukemia and lymphoma. Ann Pharmacother. 2009;43(4):714-720.
  21. Cahill BC, O'Rourke MK, Parker S, et al. Prevention of bone loss and fracture after lung transplantation: A pilot study. Transplantation. 2001;72(7):1251-1255.
  22. Cairns AP, Wright SA, Taggart AJ, et al. An open study of pulse pamidronate treatment in severe ankylosing spondylitis, and its effect on biochemical markers of bone turnover. Ann Rheum Dis. 2005;64(2):338-9.
  23. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). An assessment of bisphosphonate drugs to manage pain secondary to bone metastases. Technology Overview Issue 14. Ottawa, ON: CCOHTA; 2004.
  24. Cancer Care Ontario Practice Guideline Initiative (CCOPGI). Use of bisphosphonates in patients with bone metastasis from breast cancer. Toronto, ON: Cancer Care Ontario Practice Guideline Initiative (CCOPGI); February 2002.
  25. Cappellini MD, Cohen A, Eleftheriou A, et al. Guidelines for the Clinical Management of Thalassaemia [Internet]. 2nd Revised edition. Nicosia, Cyprus: Thalassaemia International Federation; 2008.
  26. Cardozo JB, Andrade DM, Santiago MB. The use of bisphosphonate in the treatment of avascular necrosis: A systematic review. Clin Rheumatol. 2008;27(6):685-688.
  27. Chan B, Zacharin M. Pamidronate treatment of polyostotic fibrous dysplasia: Failure to prevent expansion of dysplastic lesions during childhood. J Pediatr Endocrinol Metab. 2006;19(1):75-80.
  28. Chapurlat RD, Orcel P. Fibrous dysplasia of bone and McCune-Albright syndrome. Best Pract Res Clin Rheumatol. 2008;22(1):55-69.
  29. Chapurlat RD. Medical therapy in adults with fibrous dysplasia of bone. J Bone Miner Res. 2006;21 Suppl 2:P114-P119.
  30. Ciana G, Cuttini M, Bembi B. Short-term effects of pamidronate in patients with Gaucher's disease and severe skeletal involvement. N Engl J Med. 1997;337(10):712.
  31. Conwell LS, Chang AB. Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2012;4:CD002010.
  32. Cortet B, Flipo RM, Coquerelle P, et al. Treatment of severe, recalcitrant reflex sympathetic dystrophy: Assessment of efficacy and safety of the second generation bisphosphonate pamidronate. Clin Rheumatol. 1997;16(1):51-56.
  33. Crandall C. Combination treatment of osteoporosis: A clinical review. J Womens Health Gend Based Med. 2002;11(3):211-224.
  34. Dawson NA. Therapeutic benefit of bisphosphonates in the management of prostate cancer-related bone disease. Expert Opin Pharmacother. 2003;4(5):705-716.
  35. De La Mata J, Maese J, Martinez JA, et al. Current evidence of the management of undifferentiated spondyloarthritis: A systematic literature review. Semin Arthritis Rheum. 2011;40(5):421-429 .
  36. Devogelaer JP. Treatment of bone diseases with bisphosphonates, excluding osteoporosis. Curr Opin Rheumatol. 2000;12(4):331-335.
  37. Djulbegovic B, Wheatley K, Ross J, et al. Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev. 2002;(4):CD003188.
  38. Ebeling PR. Transplantation osteoporosis. Curr Osteoporos Rep. 2007;5(1):29-37.
  39. Fan SL, Almond MK, Ball E, et al. Pamidronate therapy as prevention of bone loss following renal transplantation. Kidney Int. 2000;57(2):684-690.
  40. Feld J, Rosner I, Avshovich N, et al. An open study of pamidronate in the treatment of refractory degenerative lumbar spinal stenosis. Clin Rheumatol. 2009;28(6):715-717.
  41. Gallacher SJ, Ralston SH, Dryburgh FJ, et al. Immobilization-related hypercalcaemia--a possible novel mechanism and response to pamidronate. Postgrad Med J. 1990;66(781):918-922.
  42. Gaudio A, Morabito N, Xourafa A, et al. Bisphosphonates in the treatment of thalassemia-associated osteoporosis. J Endocrinol Invest. 2008;31(2):181-184.
  43. Giri S, Parida JR, Dash M, Panda M. Pamidronate in treatment of calcinosis in juvenile dermatomyositis. Indian Pediatr. 2020;57(1):75-76.
  44. Goldbloom EB, Cummings EA, Yhap M. Osteoporosis at presentation of childhood ALL: Management with pamidronate. Pediatr Hematol Oncol. 2005;22(7):543-550.
  45. Gordon DH. Efficacy and safety of intravenous bisphosphonates for patients with breast cancer metastatic to bone: A review of randomized, double-blind, phase III trials. Clin Breast Cancer. 2005;6(2):125-131.
  46. Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol. 2000;18(6):1378-1391.
  47. Hodsman AB. Fragility fractures in dialysis and transplant patients. Is it osteoporosis, and how should it be treated? Perit Dial Int. 2001;21 Suppl 3:S247-S255.
  48. Hoeltzel MF, Oberle EJ, Robinson AB, et al. The presentation, assessment, pathogenesis, and treatment of calcinosis in juvenile dermatomyositis. Curr Rheumatol Rep. 2014;16(12):467.
  49. Holmes-Walker DJ, Woo H, Gurney H, et al. Maintaining bone health in patients with prostate cancer. Med J Aust. 2006;184(4):176-179.
  50. Hospach T, Langendoerfer M, von Kalle T, et al. Spinal involvement in chronic recurrent multifocal osteomyelitis (CRMO) in childhood and effect of pamidronate. Eur J Pediatr. 2010;169(9):1105-1111.
  51. Hurtado J, Esbrit P. Treatment of malignant hypercalcaemia. Expert Opin Pharmacother. 2002;3(5):521-527.
  52. Hutchinson C, Feldman BM. Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis. UpToDate Inc., Waltham, MA. Last reviewed May 2020.
  53. Institute for Clinical Systems Improvement (ICSI). Diagnosis and treatment of osteoporosis. ICSI Healthcare Guidelines. Bloomington, MN: ICSI; July 2002.
  54. Kedlaya D, Brandstater ME, Lee JK. Immobilization hypercalcemia in incomplete paraplegia: Successful treatment with pamidronate. Arch Phys Med Rehabil. 1998;79(2):222-225.
  55. Keen RW. The current status of Paget's disease of the bone. Hosp Med. 2003;64(4):230-232.
  56. Kellesarian SV, Abduljabbar T, Vohra F, et al. Does local ibandronate and/or pamidronate delivery enhance osseointegration? A systematic review. J Prosthodont. 2018;27(3):240-249.
  57. Kelly WK, Steineck G. Bisphosphonates for men with prostate cancer: Sifting through the rubble. J Clin Oncol. 2003;21(23):4261-4262.
  58. Kerrison C, Davidson JE, Cleary AG, Beresford MW. Pamidronate in the treatment of childhood SAPHO syndrome. Rheumatology (Oxford). 2004;43(10):1246-1251.
  59. Kim SD, Cho BS. Pamidronate therapy for preventing steroid-induced osteoporosis in children with nephropathy. Nephron Clin Pract. 2006;102(3-4):c81-c87.
  60. Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc. 2006;81(8):1047-1053.
  61. Lee JM, Kim JE, Bae SH, Hah JO. Efficacy of pamidronate in children with low bone mineral density during and after chemotherapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Res. 2013;48(2):99-106.
  62. Lipton A, Small E, Saad F, et al. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: A comparison to pamidronate. Cancer Invest. 2002;20 Suppl 2:45-54.
  63. Lipton A. Bone metastases in breast cancer. Curr Treat Options Oncol. 2003;4(2):151-158.
  64. Luksanapruksa P, Buchowski JM, Singhatanadgige W, et al. Management of spinal giant cell tumors. Spine J. 2016;16(2):259-269.
  65. Makitie O. Causes, mechanisms and management of paediatric osteoporosis. Nat Rev Rheumatol. 2013;9(8):465-475.
  66. Maksymowych WP, Jhangri GS, Fitzgerald AA, et al. A six-month randomized, controlled, double-blind, dose-response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum. 2002;46(3):766-773.
  67. Marco Puche A, Calvo Penades I, Lopez Montesinos B. Effectiveness of the treatment with intravenous pamidronate in calcinosis in juvenile dermatomyositis. Clin Exp Rheumatol. 2010;28(1):135-140.
  68. Massagli TL, Cardenas DD. Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury. Arch Phys Med Rehabil. 1999;80(9):998-1000.
  69. McIntyre HD, Cameron DP, Urquhart SM, Davies WE. Immobilization hypercalcaemia responding to intravenous pamidronate sodium therapy. Postgrad Med J. 1989;65(762):244-246.
  70. Miettunen PM, Wei X, Kaura D,et al. Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J. 2009;7:2.
  71. Miller PD. Optimizing the management of postmenopausal osteoporosis with bisphosphonates: The emerging role of intermittent therapy. Clin Ther. 2005;27(4):361-376.
  72. Monegal A, Guanabens N, Suárez MJ, et al. Pamidronate in the prevention of bone loss after liver transplantation: A randomized controlled trial. Transpl Int. 2009;22(2):198-206.
  73. National Comprehensive Cancer Network (NCCN). Pamidronate disodium. NCCN Drugs & Biologics Compendium. Fort Washington, PA: NCCN; 2008; 2018; 2019.
  74. Nguyen T, Zacharin MR. Pamidronate treatment of steroid associated osteonecrosis in young patients treated for acute lymphoblastic leukaemia--two-year outcomes. J Pediatr Endocrinol Metab. 2006;19(2):161-167.
  75. Ninkovic M, Love S, Tom BD, et al. Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation. J Hepatol. 2002;37(1):93-100.
  76. No authors listed. Pamidronate. GP Notebook. Cambridge, UK: Oxbridge Solutions, Ltd.; 2003. Available at: Accessed August 22, 2003.
  77. Novartis Pharmaceutical Corporation. Aredia. Pamidronate disodium for injection. Prescribing Information. T2003-44. East Hanover, NJ: Novartis; revised June 2003. 
  78. Olivieri I, Padula A, Palazzi C. Pharmacological management of SAPHO syndrome. Expert Opin Investig Drugs. 2006;15(10):1229-1233.
  79. Orcel P, Beaudreuil J. Bisphosphonates in bone diseases other than osteoporosis. Joint Bone Spine. 2002;69(1):19-27.
  80. Palmer SC, McGregor DO, Strippoli GF. Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev. 2007;(3):CD005015.
  81. Pappagallo M, Breuer B, Lin HM, et al. A pilot trial of intravenous pamidronate for chronic low back pain. Pain. 2014;155(1):108-117.
  82. Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). Blood. 2013;121(16):3085-3094.
  83. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005;(3):CD003474.
  84. Plotkin H, Rauch F, Zeitlin L, et al. Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone. J Clin Endocrinol Metab. 2003;88(10):4569-4575.
  85. Reeves HL, Francis RM, Manas DM, et al. Intravenous bisphosphonate prevents symptomatic osteoporotic vertebral collapse in patients after liver transplantation. Liver Transpl Surg. 1998;4(5):404-409.
  86. Rosen LS. New generation of bisphosphonates: Broad clinical utility in breast and prostate cancer. Oncology (Huntingt). 2004;18(5 Suppl 3):26-32.
  87. Ross JR, Saunders Y, Edmonds PM, et al.  A systematic review of the role of bisphosphonates in metastatic disease. Health Technol Assess. 2004;8(4):1-176.
  88. Royal College of Physicians, Bone and Tooth Society of Great Britain, and National Osteoporosis Society. Glucocorticoid-induced osteoporosis. Guidelines for prevention and treatment. London, UK: Royal College of Physicians; December 2002. 
  89. Rukavina I. SAPHO syndrome: A review. J Child Orthop. 2015;9(1):19-27.
  90. Saad F, Schulman CC. Role of bisphosphonates in prostate cancer. Eur Urol. 2004;45(1):26-34.
  91. Salehpour S, Tavakkoli S. Cyclic pamidronate therapy in children with osteogenesis imperfecta. J Pediatr Endocrinol Metab. 2010;23(1-2):73-80.
  92. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728-1737.
  93. Schneider D, Hofmann MT, Peterson JA. Diagnosis and treatment of Paget's disease of bone. Am Fam Physician. 2002;65(10):2069-2072.
  94. Scottish Intercollegiate Guidelines Network (SIGN). Control of pain in patients with cancer. A national clinical guideline. SIGN Publication No. 44. Edinburgh, Scotland: SIGN; 2000.
  95. Skordis N, Ioannou YS, Kyriakou A, et al. Effect of bisphosphonate treatment on bone mineral density in patients with thalassaemia major. Pediatr Endocrinol Rev. 2008;6 Suppl 1:144-148.
  96. Slobodin G, Rosner I, Feld J, et al. Pamidronate treatment in rheumatology practice: A comprehensive review. Clin Rheumatol. 2009;28(12):1359-1364.
  97. Small EJ, Smith MR, Seaman JJ, et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol. 2003;21(23):4277-4284.
  98. Smith MR. Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer. Drugs Aging. 2003;20(3):175-183.
  99. Smith MR. Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma. Cancer. 2003;97(3 Suppl):789-795.
  100. Smith MR. Management of treatment-related osteoporosis in men with prostate cancer. Cancer Treat Rev. 2003;29(3):211-218.
  101. Solomon CG. Bisphosphonates and osteoporosis. N Engl J Med. 2002;346(9):642.
  102. Soriano ER, Clegg DO, Lisse JR. Critical appraisal of the guidelines for the management of ankylosing spondylitis: Disease-modifying antirheumatic drugs. Am J Med Sci. 2012;343(5):357-359.
  103. Spirlandeli AL, Dick-de-Paula I, Zamarioli A, et al. Hepatic osteodystrophy: The mechanism of bone loss in hepatocellular disease and the effects of pamidronate treatment. Clinics (Sao Paulo). 2017;72(4):231-237.
  104. Tamion F, Bonmarchand F, Girault C, et al. Intravenous pamidronate sodium therapy in immobilization-related hypercalcemia. Clin Nephrol. 1995;43(2):138-139.
  105. Terpos E, Sezer O, Croucher PI, et al; European Myeloma Network. The use of bisphosphonates in multiple myeloma: Recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol. 2009;20(8):1303-1317.
  106. Thomas DM, Desai J. Giant cell tumor of bone. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed May 2017.
  107. Toussirot E, Wendling D. Bisphosphonates as anti-inflammatory agents in ankylosing spondylitis and spondylarthropathies. Expert Opin Pharmacother. 2005;6(1):35-43.
  108. Toussirot E, Wendling D. Late-onset ankylosing spondylitis and related spondylarthropathies: Clinical and radiological characteristics and pharmacological treatment options. Drugs Aging. 2005;22(6):451-469.
  109. Trombetti A, Gerbase MW, Spiliopoulos A, et al. Bone mineral density in lung-transplant recipients before and after graft: Prevention of lumbar spine post-transplantation-accelerated bone loss by pamidronate. J Heart Lung Transplant. 2000;19(8):736-743.
  110. U.S. Pharmacopeial Convention, Inc. USP DI Volume 1: Drug Information for the Healthcare Professional. Greenwood Village, CO: Micromedex; 2003.
  111. Van Poznak C, Somerfield MR, Barlow WE, et al. Role of bone-modifying agents in metastatic breast cancer: An American Society of Clinical Oncology-Cancer Care Ontario focused guideline update. J Clin Oncol. 2017;35(35):3978-3986.
  112. Van Poznak CH, Temin S, Yee GC, et al; American Society of Clinical Oncology. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221-1227.
  113. Voskaridou E, Terpos E. Pathogenesis and management of osteoporosis in thalassemia. Pediatr Endocrinol Rev. 2008;6 Suppl 1:86-93.
  114. Walsh SB, Altmann P, Pattison J, et al. Effect of pamidronate on bone loss after kidney transplantation: A randomized trial. Am J Kidney Dis. 2009;53(5):856-865.
  115. Ward L, Tricco AC, Phuong P, et al. Bisphosphonate therapy for children and adolescents with secondary osteoporosis. Cochrane Database Syst Rev. 2007;(4):CD005324.
  116. Wilkinson GS, Kuo YF, Freeman JL, Goodwin JS. Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: A population-based analysis. J Natl Cancer Inst. 2007;99(13):1016-1024.
  117. Wong RK. No difference between pamidronate disodium and placebo in relieving bone pain in men with advanced prostate cancer. Cancer Treat Rev. 2004;30(4):395-400.
  118. Woo SB, Hellstein JW, Kalmar JR. Narrative review: Bisphosphonates and osteonecrosis of the jaws. Ann Internal Med. 2006;144(10):753-761.
  119. Yamazaki Y, Satoh C, Ishikawa M, et al. Remarkable response of juvenile diffuse sclerosing osteomyelitis of mandible to pamidronate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104(1):67-71.